Efficacy of Combined Sofosbuvir and

Daclatasvir in Treating Hepatitis C Patients

H.A. SOEFYANI
Departemen Ilmu Penyakit Dalam
Divisi Gastro Hepatologi
Fakultas Kedokteran ULM
RSUD ULIN Banjarmasin
HCV Global Infection: Iceberg phenomena

Diagnosed with Chronic

Hep C

<10 %
Treated
symptomatic
 About 170 million people are
infected
> 90%
asymptomatic  315.000 new cases / year
 Hepatocellular carcinoma due
to HCV infection accounts for
Undiagnosed 4.1% of all carcinoma cases
 312.000 died due to HCV /year
(Sulaiman A, Selayang pandang Hepatitis C, 2004
 Disease progression in hepatitis C:
person-to-person variability
(Slow)

≥30 years after infection

Female sex, young age
Rate of disease progression

Decompensation
(~20%)

HCC
Normal Acute Chronic Chronic Cirrhosis (1–4% per
liver infection infection hepatitis (20%) year)
(80%)

Infection Stable Slowly progressive

resolves hepatitis (~75%)
spontaneously (80%)
(20%)
(Fast)

20 years after infection

Alcohol use, co-infection with HIV or hepatitis B virus

HCC = hepatocellular carcinoma Lauer G & Walker B. N Engl J Med 2001; 345: 41
 Hepatitis C is Global Problem

Distribusi Geografis Genotipe HCV:

1a, 1b
2a, 2b, 2c,
1a, 1b 3a 2a 1b
2a, 2b, 4 1b,
3a 1b,
6
4 3a
3b
1a, 1b,
2b, 3a
5a 1b,
Indonesia: 3a
1a+1b: 60 – 65%
2a: 17 – 26%

Fang JWS et al. Clin Liver Dis. 1997;1:493-514.

Reported Hepatitis C Cases in Indonesia

Hepatitis C prevalence
in Indonesia based on
National surveillance
Program: 1% - 2%
Hepatitis C can be Cure
Characteristics of HCV antiviral classes

Antiviral Genotype Resistance FDA

Class Potency Activity barrier Approved
Simeprevir
(2013)
NS3 Protease Low to Paritaprevir
+++ to ++++ 1 (and 4) moderate (2014)
Inhibitors Telaprevir
Boceprevir
(2011)

NS5B Sofosbuvir
++ to ++++ 1-6 Very High
Nucleoside/tide (2013)

NS5B Dasabuvir
++ to +++ 1 Low
Non-nucleoside (2014)

Ledipasvir
1, 4-6 Ombitasvir
NS5A Inhibitors ++++
(+/- 2,3)
Very Low (2014)
Daclatasvir
(2015)
Always combine DAAs with different targets

Combined with

Sofosbuvir-based: + Ribavirin
+ Ledispavir
+ Simeprevir
+ Daclatavir
+ Veltaspavir

Non-sofosbuvir based Ombitasvir/paritaprevir/ritonavir + dasabuvir

Ombitasvir/paritaprevir/ritonavir

Elbasvir/grazoprevir
 TERAPI DAA: TANPA SIROSIS

PegIFN, PegIFN, PegIFN, SOF, SOF/ SOF, SOF, ELB/ SOF/

GT RBV RBV,SOF RBV,SIM RBV LED DAC SIM GRA VEL

12**
1 12 24-48* ? 12 12 12
16 (+RBV)***
12

2 12 - 12 12 12 - - 12

3 Response 12 - 24 - 12 - - 12
guided
12
4 12 24-48* ? 12 12 12
16 (+RBV)***
12

5 12 - ? 12 12 - - 12

6 12 - ? 12 12 - - 12
 TERAPI DAA: SIROSIS KOMPENSATA
PegIFN, PegIFN
PegIFN, SOF, SOF/ SOF, SOF, ELB/ SOF/
GT RBV, RBV,
RBV RBV LED DAC SIM GRA VEL
SOF SIM

12 (+RBV) 12 (+RBV) 12 (+RBV) 12**

1 12 24-48* ? 24 (-RBV) 24 (-RBV) 24 (-RBV) 16 (+RBV)***
12

2 12 - 16-24 12 12 - - 12
24
3 12 - 24 - - - 12 (+RBV)
(+/- RBV)

Response 12 (+RBV) 12 (+RBV) 12 (+RBV) 12**

4
guided
12 24-48* ? 24 (-RBV) 24 (-RBV) 24 (-RBV) 16 (+RBV)***
12

12 (+RBV) 12 (+RBV)
5 12 - ? 24 (-RBV) 24 (-RBV)
- - 12

12 (+RBV) 12 (+RBV)
6 12 - ? 24 (-RBV) 24 (-RBV)
- - 12
 Monitoring Respons Terapi
Peg-IFN/ribavirin
Initiation
of 12th End of
therapy Week Therapy(EOT)

4th week 24th 24 week

week after
Therapy

DAAs

Initiation of therapy

12 week after therapy

Treatment-Naïve and Treatment-Experienced

Daclatasvir + Sofosbuvir +/- Ribavirin in Genotype 1-3

AI444040 Trial

Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

Hepatitis
web study
 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
Trial: Study Features

Daclatasvir + Sofosbuvir Trial: Features

 Design: Randomized, open label, phase 2a, using declatasvir + sofosbuvir +/-
ribavirin in treatment naive or experienced, chronic HCV GT 1-3
 Setting: United States
 Entry Criteria
- Chronic HCV Genotype 1, 2, or 3
- Treatment naïve or treatment experienced
- No evidence of cirrhosis
 Patient Groups
- N = 211 total received treatment
- N = 44 Rx naïve with GT1: DCV+ SOF +/- RBV x 24 weeks
- N = 44 Rx naïve patients with GT 2 or 3: DCV+ SOF +/- RBV x 24 weeks
- N = 123 Rx naïve or experienced with GT 1: DCV+ SOF +/- RBV x 12 weeks
 End-Points: Primary = SVR12

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
Trial Design: Treatment-Naïve 24 Week Rx
Week 0 12 24 36

n = 16 SOF × 7 days, then DCV + SOF SVR12

Rx Naïve
GT 2 or 3 n = 14 DCV + SOF SVR12

n = 44
n = 14 DCV + SOF + RBV SVR12

n = 15 SOF × 7 days, then DCV + SOF SVR12

Rx Naïve
GT 1a/1b n = 14 DCV + SOF SVR12

n = 44
n = 15 DCV + SOF + RBV SVR12

Drug Dosing
Daclatasvir
N =14 (DCV): 60 mg once daily
Sofosbuvir (SOF): 400 mg once daily
Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)
Ribavirin (RBV): GT 2,3 (800 mg/day)

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
Design: GT1 Treatment-Naïve & Experienced 12 Week Rx
Week 0 12 24

Rx Naïve n = 41 DCV + SOF SVR12

GT 1a/1b

n = 82 n = 41 DCV + SOF + RBV SVR12

Rx Experienced
GT 1a/1b n = 21 DCV + SOF SVR12
Prior Boceprevir- or
Telaprevir failure
n = 20 DCV + SOF + RBV SVR12
n = 41
Drug Dosing
Daclatasvir
N =14 (DCV): 60 mg once daily
Sofosbuvir (SOF): 400 mg once daily
Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)
Ribavirin (RBV): GT 2,3 (800 mg/day)

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
Treatment-Naïve 24 Week Rx: Results
Week 0 12 24 36

n = 16 SOF × 7 days, then DCV + SOF SVR12 = 88%

Rx Naïve
GT 2 or 3 n = 14 DCV + SOF SVR12 = 93%

n = 44 n = 14 DCV + SOF + RBV SVR12 = 86%

n = 15 SOF × 7 days, then DCV + SOF SVR12 = 100%

Rx Naïve
GT 1a/1b n = 14 DCV + SOF SVR12 = 100%

n = 44 n = 15 DCV + SOF + RBV SVR12 = 100%

Drug Dosing
Daclatasvir
N =14 (DCV): 60 mg once daily
Sofosbuvir (SOF): 400 mg once daily
Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)
Ribavirin (RBV): GT 2,3 (800 mg/day)

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
Treatment-Naïve 12 Week Rx: Results

Treatment-Naïve: GT 2 or 3 Treatment-Naïve: GT 1a or 1b

DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
GT1 Treatment-Naïve & Experienced 12 Week Rx: Results
Week 0 12 24

Rx Naïve n = 41 DCV + SOF SVR12 = 100%

GT 1a/1b

n = 82 n = 41 DCV + SOF + RBV SVR12 = 100%

Rx Experienced
GT 1a/1b n = 21 DCV + SOF SVR12 = 90%
Prior Boceprevir- or
Telaprevir failure
n = 20 DCV + SOF + RBV SVR12 = 95%
n = 41
Drug Dosing
Daclatasvir
N =14 (DCV): 60 mg once daily
Sofosbuvir (SOF): 400 mg once daily
Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)
Ribavirin (RBV): GT 2,3 (800 mg/day)

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

 Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
GT1 Treatment-Naïve & Experienced 12 Week Rx: Results

Treatment-Naïve: GT 1a or 1b Treatment-Experienced: GT 1a or 1b

DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

Phase 3

Treatment-Naïve and Treatment-Experienced

Daclatasvir + Sofosbuvir in HCV GT 1-4 and HIV Coinfection

ALLY-2 Study

Wyles DL, et al. N Engl J Med. 2015 July 21. [Epub ahead of print]

Hepatitis
web study
 Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection
ALLY-2 Trial: Study Features

ALLY-2: Features
 Design: Phase 3, open-label study of daclatasvir (DCV) plus sofosbuvir (SOF)
in treatment-naïve or experienced, chronic HCV GT 1-4 and HIV coinfection
 Setting: Multiple centers in the United States
 Entry Criteria
- Chronic HCV Genotype 1 through 4
- Treatment-naïve or treatment experienced
- Noncirrhotic or compensated cirrhosis (less than 50%)
- Stable ARV with HIV RNA < 50 copies/ml at screening and <200 copies/ml
for ≥8 weeks; and CD4 count > 100 cells/mm3
- ARVs allowed: tenofovir, emtricitabine, abacavir, lamivudine, zidovudine,
darunavir-ritonavir, atazanavir-ritonavir, lopinavir-ritonavir, efavirenz,
nevirapine, rilpivirine, dolutegravir, raltegravir, enfuvirtide, maraviroc
 End-Points: Primary = SVR12

Source: Wyles DL, et al. N Engl J Med. 2015 July 21. [Epub ahead of print]
 Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection
ALLY-2 Trial: Design
Week 0 8 12 20 24

Treatment-Naïve
N = 101 Daclatasvir + Sofosbuvir SVR12

Treatment-Naïve
N = 50 Daclatasvir + Sofosbuvir SVR12

Treatment-Experienced
N = 52
Daclatasvir + Sofosbuvir SVR12

Drug Dosing
Daclatasvir: 60 mg once daily; with efavirenz and nevirapine the dose was increased to 90 mg once daily and
with ritonavir-boosted protease inhibitors the dose was decreased to 30 mg once daily
Sofosbuvir: 400 mg once daily

Source: Wyles DL, et al. N Engl J Med. 2015 July 21. [Epub ahead of print]
 Resume

• DAA is a breakthrough for Treatment

Hepatitis C Patients
• Sofosbuvir+ Daclatasvir can be used for
All Genotype
• Sofosbuvir+ Daclatasvir generic Version is
available from 2016 in Indonesia