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EASL 2013: Sofosbuvir + Ribavirin Cures Most Genotype 2 Hepatitis C, but Genotype 3 Response Is Lower

A dual oral regimen containing the hepatitis C polymerase inhibitor sofosbuvir plus ribavirin produced high sustained virological rates overall, but this was driven by very good response among people with HCV genotype 2, while those with genotype 3 did not fare as well, researchers reported this week at the 48th EASL International Liver Congress (EASL 2013) in Amsterdam.

The advent of direct-acting antiviral agents has changed the treatment paradigm for chronic hepatitis C, but many patients and providers continue to await all-oral regimens that avoid interferon and its difficult side effects.

Gilead Science's sofosbuvir (formerly GS-7977) is a once-daily nucleotide analog that targets the HCV NS5B polymerase. Studies have shown that it has potent antiviral activity, a high barrier to resistance, and is generally safe and well-tolerated.

Investigators evaluated a simple, short-duration regimen of sofosbuvir plus weight-based ribavirin for people with HCV genotypes 2 or 3, traditionally considered "easier-to-treat."

Edward Gane from Auckland City Hospital in New Zealand presented final results from the Phase 3 FISSION trial, looking at a 12-week regimen for treatment-naive patients. David Nelson from the University of Florida College of Medicine followed with findings from the FUSION trial, comparing the oral regimen for 12 versus 16 weeks for patients who were not cured with prior interferon-based therapy.

As Gane first reported at the 2011 AASLD Liver Meeting, 12 weeks of sofosbuvir (then known as PSI-7977) plus ribavirin cured100% of previously untreated genotype 2 or 3 patients without liver cirrhosis in the smaller Phase 2 ELECTRON trial.

The 12-week post-treatment sustained virological response (SVR12) rate fell to 68% for treatment-experienced patients, however, prompting researchers to test an additional month of dual therapy. Further analysis of newly added ELECTRON arms showed that sofosbuvir plus ribavirin was not adequate for people with HCV genotype 1 -- especially prior null responders, who had an SVR12rate of just 10%.

FISSION: Treatment-naive

The FISSION trial enrolled 499 patients with genotype 2 or 3 chronic hepatitis C. Two-thirds were men, most were white, and the mean age was 48 years. Just over 70% had genotype 3 and about 43% had the favorable IL28B CC gene pattern. Participants reflected a "real-world" population: the average body mass index was high (28), 20% had compensated cirrhosis, and use of opiate substitution for injection drug users was permitted.

Participants were randomly assigned to receive either 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin for 12 weeks, or the standard-of-care (SoC) regimen of 180 mcg/week pegylated interferon plus 800 mg/day fixed-dose ribavirin for 24 weeks.

Results

• Sofosbuvir/ribavirin induced a rapid decrease in viral load, with 99% achieving rapid virological response at week 4 of therapy (vs 67% in the SoC arm).
• The same proportion remained undetectable at the end of treatment (99% also in the SoC arm).
• Treatment failure rates were similar, resulting in SVR12 rates of 67% in both arms.
• Post-treatment relapse happened more often in the sofosbuvir/ribavirin arm, while viral breakthrough during therapy was more common among SoC recipients.
• No resistance was detected in patients who experienced virological failure.
• The most interesting finding was the difference in response between genotype 2 and 3 patients.
• Among people with genotype 2, the SVR12 rate was 97% (vs 78% in the SoC arm).
• The SVR12 rate fell to just 56%, however, for people with genotype 3 (vs 63% for SoC).
• The difference was even more pronounced amongst the subset of participants with cirrhosis.
• Genotype 2 patients had high sustained response rates whether they had cirrhosis or not, at 91% and 98%, respectively.
• Among genotype 3 patients, only 34% of cirrhotics were cured, compared to 61% without cirrhosis.
• There were fewer side-effects overall (86% vs 96%), grade 3 or higher adverse events (7% vs 19%), and discontinuations for this reason (1% vs 11%) in the sofosbuvir/ribavirin arm than in the interferon-containing arm.
• Anemia was more common among interferon recipients, even though they used a lower ribavirin dose.
• No specific side effects were reported more often in the sofosbuvir-containing arm.

The researchers concluded that sofosbuvir plus ribavirin for 12 weeks was well-tolerated and met the criteria for non-inferiority to the standard 24-week pegylated interferon plus ribavirin regimen.

After his presentation Gane was asked if he was disappointed in these findings, given the high sustained response rates for genotype 2 or 3 patients in the ELECTRON trial. He replied that he was "disappointed but not surprised," given that ELECTRON was a smaller study that did not include people with cirrhosis.

FUSION: Treatment-experienced

The FUSION study enrolled 201 genotype 2 or 3 patients who had previously attempted interferon-based therapy. Again, most were white men and the mean age was 54 years. About 63% had genotype 3, one-third had cirrhosis, 30% were IL28B CC, and three-quarters were prior post-treatment relapsers -- considered more promising candidates for re-treatment than prior null responders.

Participants were randomized to receive 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin for either 12 or 16 weeks. They were also compared against a historical control SVR rate of 25% for similar patients using interferon-based therapy.

Results

• As in FISSION, viral decline was dramatic and rapid, with 97%-98% achieving undetectable viral load at week 4, and 100% at the end of either 12 or 16 weeks of treatment.
• Relapse was common after completing therapy -- usually within 4 weeks -- resulting in SVR12 rates of 50% for the 12-week oral regimen and 73% for the 16-week regimen.
• Among genotype 2 patients, response rates were high for both the 12-week and 16-week regimens, at 86% and 94%, respectively.
• Sustained response rates were much lower for genotype 3 patients --  30% and 62%, respectively -- and treatment duration had a greater impact.
• In this study, cirrhosis negatively affected response rates for both genotype 2 and 3 patients.
• While 96% and 100% of non-cirrhotic genotype 2 patients treated for 12 and 16 weeks achieved SVR12, corresponding rates fell to 60% and 78% for those with cirrhosis.
• Among genotype 3 patients, the non-cirrhotic SVR12 rates for 12 and 16 weeks were 37% and 63%, respectively, falling to 19% and 61% for cirrhotics.
• In other words, 12-week treatment cured 37% of genotype 3 non-cirrhotics and 19% of non-cirrhotics, though the 16-week regimen worked about the same for both subgroups.
• For people with genotype 3 overall, longer treatment doubled the response rate, but for cirrhotics, the rate tripled, Nelson summarized.
• Again, side effects were common overall, but serious adverse events and discontinuations for this reason were rare across the board.
• There were no notable differences in frequency of any side effects between the 12-week and 16-week groups, indicating that the extra 4 weeks had "no significant negative impact."

The investigators concluded that sofosbuvir plus ribavirin "provided a simple, well tolerated, interferon-free regimen" for treatment-experienced patients with genotype 2 or 3 HCV infection. While genotype 2 patients had high SVR rates with either 12 or 16 weeks of therapy, extending treatment duration to 16 weeks "significantly increased SVR rates" in genotype 3 patients, particularly those with cirrhosis.

Nelson said that he would feel comfortable treating genotype 2 patients for 12 weeks, though he would like more data for cirrhotics. For those with genotype 3, however, "16 weeks is a bare minimum," and an ongoing study is looking at whether 24 weeks might be better. Unfortunately, he added, the data revealed no on-treatment predictors of which patients are likely to relapse.

The FISSION and FUSION results were also published in the April 23, 2013, advance online edition of the New England Journal of Medicine, released to coincide with the conference.

The FUSION article also describes findings from POSITRON, a Phase 3 placebo-controlled trial of sofosbuvir plus ribavirin for genotype 2 or 3 patients who were "ineligible, intolerant, or unwilling" to take interferon. In this study, SVR12 rates were 93% for patients with genotype 2 and 61% for those with genotype 3.

Genotype 2 vs 3: Apples and Oranges?

In early April Gilead submitted a New Drug Application asking the U.S. Food and Drug Administration to approve sofosbuvir as part of all-oral therapy for people with genotypes 2 or 3, and as an add-on to pegylated interferon/ribavirin for patients with genotypes 1, 4, 5, or 6.

But the latest results call into question the traditional classification of HCV genotypes are easy or difficult to treat.

 Session chair and EASL Secretary General Mark Thursz brought up the issue of whether patients with genotypes 2 and 3 should continue to be "lumped together" in clinical trials and practice guidelines.

Gane responded that they clearly should not, as genotype 3 is "behaving as a harder-to-treat virus," especially when using single direct-acting antivirals.

The divergence in response between genotypes 2 and 3 is similar to the disparity that has emerged over the past couple years between HCV subtypes 1a and 1b. Viral variants that were assumed to be similar when only interferon was available have proven to be quite different in their response to new direct-acting agents, leaving researchers scrambling to re-stratify their data take this effect into account.

4/26/13

References

E Gane, E Lawitz, M Rodriguez-Torres, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naive GT2/3 HCV-infected patients (FISSION). 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 5.

DR Nelson, J Feld, KV Kowdley, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced GT2/3 HCV-infected patients: results of the phase 3 FUSION trial. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 6.

I Jacobson, EMYoshida, M Sulkowski, et al.  Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 61.

IM Jacobson, SC Gordon, KV Kowdley, et al. Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).

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 Sources

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.

Weill Cornell Medical College. Sofosbuvir is Much Safer Drug than Interferon, Which Many Patients Do Not Respond to or Tolerate. Press release. April 23, 2013.