Back HCV Treatment EASL 2015: Sofosbuvir + Interferon/Ribavirin Effective for Hard-to-Treat Genotype 3 HCV Patients

EASL 2015: Sofosbuvir + Interferon/Ribavirin Effective for Hard-to-Treat Genotype 3 HCV Patients

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A throwback regimen of sofosbuvir (Sovaldi), ribavirin, and pegylated interferon taken for 12 weeks cured 93% of patients with hepatitis C virus (HCV) genotype 3 -- substantially more than sofosbuvir plus ribavirin alone taken for 16 or 24 weeks, according to results from the BOSON study presented Saturday at the European Association for the Study of the Liver (EASL) 50th International Liver Congress in Vienna. Interferon-containing therapy for 3 months was described as "surprisingly well-tolerated."

The advent of direct-acting antiviral agents has brought about a revolution in treatment for chronic hepatitis C. As direct-acting antivirals were developed they were first tested in combination with pegylated interferon and ribavirin, the old standard of care. But researchers soon discovered that most patients could be cured using all-oral regimens without interferon, which must be injected and often causes difficult side effects.

However, people with HCV genotype 3 do not respond as well to available interferon-free regimens, and those with liver cirrhosis and non-responders to prior therapy are particularly in need of more effective treatment options.

Graham Foster from Queen Mary's University of London and fellow investigators conducted the BOSON study to explore whether returning to an interferon-containing regimen could raise cure rates for hard-to-treat genotype 2 and 3 patients.

Prior clinical trials showed that sofosbuvir plus ribavirin taken for 12 weeks cured 82% of HCV genotype 2 patients with cirrhosis, Foster noted as background. Among people with genotype 3, this dual combination taken for 24 weeks cured only 68% of cirrhotics.

The Phase 3 BOSON trial (GS-US-334-0153) included 592 participants -- 48 with genotype 2 and 544 with genotype 3 -- enrolled in the North America, the UK, Australia and New Zealand. All genotype 2 patients were both treatment-experienced and had compensated cirrhosis. Among the genotype 3 patients, about half were prior non-responders and about a third had cirrhosis.

Overall, 67% of participants were men, the mean age was 50 years, most were white, and 13% were Asian. More than two-thirds had unfavorable IL28B gene variants associated with poor interferon response and the mean baseline HCV viral load was 6.3 log.

Participants were randomly assigned to receive extended-duration therapy with 400 mg once-daily sofosbuvir plus 1000-1200 mg weight-based ribavirin for either 16 or 24 weeks, or else sofosbuvir and ribavirin with 180 mcg once-weekly pegylated interferon for 12 weeks. The primary endpoint was sustained virological response, or HCV RNA below the lower limit of quantification (<15 IU/mL) at 12 weeks after the end of treatment (SVR12).

Results

  • Looking first at the hard-to-treat genotype 2 patients, SVR12 rates were 87% for sofosbuvir plus ribavirin for 16 weeks, 100% for the dual regimen for 24 weeks, and 94% for sofosbuvir plus ribavirin with pegylated interferon for 12 weeks.
  • Turning to the larger group of genotype 3 patients, sustained response rates were 71% for sofosbuvir plus ribavirin for 16 weeks and 84% for 24 weeks, rising to 93% for sofosbuvir plus ribavirin with pegylated interferon.
  • Within the genotype 3 group, SVR12 rates were 80%, 87%, and 95%, respectively, for people without cirrhosis.
  • The most dramatic improvement in response was seen for patients with cirrhosis: 51% with sofosbuvir and ribavirin for 16 weeks, 79% for 24 weeks, and 88% with interferon.
  • Among previously untreated patients, SVR12 rates were 77%, 88%, and 95%, respectively.
  • A big improvement was also seen when adding interferon for treatment-experienced patients: 64%, 80%, and 91%, respectively.
  • The most common reason for not achieving SVR12 was relapse after the end of treatment: 27, 12, and 5 patients in the respective treatment arms.
  • 2 people in the sofosbuvir plus ribavirin 24-week arm experienced viral breakthrough while on therapy and 6 discontinued treatment early or were lost to follow-up.
  • Genetic sequencing of virus from 78 patients with virological failure revealed that 12% had treatment-emergent sofosbuvir resistance mutations.
  • All treatment regimens were generally safe and well-tolerated.
  • The most frequently reported adverse events across all treatment arms were fatigue, headache, insomnia, and nausea.
  • Flu-like symptoms and fever were more common with the interferon-containing regimen.
  • While almost all participants in all treatment arms reported some adverse events, grade 3-4 (moderate to severe) events were uncommon: 6% with sofosbuvir plus ribavirin for 16 weeks, 4% with the dual regimen for 24 weeks, and 8% with the interferon-containing regimen for 12 weeks.
  • Serious adverse events (4%, 5% and 6%, respectively) and treatment discontinuations due to adverse events (2%, 1% and <1%) were rare and occurred with similar frequency across treatment arms.
  • Grade 3-4 laboratory abnormalities, however, were more than twice as common in the interferon-containing arm (15%, 15% and 38%, respectively) owing to anemia and reduced platelet counts.

Based on these results, treatment-experienced genotype 2 patients with cirrhosis had "high SVR12 rates with all regimens," while genotype 3 patients had "higher SVR12 rates with sofosbuvir plus pegylated interferon/ribavirin than with sofosbuvir plus ribavirin for 16 or 24 weeks," the researchers concluded. They added that all three regimens were "well-tolerated with a low rate of treatment discontinuation due to adverse events."

Foster noted that these were the highest sustained response rates observed to date for this challenging genotype 3 patient population in a Phase 3 study.

Focusing on the patients he described as the "toughest of the tough" -- genotype 3 prior non-responders with cirrhosis -- the cure rate rose from just 47% for sofosbuvir plus ribavirin taken for 16 weeks to 86% for the interferon-containing regimen taken for 12 weeks. All other subgroups had SVR12 rates above 80% using the interferon-free dual regimen for 24 weeks, confirming that this is the preferred duration for difficult-to-treat patients.

The short interferon-containing regimen in this study was "by and large very well-tolerated," Foster said. This surprisingly good tolerability may be attributable to its short duration. Before the advent of direct-acting antivirals the usual course of pegylated interferon/ribavirin was 24 weeks for HCV genotypes 2 and 3 or 48 weeks for genotypes 1 and 4.

While most hepatitis C patients and providers seek to avoid interferon-containing therapy in the direct-acting antiviral era, Foster said that "interferon may still have a role to play" in niche patient populations.

"I don't think any of us are happy going back to interferon and ribavirin, but these are patients who can't wait for the next generation [of antivirals]," he said. "It is an interim solution -- I don't think any of us are pretending this is a prefect long-term option."

Asked about using sofosbuvir/ledipasvir (Harvoni) for this patient population, Foster explained that ledipasvir "doesn't have much activity" against HCV genotype 3. Sofosbuvir plus Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (Daklinza) is a potential interferon-free alternative. Gilead Sciences, which produces sofosbuvir and Harvoni, is also working on a pangenotypic NS5A inhibitor (GS-5816) with more potent activity against genotype 3.

4/26/15

Reference

GR Foster, S Pianko, C Cooper, K Agarwal, et al. Sofosbuvir + peginterferon/ribavirin for 12 weeks vs sofosbuvir + ribavirin for 16 or 24 weeks in genotype 3 HCV infected patients and treatment-experienced cirrhotic patients with genotype 2 HCV: the BOSON study. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract L05.

Other Source

Gilead Sciences. Gilead Announces Results From Studies Evaluating Sofosbuvir-Based Regimens in Chronic Hepatitis C Patients With Genotypes 2-5. Press release. April 25, 2015.