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HIV:HCV Co-infection Landscape 21 of October, 09 GESIDA, Madrid Madrid,Spain Where are we are today? Barriers to Care HCV Treatment Uptake: John Hopkins HIV Clinic • 90% Genotype 1 • 70% African American Popn. Referral associated with: 35% 65% • ALT levels • Undetectable HIV RNA 68% • CD4+ > 350 cell/mm3 • Receiving care for psychiatric condition 23% 21% • No active drug use 0.7% Mehta AIDS (2006) 20:2361-69 Reasons for Low Uptake of HCV Tmt Among Coinfected 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: APRICOT RIBAVIC ACTG5071 Barcelona PRESCO PARADIG 868 412 133 95 389 400 Peg-IFN 2a 2b 2a 2b 2a 2a Ribavirin 800mg 800mg 600 - 1g 800- 1000- 1000- HIV Viral <5,000c/ml - - - CD4 >200/mm3 >200/mm3 >100/mm3 >250/mm3 >300/mm3 >100/mm3 % 60% 48% 77% 55% 49% 100% % bridging fibrosis or cirrhosis 12 39 11 29 27 Study N= <10000c/m <10000c/m Comparison of Sustained Virological Responses in Genotype 1 Co-infected Patients 60 50 % 40 SVR 30 20 Study Ongoing 10 0 Monoinfected APRICOT RIBAVIC ACTG 5071 Low dose RBV Barcelona PRESCO PARADIGM PARADIGM 800 mg All-26/135 (19%) WD 60/275 (22%) • Caucasians 19/60 (32%) • AA 2/40 (5%) • Latinos 3/33 (9%) 32/116 (28%) 10/71 (13%) 15/76 (20%) HAART and HCV Therapy: Zidovudine Mean Change in Hgb After 4 Weeks HCV Therapy Alvarez D et al. Journal Viral Hepatitis (2006) 13:683-689 RBV Dose Reduction During 1st 12 Weeks The Future….. What is the best way for small molecules make a difference ? Increased Side Effects Higher SVR Shortened Treatment Duration Increased Drug : Drug Interactions Increased Regimen Complexity 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: $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) ? 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) • 409 patients; 89% on Antiretroviral therapy; 28% NNRTI; ~50% on a PI regimen NRTI Use NNRT Use PIs Use Other Use TDF 55% EFV 20% RTV 24% RAL 1% FTC 41% NVP 7% ATZ 19% T20 1% 3TC 36% DLV <1% KAL 17% ABC 22% ETV n/a FPV 8% AZT 16% NFV 7% d4T 6% DRV 2% ddI 1% SQV 2% IDV <1% TPV <1% 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) 18:163-167 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 Potential Low Interaction Potential PIs: Kaletra, Atazanavir, Integrase Inhib: Raltegravir NNRTI: Efavirenz NRTIs: TDF, FTC, 3TC, PIs: Fosamprenavir, Saquinavir, Nelfinavir Entry Inhib: T20 High Usage Low Usage Entry Inhib: Maraviroc 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 Potential Low Interaction Potential PIs: Kaletra, Atazanavir, NNRTI: Efavirenz High Usage NRTIs: FTC, 3TC Integrase Inhib: Raltegravir NRTIs: TDF NRTIs: SPD574 (in Low Usage PIs: Fosamprenavir, Nelfinavir, Darunavir Entry Inhib: Maraviroc, T20 NRTIs: DDI, D4T Timing of Studies Will Depend Upon Compound Profile EOT Phase 2b SVR24 Confirm Safety Profile In vitro combination studies Pivotal Phase 3 Studies Confirm Efficacy Begin ART Drug:Drug Interaction studies of Priority Compounds Phase 2/3 Co-infection Study Complete ART Drug: Drug Interaction Studies 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 .