New and emerging treatments for hepatitis C
Invited contribution by:
Dr Wendy Cheng
Head, Liver Service, Royal Perth Hospital
Adjunct Professor, Curtin Health Innovation Research Institute
The standard of care for chronic hepatitis C (HCV) is constantly evolving with the development of more efficacious drugs, shortened duration of therapy and optimisation of dosages. Using a combination of pegylated interferon and ribavirin, a sustained virological response (SVR) can be achieved in only about 50% of cases with 48 weeks of treatment.
The recent introduction of direct antiviral drugs (DAAs)—and future drugs that work on different parts of the virus' complex life cycle (or combinations of these newer drugs or these newer drugs and DAAs), and interferon-free regimens—is likely to revolutionise the treatment of chronic hepatitis C, with higher SVR and reduced toxicity. The interferon-based regimen may still be required for difficult-to-treat patient populations, such as previous non-responders to interferon-based regimens.
Direct Antiviral Agents
In mid 2011, approval in the USA and European Union of the first generation DAAs—telaprevir and boceprevir (protease inhibitors)—resulted in an increased willingness of patients with HCV genotype 1 to undertake treatment. The DAAs, in combination with pegylated interferon and ribavirin (triple therapy) has increased SVR from 50% to over 70% in treatment-naïve HCV genotype 1 patients, and with a shorter duration of treatment.1, 2 Patients who failed previous therapy have variable responses, with highest SVR in patients who relapsed (75–88%), and poorest response in patients who did not achieve an initial adequate response (30–34%).3, 4 These drugs are effective in genotype 1 patients only.
Treatment regimens for DAAs are complex, with different treatment durations and cessation rules. Boceprevir and telaprevir need to be taken 3 times per day resulting in a heavy pill-burden, although a recent study suggests that telaprevir may be taken twice daily. Patients who have failed previous therapies require treatment for 48 weeks. Treatment monitoring is more intensive due to increased toxicity—boceprevir is associated with anaemia and dysgeusia (unpleasant taste) and telaprevir with rash and bone marrow suppression. The use of DAAs in patients with cirrhosis and portal hypertension is associated with increased risk of infection and mortality. Both telaprevir and boceprevir were approved (external site) in 2012 by the Therapeutic Goods Administration (TGA) for the treatment of genotype 1, and in February 2013 they were approved for Pharmaceutical Benefits Scheme (PBS) listing.
Several second generation DAAs that are effective across all genotypes are currently under investigation. These are taken once daily, are more efficacious than their predecessors and are associated with less toxicity. In a recent small study of difficult-to-treat patients (previous null-responders), SVR of 100% was achieved with the use of two DAAs (declastavir and asunaprevir) in combination with pegylated interferon and ribavirin (quadruple therapy).5
Pegylated interferon Lambda
Pegylated interferon Lambda (PEG-IFN λ) is not associated with systemic toxicity, including bone marrow suppression (low platelet, white and red cell counts), seen in conventional interferon therapy. This is due to the interferon-λ receptor being restricted to hepatocytes (liver cells) and not widely distributed in other organs. In preliminary studies, when PEG-IFN λ is used in combination with ribavirin, it is also associated with higher SVR in patients with HCV genotype 1 patients. Patients who had previously not responded (null responders) may still require interferon-based regimens and PEG-IFN λ may have an important role to play.
Preliminary data with Sobosfuvir (GS-7977 ) used in combination with ribavirin showed SVR of 100% in genotype 3 and 90% in genotype 1 patients. A recent press release confirmed SVR of 90% (295/327) in genotype 1, 4, 5 and 6 patients but only 67% (170/250) in genotype 2 and 3 patients. Treatment duration in all groups was 12 weeks and side effects were less frequently observed compared with pegylated interferon and ribavirin.
Studies examining the effects of a combination of DAAs or combinations of drugs which work on other sites of the virus' life cycle—with or without pegylated interferon or ribavirin—are in progress. Several combinations have shown encouraging results.
It is likely that with multiple drugs being used in future treatment regimens, increased toxicity may limit their use in clinical practice.
Combination therapy using pegylated interferon and ribavirin remains an integral part of the current treatment in Australia but may be superseded by interferon-free regimens in the future. It is likely that the majority of patients with HCV will be able to achieve a ‘cure’ in the near future, with regimens associated with shorter duration of therapy and minimal toxicity.
- Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection. N Engl J Med 2011; 364:2405–2416.
- Poordad F, McCone J, Bacon BR, et al. Boceprevir for Untreated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1195–1206.
- Zeuzem S, Andreone P, Pol S, et al. Telaprevir for Retreatment of HCV Infection. N Engl J Med 2011; 364:2417–2428.
- Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1207–1217.
- Lok AS, Gardiner DF, Lawitz E, et al. Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. N Engl J Med 2012; 366:216–224.