15/12/2014
1
in partnership
with
Mount Sinai Medical Center, NYC, USA
Professor Douglas Dieterich
Five Nations Conference on
HIV and Hepatitis
The Beginning of the End for HCV in HIV:
Or the End of the Beginning ?
Douglas T. Dieterich, M.D
Professor of Medicine
Division of Liver Diseases,
Icahn School of Medicine at Mount Sinai
15/12/2014
2
Disclosure
● Consultant/Advisor, Honorarium, Advisory Board for AbbVie,
BMS, Boehringer Ingelheim, Gilead, and Roche
Change in Causes of Death in Patients with HIV
Swiss HIV Cohort Study (SHCS)
● 446 deaths between 2005 and 2009
● Causes of death
– #1 Non-AIDS defining cancers (n=85, 19.1%)
• including HCC (n=13, 2.8%)
– #2 AIDS (n=73, 16.4%)
– #3 Liver Diseases (n=67, 15.0%)
Weber R, et al. HIV Medicine. 2013;14:195–207.
When deaths due to HCC are included among liver-related deaths
(instead of non-AIDS defining cancers)
Liver Diseases = #1 Cause of Death (17.9%)
15/12/2014
3
Kaplan Meier Estimates of Events:
HIV HCV Patients
SVRNo SVR
100
0
Pro
po
rtio
n f
ree
fro
m e
ve
nt
(%)
Follow-up (months)
95
90
8515
10
5
0
12 24 36 48 60 72 84 96
Overall mortality
100
0
Pro
po
rtio
n f
ree
fro
m e
ve
nt
(%)
Follow-up (months)
95
90
8515
10
5
0
12 24 36 48 60 72 84 96
Liver-related mortality
100
0
Pro
po
rtio
n f
ree
fro
m e
ve
nt
(%)
Follow-up (months)
95
90
8515
10
5
0
12 24 36 48 60 72 84 96
Liver decompensation
100
0
Pro
po
rtio
n f
ree
fro
m e
ve
nt
(%)
Follow-up (months)
95
90
8515
10
5
0
12 24 36 48 60 72 84 96
Liver related events
p=0.010 p=0.024
p=0.010 p<0.001
SVRNo SVR
SVRNo SVR
SVRNo SVR
HCV Infection Can Be Cured in HIV + Patients
and Extend Life
● Testing and counseling
● Treatment of chronic
infection
– SVR is possible1
– SVR is durable2
– SVR prevents death3
1. Torriani FJ, et al. New Engl J Med. 2004;351:438-450.
2. Soriano V, et al. Antivir Ther. 2004;9:987-992.
3. Berenguer J, et al. Hepatology. 2009;50:407-413.
SVR – sustained virological response
Survival after HCV treatment for
493 patients with no SVR and
218 patients with SVR
Months after HCV treatment
SVRNo SVR
0
Pe
rce
nta
ge
(%
)
100
p≤0.001 by log-rank test
80
60
40
20
0
6 12 18 24 30 36 42 48
Slide 5
LH1 This slide is shown in this ICAAC abstract. I can't be sure it's not from another source however:
http://www.natap.org/2013/ICAAC/ICAAC_59.htmLynn Hayne, 13/11/2014
15/12/2014
4
Summary of Results:
Coinfection Trials Pre-DAA
SVR (%)
Study N Treatment All G1Genotype
non-1
Ribavic1 412PEG IFN α-2b + RBV 800
IFN α-2b + RBV 800
27
20
17
6
44
43
ACTG2 133PEG IFN α 2a + RBV 600
IFN α -2a + RBV 600
27
12
14
6
73
33
APRICOT3 860PEG IFN α 2a + RBV 800
IFN α -2a + RBV 800
40
12
29
7
62
20
Laguno4 93PEG IFN α-2b + W/B RBV
IFN α-2b + W/B RBV
44
21
38
7
53
47
PRESCO5 389
PEG IFN α-2a + W/B RBV
G1 48 w 31 72w 52
G2 24 w 67 48w 82
50 36 72
1. Carrat F, et al. JAMA. 2004;292:2839-2848.
2. Chung RT, et al. N Engl J Med. 2004;351:451-459.
3. Torriani FJ, et al. N Engl J Med. 2004;351:438-450.
4. Laguno M, et al. AIDS. 2004;18:F27-36.
5. Nunez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982.
17% 14%
29%
38% 36%
74%
61%
74% 74% 76%
98%
0%
20%
40%
60%
80%
100%
Fixed-dose
ribavirin
Weight-based
ribavirin
Direct-acting antiviral agents
Progression of SVR in HCV Treatment in HIV
Carrat F, et al. JAMA. 2004;292:2839-2848. Chung RT, et al. N Engl J Med. 2004;351:451-459.
Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Laguno M, et al. AIDS. 2004;18:F27-36.
Nunez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982.
15/12/2014
5
PegIFN + RBV
Telaprevir +
(750 mg q8h)
PegIFN + RBV
Telaprevir-Based HCV Therapy in HCV/HIV
Coinfection (SVR 12)
Phase 2HCV treatment-naïve, G1
No decompensated cirrhosis
PegIFN + RBV
Placebo + PegIFN + RBV
Telaprevir +
(750 mg q8h)
PegIFN + RBV
Follow-Up
Follow-Up
Follow-Up
T12/
PR48
PR48
T12/
PR48
PR48
PegIFN + RBVFollow-Up
Part A: No ART
CD4: ≥500 cells/mm3
HIV RNA ≤100K copies/mL
EFV/TDF/FTC or ATV/r + TDF + (FTC or 3TC)
Part B: ART
CD4: ≥300 cells/mm3
HIV RNA <50 copies/mL
0 12 24
Week
48 72
Dieterich D, et al. CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 46.
71
33
69
50
80
50
74
45
T/PR PR0
20
40
60
80
100
Pa
tie
nts
wit
h S
VR
(%
)
No ART EFV/TDF/FTC ATV/r/TDF/FTC Total
n/N = 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22
* Patient was defined as SVR12 if HCV RNA
was < LLOQ in the visit window
Dieterich D, et al. CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 46.
SVR Rates 12 Weeks Post-Treatment (SVR12*)
15/12/2014
6
Boceprevir Study Design
● Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV– 2:1 randomization (experimental : control)
– Boceprevir dose 800 mg TID
● 4-week lead-in with PEG2b/RBV for all patients– PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID
● Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered
open-label PEG2b/RBV+BOC via a crossover arm
Sulkowski M, et al. CROI 2012, March 5-8, 2012; Seattle, WA. Abstract 47.
Weeks 12 24 28 48 72
PEG2b
+RBV
4 wk
Placebo + PEG2b + RBV
44 wk
Boceprevir + PEG2b + RBV
44 wk
Follow-up
SVR-24 wk
Follow-up
SVR-24 wk
PEG2b
+RBV
4 wk
Arm 1
Arm 2
Futility rules
Virologic Response Over Time†
8.814.7
23.5
32.429.4
26.5
4.7
42.2
59.4
73.4
65.660.7
0
20
40
60
80
100
4 8 12 24 EOT SVR12
Treatment Week
PR B/PR
%
HC
V R
NA
Un
de
tect
ab
le
3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 9/3442/64 37/61
† Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.
Sulkowski M, et al. CROI 2012, March 5-8, 2012; Seattle, WA. Abstract 47.
15/12/2014
7
The University of Liverpool. http://www.hep-druginteractions.org.
On-treatment and Sustained Virologic
Responses Rates of Telaprevir-based
Hepatitis C Treatment
Do Not Differ Between HIV/HCV Co-infected
and HCV Mono-infected Patients
Martel-Laferrière V, Brinkley S,
Bichoupan K, Posner S, Stivala A,
Perumalswami P, Schiano T, Sulkowski M,
Dieterich DT, Branch AD
Martel-Laferrière V, et al. IAPAC. June 2-4, 2013. Miami, FL.
15/12/2014
8
Baseline Characteristics
Co-infected
(N = 33)
Mono-infected
(N = 117)P-value
Median age (IQR) 57 (52–59) 56 (51–61) 0.82
Male (% of total) 26 (78.8%) 79 (67.5%) 0.21
Race (% of total)
White
Black
Other
16 (48.5%)
14 (42.4%)
3 (9.1%)
65 (55.6%)
19 (16.2%)
34 (28.2%)
<0.01
Prior treatment response (% of total)
Naïve
Relapser
Non responder/intolerant
3 (9.1%)
5 (15.2%)
25 (75.8%)
36 (30.8%)
23 (19.7%)
58 (49.6%)
0.02
Bridging fibrosis/cirrhosis (% of total) 16 (48.5%) 40/113 (35.4%) 0.17
Baseline HCV viral load log10
IU/mL
(IQR)
6.46
(5.92–7.00)
6.46
(5.91–6.73)0.42
Martel-Laferrière V, et al. IAPAC. June 2-4, 2013. Miami, FL.
42%
70%
36%
76%
70%
61%
44%
66%
40%
58%54%
43%
0%
10%
20%
30%
40%
50%
60%
70%
80%
RVR EVR eRVR Week 24 EOT SVR12
Co-infected Mono-infected
p=0.10 p=0.07p=0.07p=0.44p=0.68p=0.91
Virologic Responses
Trend for better virologic responses in co-infected patient is
potentially explained by a selection bias
Martel-Laferrière V, et al. IAPAC. June 2-4, 2013. Miami, FL.
15/12/2014
9
HIV Co-infection Did not Increase Rates of
Discontinuation or Severe Anemia
HIV/HCV
co-infected
patients
HCV
mono-infected
patients
P-value
Discontinuation due to side effects (%) 6 (18.2%) 16 (13.7%) 0.58
Hospitalization (%) 9 (27.2%) 21 (17.9%) 0.42
Emergency room visits (%) 6 (18.2%) 16 (13.7%) 0.52
Anemia (%) 29 (87.8%) 107 (91.5%) 0.53
Severe anemia (%) 15 (45.5%) 68 (58.1%) 0.20
Rash (% of total) 5 (15.2%) 40 (34.2%) 0.04
Rectal symptoms (%) 4 (12.1%) 51 (43.6%) <0.01
Martel-Laferrière V, et al. IAPAC. June 2-4, 2013. Miami, FL.
Simeprevir in Combination with Peginterferon/Ribavirin in
Patients Co-infected with HCV Genotype-1 and HIV-1
Primary Analysis of the C212 Study
Investigational, one-pill, once-daily,
oral HCV NS3/4A protease inhibitor
● Multigenotypic: antiviral activity in patients
infected with HCV G1, 2, 4, 5 and 61–4
● SMV is being investigated in both PR and
IFN-free combinations
● Phase III trials of SMV + PR in G1 HCV
mono-infected treatment-naïve patients and
relapsers to IFN-based treatment showed
SVR12 rates of approximately 80%5-7
● Safe & well tolerated
(~3,800 patients treated to-date)1. Reesink HW, et al. Gastroenterology. 2010;138:913–921;
2. Moreno C, et al. J Hepatology. 2012;56:1247–1253;
3. Fried MW, et al. Hepatology. 2013;58:1918-1929;
4. Zeuzem S, et al. Poster presented at EASL 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB-2998;
5. Manns M, et al. EASL 2013; April 24-28, 2013; Amsterdam, Netherlands. Oral Presentation;
6. Jacobson I, et al. EASL 2013; April 24-28, 2013; Amsterdam, Netherlands. Abstract 1425;
7. Lawitz E, et al. Presented at DDW; May 18-21, 2013; Orlando, FL. Abstract 869b.
15/12/2014
10
C212 Study DesignPhase III, Open-label, Single-arm, International Trial
● Primary endpoints: SVR12, safety and tolerability
● Secondary endpoints: virologic response at other time points, meeting RGT criteria* for
shortened treatment to 24 weeks, on-treatment failure and relapse rates
● Primary analysis: All patients included in the analysis (N=106) had completed 24 weeks of
treatment, or had reached the time point of the primary efficacy endpoint SVR12 (Week 60),
or discontinued prior to that point (for those on 48 weeks of treatment)
+After PR treatment;*RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Wk 4 and undetectable at Wk 12(measured using Roche COBAS TaqMan HCV/HPS assay, v.2)
Follow-up
Follow-up
PRSMV
150 mg/PR
PR● HCV treatment-naïve
● Prior relapse+
● Partial response
● Null response
● Cirrhotic patients (F4)
RGT*
Week12 24 36
Primary analysis
SMV 150 mg/PR
PRSMV
150 mg/PR
Follow-up
48 72
PR, peginterferon-α2a + ribavirin; RGT, response-guided treatment; SMV, simeprevir; SVR12, sustained virologic response 12 weeks’ after end of treatment.
Dieterich D, et al. Presented at CROI; March 3-6, 2014; Boston, MA. Abstract 24.
60
C212
SVR12 Primary Endpoint
7479
87
70
57
0
10
20
30
40
50
60
70
80
90
100
Overall Naïves Relapsers Partial Null
SV
R1
2 (
%)
78/106 42/53 13/15 7/10 16/28
SVR12, sustained virologic response 12 weeks after end of treatment
Dieterich D, et al. Presented at CROI; March 3-6, 2014; Boston, MA. Abstract 24.
15/12/2014
11
89
7167
72
0
10
20
30
40
50
60
70
80
90
100
G1b G1a G1a with Q80K G1a without Q80K
C212
SVR12 by HCV-1 G1 Subtype and Baseline NS3
Q80K Polymorphism
16/18 62/88 20/30 42/58
G, genotype; SVR12, sustained virologic response 12 weeks’ after end of treatment
Dieterich D, et al. Presented at CROI; March 3-6, 2014; Boston, MA. Abstract 24.
SV
R1
2 (
%)
Daclatasvir (BMS-052)
● NS5a inhibitor currently under investigation as part of a QD
(60 mg) STR regimen
● Dosing recommendations from ongoing clinical trials
(specific data not public)
– PI regimens: dose reduction � 30 mg QD• ATZ/r
– NNRTIs: increase dose � 90 mg QD• Efavirenz
– NRTIs: no dose adjustment � 60 mg QD• TDF
● Birth Control: Oral contraceptive efficacy is likely to be maintained
when combined with estrogen / progestin-containing OCP
● Hepatic impairment: dosing adjustments are not anticipated
http://clinicaltrials.gov. NCT02159352 Accessed June 25, 2012
Bifano M, et al. Presented at: AASLD; November 4-8, 2011; San Francisco, CA. Abstract 1340.
Bifano M, et al. Presented at: AASLD; November 4-8, 2011; San Francisco, CA. Abstract 1362.
Bifano M, et al. Presented at: CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 618.
15/12/2014
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Drug Interactions between Sofosbuvir and HIV
Antiretrovirals in Healthy Volunteers
Kirby B, et al. Presented at: AASLD; November 9-13, 2012; Boston, MA. Abstract 1877.
TFV = tenofovir
FTC = emtricitabine
EFV = efavirenz
RPV = rilpivirine
DRV = darunavir
RTV = ritonavir
RAL = raltegravir
Effect of Co-administration of Sofosbuvir on HIV ARVs
GM
R%
(9
0%
CI)
com
bin
ati
on
/alo
ne
200
TFV
150
100
50
0
FTC EFV RPV DRV RTV RAL
AUCtau
Cmax
Ctau
143%
70%
Sofosbuvir and Peginterferon Alfa-2a/Ribavirin
for Treatment-Naïve Genotype 1–4
HCV-Infected Patients Who Are Coinfected
With HIV
Rodriguez-Torres M, et al.. Poster presented at: IDWeek 2013; October 2-6, 2013; San Francisco, CA. Poster 714.
SVR24, SVR 24 weeks after end of treatment; SVR4, SVR 4 weeks after end of treatment
0Week 6 12 16 24 36
SOF 400 mg/d +
PEG 180 µg/wk/RBV
1000–1200 mg/d
GT 1–4
SVR4 SVR12
Primary endpoint
SVR24
Study design
15/12/2014
13
96 100 10091 91
Week 2 Week 4 EOT SVR4 SVR120
25
50
75
100
HC
V R
NA
<LLO
Q
(%)
Efficacy
● No on-treatment HCV virologic breakthrough
● 2 patients did not achieve SVR12:
– Patient 1: white Latino man aged 41 years with HCV GT 1a and IL28B TT GT,
who discontinued treatment after 6 weeks due to withdrawal of consent
– Patient 2: white Latino man aged 53 years with HCV GT 1a and IL28B CT GT,
who completed study treatment and subsequently relapsed
Rodriguez-Torres M, et al.. Poster presented at: IDWeek 2013; October 2-6, 2013; San Francisco, CA. Poster 714.
89 87100 100 100 100
1 1a 1b 2 3 40
25
50
75
100
HC
V R
NA
<LLO
Q
(%)
17/19 13/15 4/4 1/1 2/2 1/1
21/2321/2323/2323/2322/23
Virologic response and SVR
SVR12 by HCV GT
Sofosbuvir label
Sofosbuvir [Prescribing information]. Gilead Sciences, Inc. 2013.
15/12/2014
14
Sofosbuvir label
Sofosbuvir [Prescribing information]. Gilead Sciences, Inc. 2013.
GT 1- 4 HIV-HCV (PHOTON-1 and 2)
● PHOTON-1 and -2: GT 1, 2, 3 (US, EU, Australia)
● PHOTON-2: GT 4 (EU, Australia)
● Broad inclusion criteria– Targeted 20% enrollment of patients with compensated cirrhosis, no platelet cutoff
– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)
● Wide range of ART regimens allowed – Undetectable HIV RNA for ≥8 weeks, on stable ART regimen
● Baseline CD4 count– ART treated: >200 cells/mm3
– ART untreated: >500 cells/mm3
Wk 0 Wk 12 Wk 24 Wk 36
SOF + RBV (n=45) SVR12
SVR12GT 1, 3, 4 TN
GT 2, 3 TE
GT 2 TN
SVR12
SOF + RBV (n=314)
SOF + RBV (n=96)
GT 3 TN SOF + RBV (n=42) SVR12
Sulkowski MS, et al. JAMA. 2014;312:353-361.
Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.
15/12/2014
15
PHOTON-1 and 2
Demographics: ART Regimens
Regimen, n (%) Total (N=497)
On ART 477 (96)
Tenofovir DF (TDF) / emtricitabine (FTC) plus
Efavirenz (EFV) 143 (30)
Raltegravir (RAL) 97 (20)
Atazanavir (ATV) / ritonavir (RTV) 83 (17)
Darunavir (DRV) / ritonavir 90 (19)
Rilpivirine (RPV) 26 (5)
Other
3TC/DRV/RTV, DRV, DRV/RTV, DRV/RTV/TDF,
ATV/FTC/RAL/RTV, DRV/EFV/RTV, DRV/FTC/RAL/RTV,
DRV/RAL/RPV/RTV, DRV/RAL/RTV, DRV/RAL/RTV/TDF
20 (4)
Sulkowski MS, et al. JAMA. 2014;312:353-361.
Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.
8189
8484
0
20
40
60
80
100
Results: SVR12
GT 1-4 HIV-HCV (PHOTON-1 and 2)
182/226 67/75 138/165 26/31
SV
R1
2 (
%)
Sulkowski MS, et al. JAMA. 2014;312:353-361.
Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.
TN
GT 1
TN + TE
GT 2
TN + TE
GT 3
TN
GT 4
Relapse, n (%) 39 (17) 3 (4) 23 (14) 5 (16)
Breakthrough, n (%) 1 (0.4) 1 (1) 1 (0. 6) 0
Lost to follow-up, n (%) 2 1 2 0
Withdrew consent, n (%) 2 3 1 0
15/12/2014
16
Results: SVR12 in GT 1 and GT 4
Cirrhosis vs No Cirrhosis (PHOTON-1 and 2)
*1 patient could not be subtyped.
Treatment-Naïve
24 Weeks SOF + RBV
82 8567
83
6465
6088
0
20
40
60
80
100
GT 1 GT 1a GT 1b GT 4
SV
R (%)
No cirrhosis Cirrhosis
14/22 11/17 3/5168/204* 147/173 20/30 7/819/23
Sulkowski MS, et al. JAMA. 2014;312:353-361.
Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.
88 88
67
91 95100 10067
100
79
0
20
40
60
80
100
49/546/6
Results: SVR12 in GT 2 and GT 3
Cirrhosis vs No Cirrhosis (PHOTON-1 and 2)
GT 2 GT 3
38/43 21/24 24/36 3/3 23/292/2
TN
12 weeks
TE
24 weeks
4/6 35/37
Sulkowski MS, et al. JAMA. 2014;312:353-361.
Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.
No cirrhosis Cirrhosis
SV
R (%)
TN
12 weeks
TN
24 weeks
TE
24 weeks
15/12/2014
17
ERADICATE
Study Design
● Open label
– LDV 90mg / SOF 400 mg STR for 12 wks
● Treatment-naïve GT-1 patients without cirrhosis
● No ribavirin administered
Wk 0 Wk 12
GT 1
(N=13)
ARV Untreated
● CD4 count stable + HIV RNA <500 copies
or
● CD4 count >500 cells/mm3
ARV Treated
● CD4 count >100 cells/mm3
● HIV RNA <40 copies
● Current ARVs ≥8 weeks
GT 1
(N=37)
Wk 36
SVR 24
ARVs: TDF/FTC, EFV, RILP and RALT
Treatment Response – Week 4
100 100 100 100 100100 10097 97 97
Wk 4 EOT SVR4 SVR8 SVR12 VR120
20
40
60
80
100
% o
f p
ati
en
ts w
ith
HC
V R
NA
< L
LOQ
ARV untreated ARV treated
13/13 37/37 13/13 37/37 36/37 13/13 13/13 36/37 13/13 36/37 49/50
Overall 98%
15/12/2014
18
ION-4: Ongoing study of LDV/SOF
in HCV/HIV Co-infection
Inclusion criteria:
● HCV treatment naïve and experienced (including PI failures)
● HCV GT 1 and 4
● HIV-1 virologic suppression for at least 6 months prior to screening
● Stable, protocol approved ARV regimen for ≥ 8 weeks prior to screening
– FTC/TDF plus EFV or RPV or RAL
● CD4 T-cell count >100 cells/mm3 at screening and no opportunistic infection
within 6 months prior to screening
● US, Canada, New Zealand
12 24Study weeks
SVR 12
GT 1 and 4
HCV/HIV co-infection
Stable HIV disease
20% cirrhotics
N = 335
LDV/SOF STR
‡
Clinicaltrials.gov NCT02073656
Fully enrolled
Data due in 1Q 2015
SOF/LDV Drug Interaction ProfileCo-administration not recommended
a) Based on drug interaction studies or predicted interaction; this information is not all inclusive
b) Coadministration of SOF/LDV with these medications is expected to decrease concentrations of ledipasvir and sofosbuvir, leading to a reduced
therapeutic effect
c) These interactions have been studied in healthy adults
d) Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir
e) The safety of increased tenofovir concentrations in the setting of SOF/LDV and elvitegravir/cobicistat/emtricitabine/tenofovir DF has not been
established
f) Coadministration of SOF/LDV with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased
risk of myopathy, including rhabdomyolysis
Cross-Discipline Team Leader Review NDA 205834 (ledipasvir/sofosbuvir)
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000CrossR.pdf. Accessed November 18, 2014.
Co-administration of SOF/LDV with the following drugs is not recommended
Anticonvulsantsb carbamazepine, phenytoin, phenobarbital, oxcarbazepine
Antimycobacterialsb rifabutin, rifampin,c rifapentine
HCV product simeprevirc,d
Herbal supplement St. John’s wortb
HIV antiretrovirals elvitegravir / cobicistat / emtricitabine / tenofovir DF,e
tipranavir / ritonavirb
Statin rosuvastatinf
15/12/2014
19
Concomitant drug class
Drug nameClinical comments
Acid reducing agentsLedipasvir solubility decreases as pH increases. Drugs that increase gastric pH are
expected to decrease concentration of ledipasvir
Antacids
(e.g., aluminum and magnesium hydroxide)It is recommended to separate antacid and SOF/LDV administration by 4 hrs
H2-receptor antagonistsb
(e.g., famotidine)
H2-receptor antagonists may be administered simultaneously with or 12 hours
apart from SOF/LDV at a dose that does not exceed doses comparable to
famotidine 40 mg twice daily
Proton-pump inhibitorsb
(e.g., omeprazole)
Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be
administered simultaneously with SOF/LDV under fasted conditions
Antiarrhythmics: digoxin
Coadministration of SOF/LDV with digoxin may increase the concentration of
digoxin. Therapeutic concentration monitoring of digoxin is recommended when
coadministered with SOF/LDV
HIV Antiretroviralsc
Efavirenz/emtricitabine/tenofovir DF
Regimens containing TDF + PI/r, including
● ATV/r + TDF/FTC b
● DRV/r + TDF/FTC b
● LPV/r + TDF/FTC
Monitor for TDF-associated adverse reactions in patients receiving SOF/LDV
concomitantly with EFV/ FTC / TDF
The safety of increased TDF concentrations in the setting of SOF/LDV and an HIV
PI/r has not been established. Consider alternative HCV or ART to avoid increases
in TDF exposures. If co-administration is necessary, monitor for TDF-associated
adverse reactions.
a) Based on drug interaction studies or predicted interaction; this information is not all inclusive. b) These interactions have been studied in healthy adults.c) Refer to the appropriate prescribing information for recommendations on renal monitoring with these medications.
SOF/LDV Drug Interaction ProfileOther potentially significant drug interactionsa
Cross-Discipline Team Leader Review NDA 205834 (ledipasvir/sofosbuvir)
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000CrossR.pdf. Accessed November 18, 2014.
SOF/LDV Drug Interaction ProfileNo clinically significant interactions
● Antiretrovirals
– abacavir
– atazanavir/ritonavira
– darunavir/ritonavira
– efavirenz
– emtricitabine
– lamivudine
– raltegravir
– rilpivirine
– tenofovir DF
● Immuno-suppressants
– cyclosporine
– tacrolimus
● Opioid
– methadone
● Oral contraceptives
● Statin
– pravastatin
● Calcium channel blocker
– verapamil
aWhen not used in combination with tenofovir DF
No clinically significant drug interactions (observed or expected)
when SOF/LDV is used with the following drugs individually
Cross-Discipline Team Leader Review NDA 205834 (ledipasvir/sofosbuvir)
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000CrossR.pdf. Accessed November 18, 2014.
15/12/2014
20
C-WORTHY Study DesignHCV Mono- and HIV/HCV Co-infected Non-cirrhotic Patients
1a+1b
1a+1b
1a+1b
D1 TW12 SVR12TW4 TW8 SVR24
1aN=30Grazoprevir + Elbasvir(50 mg) + RBV
Follow-up
N=29Grazoprevir + Elbasvir (50 mg)+ RBV
Follow-up
HCV
Sub-GT
1a+1b
Mo
no
-in
fect
ed
N=
15
9
Co
-in
fect
ed
N=
59
N=85Grazoprevir + Elbasvir (20 or 50 mg) + RBV
Follow-up
N=44Grazoprevir + Elbasvir (50 mg)No RBV
Follow-up
N=30Grazoprevir + Elbasvir (50 mg) No RBV
Follow-up
80 93 98 97 87
0
20
40
60
80
100
SV
R1
2 (
%)
24
30
43
44
79
85
26
30
28
29
C-WORTHY Primary Efficacy results SVR12; ITT
HCV Mono-infected HIV/HCV Co-infected
Treatment duration 8 weeks 12 weeks 12 weeks 12 weeks 12 weeks
RBV + RBV + RBV No RBV + RBV No RBV
LTFU* or discontinued
early not due to VF1 3 0 0 2
Breakthrough 0 1† 0 0 2
Relapse 5 2‡ 1 1 0
* LTFU=Lost to follow-up
† Breakthrough was due to HCV GT2b (minor GT2b variant at baseline)‡ One of the patients who relapsed did not receive grazoprevir and only received only elbasvir + RBV for the first
month of treatment
Only
GT1a
15/12/2014
21
95 9292 95
+ RBV No RBV0
20
40
60
80
100
SV
R1
2 (
%)
GT1a
GT1b
SVR12 RATE by subtype AND RIBAVIRIN 12 week regimens
● This figure combines mono- and co-infected patients who received 12 weeks of
treatment with grazoprevir + elbasvir with or without RBV
● It excludes 2 patients who had HCV subtypes that were not GT1a or GT1b and
30 patients who were in the 8 week, mono-infected arm
72
76
33
36
48
52
21
22
SVR12 Rates in Subgroup Analysis*
* 12 week arms only
Co-inf. Mono-inf.Subgroup
GT1b
GT1a
Female
Male
>50 years
≤50 years
IL28B Non-CC
IL28B CC
HCV RNA >2 million
HCV RNA ≤2 million
Overall SVR12=94%
50 60 70 80 90 100
% SVR12 (Mean; 95% CI)
N
4682
1345
4763
1266
1770
4259
40100
1928
3767
2262
15/12/2014
22
TURQUOISE-IPart 1 Study Design (N = 63)
● 3D: coformulated parataprevir/r/ombitasvir, 150 mg/100 mg/25
mg QD; dasabuvir, 250 mg BID
● RBV: 1000 or 1200 mg daily according to body weight in 2 divided
doses (<75 kg and ≥75 kg, respectively)
Day 1 Week 12 Week 24
Open-label treatment SVR12
All patients will be followed
for 48 weeks
after HCV treatment end3D + RBV
(N = 31)
3D + RBV
(N = 32)
SVR4
Week 36
Sulkowski MS, et al. Presented at: AIDS 2014; July 20-25, 2014; Melbourne, Australia. Abstract MOAB0104LB.
Paritaprevir (ABT-450)
10096.8
93.593.5
10096.9 96.9
RVR
(Week 4)
EOTR
(Week 12 or 24)
SVR4 SVR120
20
40
60
80
100
% p
ati
en
ts
12-week 3D + RBV 24-week 3D + RBV
TURQUOISE-1 ResultsITT Virologic Response Rates
Adapted from the Trinh presentation at HIV Glasgow on 4th November 2014
* 2 patients in the 24-week group had recurrence of HCV viremia, believed to be due to HCV reinfection
31/31 32/32 30/31 31/32 29/31 31/32 29/31
*
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23
TURQUOISE-1 ResultsIntent-to-Treat SVR12 Rates
93.5 90.6
Overall0
20
40
60
80
100
SV
R1
2,
% p
ati
en
ts
12-week 3D + RBV 24-week 3D + RBV
Adapted from the Trinh presentation at HIV Glasgow on 4th November 2014
29/31 29/32
TURQUOISE-1 ResultsIntent-to-Treat SVR12 Rates
93.5 93.890.6100
Overall Atazanavir0
20
40
60
80
100
SV
R1
2,
% p
ati
en
ts
12-week 3D + RBV 24-week 3D + RBV
Adapted from the Trinh presentation at HIV Glasgow on 4th November 2014
29/31 29/32 15/16 12/12
15/12/2014
24
TURQUOISE-1 ResultsIntent-to-Treat SVR12 Rates
93.5 93.8 93.390.6100
85
Overall Atazanavir Raltegravir0
20
40
60
80
100
SV
R1
2,
% p
ati
en
ts
12-week 3D + RBV 24-week 3D + RBV
Adapted from the Trinh presentation at HIV Glasgow on 4th November 2014
* 2 patients in the 24-week group had recurrence of HCV viremia, believed to be due to HCV reinfection
29/31
*
29/32 15/16 12/12 14/15 17/20
Real-world Data on HIV Patients with HCV G 1,2
and 3 Treated with Sofosbuvir- and/or
Simeprevir-containing Regimens
Mount Sinai Health System
● Total n = 80
● The vast majority (84%) had genotype 1
– 52/67 (77%) had genotype 1a
– 15/67 (22%) had genotype 1b
● Seven out of 80 (9%) had genotype 2
● Six out of 80 (8%) had genotype 3
● 34 (43%) patients received treatment with SMV/SOF +/- RBV
● 46 (57%) patients received treatment with SOF/RBV for 12 or 24 wks
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25
Categorical: n (%)
Continuous: median (IQR)
Gender, male 67 (84%)
Age 57 (52–61)
Race, black 20 (25%)
Ethnicity, Hispanic 30 (38%)
BMI >25 49 (61%)
History of diabetes 13 (16%)
History of hypertension 40 (50%)
History of depression prior to treatment 30 (28%)
Baseline characteristics Co-infected patients
Categorical: n (%)
Continuous: median (IQR)
Baseline HCV viral load, log IU/mL 6.31 IU/mL (IQR: 5.9X-6.7X IU/mL)
IL28B non-CC genotype 19/25 (70%)
Q80K mutation 2/4 (50%)
Treatment experienced
PEG-Interferon/ribavirinNon-responder
Partial responder
Relapser
Unknown response
PEG-Interferon alone
Telaprevir/PEG/RBV
Boceprevir/PEG/RBV
46/79 (58%)
36/46 (78%)10/36 (28%)
12/36 (33%)
9/36 (25%)
5/36 (14%)
1/79 (1%)
6/79 (8%)
3/79 (4%)
Cirrhosis, FibroScan >12.5 kPa 21/35 (60%)
Cirrhosis, biopsy 4/18 (22%)
FIB-4 score ≥3.25 41/80 (51%)
History of hepatocellular carcinoma 6/80 (8%)
History of liver transplant 2/80 (3%)
HCV Baseline Characteristics
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26
36
9285
28
95 92
Week 2 SVR4 rate SVR12 rate0
20
40
60
80
100
% u
nd
ete
cta
ble
Mono-infected
Co-infected
Week 2, SVR4, and SVR12 results are similar between
mono- and co-infected patients receiving SMV/SOF ± RBV
54/148 7/25 117/127 21/22 82/96 11/12
p=0.35
p=1.00 p=1.00
Cirrhosis among the SMV/SOF patients
● 19/34 (54%) genotype 1 patients receiving SMV/SOF +/- RBV
had cirrhosis based on FIB-4 score
● An additional 4 patients had cirrhosis based on Fibroscan
score ≥13.5 kPa and/or liver biopsy
● In all, 23/34 (67%) of SMV/SOF patients had cirrhosis
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27
SVR4 and SVR12 results for co-infected patients
receiving SMV/SOF ± RBV with and without
cirrhosis
9/10
(90%) 4/5
(80%)
12/12
(100%)
7/7
(100%)90
80
100 100
SVR4 SVR120
20
40
60
80
100
Pe
rce
nta
ge
(%
)
Non-cirrhotic
Cirrhotic
9/10 12/12 4/5 7/7
Conclusions
● HCV is a ticking time bomb for both Baby Boomers and our
health care system with and without HIV
● New medications of different classes will be approved within
months and more are coming
● The new DAAs have astonishingly high cure rates
● The cure rates in HIV patients are exactly the same in clinical
trials but are actually better in real life settings
● The only caveat is DDI’s with HIV medications
● Will we be able to treat enough patients in time to avert the
looming health care catastrophe?