An interferon-free regimen of sofosbuvir, daclatasvir and ribavirin for
12 weeks produced sustained response rates of 83% for people with hepatitis C virus (HCV) who had
advanced liver cirrhosis and 94% for people who had received liver transplants,
with similar cure rates for those with hard-to-treat HCV genotype 3, according
to findings from the ALLY-1 study presented at a late-breaker session on
Saturday at the European Association for the Study of the Liver (EASL) 50th
International Liver Congress in Vienna, Austria. More than half of study
participants with the most severe decompensated cirrhosis achieved sustained
The advent of direct-acting antiviral agents that can be used in
interferon-free regimens has brought about a revolution in treatment for
chronic hepatitis C, but there is still a need for better therapeutic options
for groups with difficult-to-treat hepatitis including people with HCV genotype
3, people with advanced liver disease and liver transplant recipients.
Bristol-Myers Squibb's phase 3 ALLY trials
interferon-free regimen containing the company's HCV NS5A inhibitor daclatasvir
(Daklinza) plus Gilead Sciences’ HCV NS5B
polymerase inhibitor sofosbuvir (Sovaldi)
in people with hepatitis C who have high unmet needs. ALLY-1 enrolled people
with advanced liver cirrhosis and transplant recipients with HCV genotypes 1-6,
ALLY-2 enrolled people with HIV and HCV co-infection with HCV genotypes 1-6 (recently presented at the 2015 Conference on Retroviruses and
Opportunistic Infections) and ALLY-3 focused on people with HCV genotype 3 (presented at the 2014 AASLD Liver Meeting).
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
A disease or infection affecting the brain.
Sofosbuvir and daclatasvir
are pangenotypic, meaning they are active against multiple HCV genotypes.
Gilead’s NS5A inhibitor ledipasvir (combined with sofosbuvir in the Harvoni coformulation), in contrast, has
minimal activity against genotype 3. Daclatasvir is approved in the European Union
and Japan, and has been submitted for approval from the US Food and Drug
As described by Fred Poordad of the University of Texas Health Science
Center, ALLY-1 enrolled 60 people
with hepatitis C and advanced liver cirrhosis and 53 people who experienced HCV
recurrence after liver transplantation.
Overall, about 65% of
participants were men, almost all were white, about a third were
Hispanic/Latino and the median age was approximately 58 years. About 60% had
previously been treated for hepatitis C. A majority (about 58%) had HCV
genotype 1a and about 19% had 1b. In addition, five people with cirrhosis had
genotype 2, six people with cirrhosis and 11 transplant recipients had genotype
3, four people with cirrhosis had genotype 4 and one transplant recipient had
The people with advanced cirrhosis
were divided into subgroups based on Child-Pugh class, an index of liver
disease severity and prognosis based on bilirubin and albumin levels, blood
clotting capacity and presence of ascites (abdominal fluid accumulation) or
hepatic encephalopathy (brain impairment). Twelve were Class A, 32 were Class B
and 16 were the most severe Class C. Most people in Class A or B had MELD
scores less than 15 (another measure of liver disease severity), while half in Class
C had a MELD score of 16-20 and a quarter had scores above 21. Sixty per cent of
people in Class B and all the participants in Class C had ascites and/or
encephalopathy – symptoms of liver decompensation. Six had hepatocellular
carcinoma (liver cancer).
In the post-transplant
cohort, 43% had absent to moderate liver fibrosis (Metavir stage F0-F2), 25%
had advanced fibrosis (stage F3) and 30% had cirrhosis (stage F4). They had
undergone transplantation at least three months prior, had no evidence of graft
rejection at enrolment and could be taking any immunosuppressant regimen.
All participants in this open-label study received 400mg
once-daily sofosbuvir, 60mg once-daily daclatasvir and ribavirin for 12 weeks.
Ribavirin was started at a dose of 600mg/day, which could be adjusted based on
tolerability. People in the cirrhosis cohort who interrupted therapy to undergo
a liver transplant could receive 12 additional weeks of extended therapy post-transplantation.
Overall, 83% of the people with advanced cirrhosis and
94% of the post-transplant participants achieved SVR12, or HCV RNA below the
lower limit of quantification (<25 IU/ml) at 12 weeks post-treatment
(SVR12). Looking just at the people with genotype 1, the corresponding cure
rates were 82% and 95%.
All but one of the 13 people who did not achieve
SVR12 relapsed after the end of treatment. People who relapsed are now being
re-treated with the same regimen for 24 weeks.
Breaking down the
advanced cirrhosis cohort further by genotype, SVR12 rates were 76% for subtype
1a, 100% for 1b, 80% for genotype 2, 83% for genotype 3 and 100% for genotype
4. In the post-transplant cohort, response rates were consistently high: 97%
for 1a, 90% for 1b, 91% for genotype 3 and 100% for the sole participant with
Looking at other
factors associated with response in the cirrhosis cohort, SVR12 rates were 92%
and 94% for CP Class A and B, but fell to 56% for Class C. This difference was
largely driven by low albumin levels, Poordad said. SVR12 rates did not differ significantly according
to demographic factors, prior treatment experience or baseline HCV RNA level.
Changes in MELD score were inconsistent, with little
change in the Class A group, and more improvement than worsening in the Class B
and C groups – including a few large declines among people with Class C. Four
of the people with cirrhosis who had hepatocellular carcinoma received a liver
transplant during treatment (including one from a donor with HCV) and all achieved
Treatment was generally safe and well-tolerated despite
advanced liver disease. The most common adverse events were headache, fatigue,
anaemia, diarrhoea and nausea. Ten people with cirrhosis and five transplant
recipients experienced serious adverse events, but none were deemed related to
the study drugs. One person with cirrhosis and one transplant recipient stopped
all treatment due to adverse events, but both nonetheless achieved SVR12. Transplant
recipients did not require modification of their immunosuppressant regimen due
to drug interactions and there were no cases of graft rejection or hepatic
"The 12-week pangenotypic regimen of
daclatasvir with sofosbuvir and ribavirin is generally safe, well-tolerated and
efficacious in HCV patients with advanced cirrhosis and post-liver transplant
recurrence," the researchers concluded. "ALLY-1 demonstrates that 12
weeks of daclatasvir + sofosbuvir + ribavirin yields high SVR rates in advanced
cirrhotic and post-transplant genotype 3 patients."
Poordad raised the
possibility that people with advanced cirrhosis might see enough improvement in
their MELD scores with treatment to lower their eligibility for
transplantation, but not enough to no longer need a new liver. "I worry we
may do more harm than good," he cautioned. Further research is needed to identify which CP
Class C patients are most likely to benefit from treatment.
EASL hepatitis C treatment guidelines released at the Liver Congress include
sofosbuvir plus daclatasvir, with or without ribavirin, as a recommended
regimen for people with HCV genotype 3.