A combination of two direct-acting antivirals developed by
Bristol-Myers Squibb (BMS) cured 90% of previously untreated people with genotype 1b hepatitis C
infection in 24 weeks, without the need for pegylated interferon or ribavirin,
Prof. Michael Manns of Hannover Medical School, Germany, reported at the 49th
Annual Meeting of the European Association for the Study of the Liver (EASL) in London last
The interferon- and ribavirin-free regimen combined the NS5A
inhibitor daclatasvir and the protease inhibitor asunaprevir. The combination is
already undergoing regulatory review in Japan and the United States for the
treatment of genotype 1b infection. The two drugs are also being tested
alongside a third agent, the non-nucleoside NS5b polymerase inhibitor
BMS-791325, in two phase III studies.
Genotype 1b is the predominant form of hepatitis C in eastern
Europe (including Russia), Turkey and southern Europe, especially Italy.
Although considered easier to treat than its counterpart genotype 1, which is
more common in north America, genotype 1b has until now required
interferon-based treatment to cure it. Genotype 1b also predominates in Japan
Along with Gilead’s sofosbuvir/ledipasvir combination, the
new BMS combination is the first hepatitis C regimen for genotype 1b that omits
both pegylated interferon and ribavirin. Pegylated interferon is poorly
tolerated by the majority of people with hepatitis C, especially those with
advanced liver disease. People lacking a favourable genetic profile (the IL28B 'CC' gene) have a poorer response to interferon-based treatment. The majority of patients taking
ribavirin develop anaemia during treatment, and some may have to discontinue
treatment as a result.
The phase III HALLMARK-Dual study presented at EASL
recruited 305 previously untreated patients, 205 previous non-responders and
235 patients who were ineligible for interferon treatment due to advanced fibrosis
or cirrhosis, depression or neutropenia, as well as treatment-experienced
patients unable to tolerate further interferon-based treatment.
Participants received daclatasvir (60mg once daily) and
asunaprevir (100mg twice daily) for 24 weeks. 102 previously untreated patients
were randomised to receive placebo treatment for 12 weeks, followed by 24 weeks
of daclatasvir and asunaprevir. The primary outcome of the study was the
proportion of participants who achieved sustained virologic response 12 weeks after
completing treatment (SVR12).
The median age of study participants ranged from 55 in the
treatment-naive arm to 60 in the interferon-intolerant arm. Between 58 and 72%
of study participants were Caucasian by study arm, while between 22 and 32%
were Asian. Sixteen per cent of treatment-naive participants had cirrhosis, as did 31% of
previous non-responders and 47% of interferon-intolerant patients.
Omitting the placebo from the virological response analysis,
90% of previously untreated patients achieved SVR12, compared to 82% of
previous non-responders and 82% of interferon-intolerant patients. There was no
difference in response rate between previous null- and partial-responders but
there was a substantial difference in response according to the reason for
interferon treatment ineligibility. Whereas 91% of those with anaemia or neutropenia
achieved SVR12, the proportion of responders fell to 80% among those with
depression and 73% among those with cirrhosis or advanced fibrosis with
thrombocytopenia. There was also a substantial difference in response according
to baseline viral load: 92% of those with HCV RNA < 800,000 achieved SVR12,
compared to 82% of those with HCV RNA > 800,000.
The majority of people who failed to achieve SVR12
experienced virologic breakthrough prior to the end of treatment (4% of
treatment-naive, 13% of non-responders and 9% of interferon-intolerant) rather
than post-treatment relapse (3%, 4% and 6% respectively).
Six patients in the previously untreated group and two in
each of the other arms discontinued treatment due to serious adverse events,
most commonly elevations in ALT/AST which resolved after treatment ceased.
Headache, fatigue, diarrhoea and nausea were the most common adverse events,
each affecting more than 10% of patients. A comparison of adverse events in the
placebo group and the previously untreated arm during the first 12 weeks of
treatment showed no difference in adverse events or grade 3/4 laboratory
abnormalities between the two groups.
Although less potent in previous non-responders than some of
the other regimens reported at the conference, daclatasvir
and asunaprevir will be an important option for patients with genotype 1b
infection outside the European Union. In Europe, Bristol-Myers Squibb is
pursuing an early approval for daclatasvir as an individual agent, so that it
may be used in combination with sofosbuvir for treatment of genotypes 1, 3 and 4
or in combination with pegylated interferon and ribavirin for treatment of
genotypes 1b and 4, as recommended in new