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Sofosbuvir/ribavirin for 24 weeks cures most genotype 3 hepatitis C patients, adding interferon may help difficult-to-treat
Liz Highleyman, 2013-11-14 17:40:00
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 at The Liver Meeting 2013, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD) held last week 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 agents 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 US 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 categorised 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 of 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 400mg once-daily sofosbuvir plus 1,000-1,200mg/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 favourable 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: 97% for treatment-naive patients without cirrhosis, 100% for treatment-naive cirrhotics, 91% for treatment-experienced non-cirrhotics and 88% for treatment-experienced cirrhotics.
Genotype 3 patients did not fare as well despite doubling the duration of therapy. Treatment-naive people had high cure rates -- 94% for non-cirrhotics and 92% for cirrhotics -- but these fell to 87% for treatment-experienced non-cirrhotics and 60% for treatment-experienced cirrhotics. Among the eleven genotype 3 patients treated for just 12 weeks before the protocol change, only three (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 across arms.
The two 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. Anaemia, 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 summarised. "In treatment-experienced HCV genotype 3 patients, SVR rates were 60% and 87% in those with and without cirrhosis, respectively."
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