1 / 47

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

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. 90% Genotype 1 70% African American Pop n . 35%. Referral associated with: ALT levels Undetectable HIV RNA

pascal
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


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

  2. Where are we are today?

  3. Barriers to Care

  4. 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

  5. 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

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

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

  8. 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%)

  9. 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

  10. The Future…..

  11. 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?

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

  13. 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) ?

  14. 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 :

  15. 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

  16. 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

  17. HCV Protease Inhibitor R7227

  18. 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

  19. 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

  20. HCV Protease Inhibitors : Prioritisation of Antiretroviral Compounds

  21. HCV Polymerase Inhibitor R7128

  22. 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.

  23. HCV Polymerase Inhibitors : Prioritisation of Antiretroviral Compounds

  24. 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

  25. 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.

More Related