Hepatitis C remains a difficult infection to treat. The standard treatment is interferon plus ribavirin, a combination dogged by side-effects, and which must be given for a year. Even then, there is only about a 50% chance of a cure, with some patient groups and viral genotypes having a particularly poor prognosis. Furthermore, often people do not realise they have HCV until chronic effects such as cirrhosis and liver cancer appear maybe 20 years after they were infected.
Recent advances have included the introduction of serine protease NS3/NS4A inhibitors that have shortened the duration of treatment, but they still need to be given in combination with standard therapy. Bristol-Myers Squibb is working on an HCV serine protease NS3 inhibitor, asunaprevir, which may permit treatment regimens without interferon.1
A panel of four double blind, placebo-controlled, sequential panel, single and multiple ascending dose studies were carried out in healthy subjects and also subjects with chronic HCV genotype 1 infection.2 In the single dose studies, both healthy and infected subjects were given doses of 10 to 1200mg or placebo, while in the multiple dose studies, the healthy subjects were given 100 to 600mg twice a day or placebo for 14 days, while those with HCV infection were given doses of 200 to 600mg or placebo for three days. In all groups, the most common side-effects with active treatment were head-ache and diarrhoea. Doses of 200 to 600mg gave rapid decreases in HCV RNA from baseline in both the single and multiple dose studies.
It is also being investigated in non-responders to standard therapy, given in combination with another novel antiretroviral agent, daclatasvir.3 A group of 10 non-responding subjects with difficult to treat genotype 1b infection were given 60mg of the NS5A replication complex inhibitor daclatasvir once a day, plus asunaprevir, initially in 600mg twice daily doses, then reduced to 200mg twice a day. All bar one of the patients completed the full 24-week course of treatment, and all nine had a sustained virologic response at both 12 and 24 weeks after treatment. HCV RNA was also undetectable two weeks post treatment in the patient who discontinued after two weeks. Again, the most common side-effects were headache and diarrhoea.
references
1. F. McPhee et al. J. Hepatol. 2010, 54 (Suppl. 1), Abst 761
2. C. Pasquinelli et al. Antimicrob. Ag. Chemother. 202, 56, 1838
3. K. Chayama et al. Hepatology 2012, 55, 742