William F. Balistreri, MD

Disclosures

March 22, 2016

In This Article

A Pangenotypic Option

Velpatasvir is a new pangenotypic NS5A inhibitor with antiviral activity against HCV replicons in genotype 1-6. In phase 2 trials, the all-oral, once-daily, fixed-dose combination of 400 mg of SOF and 100 mg of VEL, with or without RBV, resulted in high rates of SVR in a broad range of patients with HCV—including previously treated and untreated patients, those with and without compensated cirrhosis, and those infected with HCV of all six genotypes.

This fixed-dose combination of a pangenotypic drug, which is under regulatory review, was the focus of the ASTRAL studies, the results of which were reported at The Liver Meeting 2015 and in near-simultaneous publications.[11,12,13,14,15,16,17]

ASTRAL-1, a phase 3, double-blind, placebo-controlled trial of treatment with a fixed-dose combination of SOF/VEL in more than 700 treatment-naive and treatment-experienced patients with cirrhosis and infection with HCV genotype 1, 2, 4, 5, and 6, was reported by Feld and colleagues.[14] Among patients who were randomly assigned to receive SOF/VEL (400 mg/100 mg daily) once daily for 12 weeks, the overall SVR12 was 99% (100% for patients with genotype 2, 4, and 6).

Sulkowski and colleagues[15] summarized the phase 3 ASTRAL-2 study, which compared the efficacy and safety of treatment with the fixed-dose combination of SOF/VEL daily for 12 weeks with that of SOF (400 mg daily) plus RBV (1000-1200 mg daily) for 12 weeks in treatment-naive and treatment-experienced patients infected with HCV genotype 2, with and without cirrhosis. HCV RNA declined rapidly in both treatment groups, with > 90% of patients having undetectable HCV RNA at treatment week 4. The SVR4 rate for patients treated with SOF/VEL was 99%, and for patients treated with SOF/RBV, it was 96%. The most common adverse events were fatigue, headache, nausea, and insomnia; all were more frequently observed in patients who received RBV.

A phase 3, open-label trial (ASTRAL-3), reported by Mangia and colleagues,[16] enrolled patients with HCV genotype 3 at 75 sites in North America, Europe, Australia, and New Zealand. Patients were randomly assigned to receive SOF/VEL daily for 12 weeks or the standard of care with SOF (400 mg daily) plus RBV (1000-1200 mg daily) for 24 weeks.[16] HCV RNA declined rapidly in both treatment groups, with 92% and 88% of patients achieving undetectable HCV RNA after 4 weeks of treatment in the SOF/VEL and SOF/RBV treatment groups, respectively. Hemoglobin decline and total bilirubin increases were more commonly observed in the group treated with SOF/RBV, which is consistent with RBV-induced hemolysis.

HCV-infected patients with decompensated cirrhosis have significant morbidity and mortality. For many, the only treatment option is liver transplantation. DAAs offer the potential to treat HCV safely and effectively in these patients. Successful treatment is associated with an improvement in liver function.

A phase 3 study by Charlton and colleagues[17] (ASTRAL-4) evaluated the safety and efficacy of the fixed-dose combination of SOF/VEL in 267 patients with HCV genotype 1, 2, 3, 4, or 6 with decompensated (Child-Pugh class B [CPT-B]) liver disease. Patients were randomly assigned to receive SOF/VEL daily for 12 weeks, SOF/VEL plus weight-based RBV for 12 weeks, or SOF/VEL for 24 weeks. SVR12 was achieved by 94% of patients who received SOF/VEL plus RBV for 12 weeks, 83% of patients who received SOF/VEL for 12 weeks, and 86% of patients who received SOF/VEL for 24 weeks. Relapse occurred in 1% of patients with HCV genotype 1 and 8% of those with HCV genotype 3. There were no cases of virologic failure among patients with genotype 2, 4, or 6. Among patients who achieved SVR, more than one half had improvements in CPT and MELD scores by week 12, largely driven by increases in albumin and decreases in bilirubin.

The most common adverse events were fatigue, headache, and nausea. Anemia was noted in patients receiving RBV. Of note, 18% of patients experienced serious adverse events; the most common was hepatic encephalopathy and sepsis, consistent with clinical sequelae of decompensated liver disease.

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