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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 l.jpg

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

GESIDA, Madrid




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



  • 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
    PARADIGM Co-infected Patients800 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%)


    Haart and hcv therapy zidovudine l.jpg
    HAART and HCV Therapy: Zidovudine Co-infected Patients

    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….. Co-infected Patients


    What is the best way for small molecules make a difference l.jpg
    What is the best way for small molecules make a difference ? Co-infected Patients

    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 PatientsCo-infected Patients


    Drug drug interaction studies l.jpg
    Drug: Drug Interaction Studies Co-infected Patients

    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 Co-infected Patients

    • 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: Co-infected PatientsSummary 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 Co-infected Patients

    • 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 Co-infected PatientsR7227


    Hcv protease inhibitors l.jpg
    HCV Protease Inhibitors Co-infected Patients

    • 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) Co-infected Patients

    • 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 : Co-infected PatientsPrioritisation of Antiretroviral Compounds


    Hcv polymerase inhibitor r7128 l.jpg
    HCV Polymerase Inhibitor Co-infected PatientsR7128


    Hcv polymerase inhibitors l.jpg
    HCV Polymerase Inhibitors Co-infected Patients

    • 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 : Co-infected PatientsPrioritisation of Antiretroviral Compounds


    Timing of studies will depend upon compound profile l.jpg
    Timing of Studies Will Depend Upon Compound Profile Co-infected Patients

    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 Co-infected Patients

    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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