HCV cure: new treatment
paradigms for HCV infection
Sanjay Bhagani
Consultant Physician/Senior Lecturer
Royal Free Hospital/UCL
London
www.aids2014.org
HCV/HIV co-infection – ‘shades
of grey’
www.aids2014.org
Outline
• Impact of HCV in the HIV-infected patient
– The importance of treating HCV
• PegIFN/ribavirin – a bygone era
• DAAs for HCV and HCV/HIV
– IFN ‘sparing’ and IFN-free regimens
• Is this still a ‘Special Population’?
• New Guidelines
www.aids2014.org
D:A:D: Liver-related death is a frequent
cause of non-AIDS death in HIV-infected
patients
D:A:D Study: Causes of death in n=49,734 HIV-infected patients followed 1999–2011
100
Deaths (%)
80
60
40
20
0
33
29
AIDS
13
11
Liver-related
disease
Cardio
-vascular or
other heart
disease
Weber R, et al. AIDS 2012. Washington USA. Oral presentation THAB0304.
14
Non-AIDS
malignancies
Other
HIV/HCV – double-trouble for the
liver
www.aids2014.org
Chen J Nat Rev Gastroenterol Hep 2014
doi:10.1038/nrgastro.2014.17
Faster progression even when controlling for
alcohol and other co-morbidities
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Kirk D, et al. Ann Intern Med 2013; 158: 658
HIV/HCV – a contribution to multiple organ
dysfunction
•
•
•
•
Global cognitive impairment
Cognitive-motor impairment
Dementia
Peripheral neuropathy
• Cerebrovascular
disease
• Acute myocardial
infarction
• Opportunistic
infections
• Wasting syndrome
Neurologic
disease
Metabolic
disorders
Cardiovascular
Immune
activation
HIV disease
progression
• Proteinuria
• Acute renal failure
• Chronic kidney
disease
• Osteonecrosis
• Osteoporosis
• Bone fracture
Liver
disease
HIV/HCV
Immune
dysfunction
Kidney
disease
GI tract
Bone
disorders
•
•
•
•
•
• Diabetes mellitus
• Insulin resistance
•
•
•
•
Steatosis
Fibrosis
Cirrhosis
End-stage liver
disease
• Liver-related death
• Microbial
translocation
CD4 apoptosis
Abnormal T-cell responses and cytokine production
Cytotoxic T-cell accumulation in liver
Impaired CD4 recovery post-HAART
Severe immunodeficiency
Adapted from Operskalski EA and Kovacs A. Curr HIV/AIDS Rep 2011;8:12–22.
Overall and Liver-related Mortality - effect of
HAART
A) Overall-Mortality
B) Liver-related-Mortality
1,1
1,1
P<0.0001
P<0.018
,9
,7
,5
Patients with dual
ARvs
untreated Patients
,3
Cumulative survival
Cumulative survival
Patients with HAART
Patients with HAART
,9
Patients with dual
ARvs
untreated Patients
,7
,5
,3
0
1000
2000
3000
4000
5000
6000
0
Observation time[days]]
Patients under observation:
HAART-group:
93
ART-group:
55
Untreated-group: 13794
www.aids2014.org
79
46
49
33
30
37
15
32
1000
2000
3000
4000
5000
6000
Observation time[days]]
9
27
1
Patients under observation:
HAART-group:
93
ART-group:
55
Untreated-group: 13794
Qurishi N et al. Lancet, 2004
79
46
49
33
30
37
15
32
9
27
1
‘Hepatotoxcity’ commoner in coinfected patients
www.aids2014.org
Vispo, et al. AIDS 2013:27: 1187
HCV/HIV SVR24 with pegIFN and RIBAVIRIN
100
Genotype 1
SVR 14–38%
Genotype 3
SVR 44–73%
SVR (%)
75
Monoinfection
APRICOT
ACTG
RIBAVIC
Laguno et al.
PRESCO
50
25
0
G1
Genotype
G2/3
Adapted from: Fried et al, NEJM 2002;347:975-982, Torriani et al, NEJM 2004;351:438-50, Chung R, et al, NEJM 2004;351:451-9
Carrat F, et al, JAMA 2004;292:2839-42, Laguno et al, AIDS 2004;18:F27-F36, Nunez et al, JAIDS 2007;45:439-44
HCV Life Cycle and DAA Targets – drug
classes and nomenclature
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
(+) RNA
LD
..PREVIR
Translation and
NS3/4 protease
polyprotein
inhibitors
processing
..ASVIR
ER lumen
Membranous
web
ER lumen
LD
Virion
assembly
LD
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5B
polymerase
inhibitors
RNA
replication
Nucleoside/nucleotide
Nonnucleoside
…UVIR
HCV Life Cycle and DAA Targets –
drugs
Receptor binding
and endocytosis
Telaprevir
Boceprevir
Faldaprevir
Simeprevir
ABT 450/r
Asunaprevir
MK-5172
Transport
and release
Fusion
and
uncoating
Translation and
NS3/4 protease
polyprotein
inhibitors
processing
Daclatasvir
Ledipasvir
Ombitasvir
MK-8742
GS-5816
(+) RNA
ER lumen
LD
Membranous
web
ER lumen
LD
Virion
assembly
LD
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov.
2007;6:991-1000.
NS5B
polymerase
inhibitors
RNA
replication
Nucleoside/nucleotide
Nonnucleoside
Sofosbuvir
Dasabuvir
BMS-791325
ANRS studies TelapreVIH and BocepreVIH in
TE HCV GT 1 HIV/HCV co-infected patients
100
SVR24 (%)
80
100
83
80
74
BOC
TVR
81
78
71
60
40
90
81
80
71
SVR12 (%)
100
70
61
60
56
53
48
41
40
24
20
20
0
0
1. Cotte L, et al. CROI 2014; Oral #668;
2. Poizot Martin I, et al. CROI 2014. Oral #659.
0
SVR24 in HIV/HCV PEG-IFN/RBV experienced treated with PEG-IFN/RBV
+ TVR (69) or BOC (64); 4 weeks lead in + 44 weeks standard +
24 additional weeks if HCV RNA at Week 8 >15IU/mL.
ATV/r: ritonavir boosted atazanavir; TE: treatment-experienced
‘Real-life’ experience PegIFN/R +
TVR/BOC – pan-European data
% of patients who discontinued all therapy
Rx discontinuation
Rx response ITT and OT
100
80
60
50
36
40
20
8
0
platelets ≥100/µL +
albumin ≥3.5 g/dL
www.aids2014.org
platelets ≥100/µL +
albumin <3.5 g/dL or
platelets <100/µL +
albumin ≥3.5 g/dL
platelets <100/µL +
albumin <3.5 g/dL
Neukam K, Munteanu D, et al. CROI 2014
Second generation DAAs + PEG-IFN/RBV
in HIV/HCV co-infected patients
Protease inhibitors
C2121
Genotype 1a/b
• HCV treatment-naïve
 Prior PR relapsers
SMV + PR
(RGT)
 Partial response
 Null response
 Cirrhotic patients (F4)
SMV + PR
STARTVerso42
Genotype 1a/b
 Treatment Naïve
 Relapse
 15% Compensated
Cirrhotic patients (F4)
Follow-up
PR
PR
Follow-up
PR
Follow-up
FDV 240 mg
+ PR
FDV 240 mg
+ PR
PR or follow up (RGT)
PR
FDV 120 mg + PR
PR or follow up (RGT)
Nucleoside polymerase inhibitor
SOF + PR3
Genotype 1-4
• HCV treatment-naïve
SOF + PR
Follow-up
SVR4
Week 12
1. Dieterich D, et al. EACS 2013. PS9/5;
2. Rockstroh J, et al. EACS 2013 .PS9/7;
3. Rodriguez-Torres M, et al. ID Week 2013. Poster #714.
SVR12
SVR24
24
36
48
60
DAA: direct-acting antiviral agents; FDV: faldaprevir;
PR: PEG-IFN/RBV; RGT: response guided therapy; SMV: simeprevir
72
C212: SVR12 by concomitant ART use
(ITT population)
On ART
Not on ART
100
87
SVR12 (%)
80
81
75
78
70
62
58
60
50
40
20
0
70/93
8/13
Overall
35/43
7/10
Naïves
13/15
n/a
Relapsers
7/9
0*
Partial
*0/1 patients; SVR12, sustained virologic response 12 weeks after end of treatment; n/a, not applicable
15/26
1/2
Null
Proportion of patients with SVR12 (%)
STARTVerso4: SVR12
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87/123
134/185
overall population
221/308
Study 1910: SVR12
HCV RNA <LLOQ (%)
100
80
89%
60
40
20
0
17/19
1/1
2/2
1/1
GT1
GT2
GT3
GT4
LLOQ: lower level of quantification
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Rodriguez-Torres M et al. IDWeek 2013, poster 714
IFN-free DAA regimens in HIV/HCV coinfected patients
PHOTON-1 study
Naggie S, et al.
CROI 2014.
Oral #26
C-WORTHY study
Sulkowski M, et al.
EASL 2014. Oral #63
LDV/SOF STR
ERADICATE study
Osinusi A, et al.
EASL 2014. Oral #14
PHOTON-1: Virological response
100
SVR12 (%)
80
76
67
SOF + RBV
12 weeks
60
24 weeks
40
20
0
87/
114
23/
26
28/
42
22/
24
16/
17
GT 1
GT 2
GT 3
GT 2
GT 3
TN
•
94
92
88
TE
No HCV resistance (S282T) observed in virological failures (deep sequencing)
– HCV breakthrough in 2 patients due to non-adherence to SOF
– HIV breakthrough in 2 patients due to non-adherence to ART
Naggie S, et al. CROI 2014. Oral #26.
C-Worthy Virologic Response
% HCV RNA <25 IU/mL
ITT Population
100
90
80
70
60
50
40
30
20
10
0
100 100
100
100
90
29
29
30
30
TW4
29
29
90
27
30
29
29
TW8
27
30
TW12
97
90
28 26
29 29*
MK-5172 +
MK-8742 +
RBV (n=29)
MK-5172 +
MK-8742
(No RBV;
n=30)
SVR4
Week
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Virologic Failures: 1 relapse in +RBV arm;
2 breakthrough and 1 lost to follow up in No RBV arm
* One patient has not yet reached FU4
21
ERADICATE - Treatment Response
% of patients with HCV RNA
< LLOQ
ARV Untreated
100 100
100
100 100


100 100
100 100
100
100
80
60
40
20
13/
13
0
37/
37
13/
13
Week 4

ARV Treated
37/
37
13/
13
Week 8
30/
30
12/
12
EOT
22/
22
10/
10
SVR4
10/
10
SVR8
SVR12
The IFN and RBV free regimen of LDV/SOF in HCV/HIV co-infected patients resulted in
SVR12 of 100% in ARV untreated patients and SVR4 of 100% in ARV treated patients
LDV/SOF STR was generally well tolerated with no discontinuations
Actively enrolling ION-4 (target of 300 GT 1 and GT 4 HCV/HIV patients). NCT 02073656.
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Osinusi A, EASL, 2014, O14
SVR12 - PEG-IFN/RBV + TVR, SMV, FDV and SOF
in HCV GT1 TN patients: HIV+ vs HIV–
Cirrhosis
11%1 6%2
12%3 9%4
15%5 6%6
Excluded
100
SVR12 (%)
80
91
74
79
79
80
91
80
72
60
HIV+
HIV-
40
20
0
28/
38
285/
363
TVR + PR
42/
53
1,2
24 or 48 weeks
419/
521
SMV + PR
24 or 48 weeks
221/ 414/
308 520
3,4
FDV + PR
21/
23
5,6
12 or 24 weeks
1. Sulkowski M, et al. AASLD 2012. Oral #54; 2. Janssen Cilag International.
INCIVO (Telaprevir), Summary of product characteristics, September 2011;
3. Dieterich D, et al. CROI 2014 Abstract #24; 4. Jacobson I, et al. AASLD 2013.
Poster #1122; 5. Dieterich D, et al. APASL 2014. Oral‘#681; 6. Ferenci P, et al.
EASL 2013. Abstract #1416; 7. Rodriguez-Torres M, et al. ID week 2013. Poster
#714; 8. Lawitz E, et al. APASL 2013. Oral #LB-02.
296/
327
SOF + PR
7,8
12 weeks
NOTE: not head-to-head comparisons.
Comparisons of SVR12 rates of interest adjusted for important predictors of
response across the STARTVerso studies, excluding PI- and EFV-treated patients
from STARTVerso4
Adjusteda SVR12 (%)
Adjusted difference in SVR12 (95% CI)
HIV Co-infection
No (reference)
72.3
Yes
85.0
12.6 (5.7, 19.5)
Genotype
1a (reference)
74.2
1b
83.2
9.0 (4.2, 13.8)
FDV dose
120 mg (reference)
79.0
240 mg
78.3
-0.7 (-5.0, 3.6)
-20
a Adjusted
-15
-10
-5
0
5
10
15
20
for IL28B, race, fibrosis stage, baseline HCV RNA, age, baseline GGT and baseline platelet count.
www.aids2014.org
Deitrich, APASL 2014, o681
30
New online EASL HCV recommendations
Same treatment regimens can
be used in HIV/HCV patients
as in patients without HIV
infection, as the virological
results of therapy are identical
(A1)
EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf
New EASL HCV recommendations –
treatment combination options
G1, 2, 3, 4, 5,
6
SOF + PEG-IFN/RBV
12 weeks
G1, 4
SMV + PEG-IFN/RBV
12 weeks +
RGT 12/36
G4
Daclatasvir + PEG-IFN/RBV
12 weeks +
RGT 12
G1, 2, 3, 4
SOF + RBV
12–24 weeks
G1, 4
SOF + SMV (± RBV)
12 weeks
G1, 3, 4
SOF + daclatasvir (± RBV)
12–24 weeks
EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-ofhepatitis-c-summary.pdf
www.aids2014.org
S.Khoo, 15th Intl. W’shop, 2014
Conclusions
• The era of DAA based therapy has arrived
– IFN-sparing and IFN-free therapy a reality
• Responses in HIV+ similar to HIV• Beware DDIs
• Still a ‘Special Population’ – aggressive,
multi-system disease, urgent need of Rx
• Need for improved cascade of care and
access to Rx
www.aids2014.org
HCV/HIV co-infection – ‘shades
of grey’
www.aids2014.org