Liver transplantation in HIV-HCV co-infected patients

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					P-44                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          Elina Teicher



                                                                                                                                    Liver transplantation in HIV-HCV co-infected patients                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Didier Samuel
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              e-mail: elina.teicher@pbr.ap-hop-paris.fr
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              e-mail: didier.samuel@pbr.ap-hop-paris.fr
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              Telephone: + 33 1 45 59 69 43
                                 ABSTRACT                                                                                                                                                                                                                                                                                                                 Teicher E.*, Vittecoq D., Duclos-Vallés J., Azoulay D., Adam R., Castaing D., Bismuth H., Roque-Afonso A., Dussaix E., Samuel D.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Fax: + 33 1 45 59 36 16
Background:

End stage liver disease in HIV_HCV co-infected patients is an emerging problem requiring to assess the benefit

risk ratio of liver transplantation (LT). We started a prospective evaluation of LT in co-infected patients in                                                                                                                                                                                                                                                                                                                                                                           Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier, 94800 Villejuif, France.
December 1999 assessing several parameters: impact on the immune system and HIV replication, drug

interactions, mitochondrial toxicity and incidence of HCV relapse.

Methods:

Up to June 2003, eleven HIV-HCV co-infected patients without history of opportunistic infection, were

transplanted. At time of LT all patients were exposed to HAART, HIV plasma viral load was < 400 copies/mL

and the median CD4 lymphocyte count was 350 cells/mm3 (range: 103-659). Immunosuppression therapy

consisted of steroids and Tacrolimus. Anti HCV viral therapy was used when necessary and its benefit risk ratio

was prospectively evaluated. Lastly, mitochondrial toxicity on the graft was studied by spectrophotometric

analyses of the respiratory chain complexes and molecular analysis of mitochondrial DNA (mtDNA).
                                                                                                                                                                        INTRODUCTION                                                                                                                                                                                                                                                                                                           METHODOLOGY                                                                                                                                                                                                                                                                                                                                                                                                                                    RESULTS                                                                                                                                                                                                                                                                                           CONCLUSION
Results:

At time of evaluation, the median follow-up is 18 months (range: 3-45): three patients died, four, eleven and

nineteen months after LT. Seven patients are in good condition and one patient is in poor condition. None on the
                                                                                                                                                       Life expectancy in HIV infected patients has                                                                                                                                                                                                   Till June 2003, eleven HIV-HCV co-infected patients had a liver transplantation in our institution. At time of LT (see Table 1):                                                                                                                                                                                                                                                                        The median follow-up is 18 months (range 3-45). At time of evaluation (see table 2):                                                                                                                                                                                                                                                                                                                  Liver transplantation in HIV-HCV co-infected patients is
patients developed opportunistic infection. Drug interaction was under control, only one patient developed a

transient renal insufficiency. HCV replication started promptly after LT in all patients. Seven patients began                                                                                                                                                                                                                                                                                        > All patients were exposed to HAART.                                                                                                                                                                                                                                                                                                                                                                   > Three patients died after LT (mortality: 28%):
pegylated interferon (PEG-IFN) and ribavirin therapy. This treatment was stopped in three patients because of
                                                                                                                                                       dramatically increased due to the efficacy of highly                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         feasible in a very selected population. The management “a
intolerance. One patient showed a virological response and another a biochemical response and a decrease of                                                                                                                                                                                                                                                                                           > HIV plasma viral load was < 400 copies/ml and the CD4 lymphocyte count was >100 cells/ml average: 350 cells/ml,                                                                                                                                                                                                                                                                                                     • Patient 3 died 22 months after LT with HAART hepatotoxicity and severe recurrence of HVC infection on the liver graft.
liver fibrosis. At last biopsy, METAVIR score was staged F4 in two patients, F3 in one, F2 in two.                                                     active antiretroviral therapy (HAART). Liver disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         la carte” is the only way to ensure a favorable benefit risk
Microvesicular steatosis was observed in nearly all patients. The ratio mtDNA nuclear DNA was low in four                                                                                                                                                                                                                                                                                                   (range: 103-659].                                                                                                                                                                                                                                                                                                                                                                                               • Patient 6 died 4 months after LT with HAART hepatotoxicity and acute recurrence of HCV infection on the liver graft.
patients. A significant defect on the activities of respiratory chain was noted in five patients.                                                      progression to cirrhosis is much faster in HIV-HCV                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           ratio in grafted HIV-HCV co infected patients. This
Conclusion:
                                                                                                                                                                                                                                                                                                                                                                                                      > None of the patients had experienced any opportunistic infection.                                                                                                                                                                                                                                                                                                                                                   • Patient 8 died 11 months after LT with Carcinoma de pancreas
Liver transplantation in HIV -HCV co-infected patients is feasible in a very selected population. Our experience
                                                                                                                                                       co-infected patients than in HCV mono-infected                                                                                                                                                                                                 > Liver grafts were obtained from cadaveric or living donors or from patients with familial amyloidotic polyneuropathy                                                                                                                                                                                                                                                                                  > Seven patients are in good condition and one patient is in poor condition.                                                                                                                                                                                                                                                                                                                          management depends on careful monitoring of all clinical,
do not suggest a deterioration of immune deficiency. Drug interaction is not a limiting problem. The early and

severe relapse of hepatitis C suggest to start promptly an association of PEG-IFN and ribavirin. LT requires a
                                                                                                                                                       patients. End stage liver disease is an emerging                                                                                                                                                                                                     (domino program).                                                                                                                                                                                                                                                                                                                                                                                 > None of the patients develop ed opportunistic infection.                                                                                                                                                                                                                                                                                                                                            biochemical, virological and pathological parameters
multidisciplinary partnership.

                                                                                                                                                                                                                                                                                                                                                                                                      > Immunosuppression therapy consisted of steroids and Tacrolimus; single rejection episodes were treated with a bolus of                                                                                                                                                                                                                                                                                > Drug interaction was under control, only one patient developed a transient (?) renal insufficiency.
                                                                                                                                                       problem that requires to asses the benefit risk ratio                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        characterizing the post-LT period.
                                                                                                                                                                                                                                                                                                                                                                                                            methylprednisolone.                                                                                                                                                                                                                                                                                                                                                                               > HCV replication started between day 12 and month 2 post LT in all patients. Nine patients started pegylated interferon
                                                                                                                                                       of                     liver                               transplantation                       (LT).                       We                          started                                        a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    The early and severe relapse of hepatitis C suggests
                                                                                                                                                                                                                                                                                                                                                                                                      > Prophylaxis therapy of opportunistic infections consisted of Fluconazole, Cotrimoxazole and Ganciclovir.                                                                                                                                                                                                                                                                                                   (PEG-IFN) and ribavirin therapy. This treatment was stopped in four patients due to a poor tolerance.
                                                                                                                                                       prospective appraisal of LT in HIV-HCV co-infected                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           starting promptly an association of PEG-IFN and ribavirin.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              > The ratio mtDNA nuclear DNA was low in four patients. A significant defect on the activities of respiratory chain was
                                                                                                                                                                                                                                                                                                                                                                                                      > Clinical examination and liver biochemical test were performed daily                                                                                                                                                 Patient            1         2              3        4             5               6             7            8           9            10             11
                                                                                                                                                       patients in December 1999. This study addresses                                                                                                                                                                                                                                                                                                                                                                                                                        Age at LT*         29       37              43         40          43              41            49           40        63            42             46                                   noticed in five patients. Other evaluations are underway (see table 3).                                                                                                                                                                                                                                                                                                                     Mortality is higher in this selected population than in HIV
                                                                                                                                                                                                                                                                                                                                                                                                             during 14 days post LT, three times a week during the first month, once                                                                                                                                         Sex**              F        M               M           M          M              M             M            M            M               M            M


                                                                                                                                                       morbidity, mortality, impact on the immune system,                                                                                                                                                                                                    a week during three months and once a month afterwards.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Cirrhosis*

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             HIV infection*
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               1.5

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                7
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          5

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         13
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        1.5

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         15
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  1

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  16
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               1.5

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                14
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               16
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              3

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             12
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           2

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          15
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       9

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      14
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     1

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    18
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   4

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   15
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    (-) grafted patients.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Prothrom.(%)       25       26             33       18             64             48            54           30          35            73             60

                                                                                                                                                       HIV replication, drug interactions, mitochondrial                                                                                                                                                                                              > Liver biopsies were performed: after 1 month (post LT), after 6 months                                                                                                                                               V fact. (%)        32       30             55       15             57             56            50           29          55            65             62                                                                                                                                                                                                                                                                                                                                                                                                                               Mitochondrial toxicity on the graft and high frequency of
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Albumin (g/L)      42       24             27       39             29             32            25           27          25            30             36                                  Patient                                            1            2                 4                5     7        9              10               11                                      Patient             histological       mitochondrial activities **               mtDNA §                          HAART therapy *
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       lesions *
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Bilirubin (µM)    258       70             50       201            39             99            36          109          46            48             18

                                                                                                                                                       toxicity and incidence of HCV relapse.                                                                                                                                                                                                                and then every year.                                                                                                                                                                                            Creatinine (µM)    59       96             97       69             69             71            84           70         132            90         125
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Delay after LT                                 45              34                26               24    18        7                5                  3                                        2              centrilobular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    necrosis (M7)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          I 10, IV 4, CS170 (M18)                       0.2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       (M18)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 d4T-3TC-EFV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            (M8) d4T-DDI-LPV-RTV                                                                    early microvesicular steatosis. are other issues. The precise
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       (months)                                                                                                                                                                                                                                                                                            (M18) ABC-TNF-LPV/RTV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Ascites           Yes      Yes             No       Yes           Yes             No           Yes          Yes         Yes           Yes             No
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      3                 moderate          I 20, IV 0, CS 164 (M18)                      0.3                      ZDV-3TC-IDV
                                                                                                                                                                                                                                                                                                                                                                                                      > HCV and HIV RNA levels and CD4 cell counts were monitored every                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             microvesicular                                                     (M18)                 (M10) ZDV-3TC-NFV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Encephalop.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             HCV genotype
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1b
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       4c,4d
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        1a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 Yes

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 1a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                3a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               1b
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             1a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          1a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    1a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   No

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   3a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Karnovsky score                                80              80                80               50    80      80               80               70
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    steatosis (M10)                                                                                                                                                                 features of this toxicity is unclear.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       (%)                                                                                                                                                                                            4                 moderate            I 26, IV 9, CS 89 (M6)                                                    DDI-d4T-3TC
                                                                                                                                                                                                                                                                                                                                                                                                             week during the first month post-LT and monthly afterwards.                                                                                                                                                     HCV RNA (log      5.9       5.3            6.8      4.6           5.9            5.6           6.2          5,8           4            5,7        4,3                                                                                                                                                                                                                                                  microvesicular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     steatosis (M6)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         I 31, IV 14, CS 108 (M12)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           I 16, IV 3, CS 68 (M18)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      1.4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    (M12)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   (M6) EFV-NFV-3TC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             IU/mL)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       ALAT (IU/L)                                    16              35                83               18    26      49               99               89
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      5                  diffuse          I 22, IV 12, CS 110 (M6)                 5.2 (M6)                             EFV-NFV-DDI                                                                 Our experience does not suggest short term deleterious
                                                                                                                                                                                                                                                                                                                                                                                                      > Anti HCV viral therapy was used when necessary and its benefit risk                                                                                                                                                  HIV RNA           294      <50             <50      210           <50            <50           134          <50         <50           <50         <50                                     Bilirubine level (µM)                              6           18                19               70    10        7              28               28                                                         microvesicular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     steatosis (M2)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             (copies/mL)                                                                                                                                                                                                                                                                                                                                                                              7                 moderate            I 6, IV 12, CS 83 (M1)                 4,7 (M1)                       AZT-3TC-DDI

                                                                                                                                                                                                                                                                                                                                                                                                             ratio was prospectively evaluated.                                                                                                                                                                              CD4 (cells/mm3)   341      103             510      320           180            240           430          980         659           488         320
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Prothrombin time                               86              78                100              52    100    100               96              100
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    microvesicular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     steatosis (M4)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          I 30, IV 21, CS 142 (M3)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            I 11, IV 0, CS 86 (M8)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   0.1 (M3)                    (M4) AZT-3TC-NFV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             (M6) DDI-TNF-LPV/RTV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    effect on immune system. Drug interaction is not a limiting
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             HAART***          d4T      d4T             AZT      d4T           NFV            AZT           AZT         3TC          D4T           ABC         TNF                                     (%)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         I 20, IV 11, CS 114 (M12)                                          (M9) ABC-TNF-LPV/RTV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          I 24, IV 17, CS 66 (M15)
                                                                                                                                                                                                                                                                                                                                                                                                      > Monitoring of residual plasma concentration of antiretroviral
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               NVP

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               NFV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        3TC             3TC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        IDV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 DDI           EFV

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               DDI
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              3TC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             EFV
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            3TC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            DDI
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        ABC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        TNF
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     3TC

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     TNF
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   EFV

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   3TC
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               NFV

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               3TC
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       HIV RNA                                        nd              nd                nd               nd    nd      nd               Nd               Nd
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      10               Lobulaire
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    hepatitis (M6)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            I 1, IV 14,CS 122(M5)                                                       ABC-EFV-3TC                                                                 problem. LT requires a multidisciplinary partnership.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       (copies/mL)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             LT protocol§      Total   split D.         total   Liv. d.       Cad. d.      Cad. d.          total      Cad.d         Liv.d         Cad.d Total D.                                                                                                                                                                                                                                     11               Lobulaire      I 27, IV 26, CS 81 (M1)                                                           TNF-NFV-3TC

                                                                                                                                                                                                                                                                                                                                                                                                             treatment (PI and NNRTI) was made post LT and one week after                                                                                                                                                                       D.     + Cad.            D.                                                  D.                                                                                        HCV RNA (log                                   nd               6                6.6              6.5   6.7    6.7               6.1              6.6
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       hepatitis
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Microvesicular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      I 14, IV 66, CS 36 (M3)

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         d.                                                                                                                                                                                                                                                                                                                                                                         steatosis (M3)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       IU/mL)
                                                                                                                                                                                                                                                                                                                                                                                                             re-introduction of treatment.                                                                                                                                                                                                                                                                                                                                                                             CD4 (cells/mm3)                               420             190                300              160   250    310               200             480
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               Table 3: Description of mitochondrial toxicity on the liver graft. Management of HAART
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Table 1: Clinical and laboratory features of HIV-HCV coinfected patients before LT                                                                                                                                                                                                                                                                                                * The time from LT at disclosure of each of the anomalies or at therapeutic change is given
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             LT: Liver Transplantation ;* age, duration of cirrhosis and duration of HIV infection                                                                                                                                                                                                                                                                                             in months after LT (M).
                                                                                                                                                                                                                                                                                                                                                                                                      > Mitochondrial toxicity on the graft was studied by spectrophotometric                                                                                                                                                are given in years, **M:                                                                                                                                                                  HAART*                                        d4T            ABC                 NFV              NFV   ABC    EFV               ABC             TDF
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               ** Activities of the mitochondrial enzymes are expressed as nanomoles substrate utilized per
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Male, F: Female; Prothrom = prothrombin time; Total D=. Domino protocol, Cad. d.                                                                                                                                                                                                                                                                                                  minute and milligram protein of the post-nuclear supernatant obtained from frozen liver
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     EFV            TDF                 EFV              EFV   TDF    TDF               EFV             3TC
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             = Cadaveric donor, Liv.                                                                                                                                                                                                                                                                                                                                                           fragments (nmoles/min/mg). Normal values range from 13 to 31, 20 to 56 and 21 to 55
                                                                                                                                                                                                                                                                                                                                                                                                             analyses of the respiratory chain complexes and molecular analysis of                                                                                                                                           d. = living donor, patient 2 was transplanted twice because of rapid dysfunction of                                                                                                                                                     NFV            LPV                 3TC              3TC   LPV    3TC               3TC             NFV                                    nmoles/min/mg for NADH ubiquinone oxido-reductase (I: complex I of the respiratory chain,
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             the first graft.                                                                                                                                                                                                                                                                                                                                                                  cytochrome c oxidase (IV: complex IV of the respiratory chain) and citrate synthase (CS, a
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    RTV                                        RTV                                                                             Krebs cycle enzyme, which is used to measure the mitochondrial content in the sample)
                                                                                                                                                                                                                                                                                                                                                                                                             mitochondrial DNA (mtDNA).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        respectively. § mtDNA quantity is expressed as a ratio of mtDNA to nuclear DNA. A ratio >1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Table 2: Clinical and laboratory features of HIV-HCV co-infected patients after LT                                                                                                          is considered normal for liver mtDNA.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Patient 3 died 22 months after LT with HAART hepatotoxicity and severe recurrence of HVC
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   infection on the liver graft. Patient 6 died 4 months after LT with HAART hepatotoxicity and
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   acute recurrence of HCV infection on the liver graft. Patient 8 died 11 months after LT with
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Carcinoma de pancreas
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   nd = not detectable; * abbreviations of HAART therapy: d4T: stavudine EFV: efavirenz NFV:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   nelfinavir ABC: abacavir TDF: tenofovir LPV: lopinavir; RTV: ritonavir 3TC:lamivudine.




     6 months post-LT                                                                  3 years post-LT
                                                                                                                                                                                                                                                                                                                                                                                               microvesicular steatosis
                                                                                                                                                                                                                                                                                                                                                                                                    at M2 post LT
                                       genotype 1b                                                                                            Genotype 4c/4d                                                                                                 Genotype 1a                                                                                                                              Genotype 1a                                                                                                         Genotype 3a                                                                                                                                                 genotype 1a                                                                                                                      Genotype 1a                                                                                                                                                                                                                                                         Genotype 1                                                                                                                     Genotype 1a                                                                                                      Genotype 3a




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 11
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                Genotype 1a




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    10
                                       LT : 4/12/99. Liver total domino                                                                       LT 13/11/2000: Split - Cadaveric Donor                                                                                                                                                                                                                  LT 26/07/01: Living Donor                                                                                           LT 1/09/01: Total Liver, Cadaveric Donor                                                                                                                    LT 9/11/01: Liver total domino                                                                                                   LT 14/03/2002: total liver domino                                                                                                                                                                                                                                   LT: 4/02/03 Living Donor
                          1




                                                                                                                                2




                                                                                                                                                                                                                                                 3




                                                                                                                                                                                                                                                                                                                                                                                       4




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         5




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  6




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     7




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               8




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               9
                                                                                                                                                                                                                                                             LT: 16/01/01: Liver total domino                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   LT: 27/10/02 Cadaveric Donor                                                                                                                                                                                                                              LT: 2/04/03 Cadaveric Donor                                                                                      LT: 23/06/03 Liver total domino
                                                                                                                                                                                 M12: CHC
                    t




                                                                                                                            t




                                                                                                                                                                                                                                             t




                                                                                                                                                                                                                                                                                                                                                                                       t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       t




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           t
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              t
                                                                                                                                                                                   A2F1
              en




                                                                                                                           en




                                                                                                                                                                                                                                            en




                                                                                                                                                                                                                                                                                                                                                                                en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  en




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    en
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      M2: acute lobular hepatitis
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        M3: A3F2                                                                                                                                                                                                                                                   M1: PegIFN60 g/week + rivabirin 600mg/day




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       en
                                 D12: acute hepatitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 + microvesicular steatosis
                                                                                                                                                                                                         M18:CHC                                                                                                                                                                               M1: acute lobular hepatitis
                                                                                                                                                                                                                                                             M1: acute rejection       M6: acute hepatitis + ductopenia = 36%                                                                                                                                                                                                                                                 M12: CHC
                                                                                                                                                                                                A2F1 + microvesicular steatosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              D50:acute hepatitis                   M6: Lobulaire hepatitis




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 ti
           ti




                                                                                                                       ti




                                                                                                                                                                                                                                        ti




                                                                                                                                                                                                                                                                                                                                                                            ti




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                ti




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ti




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         ti




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ti




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               ti
                                                                                                                                                                                                                                                              BANFF: 1.1.1                                                                                                                                                                                  M18: CHC A1F2 + Biliary stenosis             IU/L   300                                                                                          8   Log 10                                                                                                                                                                                                   M1:Acute lobular hepatitis                                                                                                                    M1       Peg-IFN 80µg/week + Rivabirin 600mg/day                                                                                                                                                                                                  D16:acute hepatitis                      M6:Lobulaire hepatitis
                                                         M6: CHC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                A2F1                                                                                                                                                                                                                                                                                                                                                               M1 acute hepatitis




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   ti
                                                                                                                                                                                                                                                                                                     M8: CHC A2F2 + microvesicular steatosis                                                                                 M6: microvesicular steatosis                                                                                                                                                                                                                                                                                                                                                                Acute rejection BANFF: 1.1.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        D26:acute hepatitis                       M3:Lobulaire hepatitis




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      IU/L
                                                         A3F3/F4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              350




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               pa
      pa




                                                                                                                      pa




                                                                                                                                                                                                                                       pa




                                                                                                                                                                                                                                                                                                                                                                           pa




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               pa




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               pa




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        pa




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 pa




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          pa
                                                                                                                                                  M1: acute hepatitis                                 M24: CHC                                                                                                                                                                                                                                                                 Log 10
                                                                                           M36: CHC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             M18: CHC                                                                                                                                                                                      IU/L                                                                                                       Log 10                                                                                                                                                                                                                                                                   8




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  pa
                                                                                                                                                                                                                                                 IU/L                                                                                    Log 10                                 IU/L                                                                                                                                                                                                                                                                                                                                                                                                                 400                                                                                          7,2                                                                                                                                                                                                                                                                                                         350




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Log 10
                                                                                                                                                                                                        A3F4                                            70                                                                           8                                                 160                                                                                 8                                                                                                                                 7                                                                                                                                                                                                                                                                                                                               300                                                                              6,8
                                                                                             A1F3                           IU/L                                                                                                                                                                                                                                                                                                                                                                                                                                                                  A2F4                                                   IU/L     900                                                                                   8     Log 10                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         7,2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         M4: CHC A3F1+ microvesicular




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      IU/L




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Log 10
                                                                                                                                    350                                                                      8      Log 10                                                                                                                                                                                                                                                                                      250                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        250
                                                                                                                                                                    M7: CHC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       steatosis                                                                                                                                                                                                                   300
                                                                                                                                                                     A2F1                                                                               60                                                                           7                                                 140                                                                                 7                                                                                                                                                                                      800                                                                                                                                350                                                                                          7                                                                                                                           6,6                                                                                                                                                 7                                                                                                                                                                                                                                 8
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             6                                                                                                                                          7                                                                                                                                                                                                                                                                                                                                                                                                                                                     300                                                                            7
               IU/L 900                                                                                9 Log10                      300                                                                       7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              250
                                                                                                       8                                                                                                                                                                                                                             6                                                 120                                                                                 6                                    200                                                                                                                                               700                                                                                                                                300                                                M8: CHC                                   6,8                                                                                                                         6,4                                            250                                                                                                  6                                                                                                                                        200                                                                                  7
                                                                                                                                                                                                              6                                         50                                                                                 M12: microvesicular steatosis                                                                                                                                                                                                                                     5
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        6
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         A3F2                                                                                                                                                                                                                                                                                                                                                 250                                                                            6,8
                                                                                                                                    250                                                                                                                                                                                                   Ductopenia = 36% + CHC A2F2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        200
                   700                                                                                 7                                                                                                                                                                                                                             5                                                 100                                                                                 5
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  600                                                                                                                                250                                                                                          6,6                                                                                                                         6,2                                                                                                                                                                                                                                                            6,6                                                                                                                6
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        5                                                                                                                                                                                                                                                                                                                                                                                                                         5




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       IU/L
                                                                                                                                                                                                              5                                         40                                                                               M20: CHC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   M12: CHC                                                                                                                                                                                 200
                   600                                                                                 6                            200
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                150                                                                                          4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  500                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         200                                                                                                          150                                                                                  5




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Log 10
                                                                                                                                                                                                                                                                                                                                           A1F3                                                                                                                                                                                                                                                                                                                                                J7 : acute rejection        M2: intense acute lobular hepatitis +                                                                                                                      A2F1
                                                                                                                                                                                                                                                                                                                                     4                                                  80                                                                                 4                                                                                                                                                                                                                     BANFF: 2.2.3                    macrovesicular steatosis
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     200                                                                                          6,4                                        150                                                                              6                                                                                                                                                                                                                                                             6,4
                   500                                                                                 5                                                                                                      4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               4
                                                                                                                                                                                                                                                        30                                                                                                                                                                                                                                                                                                                                                   3                                                    400                                                                                                                                                                                                                                                                                                                                                                                                        150
                                                                                                                                    150
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                100
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              150                                                                           6,2                                                                                                                 4
                   400                                                                                 4                                                                                                      3                                                                                                                      3                                                  60                                                                                 3                                                                                                                                                                                                                                                                            3                                            150                                                                                          6,2                                                                                                                         5,8                                                                                                                                                                                                                                                                                          100




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    IU/L
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             100                                                                                                                                                                                                                              3




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Log 10
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  300
                   300                                                                                 3                            100                                                                                                                 20                                                                                                                                                                                                                                                                                                                                                   2                                                                                                                                                                                                                                                                                                                                                                                                                                                               100                                                                                                                              100                                                                           6                                                                                                                   3
                                                                                                                                                                                                              2                                                                                                                      2                                                  40                                                                                 2                                                                                                                                                                                                                                                                            2                                            100                                                                                          6                                                                                                                           5,6
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 50                                                                                                                                               200                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         2
                   200                                                                                 2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             1                                                                                                                                                                                                                                                                                                                               50                                                                                                                                                                                                                                                                                                                                             5,8                             50                                                                                  2
                                                                                                                                     50                                                                       1                                         10                                                                           1                                                  20                                                                                 1                                                                                                                                                                                                                                                                                                                          50                                                                                          5,8                                                                                                                         5,4                                            50                                                                                                                                50
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  100                                                                                   1
                   100                                                                                 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      1                                                                                                                                                                                                                                 1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            5,6
                      0                                                                                0                              0                                                                       0                                          0                                                                           0                                                     0                                                                               0                                      0                                                                                          0                                                      0                                                                                   0                                              0                                                                                          5,6                                          0                                                                              5,2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              0                                                                                                                                0                                                                                                            0
                                                                                                                                                                                                                                                            D4 T




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         Delay post LT                                                                                                                                                                                                                                                                                                                                                                                                                JO       M1            M2          M3       M4            M5         M6
                                                                                                                                                                                                                                                                                                                                                                                               T




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            5,4                                                                                                                 0




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      3
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          T
                      LT




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              0
                                                                                                                                                                                                                                                              eL




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   J0    M1      M2     M3       M4    M5    M6     M7    M8     M9    M10                                                          JO       M1         M2            M3           M4        M5        M6           M7                                               JO   M1          M2          M3          M4          M5          M6




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               T
                                                                                                                                          T




                                                                                                                                                                                                                                                                                                                                                                                             eL




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     2-
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        eL




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                D4
                                                                                                                                                                                                             Delay post LT                                                                                                           Delay post LT
                                                                                                                                                                                                                                                              1




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            T
                           W 1




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          1




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             eL
                                                                                                                                        eL
                               3




                                                                                                                                                                                                                                                              3
                            D4




                                                                                                                                                                                                                                                             1


                                                                                                                                                                                                                                                                              3




                                                                                                                                                                                                                                                                                          6


                                                                                                                                                                                                                                                                                                  8


                                                                                                                                                                                                                                                                                                          10


                                                                                                                                                                                                                                                                                                                   12
                                                                                                                                                                                                                                                                                                                   18
                                                                                                                                                                                                                                                                                                                   22




                                                                                                                                                                                                                                                                                                                                                                                           D4
                                              3




                                                         6




                                                                                                                                                                                                                                                                                                                                                                                                      3
                                                                        10


                                                                               12
                             1




                                                                 8




                                                                                        24
                                                                                        36




                                                                                                      Delay post LT
                                                                                                                                                                                                                                                           pr




                                                                                                                                                                                                                                                                                                                                                                                                                   3




                                                                                                                                                                                                                                                                                                                                                                                                                                   6




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Delay post LT
                                                                                                                                                                                                                                                                                                                                                                                           S1



                                                                                                                                                                                                                                                                                                                                                                                                     1




                                                                                                                                                                                                                                                                                                                                                                                                                                             8
                                                                                                                                                                                                                                                           W




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            -3
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        1



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  3




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     6



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              8
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 S1
                                                                                                                                                                                                                                                                                                                                                                                                                                                      10


                                                                                                                                                                                                                                                                                                                                                                                                                                                             12
                                                                                                                                                                                                                                                                                                                                                                                                                                                             18




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      J4




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          eL




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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          W


                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  W




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             4
                            W




                                                                                                                                                                                                                                                           2-




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      pr
                                                                                                                                              1




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       10



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 12

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      18
                                                                                                                                                                                                                                                                                                                                                                                           pr
                            2-




                                                                                                                                                                                                                                                          M


                                                                                                                                                                                                                                                                             M




                                                                                                                                                                                                                                                                                         M


                                                                                                                                                                                                                                                                                                 M
                      e




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Delay post LT




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 1




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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       8
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                -3
                                             M




                                                        M




                                                                                                                                                                                                                                                                                                                                                                                                   2-
                            M




                                                                M




                                                                                                                                                   1


                                                                                                                                                          3


                                                                                                                                                                 5


                                                                                                                                                                        7


                                                                                                                                                                                 9




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                10

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       11
                                                                                                                                                                                                                                                                                                                                                                                                                  M




                                                                                                                                                                                                                                                                                                                                                                                                                                  M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      M



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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           pr
                                                                                                                                                                                                                                                                                                                                                                                                   M




                                                                                                                                                                                                                                                                                                                                                                                                                                            M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Delay post LT




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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   W
                                                                                                                                      pr




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           D
                                                                                                                                              W




                                                                                                                                                                                         11


                                                                                                                                                                                                 18




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         s2
                                                                                                                                                                                                                                                                                                         M


                                                                                                                                                                                                                                                                                                                  M
                                                                                                                                                                                                                                                                                                                  M
                                                                                                                                                                                                                                                                                                                  M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          M




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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      M
                    pr




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           M3
                                                                                                                                                  M


                                                                                                                                                        M


                                                                                                                                                                M


                                                                                                                                                                        M


                                                                                                                                                                                 M
                                                                       M


                                                                              M




                                                                                                                                                                                                                                                         W
                                                                                       M
                                                                                       M




                                                                                                                                                                                                                                                                                                                                                                                                                                                     M


                                                                                                                                                                                                                                                                                                                                                                                                                                                            M
                                                                                                                                                                                                                                                                                                                                                                                                                                                            M




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        pr
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              S2




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   M



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               M

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      M
                                                                                                                                                                                                                                                                                                                                                                                                                                                                            Delay post LT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              M4
                                                                                                                                                                                                                                                                                                                                                                                                  W




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               M

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      M
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  M4: DEATH                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           M5




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        W
                                                                                                                                                                                       M


                                                                                                                                                                                                M




                                                                                                                                                                                                                                                                                                                                 M24: death                                                                                                                                                                                                                                                                                                                                      AZT- 3TC-EFV        DDI- 3TC-EFV     TNF- 3TC-EFV                                                                                                                                                                                                                              ABC - TDF- 3TC                        ABC- TDF- EFV                                                                      D4T-3TC-TDF                                     EFV-ABC-TDF                              Delay post LT                                                 ABC-EFV-3TC
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            Delay post TH                                                          TDF-NFV-3TC                                  Delay post LT
                                                                                                                                                                                                                                                                               AZT- 3TC- IDV                   AZT- 3TC- NFV
                                                                                                                                                   d4T- 3TC-EFV                      d4T-DDI-       ABC-TNF- LPV /RTV                                                                                                                                                                                                                                                                                                                                    EFV - NEFV - DDI                                                                                                                                                                                                                                              AZT - 3TC - DDI          AZT- 3TC-       DDI - TNF-          ABC - TNF -
                                                                                                                                                                                                                                                                                                                                                                                                        DDI-d4T- 3TC                          EFV - NEFV - 3TC                                                                                                                                                                                                                                                                    M3                                                                                                              NFV           LPV/RTV              LPV/RTV
                                 d4T- NVP- NFV                         d4T- EFV- NFV                                                                                                 LPV/RTV                                                                                                                       M12                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              M1:PegINF 50µg/week + rivabirin 600mg/day
                                                                                                                                                                            M8                      M18
                                                                                                                                                                                                           M24                                                                                                     IFN 1.5 MU +                                                                                                                                                                                                               M3                         M6       M9                       M18                                                                                                                    IFN 1.5 MU                                                                                                                                  M10
                                                                                                                                                                                                                                                                                                                      400 mg                                                                                                                                                                                                                          IFN 0.5 MU                            IFN PEG 50                                                                                                                             + 400 mg
                                                                                                                                                                                                                  PegIFN 50/ W+ 400                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           IFN PEG 80 g//W+
                                                                                                                                                                                                                                                                                                                  Ribavirin during                                                                                                                                                                                                                        X3/ +                                 g/W                                                                                                                               Ribavirin for
                                                        M6                                 M20                                                                                                                       _ribavirin/D                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Ribavirin
                                                                                                                                                                                                                                                                                                                     15 days                                                                                                                                                                                                                             400 mg                               + 400 mg                                                                                                                              3 days
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  800 mg/D
                                                             IFN 1.5 MU X 3W-PegIFN 50 g                                                                                                                                                                                                                                                                                                                                                                                                                                                               ribavirin/D                           ribavirin/D
                                                                  + 600mg ribavirin/D
                                                                                                            ALT                                                                                                              ALT                                                                                                               ALT                                                                                                                                ALT                                                                                                                            ALT                                                                                                                                                     ALT                                                                                                                            ALT                                                                                                                       ALT                                                                                                                                        ALT                                                                                                                    ALT                                                                                                                    ALT
                                                                                                            HCV RNA                                                                                                          HCV RNA                                                                                                           HCV RNA                                                                                                                            HCV RNA                                                                                                                        HCV RNA                                                                                                                                                 HCV RNA                                                                                                                        HCV RNA                                                                                                                   HCV RNA                                                                                                                                    HCV RNA                                                                                                                HCV RNA                                                                                                                HCV RNA

				
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