Transcript HIV-HCV Coinfection in the era of effective antiviral therapy

HIV-HCV Coinfection in the era
of effective antiviral therapy
Mark Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Johns Hopkins University
Baltimore Maryland USA
Liver disease is the second leading
specific causes of death amongst HIVpositive individuals in the D:A:D study
35
30
29.9
25
% of deaths 20
13.7
15
11.6
11.5
CVD
Cancer (nonAIDS)
10
5
0
AIDS
AIDS. 2010 Jun 19;24(10):1537-48.
Liver
0.00
0.25
0.50
0.75
1.00
SVR or virologic relapse following HCV
treatment was associated improved
survival
0
5
10
Time since biopsy (years)
No HCV TRT
SVR
Sulkowski MS, et al. CROI 2010. Abstract 166.
Relapse
Non-Response
15
SVR rates among HIV/HCV coinfected
patients treated with PegIFN alfa-2a/RBV
Ribavirin 800 mg/day (n=135)
Ribavirin 1000/1200 mg/day (n=275)
50
SVR (%)
40
30
26
22
20
24
20
19
13
9
10
135 275
86
176
33
5
62
0
All patients
Caucasian
Rodriguez-Torres et al. AASLD 2009
Hispanic
40
77
Black
Telaprevir and Boceprevir in HCV/HIV
coinfected patients

All contraindications to PegIFN/RBV
apply

Coadministration with other drugs
– Highly dependent on CYP3A for
clearance
– Strongly induce CYP3A

Safety and efficacy not established in
persons coinfected with HIV
Telaprevir and Boceprevir; Prescribing information, May 2011
Phase 2 studies of HCV PI + PR
Telaprevir
Boceprevir
Number of patients
TVR, 38; Control, 22
BOC, 64; Control, 34
HCV population
Naïve, genotype 1
Naïve, genotype 1
HIV population
CD4 ≥500; HIV ≤100,000 c/mL
CD4 ≥ 300; HIV ≤50 c/mL
CD4 ≥ 200 cells/mm3
HIV RNA <50 c/mL
Antiretroviral therapy
Lead-in
None (n=7)
No NNRTIs
EFV (n=16) or ATV/r (n=15) + TDF/FTC ATV/r, (n=20); DVR/r (n=16);
DRV/r (n=12); RAL(n=11)
TLV 750 mg Q8H or 1125 mg Q8H (if
BOC 800 mg Q8H + pegIFN-2b +
EFV co-admin) + pegIFN-2a + RBV
weight based RBV (600–1400
800 mg/day
mg/day)
No
Yes
Duration of PI
12 weeks
44 weeks
Duration of PR
48 weeks
48 weeks
Virologic futility rules
Week-12 <2 log10 decline
Week-24 Detectable HCV RNA
HCV PI PK measured
Week-4 or 8 or 12 HCV RNA >1000
IU/mL
Week-24 Detectable HCV RNA
Yes
ART PK measured
Yes
No
HCV regimen
Yes
Efficacy
Undetectable HCV RNA over 24 weeks:
Telaprevir (12 wks) + PR Vs. PR
% undetectable
PegRBV
100
90
80
70
60
50
40
30
20
10
0
TVRPegRBV
79
71
68
55
27
0
4
12
Treatment week
24
% Patients With Undetectable
HCV RNA
80
PEG2b/RBV
PEG2b/RBV+BOC
70.5
56.5
60
37.5
40
34.4
25
20
14.7
8.8
0
4.7
3/34
3/64
4
Sulkowski MS. IDSA 2011
5/34
24/64
8/32
8
Treatment Week
35/62
12
11/32
43/61
24
Safety and Tolerability
Telaprevir + PR
No severe rash report with TVR
TVR/PR - bilirubin AEs 27% (4/15) versus none of control (0/8)
Telaprevir + PR
Virologic Breakthrough

No HIV RNA breakthrough

HCV RNA breakthrough, 7 patients
– Efavirenz, 4 of 16
– Atazanavir/r, 3 of 15
Boceprevir + PR: Most Common Adverse
Events With a Difference of ≥10% Between
Groups
PEG2b/RBV
(N=34)
PEG2b/RBV + BOC
(N=64)
Days on study, median
166
211
Neutropenia, (%)
3%
13%
Dysgeusia, (%)
15%
25%
Vomiting, (%)
15%
25%
Pyrexia, (%)
21%
34%
Headache, (%)
12%
28%
Decreased Appetite, (%)
18%
30%
*A difference of ≥10% for patients receiving PEG2b/RBV+BOC when compared with PEG2b/RBV.
Safety Boceprevir + PR
PEG2b/RBV
(N = 34)
PEG2b/RBV +
BOC
(N = 64)
166
211
Any AE, n (%)
34 (100)
63 (98)
Serious AEs, n (%)
7 (21%)
5 (8%)
34 (100%)
61 (95%)
Study Discontinuation Due to an AE, n (%)
3 (9%)
9 (14%)
Any Drug Modification Due to an AE, n (%)
7 (21%)
12 (19%)
Days on study, median
Treatment-related Treatment-emergent
AEs, n (%)
Boceprevir + PR: Hematologic AEs
PEG2b/RBV
(N=34)
PEG2b/RBV +
BOC (n=64)
Anemia
AEs, n (%)
9 (26)
19 (30)
SAEs, n (%)
2 (6)
1 (2)
AEs leading to discontinuation, n (%)
1 (3)
1 (2)
Grade 2 (8.0 to <9.5 g/dL), n (%)
7 (21)
10 (16)
Grade 3 (6.5 to <8.0 g/dL), n (%)
1 (3)
3 (5)
Erythropoietin use, n (%)
7 (21)
17 (27)
Transfusions, n (%)
2 (6)
4 (6)
AEs, n (%)
1 (3)
8 (13)
Grade 3 (<0.75x109/L), n (%)
3 (9)
10 (16)
*
*
Neutropenia
Grade 4 (<0.5x109/L), n (%)
*To maintain blinding in this continuing study the table only shows data where events occurred in at least 1 patient in
each treatment group.
Virologic Breakthrough

HIV RNA breakthrough, 4 patients
– 2 on placebo
– 2 on BOC + ATV/r with increase HIV RNA

No HCV RNA breakthrough reported
Drug Interactions
Telaprevir – ARV Interactions
Thomas DL et al. Clin Infec Diseases 2011 in press
Boceprevir Drug Interactions with ART
(limited data)
Boceprevir
Effect on Concentration of PI or Concomitant Drug
Efavirenz
↓ boceprevir
•Plasma trough concentrations of BOC decreased when
coadministered, which may result in loss of therapeutic effect
•Avoid combination
Ritonavir
↓ boceprevir
↑ or ↓ HIV protease inhibitors
•Boceprevir concentrations decreased with ritonavir; effect of
ritonavir-boosted HIV PIs on BOC exposure is unknown
•The effect of BOC on HIV PI concentrations is unknown
Interaction studies of BOC and Atazanavir/r, Daruanvir/r, and Lopinavir/r
have been completed.
Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011.
Provisional use of HCV PIs in HIV/HCV coinfected
patients



Referral to clinical trials is strongly recommended
PegIFN + Ribavirin remains an appropriate regimen for
many co-infected patient
However, if available, data support the cautious use of
telaprevir or boceprevir + PR in carefully selected
patients:
–
–
–
–
–

No antiretroviral therapy  TVR or BOC
RAL  TVR or BOC
ATV/r  TVR
EFV  TVR (requires increase TVR dose)
Other ARVs  Insufficient data; NOT recommended
Major limitations to therapy
–
–
Efficacy and tolerability of PegIFN
Cost