- Category: Experimental HCV Drugs
- Published on Monday, 11 November 2013 00:00
- Written by Liz Highleyman
A dual oral regimen of sofosbuvir plus ribavirin led to sustained response for 93% of genotype 2 hepatitis C patients treated for 12 weeks and 85% of genotype 3 patients treated for 24 weeks, researchers reported last week at the 64th AASLD Liver Meeting in Washington, DC. A related study found that adding ribavirin to this combination may be an option for harder-to-treat individuals.
Direct-acting antiviral agents have brought about a revolution in the treatment of chronic hepatitis C virus (HCV) infection. While these drugs have been initially tested as add-ons to interferon-based therapy, many people with HCV and their providers are awaiting all-oral regimens without the difficult-to-tolerate pegylated interferon.
Gilead Science's Phase 2 ELECTRON trial showed that the nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus ribavirin taken for 12 weeks cured most people with HCV genotypes 2 or 3. An advisory committee of the U.S. Food and Drug Administration last month recommended approval for this indication, which is expected in early December.
HCV genotypes 2 and 3 have traditionally been categorized together as "easier-to-treat" relative to genotypes 1 and 4. In the past couple years, however, it has become apparent that genotypes 2 and 3 respond quite differently to some direct-acting antivirals, with 3 having lower response rates.
A poster presentation by Stefan Zeuzem from Goethe University and colleagues from several countries in Europe described results from the Phase 3 VALENCE trial (NCT01682720), which tested sofosbuvir/ribavirin for treatment-naive or previously treated genotype 2 and 3 patients.
The initial study design called for more than 300 participants with genotype 2 or 3 to be treated with 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin for 12 weeks, while a smaller number received only placebo. After other studies indicated that people with genotype 3 did better with longer therapy, the design was amended to treat genotype 2 patients for 12 weeks and genotype 3 patients for 24 weeks, dropping the placebo arm.
The analysis included a total of 419 participants: 73 genotype 2 patients, 261 genotype 3 patients (including 11 treated for 12 weeks before the protocol change) and 85 genotype 2 or 3 placebo recipients. About 60% were men, most were white, and the median age was approximately 60 years. About one-third had the favorable IL28B CC gene variant and about 20% had liver cirrhosis. About 60% were treatment-experienced, with two-thirds of these being prior relapsers and most of the rest being non-responders.
- Looking at the genotype groups as a whole, 93% of genotype 2 patients and 85% of genotype 3 patients achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks post-treatment (SVR12).
- People with genotype 2 had high response rates across the board with 12 weeks of sofosbuvir/ribavirin:
o 97% for treatment-naive patients without cirrhosis;
o 100% for treatment-naive cirrhotics;
o 91% for treatment-experienced non-cirrhotics;
o 88% for treatment-experienced cirrhotics.
- Genotype 3 patients did not fare as well despite doubling the duration of therapy:
o 94% for treatment-naive patients without cirrhosis;
o 92% for treatment-naive cirrhotics;
o 87% for treatment-experienced non-cirrhotics;
o 60% for treatment-experienced cirrhotics.
- Among the 11 genotype 3 patients treated for just 12 week before the protocol change, only 3 (27%) were cured.
- Univariate and multivariate analyses did not reveal any factors, including IL28B status, which could predict which treatment-experienced people with cirrhosis would achieve sustained response.
- Resistance was not detected in any patients who relapsed.
- Sofosbuvir/ribavirin was generally safe and well-tolerated.
- Unlike most late-stage trials of direct-acting agents, VALENCE initially had a placebo comparison group; interestingly, a substantial majority of people in the placebo, 12-week and 24-week treatment arms experienced adverse events.
- Grade 3 or worse adverse events (5%, 4%, and 7%), serious adverse events (2%, 0%, and 4%) and events leading to discontinuation (1%, 1%, and <1%) occurred with similar frequency in all 3 arms.
- The 2 most common side effects -- headache and fatigue -- occurred at similar rates in all treatment arms.
- Itching, muscle weakness, nausea, and insomnia were reported more often in the sofosbuvir/ribavirin arms, but with comparable frequency in the 12- and 24-week arms.
- Anemia, however, occurred more often with the longer ribavirin duration (8% vs 11%).
"Sofosbuvir + ribavirin for 24 weeks demonstrated SVR rates >90% in treatment-naive HCV genotype 3 patients," the researchers summarized. "In treatment-experienced HCV genotype 3 patients, SVR rates were 60% and 87% in those with and without cirrhosis, respectively."
Sofosbuvir + Pegylated Interferon/Ribavirin
Eric Lawitz from the Texas Liver Institute presented late-breaking findings from the LONESTAR-2 trial, which evaluated sofosbuvir plus pegylated interferon in treatment-experienced genotype 2 and 3 patients with or without compensated cirrhosis.
This analysis included 47 patients, evenly divided between genotype 2 and 3, who had previously failed to achieve sustained response with pegylated interferon and ribavirin. Two-thirds were men, almost all were white, and the median age was 56 years. Just over one-third had the favorable IL28B CC gene variant and 55% had cirrhosis. Most (85%) experienced viral breakthrough while on therapy or relapsed after completing treatment.
All participants were treated with 400 mg once-daily sofosbuvir, 180 mcg/week pegylated interferon, and 1000-1200 mg/day weight-based ribavirin for 12 weeks.
At 12 weeks post-treatment, 96% of genotype 2 patients and 83% of genotype 3 patients achieved SVR12. Response rates did not differ according to cirrhosis status. Among genotype 2 patients, all non-cirrhotics and all but 1 with cirrhosis (93%) achieved SVR12. Among genotype 2 patients, the SVR12 rate was 83% for both non-cirrhotics and cirrhotics -- higher than the 60% rate for cirrhotics treated with sofosbuvir/ribavirin alone in VALENCE.
There were 2 relapses in the genotype 3 group. In addition, 1 genotype 2 patient was non-adherent and discontinued treatment with detectable viral load, 1 genotype 3 patient was lost to follow-up, and another stopped early due to an adverse event.
There were 4 people (9%) who experienced serious adverse events and, as noted, 1 stopped early for this reason. A majority (60%) developed grade 3-4 laboratory abnormalities including 28% with anemia. The most common side effects were flu-like symptoms typical of interferon.
"Sofosbuvir + pegylated interferon/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients who have historically low response rates and limited treatment options," the investigators concluded. "SVR rates were similar in patients with and without cirrhosis."
In response to an audience question, Lawitz acknowledged that people with genotype 2 and 3 generally should not be analyzed together, but suggested that genotype 2 patients who do not respond to interferon -- as most do -- are a unique group.
Given the forthcoming availability of interferon-free regimens, pegylated interferon may largely go by the wayside, but it may remain useful for managing some of the most difficult-to-treat hepatitis C cases.
S Zeuzem, GM Dusheiko, R Salupere, et al. Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 1085.
E Lawitz, F Poordad, DM Brainard, et al. Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment Experienced Patients with and without Compensated Cirrhosis: Results from the LONESTAR-2 Study. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-4.
Gilead Sciences. Gilead Announces New Sustained Viral Response Data for Sofosbuvir-Based Regimens in Genotype 3-Infected Hepatitis C Patients. Press release. November 2, 2013.