1. Management of Patients Co- infected with HCV and HIV: A Close Look at the Role for DAAs Susanna Naggie, MD Assistant Professor of Medicine Division of Infectious Diseases

2. Disclosures Research: Vertex, Anandys, Synexis, Gilead, Merck, BMS Advisory Board: Vertex, Boehringer Ingelheim, Janssen Speaker: None

3. HIV & HCV 10 million people worldwide 30% of US patients with HIV have HCV HIV 40 million Hepatitis C 180 million Staples CT. Clin Infect Dis 1999

4. D:A:D Study: Liver-Related Deaths in Persons with HIV DAD Arch Intern Med;2006;166:1632 14.5% DAD Study Group, Arch Intern Med 2006 Thein et al. AIDS 2008; 22:1979

5. Treatment Response in DAA Era

6. Treatment Goal of treatment: –Clinical trial definition –Sustained virologic response –What we tell patients…

7. Who to Treat? Prior response? Risk stratification –Liver Biopsy –Fibroscan/non-invasive testing Adherence Other baseline factors –Race/ethnicity –Genotype 1 subtype

8. HCV Genome: Polyprotein Moradpour Nature Reviews 2007; 5:453-463

9. Viral Kinetic Parameters AASLD HCV Treatment Guidelines

10. PK Interactions: Telaprevir & ART ARTEffects on ARTEffects on TVRRecommendations AUCC min AUCC min Efavirenz No change  26%  47%  telaprevir dose to 1,125mg q8h Atazanavir/r-  85%  20%  15%Use standard doses Darunavir/r  40%  42%  35%  32%Do Not Co-Administer FPV/r  47%  56%  32%  30%Do Not Co-Administer Lopinavir/r  34%  43%  54%  52%Do Not Co-Administer MaravirocNo PK Data, Interaction PossibleDo Not Co-Administer Raltegravir  31%- No significant changes Use standard doses Van Heeswijk et al. CROI 2011 Abstract 119 and ICAAC 2011 Abstract A1-1738a

11. Part A: no ART Follow-up PR48 (control) PR SVR Pbo + PR T/PR TVR + PR Follow-up SVR PR Follow-up PR48 (control) PR SVR Pbo + PR T/PR TVR + PR Follow-up SVR PR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) Study 110 Design: Randomized, Double- blind, Placebo-controlled Trial of Telaprevir 2404872 Weeks 123660 SVR12 1:1 2:1 Dieterich et al. CROI 2012 Abstract 46 Barritt and Fried. Gastro 2012; 142:1314 Stopping/Futility Rules

12. % of Patients with Undetectable HCV RNA n/N= 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22 Dieterich et al. CROI 2012 Abstract 46 Study 110: SVR-12 Interim Analysis

13. PK Interactions: Boceprevir & ART ARTEffects on ARTEffects on BOCRecommendations AUCC min AUCC min Efavirenz  20%-  19%  44%Do Not Co-Administer ETR, RPVNo PK Data, Interaction PossibleDo Not Co-Administer Atazanavir/r  35%  49%No changeDo Not Co-Administer Darunavir/r  44%  59%  29%  35%Do Not Co-Administer Lopinavir/r  34%  43%  44%  35%Do Not Co-Administer FPV/r, TPV/rNo PK Data, Interaction PossibleDo Not Co-Administer MaravirocNo PK Data, Interaction PossibleDo Not Co-Administer RaltegravirNo significant changesUse standard doses Kasserra et al. 18th CROI 2011 Abstract 118; Hulskotte et al. 19 th CROI 2012 Abstract 771LB

14. 14 Randomized, double blind, placebo controlled trial of Boceprevir Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV –2:1 randomization (experimental: control) –Boceprevir dose 800 mg TID 4-week lead-in with PEG2b/RBV for all patients –PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID Weeks 12 24 28 48 72 PEG2b +RBV 4 wk Placebo + PEG2b + RBV 44 wk Boceprevir + PEG2b + RBV 44 wk Follow-up SVR-24 wk Follow-up SVR-24 wk PEG2b +RBV 4 wk Arm 1 Arm 2 Futility Rules Stopping/Futility Rules Sulkowski et al. CROI 2012 Abstract 47 Barritt and Fried. Gastro 2012; 142:1314

15. % of Patients with Undetectable HCV RNA n/N= 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61 Treatment Week SVR-12 Interim Analysis Sulkowski et al. CROI 2012 Abstract 47

16. Adverse Events Jacobson IM, et al. NEJM, 2011. Poordad F, et al. NEJM, 2011 Adverse Event, % TVR-Containing Arms Mono-infection(N=727) Co-infection (N=38) PegIFN/RBV Arms (n = 383) Pruritus45-50399-36 Nausea40-433423-31 Rash35-373423-24 Anemia37-391818-19 Diarrhea28-322418-22 Adverse Event, % BOC-Containing Arms Mono-infection (N=734) Co-infection (N=64) PegIFN/RBV Arms (N=397) Anemia494126-29 Dysgeusia37-432815-18 Telaprevir (TVR) Boceprevir (BOC)

17. Other Considerations… CharacteristicGood ResponsePoor Response HCV GT 1 subtype1b1a Fibrosis0-2>34 RaceEuropean/AsianAfrican-descent Prior treatmentRelapse>PartialNull IFN responsiveness>1log10 decline<1log10 decline IL28BCC>CTTT

18. Phase II/III Studies DrugClassTx InclusionRGTAntiretrovirals TMC-435 NCT01479868 NS3/4ANaive and experienced YRPV, Ralt, MVC, T20, TDF, FTC,3TC, ABC* BI-201335 NCT01399619 NS3/4ANaive and relapsers YDRV/r, ATV/r, Ralt, TDF, FTC, EFV, ABC, 3TC, MVC BMS-790052 NCT01471574 NS5ANaiveYAll except PI + NNRTI combo *Ouwerkerk-Mahadevain 19 th CROI Abstract 49

19. In a nutshell… Access to DAA is improving –Daily dosing/fewer AEs –FDA approval 1.5 years IFN-sparing is coming Assess severity of liver disease Consider HCV therapy –Treat those who can’t wait OR –Treat those who will be cured –Clinical Trial