Previously Untreated Hepatitis C Patients Successfully Treated with Ledipasvir and Sofosbuvir

A 12-week, single-tablet regimen consisting of the nucleotide polymerase inhibitor, sofosbuvir, and the NS5A inhibitor, ledipasvir, was shown to be highly effective in previously untreated patients with hepatitis C genotype 1, according to results of a recent study [N Engl J Med. DOI:10.1056/NEJMoa1402454]. Extending treatment to 24 weeks or adding ribavirin did not provide any further benefit.

Therapeutic regimens for hepatitis C are still likely to include weekly injections of recombinant human interferon-alfa and ribavirin, both of which are associated with multiple adverse effects. Ledipasvir has potent antiviral activity against hepatitis C genotypes 1a and 1b, and sofosbuvir is approved for treating genotypes 1 through 4 in combination with ribavirin, with or without peginterferon.

Although interferon-free combinations have been recommended by some professional organizations, the supporting data are based on small, phase 2 trials. After the phase 3 ION-2 trial showed positive results in previously treated patients given sofosbuvir and ledipasvir, Nezam Afdhal, MD, Beth Israel Deaconess Medical Center, and colleagues conducted ION-1, a phase 3, multicenter, randomized, open-label trial to assess the efficacy and safety of 12 or 24 weeks of ledipasvir and sofosbuvir, with or without ribavirin, in previously untreated patients with chronic hepatitis C genotype 1, including patients with compensated cirrhosis. The primary efficacy end point was a sustained virologic response (SVR) at 12 weeks after the end of treatment.

The trial consisted of 865 patients, the majority of whom (67%) had hepatitis C genotype 1a infection; 16% had cirrhosis; 12% were black; and 70% had the non-CC IL28B allele. All patients received a fixed-dose combination tablet containing 90 mg of ledipasvir and 400 mg of sofosbuvir, given orally, once daily, with ribavirin administered orally twice daily. They were then randomized to 1 of 4 treatment groups: (1) ledipasvir and sofosbuvir for 12 weeks; (2) ledipasvir and sofosbuvir for 24 weeks; (3) ledipasvir and sofosbuvir plus ribavirin for 12 weeks; and (4) ledipasvir and sofosbuvir plus ribavirin for 24 weeks.

During treatment, patients underwent standard laboratory testing, measurement of serum hepatitis C ribonucleic acid level, assessment of vital signs, electrocardiography, and symptom-directed physical examinations. The researchers used the Clopper-Pearson method to determine the rate of SVR at 12 weeks after the end of treatment in each cohort.

Results showed the rates of SVR in all 4 groups were superior to the historical rate of 60% (P<.001 for all comparisons). Post-treatment rates of virologic response are shown in the Table. Only 3 of 865 patients experienced virologic failure.

According to the intention-to-treat analysis, the rates of SVR in the treatment groups ranged from 94% to 100% among patients with cirrhosis, 97% to 99% among patients with hepatitis C genotype 1a infection, 97% to 99% among patients having a non-CC IL28B allele, and 91% to 100% among black patients.

A total of 10 patients discontinued treatment due to adverse events, all of whom were in 24-week treatment groups. Most patients (79%-92%) experienced at least 1 adverse event, most of which (93%) were mild to moderate. The most common adverse events included fatigue, headache, insomnia, and nausea. Patients who also received ribavirin experienced higher rates of adverse events associated, including fatigue, insomnia, asthenia, rash, cough, pruritus, and anemia.

In an interview with First Report Managed Care, Dr. Afdhal concluded, “The ION trials confirm that interferon-free, ribavirin-free treatment can cure 95% of [hepatitis C] genotype 1 patients with a simple and safe regimen of 1 pill [taken] once per day. This will bring great opportunity for the eradication of [hepatitis C] in the United States, and [gives] hope to the many patients suffering from liver disease.”