Sofosbuvir plus ribavirin in Asian patients with chronic genotype 2 hepatitis C virus infection: history of a success?

PEGylated interferon alpha (PegIFN) plus ribavirin (RBV) administered for 24 weeks has long been the standard treatment for patients with genotype 2 hepatitis C virus (HCV) infection (1). In patients infected with HCV genotypes 2 and 3 with a rapid viral response and low baseline viral load (<400 000– 800 000 IU/ml), treatment duration could be shortened to 16 weeks, and in some patients with unfavourable predictive factors, the recommendation was to extend treatment to 48 or 72 weeks (1). Sustained virologic response (SVR) rates with this combination were estimated to be approximately 70–85% in Asia, Europe and North America (2–4). The standard of care for genotype 2-infected patients did not change with the 2011 approval of the first direct-acting antivirals (DAA), telaprevir and boceprevir, which were effective only in genotypes 1 and 4 (5). Despite the relatively high rate of SVR with the combination of PegINF and RBV in na€ıve patients, PegINF is poorly tolerated and has some contraindications, especially in patients with advanced liver disease (1). Moreover, non-responders to that combination had no alternative and effective treatment because of the low rate of SVR associated with retreatment using the same combination (1). The discovery and development of DAA against genotype 2 HCV are likely to provide these patients with effective and more tolerable interferon-free (IFNfree) therapies (6). Sofosbuvir (SOF), an oral nucleotide analogue inhibitor of the HCV-specific NS5B polymerase with in vitro activity against all HCV genotypes, was licensed in the European Union in 2014 (7). IFN-free combinations have since been broadly used across Europe, the United States, Canada, Australia and New Zealand, initially as part of early access programmes and primarily in patients with advanced liver disease (fibrosis METAVIR score F3 or F4) (7). SOF in combination with RBV for 12 weeks is very effective in genotype 2 patients, yielding SVR rates in the order of 80–95% (7). These rates of response have been described in four Phase III trials. In the FISSION trial, treatment-na€ıve patients treated for 12 weeks exhibited an overall SVR rate of 95%; SVR rates in patients with cirrhosis were 83% and 97% without cirrhosis (8). In patients considered ineligible or intolerant to PegIFN (POSITRON trial), SVR rates reached 93% (9). In the FUSION trial (9), SVR was achieved in 82% of patients treated for 12 weeks and in 89% of patients treated for 16 weeks; in patients with cirrhosis, SVR was 60% and 78% for 12 and 16 weeks respectively. These results indicate that patients with cirrhosis may benefit from more than 12 weeks of therapy. In the VALENCE trial (10), the SVR rates after 12 weeks of treatment varied from 88% in treatment-experienced cirrhotic patients to 97–100% in na€ıve patients. In all of these studies, no virological breakthroughs were observed in treatment-adherent patients, and relapses were not associated with the selection of resistant HCV variants (7). The combination of SOF and RBV also exhibited an acceptable safety profile. The rate of premature discontinuation because of adverse events (AE) was low (1–2%) and similar to patients receiving placebo (7). Some adverse events associated with RBV therapy — fatigue, insomnia and anaemia — were higher. These AE were comparable in patients receiving 12 or more weeks of treatment and in cirrhotic patients (9). The proportion of patients with moderate (grade 3) and severe (grade 4) AE was approximately 1–6% (10, 11), with a proportion of discontinuation approximately 1% (11). Because of the reasons mentioned above, the IFNfree combination of SOF and RBV may be the best first-line treatment option for patients infected with HCV genotype 2 in Europe (7). Patients with this infection must be treated with daily weight-based RBV (1000 or 1200 mg in patients <75 kg or ≥75 kg respectively) and daily SOF (400 mg) for 12 weeks. Treatment-experienced patients with cirrhosis may need longer treatments (16, 20, 24 weeks) (7, 9–11). Other options may be useful in the small number of patients who fail this medication regimen. In settings where these options are not available, the combination of PegIFN and RBV remains acceptable (7). Genotype 2 is more prevalent in Asia than in Europe, with rates of genotype 2 HCV-infection in Japan