Daclatasvir plus sofosbuvir with or without ribavirin in genotype 3 patients from a large French multicenter compassionate use program.
Hezode C. et al.
AASLD 2015, Abstract 206

Patients with genotype 3 and advanced liver disease from 221 centers have been included since March 2014 to October 2014. All patients received DCV+ SOF QD for 12 or 24 weeks, with RBV added at the physician's discretion. Data on SVR12 was presented for 284 patients, of whom 20.6% received DCV + SOF for 12 weeks, 58.9% DCV + SOF for 24 weeks, 1.8% DCV + SOF + RBV for 12 weeks, and 18.8% the triple combination for 24 weeks.

SVR12 was achieved in 86.6% with DCV + SOF, 81,0% for 12 weeks (47/58) and 88.6% for 24 weeks (147/166), with rates of 96% and 100% in non-cirrhotics, respectively, and 69.7% and 85.9% in cirrhotics, respectively. Ribavirin did not add benefit when treatment was given for 24 weeks.

Expert's Commentary

HCV genotype 3 (GT-3) infected patients are considered among the few remained special populations in the era of direct acting antiviral (DDAs). As shown by initial studies on IFN-free combination regimens, this challenging population achieves unsatisfactory rates of SVR after sofosbuvir and ribavirin 24-week treatment. However, using daclatasvir (DCV) and sofosbuvir (SOF) for 12 or 24 weeks, improvements in response rates were shown in GT-3 patients, in particular if naïve. One of the common aspects in the trials using DDAs is the limited number of patients with cirrhosis enrolled in phase II and III studies. To overcome this limitation, large real life experiences are currently providing number of patients large enough to support stronger conclusions, either on efficacy or on safety.

This was the case of the French Temporary Authorisation for Use (ATU) on patients with advanced disease. The French ATU program for DCV provided early, pre-market-authorization access to DCV for HCV patients with advanced liver disease and no other HCV treatment options.

This real life study explored efficacy and safety of treatment with daclatasvir and sofosbuvir in 561 patients with GT-3 infection. Although safety data were not available in 93 of the 561 patients enrolled in this study, the 468 subjects whose date are complete represent the largest real life population of GT-3 infected patients with homogeneous characteristics of liver disease severity currently evaluated. Of the study endpoints, safety evaluation was based on serious adverse events (SAEs), AEs, and treatment discontinuation.

Cirrhosis was present in about 222/284 patients. In 74 patients (29%) albumin levels were <3.5 g/dl, in 38% platelet counts was < 100,000 mm 3 ; in 15% of patients cirrhosis of Child-Pugh class B or C was diagnosed. Patients in pre-liver and renal transplant were included. Fourteen percent of patients were HIV co-infected. Despite the advanced disease, no major side effects were observed during treatment or follow-up. Only seven patients died (1.5 %). Five of these deaths were considered unrelated to treatment, a patient had a multi-organ failure of unreported causality. The remaining patient died of unknown cause. Side effects unrelated to treatment were reported in 9% of patients. Overall, only 0.4% of subjects reported serious adverse events considered treatment-related. Discontinuation due to side effects were registered in only 0.6% of cases. No drug-to-drug interactions were reported despite these patients were taking multiple concomitant medications.

Given the difficult-to-treat population treated in this large real life study, we should focus not only on efficacy but also on safety. According with the evidence provided by this French ATU program, although derived from an interim analysis, a widespread use of DCV + SOF combination can be promoted, even in patients with advanced cirrhosis

Alessandra Mangia, San Giovanni Rotondo, Italy