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Il Paziente coinfetto HIV-HCV non
più «special population?»
Franco Maggiolo
USS Patologie HIV Correlate e Terapie Innovative
AO Papa Giovanni XXIII, Bergamo
Disclosures
Consultancy and advisory boards
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline,
Tibotec, Merck Sharp and Dome ;
Lecture fees
Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp and
Dome;
Research and educational grants
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline,
Jansen-Cilag and Roche.
HCV
HIV
Virus a RNA
Coinfection
Transmission:
Blood
Sexual intercourse
MTC
Clinics:
Acute infection often asymptomatic
Latency
Prevalence of patients living with disease
(Bergamo HIV cohort. 1236 patients starting cART between 1998 and 2009)
6
% of subjects
5
4
3
2
1
0
diabetes
cardiovascular
diseases
general population
cirrhosis
neoplastic
disease
Bergamo cohort
Leone S, et al. Infection 2011.
HCV
HIV
Virus a RNA
Coinfection
Transmission:
Blood
Sexual intercourse
MTC
Clinics:
Acute infection often asymptomatic
Latency
Pathogenetic
interactions
HCV Coinfection vs Monoinfection: Cumulative
Incidence of Decompensation
• 10-year hepatic decompensation risk 83% higher in coinfected patients
– Adjusted HR 1.83 (95% CI: 1.54-2.18)
0.2
HIV/HCV coinfected
HCV monoinfected
0.1
0.074
0.048
P < .001
0
0
1
2
3
4
5
6
7
8
Yrs to Hepatic Decompensation
Lo Re V, et al. IAC 2012. Abstract WEAB0102.
9
10
Effect of cART on development of ESLD in in
haemophilics with HCV and/or HIV
HIV+ cART
HIVHIV+ NO cART
Ragni MV, et al. Haemophilia 2009
CD4 nadir and fibrosis progression in HIV/HCV
coinfected subjects
Reiberger T, et al. J. Viral Hepatitis 2010
Yearly death rate (cirrhosis)
4
general
population
Death rate x 1000 subjects
3,5
3
Bergamo
cohort
2,5
2
general
population
(corrected)
1,5
1
0,5
0
15-24 25-34 35-44 45-54 55-64 65-74
75+
Age groups
2
1,5
1,7
OR 10.5 95% CI 2.5-44.8 (P < 0.0001)
1
OR 35.0 95% CI 15.5-78.8 (P < 0.0001)
0,5
0,156
0,0507
0
Leone S, et al. Infection 2011.
TOT
Patients with event
Bergamo HIV cohort
Non AD cancer
Cardiovascular disease
Diabetes
Cirrhosis
P < 0.0001
HCV
HIV
Virus a RNA
Coinfection
Transmission:
Blood
Sexual intercourse
MTC
Clinics:
Acute infection often asymptomatic
Latency
Pathogenetic
interactions
CURE
CHRONICITY
SVR, %
HIV/HCV Co-infected
Laguno M, AIDS 2004; Chung RT NEJM 2004;
Torriani FJ NEJM 2004; Carrat F, JAMA 2004
Study 110: Telaprevir + PegIFN/RBV in GT1
HCV/HIV Coinfection
•
Phase II randomized controlled trial[34]
– Telaprevir TID + pegIFN/RBV vs
pegIFN/RBV alone for 48 weeks
•
•
HCV treatment-naive HIV+ patients (N
= 60)
No HIV breakthrough
Safety and tolerability
– Increased pruritus, headache, nausea,
rash, and dizziness with telaprevirbased therapy
80
SVR (%)
•
100
– Anemia: 18% in both groups
•
SVR comparable to GT1 HCVmonoinfected patients (75%)[35]
80
74
71 69
No ART
EFV/TDF/FTC
ATV/ritonavir
+ TDF/FTC
Total
60
50 50
40
45
33
20
n/N =
0
34. Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96.
35. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
5/
7
11/
16
12/
15
28/
38
Telaprevir +
PegIFN/RBV
2/
6
4/
8
4/
8
10/
22
PegIFN/RBV
STARTVerso 4: Faldaprevir + PegIFN/RBV in GT1
HCV/HIV–Coinfected Pts
•
Interim analysis of phase III STARTVerso 4 trial
–
79% white/13% black, 78% GT1a HCV, 4% not on ART, 27% on EFV-based ART, 22% on ATV/RTV or
DRV/RTV-based ART, 47% on RAL-based or “other” ART
Randomization or allocation
based on ART regimen
Patients coinfected
with HIV and GT1
HCV, HCV
treatment naive or
previous relapser
(N = 308)
Wk 12*
Faldaprevir 240 mg QD +
PegIFN/RBV
Wk 24
Faldaprevir 240 mg QD +
PegIFN/RBV
Wk 48
PegIFN/RBV
RGT†
PegIFN/RBV
Faldaprevir 120 mg QD +
PegIFN/RBV
No further tx
PegIFN/RBV
RGT†
No further tx
*At Wk 12, pts receiving 240 mg QD + P/R were rerandomized 1:1 to continue triple therapy or to P/R to Wk 24.
†At Wk 24, pts with ETS were rerandomized to continued P/R vs no further treatment; pts without ETS continued P/R to
Wk 48. ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.
Dieterich D, et al. CROI 2013. Abstract 40LB.
Wk 12 Response (%)
Preliminary Outcomes With Faldaprevir +
PegIFN/RBV in Coinfected Patients
Wk 12 Response on Therapy
(SVR Data Not Yet Available)[1]
Treatment naive < LLoQ
Treatment naive < LLoQ TND
Relapser < LLoQ
Relapser < LLoQ TND
100
91
93
86
82
80
60
40
20
n/N =
0
206/
239
195/
239
64/
69
• AE profile consistent with
pegIFN/RBV AE profile[1]
• Separate PK and DDI study
conducted[2]
– Effects of FDV on ARV:
small increases in exposure to
DRV/RTV and TDF; not
considered clinically relevant
– Effects of ARV on FDV:
FDV AUC ↑ 130% with DRV/RTV,
↓ 22% with TDF,
↓ 30% with EFV
63/
69
1. Dieterich D, et al. CROI 2013. Abstract 40LB. 2. Sabo JP, et al. CROI 2013. Abstract 35.
Reproduced with permission.
SOF + PegIFN + RBV in Treatment-Naïve HIV/HCV
Co-infected Patients
Phase 2 Study 1910 Design
• Single-centre, open-label, single-arm trial to assess the safety and efficacy of a
12-week course of SOF + PegIFN + RBV for the treatment of patients with
chronic HCV, co-infected with HIV
Week
HCV GT 1–4
Treatment-naïve,
on stable HIV ARV
N=23
0
12
16
24
36
SVR4
SVR12
Primary endpoint
SVR24
SOF 400 mg QD +
PegIFN alfa-2a 180 µg/week +
RBV 1000‒1200 mg/day
No response guided therapy
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
SOF + PegIFN + RBV in HIV/HCV Coinfection
Patients with HCV RNA <LLOQ (%)
Virologic Response and SVR12
100
96
100
100
91
91
90
80
70
60
50
40
30
20
10
22/23
23/23
23/23
21/23
21/23
Week 2
Week 4
EOT
SVR4
SVR12
0
 There was no on-treatment HCV or HIV virologic breakthrough
 Relapse occurred in 1 patient and accounted for all virologic failures
 Two patients discontinued treatment early due to adverse events, one of whom achieved
SVR12 after receiving 8 weeks of SOF + PegIFN + RBV
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
PHOTON-1: Virologic Response Rates
HCV RNA < LLOQ (%)
100
96
100
96
Wk 4
EOT
SVR12
98
88
76
80
67
60
40
20
n/N =
0
110/
114
103/
103
87/
114
Genotype 1
SOF + RBV 24 Wks
•
•
96
100
25/
26
22/
23
23/
26
Genotype 2
41/
41
39/
40
28/
42
Genotype 3
SOF + RBV 12 Wks
Breakthrough only in the setting of noncompliance
Regimen effective across several types of ART: PIs, NNRTIs, integrase inhibitors
Sulkowski M, et al. AASLD 2013. Abstract 212. Reproduced with permission.
C-WORTHY
HCV-PI + NS5A for HIV/HCV coinfection
Sulkowski et al, EASL 2014 abstract O63
ERADICATE
LDV/SOF Fixed Dose Combination for
Study (NIAID)
Treatment of HCV GT 1 Coinfected with HIV
LDV/SOF once daily for 12 weeks in GT 1, treatment naïve subjects
with stable HIV
Study Weeks
n=50
GT 1, TN,
stable HIV
disease
12
24
ARV Untreated: LDV/SOF 400/90mg
ARV Treated*: LDV/SOF 400/90mg
Median age (range)
Male, n (%)
African American, n (%)
Median BMI (range)
Genotype 1a, n (%)
Median HCV RNA log10 IU/mL (range)
HAI Stage 3 Fibrosis, n (%)
Median CD4 T-cell count (range)
*Permitted ARV regimens: TDF/FTC, EFV, RILP, RALT
Osinusi A, EASL, 2014, Abstract O14
8
SVR 12
SVR 4
ARV Untreated
ARV Treated
n=13
59 (48–63)
n=37
58 (34–75)
7 (54)
10 (77)
26 (22–35)
9 (75)
6.07
(4.05–7.29)
30 (81)
32 (86)
26 (19–41)
30 (81)
5.97
(4.80–7.05)
5 (38)
8 (22)
687
(319–1287)
576
(113–1612)
Interim results
ERADICATE Study (NIAID)
Treatment Response
13/
13
•
•
37/
37
13/
13
37/
37
13/
13
27/
27
12/
12
21/
21
10/
10
10/
10
The IFN/RBV free regimen of LDV/SOF in HIV/HCV coinfected patients resulted in SVR12 of
100% in ARV untreated patients and SVR4 of 100% in ARV treated patients
The regimen was well tolerated with no discontinuations
Osinusi A, EASL, 2014, Abstract O14
Access to therapy in the Veteran Affairs System
(2002 - 2007)
• 619/8138 (7%) of HIV/HCV co-infected patients
received at least two prescriptions of PegIFN and
ribavirin
• 103/619 (17%) treated patients achieved a SVR
• About 1% of the total HIV/HCV co-infected
population achieved a SVR
Ioannou AASLD 2013 abstract 37
Access to therapy for first generation hcv
protease inhibitors in Switzerland
(9/2011-8/2013)
Haubitz et al CROI 2014 P524
Il Paziente coinfetto HIV-HCV non più «special population?»
NO
YES
HIV/HCV coinfected
HCV monoinfected
0.074
0.1
0.048
0
P < .001
0
1
2 3
4
5
6 7
8
Yrs to Hepatic Decompensation
9
10
13 37
/ /
13 37
13 37
/ /
13 37
13 27
/ /
13 27
12 21
/ /
12 21
10
/
10
10
/
10