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EASL 2013: Sofosbuvir + Interferon/Ribavirin Cures 90% of People with Hard-to-Treat HCV Genotypes

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Adding the second-generation HCV polymerase inhibitor sofosbuvir (formerly GS-7977) to pegylated interferon plus ribavirin led to a sustained response rate of 89% for treatment-naive patients with HCV genotype 1 in the NEUTRINO study, researchers reported at the EASL International Liver Congress(EASL 2013) last week in Amsterdam. High rates were also seen for the less common genotypes 4, 5 and 6.

While all-oral direct-acting antiviral (DAA) regimens for chronic hepatitis C are eagerly anticipated, many patients with progressive liver disease cannot afford to wait. Adding the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek or Incivo) to interferon-based therapy can shorten treatment and increase response, but these drugs have difficult dosing regimens and come with side effects of their own. Several next generation DAAs are easier to take and better tolerated.

Eric Lawitz from the University of Texas Health Science Center and colleagues conducted an open-label, non-randomized phase 3 clinical trial to evaluated the safety and effectiveness of 400 mg once-daily sofosbuvir plus 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1,000-1,200 mg/day weight-based ribavirin.

All participants were treated for 12 weeks, with no response-guided therapy. The standard duration of pegylated interferon/ribavirin alone is 48 weeks for people with genotype 1 and 24 weeks for those with genotypes 2 or 3.

NEUTRINO enrolled 327 previously untreated chronic hepatitis C patients with HCV genotypes 1, 4, 5, and 6. These genotypes have traditionally been considered "hard to treat," but as several studies at the congress showed, all may not be equally difficult, just as genotypes 2 and 3 are not equally "easy to treat".

Just over 60% of participants were men and the mean age was 52 years. The study had broad inclusion criteria and enrolled "a good representation" of the U.S. hepatitis C patient population, Lawitz said.

Looking at predictors of poorer treatment response, 17% were black and 70% had unfavorable (non-CC) IL28B gene variants. The mean body mass index was 29 (with 30 being the cut-off for obesity) and 17% had liver cirrhosis. People using opiate substitution therapy were included.

Most patients (89%) had HCV genotype 1, though the proportions with subtypes 1a and 1b were not reported. 28 people, or about 9%, had genotype 4 (most commonly found in the middle-east and Africa, especially Egypt), while 7 people, or about 2%, had genotypes 5 (found mostly in South Africa) or 6 (found mostly in Asia).

Results

  • By week 4 of treatment, 99% of participants overall had rapid virological response.
  • The same proportion still had undetectable HCV RNA at the end of the 12-week course of treatment.
  • At 12 weeks post-treatment, 90% overall achieved sustained virological response (SVR12), exceeding an estimated historical control rate of 60% for similar patients using pegylated interferon/ribavirin alone.
  • By genotype, 89% of people with genotype 1 achieved SVR12, as did all but 1 patient with genotype 4 (96%) and all 7 patients with genotypes 5 or 6 (100%).
  • A sub-group analysis showed that HCV subtype 1b had a lower response rate -- contrary to most DAA studies, which find 1a harder to treat; Lawitz explained that in this study people with subtype 1b were disproportionately likely to have unfavorable IL28B variants.
  • Genotypes 4, 5, and 6 were associated with better treatment response.
  • People with cirrhosis had similar response rates as non-cirrhotics at weeks 4 and 12 on treatment (96% and 100%, respectively), but this fell to 80% at post-treatment week 12.
  • Black patients, people with IL28B non-CC variants, and people with higher baseline viral load were somewhat less likely to achieve sustained response, but all achieved SVR12 rates of at least 80%.
  • All virological failures were attributable to relapse, with no viral breakthroughs during treatment.
  • Genetic sequencing revealed no S282T resistance mutations and no other NS5B substitutions causing reduced susceptibility to sofosbuvir or ribavirin.
  • Treatment with triple therapy was generally safe and well tolerated.
  • Almost all participants (98%) completed the study, with 7 total early discontinuations, 5 (2%) of which were due to adverse events.
  • About one-third of participants experienced side effects -- the most common being fatigue (59%), headache (36%), and nausea (34%) -- but serious adverse events were rare (1%).
  • Looking at side effects associated with other DAAs, 18% of patients experienced rash, 23% developed moderate anemia, and 2% had severe anemia.

Sofosbuvir + pegylated interferon + ribavirin for 12 weeks "resulted in 90% SVR12 rate," which was "statistically superior to historical control SVR rate of 60%," the investigators concluded. "Sofosbuvir was well tolerated without any additive effects of sofosbuvir to the expected safety profile of [pegylated interferon + ribavirin]."

Lawitz added that the sustained response rate of more than 80% for cirrhotic patients "is the highest reported in cirrhosis yet."

Since the overall response rate with 12 weeks of therapy was so good, an audience member asked if treatment could potentially be shortened even further. Lawitz replied that a shorter regimen is "worth studying" in a clinical trial. However, he noted, the study did not identify any on-treatment predictors (such as early viral kinetics) to indicate which patients are likely to relapse.

Even though this regimen still includes interferon and ribavirin, "from the patients' point of view, 12 weeks is a major breakthrough," said EASL Secretary-General Mark Thursz at a press conference highlight hepatitis C findings.

Results from the NEUTRINO study were also published in the April 23, 2013, advance online edition of the New England Journal of Medicine.

5/3/13

References

E Lawitz, D Wyles, M Davis, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1411.

E Lawitz, A Mangia, D Wyles, et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).

Other Source

Gilead Sciences. Data from Phase 3 Studies of Gilead’s Sofosbuvir for Hepatitis C To Be Presented at 48th Annual EASL Meeting; Findings Published Online Today in The New England Journal of Medicine. Press release. April 23, 2013.