Transcript HCV Protease Inhibitors

HIV:HCV Co-infection Landscape
21 of October, 09
GESIDA, Madrid
Madrid,Spain
Where are we are today?
Barriers to Care
HCV Treatment Uptake: John Hopkins HIV Clinic
• 90% Genotype 1
• 70% African American
Popn.
Referral associated with:
35%
65%
• ALT levels
• Undetectable HIV RNA
68%
• CD4+ > 350 cell/mm3
• Receiving care for
psychiatric condition
23%
21%
• No active drug use
0.7%
Mehta AIDS (2006) 20:2361-69
Reasons for Low Uptake of HCV Tmt Among Coinfected 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
PARADIG
868
412
133
95
389
400
Peg-IFN
2a
2b
2a
2b
2a
2a
Ribavirin
800mg
800mg
600 - 1g
800-
1000-
1000-
HIV Viral
<5,000c/ml
-
-
-
CD4
>200/mm3
>200/mm3
>100/mm3
>250/mm3
>300/mm3
>100/mm3
%
60%
48%
77%
55%
49%
100%
% bridging
fibrosis or
cirrhosis
12
39
11
29
27
Study
N=
<10000c/m <10000c/m
Comparison of Sustained Virological Responses
in Genotype 1 Co-infected Patients
60
50
% 40
SVR
30
20
Study
Ongoing
10
0
Monoinfected
APRICOT
RIBAVIC
ACTG 5071
Low dose RBV
Barcelona
PRESCO
PARADIGM
PARADIGM
800 mg
All-26/135 (19%)
WD
60/275 (22%)
• Caucasians 19/60 (32%)
• AA
2/40 (5%)
• Latinos 3/33 (9%)
32/116 (28%)
10/71 (13%)
15/76 (20%)
HAART and HCV Therapy: Zidovudine
Mean Change in Hgb After 4
Weeks HCV Therapy
Alvarez D et al. Journal Viral Hepatitis (2006) 13:683-689
RBV Dose Reduction During 1st 12 Weeks
The Future…..
What is the best way for small molecules make a
difference ?
Increased Side Effects
Higher SVR
Shortened Treatment
Duration
Increased Drug : Drug
Interactions
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
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)
• 409 patients; 89% on Antiretroviral therapy; 28% NNRTI; ~50% on a PI regimen
NRTI
Use
NNRT
Use
PIs
Use
Other
Use
TDF
55%
EFV
20%
RTV
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%
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
PIs: Kaletra, Atazanavir,
Integrase Inhib: Raltegravir
NNRTI: Efavirenz
NRTIs: TDF, FTC, 3TC,
PIs: Fosamprenavir, Saquinavir,
Nelfinavir
Entry Inhib: T20
High Usage
Low Usage
Entry Inhib: Maraviroc
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
PIs: Kaletra, Atazanavir,
NNRTI: Efavirenz
High Usage
NRTIs: FTC, 3TC
Integrase Inhib: Raltegravir
NRTIs: TDF
NRTIs: SPD574 (in
Low Usage
PIs: Fosamprenavir,
Nelfinavir, Darunavir
Entry Inhib: Maraviroc, T20
NRTIs: DDI, D4T
Timing of Studies Will Depend Upon Compound Profile
EOT
Phase
2b
SVR24
Confirm
Safety Profile
In vitro
combination
studies
Pivotal Phase 3
Studies
Confirm
Efficacy
Begin ART Drug:Drug
Interaction studies of
Priority Compounds
Phase 2/3
Co-infection
Study
Complete ART Drug:
Drug Interaction
Studies
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 .