Commentary: sofosbuvir for treatment of hepatitis C virus genotype 2 or 3 infection in patients without treatment options.

Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality world-wide. In the setting of cirrhosis, complications such as ascites, hepatic encephalopathy, or esophagogastric variceal bleeding may develop in afflicted patients. Furthermore, hepatocellular carcinoma is not uncommon in the setting of cirrhosis. Chronic HCV is the leading indication for liver transplantation in the United States. Chronic HCV is characterized by different genotypes (GTs). GT 1 is the most common in the United States. The direct-acting antiviral agents telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) are approved for use only for GT 1. GT 2 and 3 are less common in the United States, but a significant number of patients are affected. The standard therapy for HCV GT 2 or 3 is a course of pegylated interferon (PEG) and ribavirin (RBV) for 24 weeks.1-3 Sustained virologic response (SVR) rates of 70% to 85% are to be expected. Nevertheless, 15% to 30% of treated patients either experience virologic relapse or nonresponse and, thus, fail therapy. PEG and RBV therapy is complicated by numerous adverse effects, including flulike symptoms, psychiatric symptoms, cytopenias, thyroid issues, hair loss, and skin rash among others.2,4 Many patients are fearful of these adverse effects and elect not to pursue therapy. Furthermore, many patients have contraindications to therapy with PEG and are ineligible for therapy. These include patients with psychiatric diseases such bipolar disorder or depression, autoimmune disease such as rheumatoid arthritis or psoriasis, and cytopenias. Patients with HCV GT 2 or 3 who have failed therapy or who are ineligible or refuse to take PEG have no therapeutic options and represent a significant unmet medical need. Well-tolerated and more efficacious regimens are sought. An ideal regimen would be effective in patients who have failed standard therapy. In addition, the regimen would not include PEG, the medication that is responsible for most of the adverse effects with the standard regimen. An oral regimen that is administered over a relatively short time period with a favorable daily dosing schedule and without drug-drug interactions would be optimal. Sofosbuvir (SOF) is an oral nucleotide analogue inhibitor of the HCV-specific NS5B polymerase enzyme. In vitro studies have shown that SOF has pangenotypic activity.3’5 In phase 2 trials, excellent tolerability and efficacy were observed in a small number of patients with HCV GT 2 or 3 who were either treatment-naive or treatment-experienced.4,6,7 POSITRON was a multicenter, randomized, blinded, placebo-controlled trial assessing SOF 400 mg once daily plus RBV (1000-1200 mg in divided doses based on weight) for 12 weeks in patients with HCV GT 2 or 3 who previously did not tolerate interferon, who had contraindications for interferon, or who had refused interferon. FUSION was a multicenter, randomized trial assessing SOF and RBV at the aforementioned dosages for either 12 or 16 weeks in patients with HCV GT 2 or 3 who had previously not achieved SVR after a previous course of PEG plus RBV. Patients with cirrhosis were included in both trials. The primary endpoint was SVR12 identified by undetectable HCV RNA 12 weeks after discontinuation of antiviral therapy. The FUSION trial compared SVR rates with an expected historical control SVR of 25%. These studies’ findings represent a substantial advance in the treatment of chronic HCV infection. These are the first published phase 3 trials examining an interferon-free regimen (ie, SOF and RBV) in patients with HCV GT 2 or 3. FUSION is the first study that assessed a therapeutic option for patients with HCV GT 2 or 3 that have previously failed therapy. POSITRON is the first study that has been published investigating patients with GT 2 or 3 in whom interferon was not an option. Although patients with GT 2 or 3 HCV infection are not as common as GT 1 in the United States, physicians who care for patients with HCV have patients in their practice who have failed standard therapy, who have not tolerated therapy, who have contraindications to therapy, or who refuse therapy that would be appropriate. These studies present several interesting findings. First, an oral regimen (interferon-free) is shown to be effective in patients with GT 2 or 3. Interestingly, RBV appears to be well tolerated when given in a setting without interferon. Fatigue, insomnia, and anemia were reported in a relatively small number of patients on active treatment compared with patients receiving placebo in the POSITRON trial. The adverse events were mild and tolerable. Patients with GT 3 did less well than those with GT 2. This has previously been reported with PEG-plus-RBV therapy as well.5,8 In patients with GT 2, patients do extremely well with a 12-week course of SOF plus RBV. In patients with GT 3, SVR is lower. Although SVR12 is reasonable in a group of patients without other therapeutic options, the efficacy in this population is not optimal. In particular, cirrhotic patients with GT 3 do not do well with SOF plus RBV. For patients with GT 3 who did not achieve SVR after a previous course of PEG plus RBV, a 16-week course is favorable compared with a 12-week course. GT 2 patients do better than GT 3 patients. A 12-week course for noncirrhotic patients who have previously failed therapy may suffice. However, for cirrhotic patients with GT 2, a 16-week course appears to be of more benefit. The optimal length of therapy with SOF and RBV for patients with cirrhosis and GT 2 or 3 who previously failed standard therapy is unclear. Sixteen-week regimens provided increased efficacy compared with 12-week regimens. Longer regimens must be investigated in clinical trials. Furthermore, additional viral suppression with direct-acting antiviral agents with different mechanisms of action or with immunomodulating agents may be helpful to augment SVR. Future studies are awaited.