HIV:HCV Co-infection Landscape21 of October, 09

Madrid,Spain

GESIDA, Madrid

Where are we are today?

Barriers to Care

HCV Treatment Uptake: John Hopkins HIV Clinic

35%

65%

68%

23%

21%

0.7%

• 90% Genotype 1

• 70% African American Popn.

Mehta AIDS (2006) 20:2361-69

Referral associated with:

ALT levels

• Undetectable HIV RNA

• CD4+ > 350 cell/mm3

• Receiving care for psychiatric condition

• No active drug use

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:

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 - 1g800-

1200mg1000-

1200mg1000-

1200mg

HIV Viral Load

<5,000c/ml

-<10000c/

ml<10000c/

ml- -

CD4 Status

>200/mm3

>200/mm3

>100/mm3

>250/mm3

>300/mm3

>100/mm3

% Genotype

160% 48% 77% 55% 49% 100%

% bridging

fibrosis or cirrhosis

12 3911

(cirrhosis)29 27

Study Ongoing

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

0

10

20

30

40

50

60

Monoinfected APRICOT RIBAVIC ACTG 5071 Barcelona PRESCO PARADIGM

Low dose RBV

Study Ongoing

% SVR

PARADIGM

800 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

Alvarez D et al. Journal Viral Hepatitis (2006) 13:683-689

Mean Change in Hgb After 4 Weeks HCV Therapy

RBV Dose Reduction During 1st 12 Weeks

The Future…..

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

Higher SVR

Shortened Treatment Duration

Increased Drug : Drug Interactions

Increased Regimen Complexity

Increased Side Effects

Or will we have to wait for IFN and/or RBV – sparing regimens?

Looking Ahead to Drug:Drug Interaction Studies for

Co-infected Patients

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)

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 :

Antiretroviral Use In Co-infected Patients:Summary of ART use at Baseline in the PARADIGM Study (US/Spain/Portugal)

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 <1% KAL 17%

ABC 22% ETV n/a FPV 8%

AZT 16% NFV 7%

d4T 6% DRV 2%

ddI 1% SQV 2%

IDV <1%

TPV <1%

• 409 patients; 89% on Antiretroviral therapy; 28% NNRTI; ~50% on a PI regimen

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

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)

• 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

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

HCV Polymerase Inhibitor R7128

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

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

Timing of Studies Will Depend Upon Compound Profile

Phase 2b

EOT

SVR24 Pivotal Phase 3 Studies

In vitro combination

studies

Confirm Safety Profile

Begin ART Drug:Drug

Interaction studies of Priority

Compounds

Phase 2/3 Co-infection

Study

Complete ART Drug: Drug Interaction

Studies

Confirm Efficacy

Conclusions1-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.