HIV:HCV Co-infection 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
APRICOT RIBAVIC ACTG5071 Barcelona PRESCO PARADIGM
N 868 412 133 95 389 400
Peg-IFN 2a 2b 2a 2b 2a 2a
Ribavirin 800mg 800mg 600 - 1g 800-1200mg 1000-1200mg 1000-1200mg
HIV Viral Load lt5,000c/ml - lt10000c/ml lt10000c/ml - -
CD4 Status gt200/mm3 gt200/mm3 gt100/mm3 gt250/mm3 gt300/mm3 gt100/mm3
Genotype 1 60 48 77 55 49 100
bridging fibrosis or cirrhosis 12 39 11 (cirrhosis) 29 27 Study Ongoing
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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

NRTIs Use () NNRTIs Use () PIs Use () Other Use ()
TDF 55 EFV 20 RTV (ld) 24 RAL 1
FTC 41 NVP 7 ATZ 19 T20 1
3TC 36 DLV lt1 KAL 17
ABC 22 ETV n/a FPV 8
AZT 16 NFV 7
d4T 6 DRV 2
ddI 1 SQV 2
IDV lt1
TPV lt1
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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
High Interaction Potential Low Interaction Potential
High Usage PIs Kaletra, Atazanavir, Ritonavir NNRTI Efavirenz Integrase Inhib Raltegravir NRTIs TDF, FTC, 3TC,
Low Usage PIs Fosamprenavir, Saquinavir, Indinavir, Nelfinavir Entry Inhib Maraviroc Entry Inhib T20 NRTIs DDI, D4T
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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
Interaction Potential Low Interaction Potential
High Usage NRTIs FTC, 3TC PIs Kaletra, Atazanavir, Ritonavir NNRTI Efavirenz Integrase Inhib Raltegravir NRTIs TDF
Low Usage NRTIs SPD574 (in development) PIs Fosamprenavir, Saquinavir, Indinavir, Nelfinavir, Darunavir Entry Inhib Maraviroc, T20 NRTIs DDI, D4T
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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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