Learning Objectives. Disclosures (Activity w/i 12 months) WHY DISCUSS HCV/HIV COINFECTION? HCV/HIV Effect on Health Utilization in A5001

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1 Learning Objectives HCV/HIV COINFECTION Soup to Nuts Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati College of Medicine At the conclusion of this presentation, participants should be able to: State the epidemiology and natural history of HCV/HIV coinfection Appraise the efficacy of current treatment modalities for patients with HCV/HIV in order to better counsel patients about management options Disclosures (Activity w/i 12 months) Research Support (to institution): Roche, Schering, SciClone, Vertex, GSK, HGS, Gilead, BMS Advisory Board/Consulation: BMS, SciClone, Vertex, Merck, Valeant, Anadys WHY DISCUSS HCV/HIV COINFECTION? People living with HIV are increasing in number Liver disease is an IMPORTANT outcome that ID caregivers are often ill-prepared to evaluate and manage Gastroenterologists are frequently uncomfortable with HIV management and with HIV-infected patients Causes of Death in Coinfection French Mortality 2 Cohort HCV/HIV Effect on Health Utilization in A HCV/HIV rate* (9%CI) HIV rate* (9%CI) Adjusted rate ratio (9%CI) Nights in hospital 14.2 ( ).8 (.6.9) 2. ( ) ESLD AIDS Cancer-AIDS Unrelate Cardiovascular Bacterial Drug Overdose Accident Unknown Other Emergency department visits 6.3 (.8 6.8) 3.4 (3.2 3.) 1. (1.2 2.) Among patient with markers of HBV or HCV infection Disability days 112. ( ) 67.6 ( ) 1.6 ( ) Salmon-Ceron et al., J HEPATOL 2 Linus et. al. CROI 28 Oral #12

2 ETIOLOGIES OF LIVER INJURY WHO SHOULD BE TESTED? HCV or HBV Mitochondrial Injury Immune Reactivation HIV-infected patients should be tested routinely for evidence of chronic HCV infection Alcohol Or other Drugs HIV ART Initial testing for HCV should be performed using the most sensitive immunoassays licensed for detection of antibody to HCV (anti-hcv) USPHS GUIDELINES, MMWR, 29 Updated ALT Ranges ROLE OF HCV RNA TESTING To confirm the presence of chronic infection, all HCV-seropositive persons should be tested for plasma HCV RNA using a qualitative or quantitative assay Newly calculated healthy limits are indicated in each panel. A) Male participants. B) Female participants. To convert the alanine aminotransferase thresholds to nkat/l, multiply by 16,667. Prati, et al. 22, Ann of Int Med Quantitative HCV RNA level (i.e., viral load) does not correlate with degree of liver damage and does not serve as a surrogate for measuring disease severity, but it does provide important prognostic information about the response to antiviral therapy USPHS GUIDELINES, MMWR, 29 6A 6B 7B 11A 8B 4A 9A 2C A 2A 1A 2B 1C 1B 1% 1A 3A Patient

3 HCV ANTIBODY PREVALENCE in HIV-INFECTED PATIENTS EPIDEMIOLOGY & NATURAL HISTORY % HCV/HIV Prevalence Composite Estimates HCV VIRAL LOAD Copies/ml HCV HCV/HIV U.S. ACTG Sherman KE et. al., CID 22 Rockstroh JK et. al. JID, 2 EUROSIDA Sherman Sherman et. al, CID, 22 Bonacini et. al.,j VIRAL HEP, 1999 Bonacini GENOTYPE DISTRIBUTION EVALUATION OF FIBROSIS 1b 22.7% 1a.% 3a 9.1% 1a/2 1.% 4c/4d 1.% 4a 1.% 2a/2c 1.% 2 1.% 2b 3.% 1a/1b 7.6% Liver biopsy is the only reliable method to assess degree of hepatic fibrosis and is useful to provide prognostic information and guide therapeutic decisions Advanced fibrosis/cirrhosis Consider treatment sooner Screen for HCC Screen for Portal Hypertension Sherman et. al., CID, 22 MMWR, 29

4 Fibrosis Grades (METAVIR scoring system) Rates of Liver Fibrosis Progression HIV positive (n = 122) 1 Matched controls (n = 122) Simulated controls (n = 122) Duration of HCV Infection (years) Benhamou Y et al., Hepatology, 1999 FACTORS ASSOCIATED WITH FIBROTIC PROGRESSION IN HIV- INFECTED PATIENTS Alcohol> gms/day CD4+ < 2 cell/mm 3 Age at Time of HCV Infection (>2) No Protease Inhibitor Therapy Benhamou et. al., HEPATOLOGY, 21 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, % Patients With Mild Fibrosis ( F1) on First Biopsy 8% 2% -1 No Change 1 >2% of patients with mild fibrosis on initial biopsy had 2 stage progression in fibrosis score 14% 12% 6% 2% 4% 2% 2 Change in Ishak Score From First to Second Biopsy PREVENTION STRATEGIES Vaccinate ALL HCV/HIV patients for Hepatitis A Hepatitis B Screen for HCV in HCV negative patients Discuss safe sexual practices and high risk sexual and parenteral exposure behaviors Sulkowski M et al. AIDS, 27 EFFECT OF HAART ON LIVER RELATED MORTALITY IN HCV/HIV INFECTED PATIENTS TREATMENT & MANAGEMENT PRINCIPLES HIV HCV Qurishi N et. al., LANCET, 23

5 ART HEPATOTOXICITY DRUG MECHANISM MANIFESTATION NRTI AZT d4t ddi ddc Abacavir Protease Inhibitors Ritonovir Tipranovir Darunavir Atazanavir Indinivir NNRTI Nevirapine Impaired mitochondrial polymerase gamma function Immune Mediated Hypersensitivity?Inhibition of retinoic acid binding protein UDP-glucuronyl transferase competition Impaired mitochondrial polymerase gamma Immune-mediated hypersensitivity Lactic Acidosis Eosinophilic injury Hepatocellular injury Unconjugated hyperbilirubinemia Lactic Acidosis Eosinophilic injury Sherman et. al., CID, 26 ART EFFECT ON HCV U/L ART INITIATION ART Subjects (means) ART Treatment (weeks) Sherman et. al., CROI 29 Abs #847 log M3 U/L ALT IU/L HCV log HIV log HCV TREATMENT Standard of Care 29 Genotype 1 or 4 Genotype 2 or 3 Peg IFN alfa 2a or 2b + wt. Ribavirin for 48 wks EVR Evaluation 4-4% Confirm HCV Present Determine VL and Genotype Evaluate Histology Evaluate Contraindications to Rx Early d/c Pooled -% Peg IFN alfa 2a or 2b + ribavirin 8 mg/qd for 24 wks 7-8%% PEG-IFN + RIBAVIRIN Metanalysis for Carrat et al..32 (.27.37) Torriani et al..33 (.31.4) Chung et al..328 (.27.38) Perez-Olmeda et al..328 (.28.38) Moreno et al..332 (.28.38) Laguno et al..341 (.29.39) Cargnel et al..329 (.28.39) Pooled estimate.333 (.29.37) TREATMENT RECOMMENDATIONS in HIV PegIFN + Ribavirin is the recommended treatment (A1) Genotype % Genotype 2, % Many experts recommend weight-based ribavirin (A2) 48 Weeks of Therapy in All Patients (A1) Acute HCV should be treated with same regimen for >24 weeks (B3) Shire et. al., J VIRAL HEP, 27 USPHS GUIDELINES, MMWR, 29

6 Early virologic response has 1% negative predictive value Issues Limiting Treatment of HCV Week 12 (N = 16) Yes 2 log 1 drop or neg HCV RNA No n = 43 (41%) n = 63 (9%) No No n = 22 (1%) n = 21 (49%) n = (%) n = 63 (1%) Inexperience using agents Liver Disease too Advanced Psychiatric complications Anemia Neutropenia Weight loss Drug Interactions Chung et. al., 24, NEJM 36 ACTG Sites PegIFN alfa 2a + Wt-based ribavirin STUDY DESIGN STEP 3 2 log drop or RNA Neg NR 12 Weeks 6 Weeks * PegIFN + Wt-based ribavirin (72 Weeks Total Treatment) PegIFN alfa 2a MAINTENANCE UNTREATED CONTROL 24 Wks FIBROSIS CHANGE Paired Sample Analysis STEP 1 72 Weeks STEP 2 Liver Biopsy Liver Biopsy Liver Biopsy *= Direct Entry of Nonresponders from Comparable Non-study Treatments Sherman et. al., CROI, 28 Timing of Discontinuation of Treatment Of those who prematurely D/C d Rx, % D/C d between W (6%) subjects completed 72 wks rate 63% (9% CI: 3% -73%) Naïve 48/67 (72%) Prev Tx 12/28 (43%) P=.1 Chung et. al. CROI 29 NEW HCV AGENTS Entry Inhibitors Protease Inhibitors Polymerase Inhibitors Nuc Non-nucs Cyclophilin Inhibitors Immune modulators and DNA vaccines

7 Pre-existing mutation HCV/HIV Coinfected Patients Comparison of signature mutations for NS3 protease inhibitor Design 38 coinfected patients sequenced 2 monoinfected sequences from GenBank analyzed A16G/T changes evaluated Results Mutation found in 7.8% of coinfected vs..8% of monoinfected (p<.2) All changes in coinfected among those who received prior HIV protease inhibitors LIVER TRANSPLANTATION VIABLE OPTION EARLY REFERRAL CRITICAL NIH SOT PROTOCOL Morsica et. al, AASLD 26 Abs 436 END STAGE LIVER DISEASE MELD Ascites Encephalopathy PT> 3 seconds (INR>1.3) Varices (bleeding or nonbleeding) Bilirubin PT (INR) Creatinine NIH Pilot Study Outcomes and miles to go before we sleep. paraphrased from Robert Frost Roland et. al., Int. AIDS Conf, 26, Updated 27