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. 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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hcv treatment uptake john hopkins hiv clinic
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
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
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
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%)
haart and hcv therapy zidovudine
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

what is the best way for small molecules make a difference
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?

drug drug interaction studies
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
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
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
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 inhibitors
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
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 polymerase inhibitors
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.
timing of studies will depend upon compound profile
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
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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