Docstoc

Slide 1 - University of Hawaii

Document Sample
Slide 1 - University of Hawaii Powered By Docstoc
					    Optimizing Care for the
HIV-Hepatitis Coinfected Patient

                        Mark Holodniy, MD
                          Professor of Medicine
                           Stanford University
                           Stanford, California




  Sponsored by The Academy for                    Supported by an educational
  Continued Healthcare Learning                   grant from Abbott
Intended Audience
This activity is intended for HIV specialists from a wide range of
disciplines, including but not limited to internal medicine, family practice,
and infectious disease physicians. Pharmacists, nurses and other
healthcare professionals focusing on HIV care are also encouraged to
attend.
In accordance with PhRMA guidelines, this program is intended for
healthcare professionals only.

Activity Purpose
To update physicians, pharmacists, nurses and other health care
professionals, on recent advances in HIV research and the management
of HIV infectious disease.

Method of Participation
This activity will consist of a lecture meeting with collateral slides,
syllabus, and interactive question and answer session.
Accreditation
The Academy for Continued Healthcare Learning (ACHL) is accredited by the
Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing medical education for physicians.
Designation
The Academy for Continued Healthcare Learning (ACHL) designates this
educational activity for a maximum of 1.0 AMA PRA Category 1 CreditTM.
Physicians should only claim credit commensurate with the extent of their
participation in the activity.

The Academy for Continued Healthcare Learning (ACHL) is accredited by the
Accreditation Council for Pharmacy Education (ACPE) as a provider of
continuing pharmacy education. In order to receive credit, pharmacists must
complete the activity requirements and evaluation at the conclusion of the
program. This activity has been approved for a maximum of 0.1 CEU.
ACPE Universal Program Number (UPN): 396-000-06-013-L02
Initial Release Date: 01/20/06
The Academy for Continued Healthcare Learning (ACHL) has been
reviewed and approved as an Authorized Provider by the International
Association of Continuing Education and Training (IACET). ACHL has awarded
0.1 CEU to participants who         successfully complete this program.
IACET CEU credit may be used toward nursing credits. Contact your local
accrediting body for details.
               Disclosure Statements
The Academy for Continued Healthcare Learning (ACHL) requires that the
faculty participating in a CME/CE activity disclose to the participant any
relevant affiliation or other financial relationship (1) with the
manufacturers of any commercial product(s) and/or provider(s) of
commercial services discussed in an educational presentation, and (2)
with any commercial supporters of the activity. The ACHL also requires
participating faculty to disclose when unapproved/unlabeled uses of a
product are discussed in a CME/CE activity.
Mark Holodniy, MD, has no relevant affiliations or financial relationships
to disclose.

The ACHL staff members and others involved with the planning,
development, and review of the content for this activity have no relevant
affiliations or financial relationships to disclose.
                              Disclaimer
The content for this activity was developed independently of the commercial
supporter. All materials are included with permission. The opinions expressed are
those of the faculty and are not to be construed as those of the publisher or grantor.

This educational activity was planned and produced in accordance with the ACCME
Essential Areas and Elements, Policies, and Standards for Commercial Support as
well as the ACPE Criteria for Quality and Interpretive Guidelines. Recommendations
involving clinical medicine in a continuing medical education (CME/CE) activity must
be based on evidence that is accepted within the profession of medicine as adequate
justification for their indications and contraindications in the care of patients. All
scientific research referred to, reported or used in CME/CE in support or justification
of a patient care recommendation must conform to the generally accepted standards
of experimental design, data collection and analysis.

Participants are advised that one or more presentations in this CME/CE activity may
contain references to unapproved or unlabeled uses of drugs or devices. Participants
should note that the use of these agents outside current approved labeling is
considered investigational and are advised to consult current prescribing
information for these products.
          Housekeeping Information

• Please refer to the syllabus for complete CME/CE credit
  information

• Please return your completed enrollment/evaluation forms to the
  Meeting Host before you leave

• Please turn your cell phones to off or vibrate
                Learning Objectives

Upon completion of this activity, participants should be able to

• Describe liver-related adverse events in HIV-Hepatitis coinfected
  patient

• Examine associated hepatotoxicity with different treatment
  modalities

• Review treatment options, taking into consideration hepatic safety
      Liver-Related Adverse Events

• Liver-related adverse events are the most common grade 4
  adverse events in HIV positive patients
• Hospitalizations for liver related events are more common
  than hospitalizations for opportunistic infections or for IDU
  related events
• Liver toxicity of ARV agents should be seriously considered
  before initiating therapy
                           Most Common Grade 4 Events:
                                  CPCRA Cohort
                       3    Liver
                             2.6                                  Incidence
per 100 Person-Years




                       2
                                         Neutropenia
                                             1.5
                                                        Anemia
                                                          1.1           CVD          Pancreatitis
                                                                        0.9             0.9       Psychiatric
                       1                                                                             0.8           Renal
                                                                                                                    0.6



                       0
                                            Hazard Ratio For Death by Grade 4 Event (95% CI)
                             3.49           1.02          1.76           7.08            3.40          1.91          4.60
                           (2.38-5.12)    (0.61-1.72)   (0.99-3.09)   (4.15-12.05)     (1.82-6.33)   (0.79-4.63)   (2.45-8.66)
                            P=.0001          P=.93        P=.051        P=.0001         P=.0001         P=.15       P=.0001

        N=2947; CPCRA=Terry Beirn Community
        Programs for Clinical Research on AIDS.
                                                                                        Reisler RB, et al. JAIDS. 2003;34:379-386.
   Prevalence of HIV/HCV Coinfection
                                                                             HIV/HCV Coinfection
• Johns Hopkins HIV clinic                                        100      Prevalence by Risk Factor
   – Urban setting




                                 Prevalence of Antibody HCV+, %
                                                                          84%
   – Prospective, longitudinal                                     80
     database
   – HCV-coinfection clinic                                        60
     established in 1997
                                                                                                           45%
• 1742 HIV-infected                                                40
  patients screened for
  HCV infection (1997-                                             20                14%
  2000)                                                                                         10%

   – HCV+: 798 patients                                             0
                                                                          IDU      Hetero- Homo-         Entire
                                                                                   sexual sexual         Cohort
                                                                                    Sex     Sex

                                                                  Sulkowski MS, et al. Hepatology. 2000;32. Abstract 204.
        Impact of HIV Infection on
     HBV and HCV Disease Progression
  • Impact of HIV infection        HBV or HCV Disease Course

       – Accelerates the course       HBV or HCV Infection
         of HBV and HCV
                                                 15%         85%
         infection                 Recovery                          Chronic
  • Liver disease
                                                     68%            17%
    associated with HBV
    or HCV infection                         Stable                 Cirrhosis
       – A leading cause of                         13%              4%
         morbidity and mortality
                                           Slowly                     HCC
         among HIV-infected
                                         Progressive                  ESLD
         patients
                                            Thomas DL, et al. JAMA. 2000;284:450-456.
                                      Benhamou Y, et al. Hepatology. 1999;30:1054-1058.
HCC=hepatocellular carcinoma.         Graham CS, et al. Clin Infect Dis. 2001;33:562-569.
                                    Bodsworth NJ, et al. J Infect Dis. 1991;163:1138-1140.
ESLD=end-stage liver disease.                   Gilson RJ, et al. AIDS. 1997;11:597-606.
 Rapid Progression of Liver Disease
   in HIV/HCV Coinfected Patients
• Prospective study of fibrosis progression in 67 coinfected patients
• 2 biopsies, median time between biopsies was 2.84 years

                            Patients With Mild Fibrosis (≤F1) on First Biopsy
                  60
                                52%
                  50
                                               >25% of patients with mild fibrosis
    Patients, %




                  40                             on initial biopsy had ≥2 stage
                  30                             progression in fibrosis score

                  20                    14%    12%
                       8%                               6%
                  10                                                      4%
                                                                 2%                 2%
                  0
                       -1        No      1      2        3        4         5        6
                               Change

                       Change in Ishak Score From First to Second Biopsy

                                              Sulkowski M, et al. 12th CROI. Boston. 2005. Oral abstract 121.
 Survival of Patients Coinfected With
   HIV and Hepatitis B or C Virus
• Cohort study                                                HIV or Liver Mortality
   – 472 HIV patients followed                    30
                                                                    HIV Mortality
                                                                                                 28%
     for 8343 patient-months                            25%         Liver Mortality
       •   HIV alone (n=126)
                                                                                           22%
       •   HIV/HBV (n=72)
                                                  20
       •   HIV/HCV (n=256)




                                   Mortality, %
                                                                   18%
                                                                               17%
       •   HIV/HBV/HCV (n=18)                                            15%

• Variables associated                                                               13%

  with liver death in the                         10
  cohort coinfected with                                      6%
  HCV, HBV, or both
  (n=346)
                                                   0
   – 0 to 2 antiretroviral drugs
                                                           HIV     HIV/HBV HIV/HCV           HIV
   – CD4 <200 cells/µL                                                                     HBV/HCV

                                                       Bonacini M, et al. AIDS. 2004;18:2039-2045.
Association Between CD4 Cell Count
     and Liver-Related Death
• D:A:D Study
   – Prospective study with 23 441 people with HIV
   – 1248 deaths between 2000-February 2004
• Leading causes of death:
   –   AIDS, 30%
   –   Liver-related death 14% (79% associated with chronic hepatitis)
   –   Heart disease 9%
   –   Non-AIDS malignancies, 8%
• Relative risk of death for persons with CD4 <50 cells/mm3 as
  compared with persons with CD4 >500 cells/mm3

         Category                    RR          95% CI             P
         AIDS                       96.4       61.6-150.7       <.0001
         Liver-Related              26.6       12.9-54.7        <.0001
         Non-AIDS Malignancies      23.5        9.4-58.7        <.0001


                                        Weber, R, et al. 12th CROI. Boston. 2005. Abstract 595.
                HAART and the Impact of HIV RNA,
                  CD4, or Both on Liver Fibrosis

                             0.2                          0.196
                                                                         P=.005                    P=.005
                                               P=.04
                                                                                                            0.162
Ishak Fibrosis Units/Year




                            0.16                                                  0.155
                                   P=.005     0.145
                                   0.122                          0.121                     0.123
                            0.12


                            0.08


                            0.04


                              0
                                   <400      400-99K      ≥100K   ≥350            <350      <400            ≥400

                                            HIV RNA                       CD4             HIV RNA (copies/mL) +
                                            (copies/mL)             (cells/mm3)           <500 CD4 cells/mm3

                                                                    Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.
       HAART and Liver Fibrosis in
       HIV/HCV Coinfected Patients
• HAART may slow fibrosis progression
   – HIV/HCV coinfection versus HCV monoinfection post-HAART: No
     difference in:
      • Fibrosis progression rate (P=.29)
      • Fibrosis stage (P=.87)
      • Necroinflammatory grade (P=.89)
• Fibrosis progression rate (FPR) in Coinfected patients:
   - Strongly correlated with HIV RNA levels
      - Coinfected patients with any HIV RNA >400 copies/mL had a faster
        FPR than coinfected patients with HIV RNA <400 copies/mL (P=.004)
      - Coinfected patients with HIV RNA <400 copies/mL had a similar FPR
        to HCV monoinfected patients (P=.253)
   - Increased with CD4 cell counts <500 cells/mm3 combined with
     HIV RNA >400 copies/mL (P=.005)
                                            Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.
  Impact of HAART and ART on Mortality
     in HIV/HCV Coinfected Patients
                                                                         Overall Mortality
• Bonn cohort (1990-2002)                             1




                              Cumulative Survival
                                                                                  HAART*
   – 285 HIV/HCV coinfected                         0.8
     patients                                       0.6
• Liver-related mortality                                                                       ART
                                                    0.4
  rates per 100 person-                                       *P<.001                   No therapy
  years                                             0.2
                                                          0    1000     2000   3000 4000     5000     6000
   – HAART: 0.45                                                               Days
   – ART: 0.69
                                                                      Liver-Related Mortality
   – No therapy: 1.70                                1
                              Cumulative Survival
                                                                                  HAART*
• Predictors for liver-                             0.8
                                                                                                ART

  related mortality                                 0.6
                                                                                         No therapy
   – No HAART
   – Low CD4 cell count                             0.4
                                                              *P=.018
   – Increasing age                                 0.2
                                                          0    1000     2000   3000 4000     5000     6000
                                                                               Days

                                                                Qurishi N, et al. Lancet. 2003;362:1708-1713.
Summary: Clinical Implications of Liver Damage
 and Benefits of HAART in Coinfected Patients

• Liver damage in HIV-infected patients causes
  significant morbidity and mortality
• HIV infection accelerates the course of viral
  hepatitis
• Patients with low CD4 cell counts have an
  increased risk of liver-related death
• HAART
  –   Can be tolerated by coinfected patients
  –   Controls HIV
  –   May slow the progression of fibrosis, especially PIs
  –   Improves immune status
  –   Improves survival
Balancing HAART and
    Hepatic Safety
       NRTIs
       NRTI-Related Hepatotoxicity

• Syndrome of mitochondrial toxicity
  – Mitochondria have their own DNA (mtDNA) that
    encodes 13% of mitochondrial proteins
  – NRTIs inhibit mitochondrial DNA synthesis, causing
    mitochondrial dysfunction and cellular toxicity
• High-risk drugs
  – Stavudine, didanosine, zalcitabine
• Low-risk drugs
  – Abacavir, zidovudine, lamivudine


                              Fleischer R, et al. Clin Infect Dis. 2004;38:e79-e80.
  Association of Dideoxynucleoside
  Analogues With Hepatic Steatosis
• Retrospective chart review of 179 HIV/HCV coinfected patients
• Univariate analysis
   – Factors associated with steatosis; Dideoxynucleosides (P=.029) and the
     number of nucleoside analogues (P=.042)
   – Use of protease inhibitors was not associated with steatosis
• Multivariate analysis

                                   Odds Ratio          95% CI            P
     Dideoxynucleosides                6.0            (1.9-18.9)       .002

     Other nucleoside analogues        3.0            (1.05-8.4)        .04
     HCV genotype 3                    3.7           (0.92-14.5)       .065



                                   McGovern B, et al. 12th CROI. Boston. 2005. Abstract 950.
Balancing HAART and
    Hepatic Safety
      NNRTIs
     NNRTI-Related Hepatotoxicity

• Incidence of ALT or AST elevations in
  randomized trials
   – Grade 3 (>5 x ULN) and 4 (>10 x ULN): 8% to 16%
• Hepatitis coinfection increases the risk of
  hepatotoxicity
• Nevirapine
   – Fatal hepatic necrosis
      • US FDA “warning”
                                            Sulkowski MS, et al. Hepatology. 2002;35:182-189.
                      Reisler R, et al.   1stIAS Conference. Buenos Aires, 2001. Abstract 43.
                                              Stern J, et al. JAIDS. 2003;34(suppl 1):S21-S33.
                                                   Wit FW, et al. J Infect Dis. 2002;186:23-31.
                                                van Leth F, et al. Lancet. 2004;363:1253-1263.
                                                    Gallant JE, et al. JAMA. 2004;29:191-201.
Risk Factors for Severe, Life-Threatening
     Hepatotoxicity With Nevirapine
• Women with CD4 cell counts >250 cells/mm3
   – Have a 12-fold higher risk versus women with <250
     cells/mm3
   – Can be fatal
• Greatest risk of severe and potentially fatal
  hepatic events often associated with rash
   – Occurs in first 6 weeks of nevirapine therapy
   – Close monitoring recommended. In some cases,
     hepatic injury progresses despite discontinuation of
     treatment
• Nevirapine should not be used for chronic
  therapy among women with CD4 >250 cells/mm3
  when other options exist
         Viramune [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2005.
 Meta-Analysis of AACTG Studies:
Odds Ratio of Severe Hepatotoxicity
• Retrospective analysis of 21
                                                                           Incidence of
  AACTG studies                                                               Severe
   – 9003 patients                                                        Hepatotoxicity
                                                                             (95% CI)
       • Single and double NRTIs
       • Triple regimens including           Efavirenz (n=65)                   10.8
                                                                             (3.3-18.3)
         NRTIs, NNRTIs, and PI
                                             Nevirapine (n=594)                 8.9
• Overall incidence                                                          (6.6-11.2)
   – Severe hepatotoxicity: 10%              Delavirdine (n=137)                 3.6
       • 23% discontinued due to severe                                       (0.5-6.7)
         hepatotoxicity                      Total NNRTI (n=796)                 8.2
   – Liver-related mortality: 0.3%                                           (6.3-10.1)
       • NRTI-based regimen: 0.46%          Grade 3 or 4 elevations (>5 x ULN).
       • NNRTI or PI-based regimen:
         0.13%
                              Reisler R, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 43.
   2NN Study: Severe Hepatotoxicity in
Patients Receiving NNRTI-Based Regimens
•   Treatment-naïve patients                                        Grade 3/4 Hepatotoxicity
     – 1216 enrolled
                                                           15
     – HBV coinfected: 5.2%                                     13.6%
     – HCV coinfected: 9.5%
•   NNRTI + d4T + 3TC
     –   Nevirapine qd (400 mg)
                                                           10                                        9.1%
     –   Nevirapine bid (200 mg)                                             8.3%



                                             Patients, %
     –   Efavirenz qd (600 mg)
     –   Nevirapine + efavirenz qd
         (400 + 800 mg)
                                                           5                             4.5%
•   2 nevirapine-attributed deaths
     – Fulminant hepatitis,
       pancreatitis, renal failure
     – Stevens-Johnson syndrome
       (recovered)                                         0
          • Later developed septicemia
            due to a methicillin-resistant                       QD          BID     Efavirenz Efavirenz +
            Staphylococcus aureus                               (n=220)    (n=387)    (n=400)  Nevirapine
            infection                                                                              (n=209)
                                                                   Nevirapine

                                                                    van Leth F, et al. Lancet. 2004;363:1253-1263.
      Study 006: Patients With
Hepatitis C and/or Hep B Coinfection
• Seropositive for hepatitis                                   ALT and AST >5 Times ULN
  B and C at study entry                                  25        Efavirenz-containing regimens
                                                                    Indinavir + 2 NRTIs
   – 137 patients treated with
                                                                  20%
     efavirenz-containing                                 20
     regimens
   – 84 patients treated with                             15




                                           Patients (%)
                                                                                     13%
     indinavir + 2 NRTIs
• Discontinuations due to                                 10
  liver or biliary system                                               7%                  7%

  disorders were similar                                  5
  (2% to 3%)
                                                          0
                                                                    ALT                 AST

                    Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2003.
          Summary of NNRTIs and
             Hepatic Safety
• There appears to be a modest class effect of NNRTIs
  on abnormal liver enzyme levels
• Rate of serious clinical (symptomatic) hepatotoxicity,
  ALT and/or AST levels >5 times ULN is relatively low
   – May be significantly higher in patients coinfected with
     HBV or HCV
• Unique hepatic event associated with nevirapine
   – Immune-mediated
   – Associated with rash
   – Occurs almost exclusively within the first 6 weeks of
     nevirapine treatment
Balancing HAART and
    Hepatic Safety
        PIs
         PI-Related Hepatotoxicity

• Incidence of ALT and/or AST elevations in
  registration trials
   – Grade 3 (>5 x ULN) and 4 (>10 x ULN): 1% to 9%
• Full-dose ritonavir
   – Only PI identified as an independent risk factor for
     severe hepatic injury
• Boosting doses of ritonavir (≤200 mg/d)
   – Not associated with significantly higher incidence of
     severe hepatotoxicity versus other PIs
• Less data on newer PIs
   – Atazanavir or fosamprenavir
                          Sulkowski MS, et al. Clin Infect Dis. 2004:38(suppl 2):S90-S97.
   Incidence and Risk Factors of
  HAART-Associated Hepatotoxicity
• Retrospective cohort analysis (n=560)
• Risk factors for grade 4 liver enzyme elevations (HR
  [95% CI])
    –   Female sex: 2.8 [1.3-5.8]
    –   Baseline ALT levels (per 10 U/L increase): 1.05 [1.01-1.11]
    –   Chronic HCV infection: 5.0 [2.3-10.7]
    –   Chronic HBV infection: 9.2 [4.1-20.6]
    –   Recent discontinuation of lamivudine: 6.8 [2.1-22.7]
    –   Recent start of nevirapine:* 9.6 [3.2-28.3]
    –   Recent start of full-dose ritonavir:* 4.9 [2.0-12.1]
    –   No increased risk if ritonavir dose ≤200 mg bid
 *12-week  period after start of drug.
 †Patients without NRTIs experience using first-line ARV versus subsequent regimens.


                                                              Wit FW, et al. J Infect Dis. 2002;186:23-31.
    Hepatotoxicity Associated with PI-Based
    Regimens ± Low-Dose Ritonavir: Design
•   Prospective study (n=1161)
     – Evaluate grade 3/4 AST/ALT                     1st PI-Containing Regimen
       elevations of PIs
     – Median follow-up: 211−365 days
•   Baseline characteristics             Saquinavir/r                              Nelfinavir
                                                           24%
     – Age*: 37 years
     – Male: 73%
     – African American: 77%                                                 51%
                                                         8%
     – HCV+: 46%                        Indinavir/r

     – HbsAg+: 10%                                        9%
     – ALT*: 30 IU/L                        Indinavir            8%
     – CD4*: 168 cells/mm3
                                                        Lopinavir/r
     – HIV RNA*: 4.7 log10 copies/mL


     *median                                     Sulkowski MS, et al. Hepatology. 2003;38:698A.
                                                 Sulkowski MS, et al. AIDS. 2004;18:2277-2284.
     Risk Factors for PI-Associated
       Drug-Induced Liver Injury
                                                              Relative Risk
• No increased risk                                             of Severe
  observed with lopinavir/r                                   Hepatotoxicity
  and nelfinavir                                                (95% CI)

   – Results consistent with     HCV+                         1.73 (1.14-2.63)
     data from the randomized    CD4 >50 cells/mm3            0.51 (0.33-0.79)
     control trial by Walmsley   HIV RNA >10,000
                                                              2.59 (1.08-6.18)
     (Study 863)                 copies/mL
• HIV/HCV-coinfected             Indinavir                    2.30 (1.06-4.98)
  patients                       Indinavir/RTV                2.73 (1.33-5.63)
   – 84% had no drug-induced     Saquinavir/RTV               2.39 (1.47-3.89)
     liver injury                Multivariate analysis



                                         Sulkowski MS, et al. Hepatology. 2003;38:698A.
                                         Sulkowski MS, et al. AIDS. 2004;18:2277-2284.
Study 863: 60-Week Safety of Lopinavir/r
   and Nelfinavir by Hepatitis Status
• Hepatitis B/C-positive patients
   – Patients with ALT/AST >3x ULN were excluded at screening
     regardless of hepatitis status
• Lopinavir/r patients (n=57) tended to have a lower
  incidence of grade 3/4 AST and ALT elevations
  compared with nelfinavir-treated patients (n=68)
   – AST: lopinavir/r 4% versus nelfinavir 13%
   – ALT: lopinavir/r 12% versus nelfinavir 17%
• Similar incidence of discontinuations due to hepatic
  adverse events in both groups (4%)
• No discontinuations due to elevated liver enzymes in
  either group
• No hepatic-related events resulted in death


                      Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.
   Study 863: Selected Adverse Events
      and Laboratory Abnormalities
                                                            Patients (%)
                                Lopinavir/r      Lopinavir/r        Nelfinavir        Nelfinavir
                                HBV/HCV+         HBV/HCV–          HBV/HCV+          HBV/HCV–
                                  (n=57)          (n=269)            (n=68)           (n=259)
  Glucose (250 mg/dL)                  2               2                 3                 1
  AST (>5 x ULN)                       4               3                13                 2†
  ALT (>5 x ULN)                      12               3*               17                <1†
  Total cholesterol                   10               11                8                 6
  (>300)
  Triglycerides                       10               11                0                 3
  (>750 mg/dL)
  Amylase                              4               3                 3                 2
  (>2 x ULN)
*P<.05 and †P<.001 vs hepatitis positive


                                    Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.
             Study 863: Demographics of
             HIV/HCV Coinfected Patients
                                                      Lopinavir/r                   Nelfinavir
                                                        (n=29)                       (n=41)
  HIV RNA (log10 copies/mL)
    Median (range)                                5.12 (3.02-6.28)              5.02 (2.98-6.72)
  CD4 (cells/mm3)
    Median (range)                                  205 (2.5-868)                 186 (15-818)

  HCV RNA (log10 IU/mL)
    Median (range)                                6.28 (1.70-7.32)              6.45 (2.95-7.36)
                                                          (n=22)                       (n=35)
  ALT (IU/L)
    Median (range)                                   44 (16-265)                   39 (14-100)
All patients received lamivudine + stavudine.
HCV Genotype 1: 71% of patients.

                                            Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.
         Study 863 HIV/HCV-Coinfected Patients:
           CD4 Cell Counts Through 48 Weeks
                        250          On-Treatment

                                         Lopinavir/r + d4T + 3TC                                             234
 CD4 Change From Baseline




                                         Nelfinavir + d4T + 3TC
                        200
                                                                                                             184
       (cells/mm3)




                        150


                        100


                            50
                                                                                                        P=0.247
                             0
                                 0           8         16            24         32           40           48
                                                                   Weeks
LPV/r       (n=29)                                                  (n=23)                               (n=20)
Nelfinavir (n=41)                                                  (n=34)                               (n=35)

                                                            Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.
        Study 863 HIV/HCV-Coinfected Patients:
       Time to HIV RNA <400 and <50 Copies/mL
                               HIV RNA                                                       HIV RNA
                            <400 Copies/mL                                                 <50 Copies/mL
              100                                    100%                    100                              100%
                                                                                       Lopinavir/r (n=29)
                                                                                       Nelfinavir (n=41)

               80                                    87%                      80
                                                                                                              73%
Patients, %




                                                               Patients, %
               60                                                             60


               40                                                             40


               20            Lopinavir/r (n=29)                               20
                             Nelfinavir (n=41)                                         First evaluated
                                                  P=.274                               at 24 weeks           P=.308
                0                                                              0
                    0   6    12 18 24 30 36 42 48                                  0   6    12 18 24 30 36 42 48
                                    Weeks                                                            Weeks
    All patients received lamivudine + stavudine.
                                                    Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.
            Study 863 HIV/HCV-Coinfected Patients:
                 Mean ALT Through 48 Weeks
                  90       On-Treatment
                                                       †
                  80

                  70
                                                                    *
 Mean ALT, IU/L




                  60
                                                                                                  63
                                   *
                  50
                                                                                                  44
                  40

                  30

                  20
                                                                   Lopinavir/r + d4T + 3TC
                  10
                                                                   Nelfinavir + d4T + 3TC
                  0
                       0           8      16          24           32           40           48
                                                   Weeks
LPV/r       (n=29)                                  (n=24)                                  (n=21)
Nelfinavir (n=41)                                  (n=37)                                  (n=35)
*P<.05 and †P<.01 vs LPV/r.
                                               Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.
  Meta-Analysis of Lopinavir/Ritonavir
 Efficacy in HIV/HCV Coinfected Patients
• 48-week exposure data from 8 clinical trials
  – 819 adult HIV-infected patients
     • Hepatitis positive: 132 patients with HCV and/or HBV
       coinfection
     • Hepatitis negative: 687 patients
• 5-year exposure data from Study M97-720
• Lopinavir/ritonavir
  – At least as safe as nelfinavir
  – 6.9% to 12.8% experienced grade 3+ ALT elevations
  – Overall coinfected patients did have 3 to 4 fold higher
    risk of ALT and AST elevations versus those without
    hepatitis
                            da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.
                             Meta-Analysis: Virologic Outcomes
                                  With Lopinavir/Ritonavir
                                     Treatment-Naïve                                                          Treatment-Experienced
                        100                          Hepatitis negative                                 100
                                                         (n=433)
HIV RNA <400 copies/mL, %




                                                                             HIV RNA <400 copies/mL %
                            80                Hepatitis positive                                         80
                                                  (n=75)                                                                         Hepatitis negative
                                                                                                                                     (n=254)
                            60                                                                           60
                                                                                                                                 Hepatitis positive
                                                                                                                                     (n=57)
                            40                                                                           40


                            20                                                                           20

                                                               P=0.205                                                                     P=0.562
                             0                                                                            0
                                 0   8   16     24      32     40   48                                        0   8   16    24      32     40     48
                                              Week                                                                         Week
            All patients received lamivudine + stavudine.
                                                                      da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.
    Meta-Analysis: Week 48 CD4 Cell Gain With
      Lopinavir/Ritonavir by Hepatitis Status
                               Treatment-Naïve                                                      Treatment-Experienced
                         250               P=.69                                              225
                                                                                                                   P=.17
                                                      219




                                                                      CD4 Change, cells/mm3
                                 211                                                          200
 CD4 Change, cells/mm3




                         200                                                                  175

                                                                                              150
                         150
                                                                                              125                            114
                                                                                              100
                         100                                                                             82
                                                                                              75

                          50                                                                  50

                                                                                              25

                           0                                                                   0
                               Hepatitis           Hepatitis                                           Hepatitis           Hepatitis
                               Positive            Negative                                            Positive            Negative
                                (n=51)              (n=377)                                             (n=39)              (n=181)

All patients received lamivudine + stavudine.
                                                               da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.
          Meta-Analysis Findings

• A higher percentage of HIV/HCV coinfected
  patients treated with lopinavir/ritonavir maintained
  HIV RNA levels <400 and <50 copies/mL
  compared with nelfinavir-treated patients
• Lopinavir/ritonavir appears at least as safe as
  nelfinavir in HIV/HCV coinfected patients
   – A minority of patients (6.9% to 12.8%) experienced
     grade 3+ ALT elevations
• Lopinavir/ritonavir appears to be equally effective
  against HIV infection in HCV positive and
  negative patients
                         da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.
Study 418: HIV RNA <50 Copies/mL Through Week
    48 by Baseline Hepatitis Status (ITT NC=F)
                                          100
  Proportion with HIV RNA <50 copies/mL




                                          80



                                          60



                                          40
                                                                     QD - Hepatitis B/C negative (n=95)
                                                                     QD - Hepatitis B/C positive (n=19)
                                          20
                                                                     BID - Hepatitis B/C negative (n=60)
                                                                     BID - Hepatitis B/C positive (n=15)
                                           0
                                                0   8   16        24              32            40            48
                                                                 Weeks
                                                             Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.
Study 418: CD4 Count Mean Change From
  Baseline by Baseline Hepatitis Status
                                            225       QD - Hepatitis B/C negative (n=95)
 CD4 count change from baseline, Cells/µL




                                            200       QD - Hepatitis B/C positive (n=19)
                                                      BID - Hepatitis B/C negative (n=60)
                                            175       BID - Hepatitis B/C positive (n=15)

                                            150

                                            125

                                            100

                                            75

                                            50

                                            25

                                             0
                                                  0     8           16           24             32            40            48
                                                                                Weeks
                                                                           Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.
       Study 418 Incidence of Resistance
               Through Week 48
                                                             LPV/r 800/200 LPV/r 400/100
                                                                mg QD         mg BID
                                                                (n=115)       (n=75)
 Patients eligible for resistance testing1                            11                   11

 Genotypic results available                                         8/11                  7/11
 Lopinavir resistance2                                               0/8                   0/7
 Tenofovir resistance3                                               0/8                   0/7
 Emtricitabine resistance4                                           2/8                   1/7

1HIV RNA >500 copies/mL any time during Weeks 12-24. All samples >500 copies/mL
were submitted for testing
2LPV/r resistance: emergence of primary or active site mutation at protease positions
8, 30, 32, 46, 47, 48, 50, 54, 82, 84, 90, with phenotypic LPV resistance FC > 2.5 vs WT
3TDF resistance: emergence of K65R or any TAM (41, 67, 70, 210, 215, 219) in RT
4FTC resistance: emergence of M184V mutation in RT



                                    Molina JM, et al. XV IAC. Bangkok, Thailand. 2004. Abstract WePe5701.
 Summary of PIs and Hepatic Safety

• Rate of serious clinical (symptomatic)
  hepatotoxicity, ALT and/or AST levels >5 times
  ULN is relatively low
  – Boosting doses of ritonavir not associated with
    significantly higher incidence of severe hepatotoxicity
    versus other PIs
• Patients coinfected with HBV and/or HCV
  – Greater risk of hepatotoxicity
  – Lopinavir/ritonavir appears at least as safe as nelfinavir
  – Boosted PIs can help suppress resistance to other
    ARV agents
  – More data for atazanavir and fosamprenavir are
    needed in this patient population
Conclusions
               Conclusions

• High prevalence of HIV-hepatitis
  coinfection
• HIV RNA and CD4 are correlated with
  fibrosis progression in coinfected patients
• Use of NNRTIs is associated with
  increased risk of hepatotoxicity
• For PI regimens, no increased risk if
  ritonavir dose <200 mg bid
          Conclusions, cont.

• Patients treated with boosted PIs tend to
  have a lower incidence of grade 3/4 AST
  and ALT elevations than patients treated
  with nelfinavir
• Boosted PIs tend to suppress HIV RNA
  better than nelfinavir in HIV/HCV
  coinfected patients
• Boosted PIs can help suppress resistance
  to other ARV agents (eg, tenofovir DF)
    Recommended Regimens for
Treatment-Naïve Patients: DHHS 2006
                                          Preferred Regimens
            Lopinavir/ritonavir                                                Efavirenz* +
        (400/100 mg [2 tablets] bid or                                 (ZDV or TDF) + (3TC or FTC)
         800/200 mg [4 tablets] qd) +
           ZDV + (3TC or FTC)
                                            Alternative Regimens
                        PI-Based                                                        NNRTI-Based
  Atazanavir†, fosamprenavir, ritonavir‡-boosted                    Efavirenz* + (3TC or FTC) + (ABC or ddI or d4T)
   fosamprenavir, ritonavir‡-boosted indinavir,                     Nevirapine§ + (3TC or FTC) + (ZDV or d4T or ddI
   nelfinavir, or ritonavir‡-boosted saquinavir¶:                                   or ABC or TDF)
              All used in conjunction with
    (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI)                                      Triple NRTI
         Lopinavir/ritonavir + (3TC or FTC) +                                        Abacavir + 3TC + ZDV
             (d4T or ABC or TDF or ddI)                                 (only when a preferred or an alternative NNRTI-
                                                                      or PI-based regimen cannot or should not be used)
*Not recommended for use in 1st trimester, or in women with high pregnancy potential.
†Ritonavir 100 mg/day recommended when tenofovir DF is used with atazanavir.
‡ Low-dose: 100 to 400 mg/day as a pharmacologic booster.
§Adult females and males with CD4 cell counts <250 and <400 cells/mm3, respectively.
¶Soft-gel or hard gel capsules, or tablets.
                                                                               Available at: http://aidsinfo.nih.gov/Default.aspx.
             Post Presentation
            CME/CE Information
• Please return the completed enrollment/evaluation
  forms to the Meeting Host before you leave
• Certificate will be mailed to you within ~6 weeks
• Please refer to the syllabus for complete
  accreditation information
• Inquiries/concerns may be directed to the CME
  Administrator at (773) 308-7950, ext. 114
Thank You!
   Case 1- HCV Diagnosis in HIV
         Infected Patient
• 43 y/o WM, unemployed, h/o IDU, found to be
  HIV positive last year. No f/u until today when he
  presents to clinic for evaluation
• You obtain labs and determine that his CD4
  count is 227 (14%), HIV VL 84,000, Hemoglobin
  13, ALT 51 and HCV Ab, HBV sAg are negative.
  No current meds.
• Given his HIV VL and CD4 count ARV Rx is
  recommended.
• In your consideration about ARV regimens in
  this patient, you discuss potential liver toxicity.
• Despite negative hepatitis serologies is any
  further or repeat testing warranted?
    Case 2- HIV Treatment in the
    HIV/HCV Coinfected Patient
• 37 y/o AAF was diagnosed with HIV/HCV about
  4 years ago. Remote h/o IDU and minimal
  ETOH intake. Has ongoing depression. Works
  as a medical assistant. Current meds are Zoloft
  and as needed ibuprofen.
• Current Labs today: HCV VL 7.1M genotype 1b,
  Chol 220 (LDL 131), ALT 51
• CD4 count has been in the 400s, HIV VL 12,000,
  but over the last couple of years has drifted
  down to 300 (17%) and the HIV VL is now
  47,500.
• What type of ARV regimen would you consider
  using in this patient?
   Case 3- HCV Treatment in the
    HIV/HCV Coinfected Patient
• 51 y/o HM with HIV/HCV for over 10 years.
  Intermittently employed as a house painter. H/o
  HTN, smoker, on ARV Rx (Sustiva, Truvada)
  with an undetectable HIV VL and CD4 count 451
  (21%). His BMI is 29. Other labs include HCV VL
  27.5M genotype 1a, ALT 67, Chol 247 (LDL
  185), TG 97
• Liver biopsy 2 years ago showed grade 2
  fibrosis and no cirrhosis.
• Although adherent to meds, he has missed a
  few appointments.
• Is this patient a candidate for HCV Treatment?
  What factors go into your decision?

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:10
posted:10/8/2012
language:English
pages:56