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					     Prophylactic Use of Low-Dose On-Demand
Intramuscular Hepatitis B Immune Globulins (HBIG)
 and Lamivudine (LAM) After Liver Transplantation

       Sedat Karademir, Hüseyin Astarcıoğlu, Mesut Akarsu,
        Sevda Özkardeşler, Deniz Özzeybek, Arzu Sayıner,
         Mert Akan, Ethem Tankurt, İbrahim Astarcıoğlu

   Dept of General Surgery, Gastroenterology, Microbiology and Anesthesiology and Reanimation,
              Dokuz Eylül University, School of Medicine, İnciraltı, İzmir, TURKEY
  Liver Transplantation for Hepatitis B
      Hepatitis B immunoglobulins (HBIG)

 reduced the rate of HBV recurrence after LT from
  75% to 36%
 extremely expensive and drug availability is limited
 benefit was mainly seen in patients with low HBV
  DNA replication
  Liver Transplantation for Hepatitis B
                     Lamivudine
                     (nucleoside analog)


 a potent anti-HBV drug (control of HBV replication
  at pre- and posttransplantation)
 cheap and easily applied
 drug resistance (selection of HBV mutants)
 posttransplant monotherapy resulted in high rates of
  HBV recurence
  Liver Transplantation for Hepatitis B
             HBIG plus Lamivudine

 was accepted as superior to monotherapy with HBIG
  or with antiviral agents due to concerns that
  mutations may occur
 reduced the recurrence rate to 20% or less
 development of LAM resistance is a problem
  Liver Transplantation for Hepatitis B
                Adefovir dipivoxil
                    (nucleotide analog)


 treats both wild-type and LAM resistant HBV strains
  developed during pre- of posttransplantation
 has extended the applicability of LT in the face of
  LAM-R.
Liver Transplantation for Hepatitis B


  In the era of these powerful antivirals
(nucleos[t]ide analogs), the optimum dose,
 duration and route of HBIG are not clear!
  Liver Transplantation for Hepatitis B

 Dokuz Eylül University Hospital (1998-2004)
 40 pts (21 LRLT) underwent LT with HBV related
  ESLD.
 Post-transplant HBV Prophylaxis:

       Low-dose, IM and “on-demand” HBIG
                        +
            Lamivudine ( Adefovir)
                          Induction

                √ HBsAb       √ HBsAb      √ HBsAb
                  HBsAg         HBsAg        HBsAg



 IM
4000     IM IM IM IM IM                 HBsAg: neg
        2000 2000 2000 2000 2000        HBsAb> 200 IU
                    3              6             days
Tx

     + Lamivudin 100 mg/day
                Maintenance




 HBsAb<100 IU  1200-2000 IU HBIG - IM
 HBV DNA: q3-6 mo and when needed
               HBV recurrence


 HBsAg +
 HBV DNA +
   – Detection by PCR
   – >1 log10 increment
 Elevation in LFT
 Histology / liver biopsy
                                                                  Post-LT HBV      HBV     Follow-up
    HBV DNA status at the time of LT   N    HbeAg (+) HDV (+)     prophylaxis†     recur   (months)




A   DNA (-)*, no LAM pre-LT            22     0/22      4/22      LAM  HBIG        0       23 (2-95)


B   DNA (-) after LAM pre-LT           11     4/11      1/11      LAM  HBIG        0      14.2 (6-28)


C   DNA (+) after LAM-R but no ADV     3      1/3        0        LAM  HBIG        0      22R, 28R,20

D   DNA (+), no antiviral pre-LT       2      2/2        0        LAM  HBIG        0      12 and 16


E   DNA (-) after LAM-R plus ADV       2      2/2        0      LAM  ADV  HBIG    0      10 and 12
    NON-REPLICATORS
    NON- REPLICATORS


                                                                                       HBV     Follow-up
     HBV DNA status at the time of LT   N    HbeAg (+) HDV (+) Post-LT HBV prophylaxis recur   (months)




A    DNA (-), no LAM pre-LT             22     0/22      4/22        LAM  HBIG          0      23 (2-95)


B    DNA (-) after LAM pre-LT           11     4/11      1/11        LAM  HBIG          0     14.2 (6-28)


C    DNA (+) after LAM-R but no ADV     3       1/3       0          LAM  HBIG          0     22R, 28R,20

D    DNA (+), no antiviral pre-LT       2       2/2       0          LAM  HBIG          0     12 and 16


E    DNA (-) after LAM-R plus ADV       2       2/2       0       LAM  ADV  HBIG       0     10 and 12
    REPLICATORS


                                                                                       HBV     Follow-up
     HBV DNA status at the time of LT   N    HbeAg (+) HDV (+) Post-LT HBV prophylaxis recur   (months)




A    DNA (-), no LAM pre-LT             22     0/22      4/22        LAM  HBIG          0      23 (2-95)


B    DNA (-) after LAM pre-LT           11     4/11      1/11        LAM  HBIG          0     14.2 (6-28)


C    DNA (+) after LAM-R but no ADV     3       1/3       0          LAM  HBIG          0     22R, 28R,20

D    DNA (+), no antiviral pre-LT       2       2/2       0          LAM  HBIG          0     12 and 16


E    DNA (-) after LAM-R plus ADV       2       2/2       0       LAM  ADV  HBIG       0     10 and 12
    REPLICATORS


                                                                                       HBV     Follow-up
     HBV DNA status at the time of LT   N    HbeAg (+) HDV (+) Post-LT HBV prophylaxis recur   (months)




A    DNA (-), no LAM pre-LT             22     0/22      4/22        LAM  HBIG          0      23 (2-95)


B    DNA (-) after LAM pre-LT           11     4/11      1/11        LAM  HBIG          0     14.2 (6-28)


C    DNA (+) after LAM-R but no ADV     3       1/3       0          LAM  HBIG          0     22R, 28R,20

D    DNA (+), no antiviral pre-LT       2       2/2       0          LAM  HBIG          0     12 and 16


E    DNA (-) after LAM-R plus ADV       2       2/2       0       LAM  ADV  HBIG       0     10 and 12
                     Survival

 Five deaths (2 to 12 months ) unrelated to HBV
 Cumulative survival at 1 year : 86%
 The remaining 35 survivors are alive (median of 18
  months (range, 8 to 95 months) after transplantation
  with normal graft function and serum HBsAg
  negativity
           Induction HBV prophylaxis

 HBsAg seronegativity and HBsAb >200 IU were
  achieved at a median of 8 days (range, 4 to 17 days)
  post-transplantation.
 To reach the goal, the median dose of 18000 IU
  (range, 10000 IU and 36000 IU) HBIG IM were
  given
                 Maintenance HBV prophylaxis
The total cumulative dose of HBIG consumed / year after LT

                50000

                40000
    HBIG (IU)




                30000

                20000


                10000


                   0
                        1 yr    2 yrs   3 yrs         4 yrs   5 yrs   6 yrs

   Mean HBIG (IU)       34014   5258    5090          4600    2900    2800
   Patients (n)          22      10      5              4      4       2
                                        Postransplant years
 The Total Dose and Duration of HBIG Needed To Achieve
     HBsAg (-) and HBsAb >200 IU During Induction




                   Replicators      Non-replicators
                                                      p
                     n=18               n= 22
Postop days         9.15  3.1         9.4  3.9      NS
IM HBIG (IU)      18,031 4,920     20,189 7,915     NS
The Total Dose of HBIG Needed to Maintain HBsAb >100 IU
                 (First posttransplant year)



                 Replicators      Non-replicators   p
IM HBIG (IU)     28,940  5705    40,680  9579     0.3
HBsAb values during first month
                                        333 (125 ;1000)   471 (128 ; 1000)

                                 1000
         Serum Hbs Ab measures
              (IU, median)




                                 500




                                   0


                                        Non-replicators     Replicators
HBsAb values between 1 month- 1 year posttransplant

                                       85 (48 ; 325)     99,5 (38 ; 286)

                                 400




                                 300
         Serum Hbs Ab measures
              (IU, median)




                                 200




                                 100




                                  0

                                       Non-replicators      Replicators
                                               1 of 5


The survival advantage of achieving HBV
DNA negativity at the time of LT

 Our findings with low-dose intramuscular HBIG
  administration are favorable in either HBV replicators
  and non-replicators who maintain HBV DNA
  negativity at the time of surgery.
                                                2 of 5
Dose-sparing
 Although, individual profiles are highly variable, the
  total amount of HBIG consumed in our series are
  considerably low compared with those reported by
  other investigators using standard high-dose HBIG
  combination prophylaxis (~100,000 -190,000 IU for
  the first year)
                                                3 of 5
HBsAg seronegativity at induction
 High dose IV HBIG infusion has been the route of
  choice to achieve early and rapid naturalization of the
  circulating HBV particles in order to prevent the
  reinfection of newly transplanted liver graft
 However, our data show that with the combination of
  lamivudine + IM, low-dose HBIG, persisting HBsAg
  positivity (4 – 17 days) (slow clearance) after
  transplantation may not add further risk for HBV
  recurrence.
                                              4 of 5
HBV recurrence


 HBV recurred in only two recipients who were
  already in high risk for reinfection due to pre-
  transplant LAM-R, HBV DNA positivity at surgery
  and unavailability of ADV for salvage therapy
 Even they were successfully salvaged by adding
  ADV to their prophylaxis regime after the recurrence
  was occurred
                                                5 of 5
IM injections

 none of our patients have rejected the treatment, but
  temporarily requested additional medication for pain
  relief.
 Our data, although uncontrolled, suggest that in
  combination with nucleos(t)ide analogs, low-dose,
  intramuscular and on-demand HBIG administration
  may be a reasonable strategy for long-term HBV
  prophylaxis after LT.
 This may allow more appropriate use of HBIG with
  associated cost savings and better utilization of
  potentially scarce resources.
END

				
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