The standard of care for hepatitis C virus (HCV) infection is a combination of peginterferon and ribavirin. An increased understanding of the basic biology of the virus has led to the identification of specific proteins involved in the replication of the virus which can be targeted by protease and polymerase inhibitors.
The advent of novel protease inhibitors, such as telaprevir and boceprevir, has affected the landscape of therapy for HCV infection. These agents come with a number of inherent limitations:
• They do not have antiviral activity in HCV genotypes other than the predominant genotype 1, which leaves at least five other HCV genotypes without coverage.
• They can promote viral resistance and have multiple pharmacokinetic interactions with other drugs.
• They need to be administered with peginterferon and ribavirin, two drugs with extensive and well-established side-effect profiles that are aggravated by the addition of telaprevir or boceprevir.
The current therapy for HCV infection revolves around side-effect management in patients receiving interferon, who require intense monitoring. There is a need for less toxic therapeutic options.
In the New England Journal of Medicine, two research teams reports findings from four trials of sofosbuvir, a novel polymerase inhibitor, in patients with HCV infection. In three randomised trials (FISSION, POSITRON, FUSION), patients with HCV genotype 2 or 3, as seen in everyday clinical practice, including patients who had received no previous treatment, those who were unwilling to take interferon or had unacceptable side effects, and those who did not have a response to previous therapy, were recruited. All the studies had a similar end point: a sustained virologic response (SVR) at 12 weeks after the end of therapy.
The POSITRON study evaluated a population that was not deemed to be eligible for interferon-based therapy and compared 12 weeks of sofosbuvir plus ribavirin with placebo. The primary reasons for ineligibility were a preexisting psychiatric disorder (57%) or autoimmune disorder (19%). The rate of a SVR in the overall population was 78% with sofosbuvir and ribavirin; none of the patients in the placebo group achieved this primary end point (p<0.001). The rate of a SVR at 12 weeks was 93% in those with genotype 2 infection and 61% in those with genotype 3 infection.
The FUSION study, which targeted patients without a sustained response to interferon-based therapy, compared a 12-week regimen of sofosbuvir–ribavirin with a 16-week regimen. Four additional weeks of treatment made a difference, with an increase in the rate of SVR from 50% to 73% (p<0.001). The rate of SVR also increased from 86% to 94% in patients with genotype 2 infection and from 30% to 62% in those with genotype 3 infection with 16 weeks treatment. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%).
Although the data from the four trials are considered encouraging, only three of the four studies were randomised, and only one was placebo-controlled (POSITRON). In addition, the results for sofosbuvir in these studies falls short of the findings reported for the drug in an earlier study, in which the rate of SVR was 100%. One reason put forward for the difference may be that the design of that study was less rigorous than the design of these current studies. Furthermore, the end point used in the four studies differed from that used in the earlier study as the FDA only recently approved an end point of a SVR at 12 weeks (rather than previously approved 24 weeks) as acceptable for HCV trials.
An editorial notes that the data from the sofosbuvir trials suggest a radical change in clinical practice may be coming but caution is needed since long-term data in larger populations are lacking, and rare but irreversible adverse events still may emerge with wider use of sofosbuvir. However, in its favour, a sofosbuvir–ribavirin regimen is associated with a low incidence of side effects, relatively short duration of treatment, and pangenotypic properties. The likely next step is to combine sofosbuvir with other direct-acting antivirals to enhance its potency.
In April 2013, Gilead Sciences filed for a licensing application in the US for sofosbuvir, for use in combination with oral ribavirin to treat patients with HCV genotypes 2 and 3, as well as alongside ribavirin and pegylated interferon (peg-IFN) to treat genotypes 1, 4, 5 and 6. A licensing application in the EU is expected to be filed in the second quarter of 2013.
Currently in the UK, NICE has approved the use of
• Boceprevir (TA 253) in combination with peginterferon alfa and ribavirin as an option for the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease, who are previously untreated or in whom previous treatment has failed
• Telaprevir (TA 252) in combination with peginterferon alfa and ribavirin as an option for the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease, who are previously untreated or in whom previous treatment with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin has failed, including people whose condition has relapsed, has partially responded or did not respond.