Although an interferon-free combination of antiviral drugs developed by Bristol-Myers Squibb to treat hepatitis C was highly effective in curing the infection in previous null responders to treatment with HCV genotype 1b infection, some new antiviral drugs may still need to be administered with interferon in harder-to-treat patients with HCV genotype 1a, researchers reported on Sunday at The Liver Meeting 2012, the 63rd meeting of the American Association for the Study of Liver Diseases (AASLD), in Boston.
The study found a very high rate of sustained virologic response (SVR12) in people with HCV genotype 1a amongst patients who received new direct-acting antivirals with pegylated interferon and ribavirin.
The findings came from a phase 2a study of asunaprevir, an HCV protease inhibitor, combined with daclatasvir, an inhibitor of the HCV NS5A protein. The drugs are being developed by Bristol-Myers Squibb, potentially for use in combination. The study was designed to evaluate once- and twice-daily dosing of asunaprevir in combination with daclatasvir, with or without pegylated interferon and ribavirin.
Like a number of other studies presented at this meeting, the trial was designed to give a preliminary picture of the potential of these agents to cure hepatitis C infection when used without interferon or ribavirin. The side-effects of interferon, and the fact that some people fail to respond to interferon due to genetic characteristics or due to resistance induced by prior treatment, make the identification of interferon-free regimens essential for people who have failed to respond to a previous interferon-containing regimen.
Interferon-free treatment will also be highly attractive for anyone needing treatment for the first time, because it is likely to come with fewer side-effects, and treatment may be completed in six or even three months.
However, research studies are also evaluating the use of new regimens with and without ribavirin, because this drug causes anaemia, causing treatment regimens to be terminated prematurely owing to poor tolerance.
The randomised study was open-label and involved people with genotype 1 HCV infection. This study excluded patients with cirrhosis. All had previously received standard therapy with pegylated interferon and ribavirin but were classified as null responders, having failed to achieve a sustained virological response (SVR).
A total of 101 people were recruited to the study. There was a high prevalence of factors associated with a poorer response to treatment in the study population. Over 95% of participants lacked the IL28B 'CC' mutation, which predicts a favourable response to interferon treatment, and 89% had a hepatitis C viral load above 10 million IU/ml.
Participants with HCV genotype 1b infection were randomised to one of four treatment arms, consisting of 24 weeks of the HCV protease inhibitor daclatasvir (60mg once daily) plus:
- asunaprevir (200mg twice daily) (n=18, restricted to participants with genotype 1b).
- asunaprevir (200mg once daily) (n=20, restricted to participants with genotype 1b).
- asunaprevir (200mg twice daily) plus pegylated interferon and ribavirin (n=20).
- asunaprevir (200mg once daily) plus pegylated interferon and ribavirin (n=21).
Participants with HCV genotype 1a infection were randomised to receive one of the two pegylated interferon-containing regimens, due to the higher risk of viral breakthrough and consequent null response in this group of patients.
A fifth treatment group (daclatasvir 60mg qd plus asunaprevir [200mg twice daily] plus ribavirin [n=22]) was recruited separately and consisted of participants with genotype 1a or 1b infection.
Ninety-five per cent of participants who received the four-drug, interferon-containing regimens achieved an HCV viral load below the lower limit of quantification (LLOQ, 25 iu/ml) at week 4 of treatment and all participants had HCV RNA < LLOQ at week 12.
Ninety-five per cent of participants (39 of 41) had a sustained virologic response twelve weeks after the completion of treatment (SVR12), suggesting that these interferon-containing regimens are highly effective and comparable in efficacy to other regimens that have tested a combination of new antiviral drugs in combination with pegylated interferon and ribavirin.
Only two cases of post-treatment virological relapse were observed, one at week 4 and one at week 12 after completion of treatment.
The vast majority of participants (36 of 41) receiving interferon-containing regimens had HCV genotype 1a infection.
In the dual-treatment group (genotype 1b only), 78% of participants receiving asunaprevir twice daily and 65% receiving asunaprevir once daily achieved a sustained virologic response (SVR12). Eight cases of viral breakthrough occurred; HCV RNA was re-suppressed with the addition of pegylated interferon and ribavirin in all cases. In five cases, naturally existing HCV variants with resistance to daclatasvir were found to have been present prior to treatment.
The study found that, in the triple-therapy arm, 56% of participants with genotype 1a infection experienced viral breakthrough in the absence of interferon, compared with none of the genotype 1b patients. This result confirmed the findings of a previous study, which also found a higher rate of viral breakthrough in participants with genotype 1a who received daclatasvir and asunaprevir without ribavirin.
These findings led the investigators to conclude that the interferon-free combination of daclatasvir and asunaprevir with ribavirin should not be pursued in harder-to-treat genotype 1a null responders.
“These data suggest that interferon-free treatment regimens for genotype 1 patients may need to be tailored according to subgenotype,” Dr Anna Lok told the meeting.
No participant stopped taking either daclatasvir or asunaprevir because of side-efects.
The most common side-effects among people taking the dual combination of daclatasvir and asunaprevir were headache, diarrhoea, weakness and nausea. These side-effects were also observed in participants taking the four-drug regimen, among whom hair loss and irritability were also common.
The authors concluded that the four-drug combination of daclatasvir and asunaprevir with pegylated interferon and ribavirin is highly effective for patients with either genotype 1a or genotype 1b who did not respond to earlier treatment with pegylated interferon and ribavirin. Preliminary data also suggested that treatment with daclatasvir/asunaprevir alone was effective, but only in people with genotype 1b infection.
Lok AS et al. Sustained virologic response in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5A inhibitor and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV). 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, abstract 79, 2012.