Genotype 3: Treat now or wait for something better?

Hepatitis C virus (HCV) infection is a worldwide phenomenon that affects 130 to 150 million people globally, with 500,000 of these individuals expected to die of HCVrelated complications annually. Of the six major genotypes, genotype 3 (GT3) is the most aggressive, with increased progression to fibrosis and cirrhosis. Until now, the treatment regimens for GT3 included combinations based on a backbone of sofosbuvir (SOF) and ribavirin (RBV) and have had only limited success. The phase 3 FISSION trial showed noninferiority of 12-week combination SOF 1 RBV to 24-week pegylated interferon (PEG-IFN) 1 RBV in previously untreated patients with genotype 2 (GT2) and GT3. Sustained virologic response at 12 weeks (SVR12) in this study was 56% in the GT3 group receiving SOF 1 RBV versus 63% in those receiving PEG-IFN 1 RBV. Two subsequent phase 3 trials, POSITRON and FUSION, assessed the combination of SOF 1 RBV in PEG-IFN–intolerant or –ineligible patients and PEG-IFN nonresponders, respectively. In POSITRON, SVR12 for GT3 was 61%; 68% for those without cirrhosis and 21% for those with cirrhosis. The FUSION trial showed SVR12 of 30% (37% in patients without cirrhosis, 19% in patients with cirrhosis) and 62% (63% in patients without cirrhosis, 61% in patients with cirrhosis) at 12 and 16 weeks, respectively, for GT3. In both FISSION and FUSION trials, response rate was lower in patients with GT3 compared with GT2. The VALENCE trial extended treatment duration to 24 weeks. SVR12 was 85% overall, 91% in patients without cirrhosis and 68% in patients with cirrhosis. In all of these studies, SOF was given as a 400 mg daily dose, whereas RBV was weight based: 1000 mg for those less than 75 kg and 1200 mg for those 75 kg. The results of the VALENCE trial set the standard of GT3 for treatment in 2013 and 2014 with a very expensive regimen that was less than optimal for patients with cirrhosis. Daclatasvir (DCV; BMS-790052, DAKLINZA) is a newly approved pan-genotypic nonstructural protein 5A (NS5A) inhibitor against GT 3 HCV. It was approved for use in Europe in August 2014 and in the United States in July 2015. Clinical studies show the picomolar half-maximum effective concentration (EC50) is 146 6 34 pM against HCV GT3 specifically with mean plasma elimination half-life of 10 to 14 hours. In vitro studies showed that DCV is a potent inhibitor of NS5A sequences with EC50s of 120 to 870 pM for the three HCV GT3a strains. In vitro resistance was associated with variants at L31, Y93, M28, and A30. Only Y93 may have an associated worse clinical response. The safety record of DCV has been demonstrated in more than 1900 patients in clinical studies and now in many more patients who have been treated in the last year in the European Union and Japan since the drug was approved in those countries. Hence it should offer a logical choice for treatment of our patients with GT3 in the United States who have been waiting for better options. However, there are some important caveats to consider before treating with DCV. First, the approval in the United States was based primarily on the phase 3 ALLY-3 study that evaluated only a 12-week course of DCV plus SOF. Dosing for SOF was the standard 400 mg once daily, whereas for DCV, 60 mg was administered daily. The trial was RBV-free, and the treatment duration was 12 weeks. The primary endpoint was SVR12 for both treatment-naive (n 5 101) and treatment-experienced (n 5 51) patients. SVR12 was 90% in treatment-naive patients and 86% in treatment-experienced patients. SVR12 was 96% versus 63% in those without and with cirrhosis, respectively. This is clearly not an acceptable treatment failure rate for patients with cirrhosis, and a longer regimen trial is currently under way for cirrhosis, evaluating a 12-week versus 16-week duration with RBV. With regard to adverse events