Interferon-Free Antiviral Regimen for Hepatitis C Patients without Cirrhosis

A recent study has shown that an 8-week regimen consisting of the antiviral agents ledipasvir and sofosbuvir was just as effective as a 12-week regimen in previously untreated patients with hepatitis C without cirrhosis [N Engl J Med. DOI: 10.1056/NEJMoa1402355]. The addition of ribavirin did not provide any additional benefit.

It has increasingly become recognized that safe, effective, short-term treatment regimens are essential in a broad range of patients with hepatitis C. Kris V. Kowdley, MD, Virginia Mason Medical Center, and colleagues conducted a phase 3 study that consisted of previously untreated patients with hepatitis C genotype 1 without cirrhosis. The purpose of the trial was to examine the efficacy of ledipasvir and sofosbuvir in a shortened treatment duration of 8 weeks, with or without ribavirin, compared with ledipasvir and sofosbuvir alone for 12 weeks. Treatment was given as a single tablet containing 90 mg of ledipasvir and 400 mg of sofosbuvir, taken orally once daily. Ribavirin was administered orally twice daily. The primary efficacy end point was a sustained virologic response (SVR) at post-treatment week 12 (defined as a hepatitis C ribonucleic [RNA] acid level of <25 IU/mL). A secondary end point was noninferiority of the 8-week regimen compared to the other treatment regimens.

During treatment, researchers measured serum hepatitis C RNA levels, monitored vital signs, and performed standard laboratory testing, electrocardiography, and symptom-directed physical examinations. Adverse events were recorded and graded. The researchers used the Clopper-Pearson method to calculate the rate of SVR at 12 weeks post-treatment.

There were 647 patients included in the trial; 215 patients in the ledipasvir/sofosbuvir 8-week group, 216 patients in the ledipasvir/sofosbuvir plus ribavirin 8-week group, and 216 patients in the ledipasvir/sofosbuvir 12-week group. Most patients (80%) had hepatitis C genotype 1a infection, 19% were black, and 6% were Hispanic. Approximately 75% had a non-CC IL28B genotype.

The results showed that the rates of SVR were superior to the adjusted historical control rate of 60% (P<.001 for all comparisons). Post-treatment rates of virologic response are shown in the Table (below). Results of the secondary analysis of noninferiority showed the rate of SVR among patients in the 8-week ledipasvir/sofosbuvir only group was noninferior to the other 2 treatment groups. Patients with characteristics typically associated with poor response to interferon-based treatment (eg, non-CC IL28B genotype, genotype 1a, and black), experienced rates of SVR similar to other patients without these factors.

None of the patients experienced virologic breakthrough during treatment. A total of 23 patients had a virologic relapse after treatment: 11 (5%) in the 8-week ledipasvir/sofosbuvir group, 9 (4%) in the 8-week ledipasvir/sofosbuvir plus ribavirin group, and 3 (1%) in the 12-week group. Fatigue, headache, and nausea were the most common adverse events and were experienced less by patients in the groups that did not take ribavirin (67% and 69%, respectively, for the 8- and 12-week groups) compared with 76% for the group that took ribavirin. These patients experienced adverse events more commonly associated with ribavirin therapy, including fatigue, headache, nausea, insomnia, irritability, rash, pruritus, cough, and anemia.

“These data are truly groundbreaking, because we now have the prospect of curing the vast majority of our patients who have chronic hepatitis C without cirrhosis with a simple, 8-week regimen of 1 pill [taken] once a day without any side effects,” Dr. Kowdley commented in an interview with First Report Managed Care. Although 8 weeks appears to be the shortest effective treatment duration at this time, the researchers believe that adding a third direct-acting antiviral agent to ledipasvir and sofosbuvir may allow for further shortening of the regimen to 6 weeks.