Areas of Interest. HCV Epidemiology, Natural History HCV Treatment. HBV Epidemiology and Prevention. Monoinfected Coinfected

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1 CROI 2011 UPDATE Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases Univ. of Cincinnati College of Medicine

2 Areas of Interest HCV Epidemiology, Natural History HCV Treatment Monoinfected Coinfected HBV Epidemiology and Prevention

3 ACUTE HCV EPIDEMIOLOGY Phylogenetic analysis of acute HCV in MSM from New York, SF, Philadelphia, LA, San Diego N=73 Limited mixing either between cities or between U.S. and Europe Fierer D et al, CROI 2011 Abs 112

4 SPONTANEOUS CLEARANCE OF ACUTE HCV IN HCV/HIV- Role of IL28b 80 Patients with Acute HCV CC n=38 Non-CC n= 42 Spontaneous Clearance Could be assessed in 38 (others started treatment too early) 8/38 had spontaneous clearance 5 CC (CC was present in 47.5% of population) 3 CT/TT Neukam K et al, CROI 2011, Abs 945

5 FOUNDER VIRUS HCV Single genome amplification and sequencing Viral sequences from acutely infected subjects showed 1 or more low-diversity lineages (<0.2% diversity) 1-12 (median 3) founder genomes could be found in every subject examined No evidence of recombination, selection or hypermutation Hui et al., CROI 2011

6 Liver Fibrosis in African-Americans N=105 Subjects enrolled in DC Partnership for HIV Median duration of HCV estimated to be 30 years 92% of subjects A-A Median CD4 503 Fishbein D, et al. CROI, Non-Cirrhotic Cirrhotic

7 ITPA Gene Variants in HCV/HIV ITPA Gene Encodes enzyme that catalyzes Inosine Triphosphate Two relevant SNPs Prospective study in Barcelona N=173 HCV/HIV Baseline Hgb 14.5 Hgb decrease Guardiola J et al, CROI 2011, Abs 480

8 EVR % HIGH DOSE RIBAVIRIN INDUCTION PERICO STUDY PegIFN + RBV vs PegIFN + RBV 2000 mg/day 4 weeks then standard dosing N= 326 EVR Rate Evaluated P= Standard dose High Dose Labarga P et al, CROI 2011, Abs 962

9 % SVR LDL RECEPTOR AND HCV TREATMENT RESPONSE IN HCV/HIV LDL Receptor is Utilized by HCV for Entry LDLR SNP Analyzed N=184 treated with SOC SVR Geno % Geno % CC TT/TC Pineda et al, CROI 2011, Abs Geno 1,4 Geno 2,3

10 % SVR Phase 3 Randomized, Placebo controlled trial HCV Genotype 1 Treatment naïve subjects in 2 cohorts Non-Black (Blue bars) Black (Red bars) BOC 800 mg q8h; pegifn alfa-2b 1.5 µg/kg/wk; weight-based RBV mg/day with lead-in Response guided therapy vs. 48 week Sulkowski et al., CROI 2011 Abs 115 Boceprevir SPRINT RGT 48 week 23 PR48

11 % SVR BOCEPREVIR RESPOND-2 Phase 3 Randomized, Controlled Trial in Nonresponder subjects N= 3 Prior Null responders excluded Partial: >2 log drop at 12 weeks Three arms RGT (32 vs. 48) BPR48 PR NR Relapsers Gordon et al. CROI 2011, Abs 116

12 TELAPREVIR Pooled Analysis ADVANCE/ILLUMINATE N= 903 Early response and SVR examined All subject in T12PR arm vs. PR control arm from ADVANCE Week 1 to 4 data by interval and RVR/SVR cumulative. Week 3 not shown % T12/PR PR Sherman et al., CROI 2011, Abs 957

13 Effect of Telaprevir on HIV PIs van Heeswijk et al., CROI 2011, Abs 119

14 Effect of HIV PI s on Telaprevir van Heeswijk et al., CROI 2011

15 Boceprevir Metabolism and DDI s Substrate of aldoketoreductase primary pathway Substrate of CYP3A4/5 Coadministration of EFV (CYP3A4/5 inducer) decreased BOC mean exposure (AUC) 19% to 44% and increased efavirenz mean exposure 11% to 20% Not boosted by RTV Strong CYP3A4 inhibitor without evidence of induction Midazolam AUC markedly increased Substrate for the efflux inhibitor P-glycoprotein (P-gp) No interactions with tenofovir Kasserra C et al. CROI 2011

16 HBV MORTALITY IN MACS HCV 1 Relative Risk 95% CI P-value HBV vs. HCV Age> vs. < HBV Active ARV- TDF vs. non Falade-Nwulia et al, CROI 2011, Abs 968

17 HBV VACCINATION IN HIV n= 163 ug dose recombinant HBV given IM Time 0, 1, 2, 6 months Low CD (<350 cells/mm) associated with poorer response rates in multivariate analysis Potsch D et al, CROI 2011, Abs rd Dose 4th Dose