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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

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

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Hiv hcv co infection landscape 21 of october 09 madrid spain l.jpg

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

GESIDA, Madrid


Where are we are today l.jpg

Where are we are today?


Barriers to care l.jpg

Barriers to Care


Hcv treatment uptake john hopkins hiv clinic l.jpg

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


Reasons for low uptake of hcv tmt among co infected patients l.jpg

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 l.jpg

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


    Comparison of sustained virological responses in genotype 1 co infected patients l.jpg

    Comparison of Sustained Virological Responses in Genotype 1 Co-infected Patients

    % SVR

    Study Ongoing

    Low dose RBV


    Paradigm 800 mg wd all 26 135 19 60 275 22 l.jpg

    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%)


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    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


    The future l.jpg

    The Future…..


    What is the best way for small molecules make a difference l.jpg

    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?


    Looking ahead to drug drug interaction studies for co infected patients l.jpg

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


    Drug drug interaction studies l.jpg

    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) ?


    Prioritization of art drug drug interaction studies l.jpg

    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 :


    Slide32 l.jpg

    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


    Feedback l.jpg

    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 l.jpg

    HCV Protease Inhibitor R7227


    Hcv protease inhibitors l.jpg

    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 l.jpg

    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 l.jpg

    HCV Protease Inhibitors : Prioritisation of Antiretroviral Compounds


    Hcv polymerase inhibitor r7128 l.jpg

    HCV Polymerase Inhibitor R7128


    Hcv polymerase inhibitors l.jpg

    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 l.jpg

    HCV Polymerase Inhibitors : Prioritisation of Antiretroviral Compounds


    Timing of studies will depend upon compound profile l.jpg

    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


    Conclusions l.jpg

    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.


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