A combination of two experimental direct-acting antivirals developed
by AbbVie cured 93 to 97% of people with genotype 3 hepatitis C infection after
a 12-week course of treatment, Paul Kwo of Indiana University School of Medicine
reported on Monday at the 2015 AASLD Liver Meeting in San Francisco.
Genotype 3 infection is associated with an increased risk of
fibrosis progression and liver cancer (hepatocellular carcinoma) compared to
other genotypes, making affordable and effective treatment options for this
group of patients an important unmet need.
Genotype 3 hepatitis C infection is more difficult to cure
than other genotypes of hepatitis C, requiring a longer course of treatment
with most regimens. The only currently approved 12-week interferon-free regimen for treatment
of genotype 3 consists of daclatasvir (Daklinza)
and sofosbuvir (Sovaldi). Almost 30%
of worldwide hepatitis C infections are estimated to be genotype 3, with a
particular concentration in the Indian sub-continent and among populations of
Indian origin living elsewhere. Genotype 3 is also widespread in the Russian
Federation, Scandinavia, Thailand, Brazil and Australia.
The SURVEYOR-2 study assessed the effectiveness and safety
of two experimental next-generation direct-acting antivirals, with or without
ribavirin, at different doses. ABT-493 is an HCV NS3/4A protease inhibitor
active against all genotypes of hepatitis C. ABT-530 is a NS5A inhibitor also
active against all genotypes of HCV. Both agents are active against common
variants that confer resistance to first-generation agents of their classes.
ABT-493 is more potent against genotype 3 than other HCV protease inhibitors, including
products being developed by Merck (grazoprevir) and Gilead (GS-9451), and
ABT-530 has demonstrated higher potency than most other NS5A inhibitors across
all genotypes.
The SURVEYOR-2 study recruited 120 people with genotype 3
infection, who were randomised to one of four 12-week regimens:
- ABT-493 (300mg) and ABT-530 (120mg)
- ABT-493 (200mg) and ABT-530 (120mg)
- ABT-493 (200mg) and ABT-530 (120mg) and
ribavirin
- ABT-493 (200mg) and ABT-530 (40mg)
All agents were dosed once daily.
The study recruited previously untreated people or previous
null responders to pegylated interferon and ribavirin, with no evidence of
cirrhosis. There was some variation across study arm in demographic
characteristics, notably in the proportion of men (48 to 63%) and F3 fibrosis (10 to 23%). The mean HCV viral load ranged from 6.3 to 6.7 log10/IU/ml
across the four study arms.
Twelve weeks after the completion of treatment, rates of
sustained virological response (SVR12) ranged from 83% in the ABT-493 (200mg)
and ABT-530 (40mg) arm to 93% in the two remaining ribavirin-sparing arms and
94% in the ribavirin-containing arm. In a per-protocol analysis which excluded
non-virological failures, sustained virological response rates were highest
(97%) in the ABT-493 (300mg) and ABT-530 (120mg) arm and in the
ribavirin-containing arm. A single on-treatment viral breakthrough occurred in
both the ribavirin arm and the ABT-493 (200mg) and ABT-530 (40mg) arms, leading
researchers to conclude that ABT-493 300mg and ABT-530 120mg were most likely
to prevent viral breakthrough. This dose will now be taken forward in further
studies in patients with cirrhosis and as a shorter, 8-week treatment course in patients without cirrhosis.
The number of treatment-experienced participants in the
study was very low due to the exclusion of people who had taken direct-acting
antivirals in addition to pegylated interferon and ribavirin, and so it is
difficult to draw meaningful conclusions.
Two severe drug-related adverse events were reported: one
case of decreased haemoglobin in the ribavirin-containing arm and one increase
in creatine phosphokinase (CPK) in the ABT-493 (300mg) and ABT-530 (120mg) arm.
Commonly reported side effects were fatigue, headache and nausea, and most
adverse events were mild or moderate. Laboratory abnormalities were most
frequently reported in the ribavirin group (three cases of grade 2 haemoglobin
decrease).