HIV:HCV Coinfection Landscape 21 of October, 09 Madrid,Spain

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HIVHCV Co-infection Landscape21 of October,
09Madrid,Spain

• GESIDA, Madrid

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Where are we are today?
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Barriers to Care
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HCV Treatment Uptake John Hopkins HIV Clinic

• 90 Genotype 1
• 70 African American Popn.

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• Referral associated with
• ?ALT levels
• Undetectable HIV RNA
• CD4 gt 350 cell/mm3
• Receiving care for psychiatric condition
• No active drug use

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68
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Mehta AIDS (2006) 202361-69
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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

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Key Pivotal Studies of Treatment of Chronic HCV
in HIV-infected Persons
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Comparison of Sustained Virological Responses in
Genotype 1 Co-infected Patients
SVR
Study Ongoing
Low dose RBV
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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)
13683-689
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The Future..
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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?
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Looking Ahead to DrugDrug Interaction Studies
for Co-infected Patients
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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)
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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

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Antiretroviral Use In 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

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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

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HCV Protease Inhibitor R7227
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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) 18163-167
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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
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HCV Protease Inhibitors Prioritisation of
Antiretroviral Compounds
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HCV Polymerase Inhibitor R7128
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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.

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HCV Polymerase Inhibitors Prioritisation of
Antiretroviral Compounds
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Timing of Studies Will Depend Upon Compound
Profile
EOT
Phase 2b
SVR24
Pivotal Phase 3 Studies
Confirm Safety Profile
Confirm Efficacy
Phase 2/3 Co-infection Study
In vitro combination studies
Begin ART DrugDrug Interaction studies of
Priority Compounds
Complete ART Drug Drug Interaction Studies
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Conclusions

• 1-HIV/HCV CO-INFECTED PATIENTS SHOULD BE
  CONSIDERED FOR THERAPY NOW.
• 2-BASE TREATMENT DECISIONS ON STAGING,CO-MORBIDIT
  IES 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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