HIV:HCV Co-infection Landscape 21 of October, 09 Madrid,Spain

1. HIV:HCV Co-infection Landscape21 of October, 09Madrid,Spain GESIDA, Madrid

3. Where are we are today?

4. Barriers to Care

5. HCV Treatment Uptake: John Hopkins HIV Clinic • 90% Genotype 1 • 70% African American Popn. 35% • Referral associated with: • ALT levels • Undetectable HIV RNA • CD4+ > 350 cell/mm3 • Receiving care for psychiatric condition • No active drug use 65% 68% 23% 21% 0.7% Mehta AIDS (2006) 20:2361-69

6. Reasons for Low Uptake of HCV Tmt Among Co-infected Patients • Lower SVR rates than mono-infected patients • High rates of treatment ineligibility • Medical • Psychiatric • Drug-drug interaction issues • Non adherence to medical visits • Concomitant alcohol/drug use • Low referral rates • Access

7. Key Pivotal Studies of Treatment of Chronic HCV in HIV-infected Persons:

8. Comparison of Sustained Virological Responses in Genotype 1 Co-infected Patients % SVR Study Ongoing Low dose RBV

9. PARADIGM800 mg WDAll-26/135 (19%) 60/275 (22%) • Caucasians 19/60 (32%) 32/116 (28%) • AA 2/40 (5%) 10/71 (13%) • Latinos 3/33 (9%) 15/76 (20%)

25. HAART and HCV Therapy: Zidovudine Mean Change in Hgb After 4 Weeks HCV Therapy RBV Dose Reduction During 1st 12 Weeks Alvarez D et al. Journal Viral Hepatitis (2006) 13:683-689

27. The Future…..

28. What is the best way for small molecules make a difference ? Increased Side Effects Higher SVR Increased Drug : Drug Interactions Shortened Treatment Duration Increased Regimen Complexity Or will we have to wait for IFN and/or RBV – sparing regimens?

29. Looking Ahead to Drug:Drug Interaction Studies for Co-infected Patients

30. Drug: Drug Interaction Studies Simmen Poster 507, Int Liver Congress (2008) • Duration typically 1-14 days • preparation 3 months • conduct 2-3 months • Cost: $500-750K per study maximum two drugs. • Healthy volunteer preferred over Patient studies when possible Advantages • Easier to recruit • Avoids exposure of virus to sub-optimal drug levels Potential Disadvantage • Do HCV infected patients behave like healthy individuals (TMC435350 data) ?

31. Prioritization of ART Drug : Drug Interaction Studies • knowledge of metabolism • e.g. cytochrome P450 involvement (inhibitor vs inducer vs substrate) • knowledge of mechanism of action and in vitro combination work • e.g. competition for nucleoside phosphorylation • overlapping safety concerns • e.g. anemia – AZT and ribavirin • frequency of ART use in co-infected patients • e.g. tipranavir :

32. Antiretroviral Use In Co-infected Patients:Summary of ART use at Baseline in the PARADIGM Study (US/Spain/Portugal) • 409 patients; 89% on Antiretroviral therapy; 28% NNRTI; ~50% on a PI regimen

33. Feedback • Protease Inhibitors • Tipranavir : low usage, hepatotoxocity • Darunavir : low usage currently but should this be prioritized • Nucleosides • AZT : high usage but anemia risk with ribavirin • ABC : high usage but potential interaction with ribavirin • Non-nucleosides • Nevirapine : hepatotoxicity • Etravirine : low usage currently, Cyp interactions • TMC-278 : in Phase 3 development • Integrase Inhibitors • Elvitegravir (GS 9137): RTV boosted, in development

34. HCV Protease Inhibitor R7227

35. HCV Protease Inhibitors • Telaprevir and Boceprevir protease inhibitors appear to be metabolized by cytochrome enzymes. • Telaprevir and Boceprevir can be ‘boosted’ by low dose ritonavir in vitro. • Only rat and in vitro data available – no published human data Kempf AAC (2007) 18:163-167

36. HCV Protease Inhibitors : R7227 (ITMN-191) • R7227 is metabolically cleared by several cytochrome P450 isoforms • CYP 3A4 important, currently characterizing profile. • R7227 CYP 3A4 induction and/or inhibition potential being characterized. • No safety issues to consider to date. Main Prioritization Criteria therefore: • ARTs which interact with CYP • Frequently used ART Seiwert et al abstract T1793 DDW 2006

37. HCV Protease Inhibitors : Prioritisation of Antiretroviral Compounds

38. HCV Polymerase Inhibitor R7128

39. HCV Polymerase Inhibitors • A primary concern will be whether competition for phosphorylation causes reductions in intracellular triphosphate levels. • In vitro combination studies do not always accurately predict in vivo interactions. • E.g. SPD754 and 3TC • Not metabolized by CYP – low risk of protease inhibitor interactions • R7128 is a cytidine/uridine analogue with potential intracellular competition with other cytidine analogues (e.g. 3TC, FTC, SPD754). • Other consideration would be safety, but in 28 day study no hematological or other toxicity was identified.

40. HCV Polymerase Inhibitors : Prioritisation of Antiretroviral Compounds

41. Timing of Studies Will Depend Upon Compound Profile EOT Pivotal Phase 3 Studies Phase 2b SVR24 Confirm Safety Profile Confirm Efficacy Phase 2/3 Co-infection Study In vitro combination studies Begin ART Drug:Drug Interaction studies of Priority Compounds Complete ART Drug: Drug Interaction Studies

46. Conclusions 1-HIV/HCV CO-INFECTED PATIENTS SHOULD BE CONSIDERED FOR THERAPY NOW. 2-BASE TREATMENT DECISIONS ON STAGING,CO-MORBIDITIES AND VIROLOGIC RESPONSES. 3-ALL GENOTYPE 1 PATIENTS WITH SIGNIFICANT STAGING (F2 OR MORE ) SHOULD BE CONSIDERED FOR THERAPY NOW. ALL GENOTYPE 2/3 PATIENTS ,INDEPENDENT OF STAGING SHOULD BE TREATED TODAY. 4-BE AGGRESSIVE DEALING WITH CO-MORBID CONDITIONS, MOST ARE MANAGEABLE WITH ADDITIONAL PROFESSIONAL HELP ,AND MORE FREQUENT FOLLOW UPS. 5-PEG IFN ALFA 2a AND RBV TREAMENT CAN BE TAILORED ACCORDING TO VIROLOGICAL RESPONSE SHORTEN FOR RVR, LONGER FOR DELAYED RESPONSE. 6-NEW THERAPIES WITH SMALL MOLECULES ARE PROMISING BUT ARE 3 OR MORE YEARS AWAY, MOST HIV/HCV PATIENTS CAN NOT WAIT . TREATMENT WILL BE MORE COMPLEX AND MAY REQUIRE :NO ART, CHANGE IN ART OR IFN OR RBV SPARRING REGIMENS.