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

Where are we are today?

Barriers to Care

HCV Treatment Uptake: John Hopkins HIV Clinic 35% 65% 68% 23% 21% 0.7% 90% Genotype 1 70% African American Pop n. Mehta AIDS (2006) 20: Referral associated with:  ALT levels Undetectable HIV RNA CD4+ > 350 cell/mm 3 Receiving care for psychiatric condition No active drug use

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

Key Pivotal Studies of Treatment of Chronic HCV in HIV-infected Persons: APRICOTRIBAVICACTG5071BarcelonaPRESCOPARADIG M N= Peg-IFN2a2b2a2b2a Ribavirin800mg g mg mg HIV Viral Load <5,000c/ml- <10000c/m l -- CD4 Status >200/mm 3 >100/mm 3 >250/mm 3 >300/mm 3 >100/mm 3 % Genotype 1 60%48%77%55%49%100% % bridging fibrosis or cirrhosis (cirrhosis) 2927 Study Ongoing

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

PARADIGM 800 mg WD All-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%)

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

The Future…..

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

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

Drug: Drug Interaction Studies Duration typically 1-14 days –preparation 3 months –conduct 2-3 months Cost: $ K 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 (TMC data) ? Simmen Poster 507, Int Liver Congress (2008)

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 :

Antiretroviral Use In Co-infected Patients: Summary of ART use at Baseline in the PARADIGM Study (US/Spain/Portugal) NRTIsUse (%)NNRTI s Use (%)PIsUse (%)OtherUse (%) TDF55%EFV20%RTV (ld) 24%RAL1% FTC41%NVP7%ATZ19%T201% 3TC36%DLV<1%KAL17% ABC22%ETVn/aFPV8% AZT16%NFV7% d4T6%DRV2% ddI1%SQV2% IDV<1% TPV<1% 409 patients; 89% on Antiretroviral therapy; 28% NNRTI; ~50% on a PI regimen

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

HCV Protease Inhibitor R7227

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:

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

HCV Protease Inhibitors : Prioritisation of Antiretroviral Compounds High Interaction PotentialLow Interaction Potential High Usage PIs: Kaletra, Atazanavir, Ritonavir NNRTI: Efavirenz Integrase Inhib: Raltegravir NRTIs: TDF, FTC, 3TC, Low Usage PIs: Fosamprenavir, Saquinavir, Indinavir, Nelfinavir Entry Inhib: Maraviroc Entry Inhib: T20 NRTIs: DDI, D4T

HCV Polymerase Inhibitor R7128

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.

HCV Polymerase Inhibitors : Prioritisation of Antiretroviral Compounds Interaction PotentialLow Interaction Potential High UsageNRTIs: FTC, 3TC PIs: Kaletra, Atazanavir, Ritonavir NNRTI: Efavirenz Integrase Inhib: Raltegravir NRTIs: TDF Low Usage NRTIs: SPD574 (in development) PIs: Fosamprenavir, Saquinavir, Indinavir, Nelfinavir, Darunavir Entry Inhib: Maraviroc, T20 NRTIs: DDI, D4T

Timing of Studies Will Depend Upon Compound Profile Phase 2b EOT SVR 24 Pivotal Phase 3 Studies In vitro combination studies Confirm Safety Profile Begin ART Drug:Drug Interaction studies of Priority Compounds Phase 2/3 Co-infection Study Complete ART Drug: Drug Interaction Studies Confirm Efficacy

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.