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AASLD 2014: Sofosbuvir + Simeprevir Shows Good Results in Real-World Use

Regimens containing sofosbuvir (Sovaldi) -- including sofosbuvir plus simeprevir (Olysio) -- work well for people with hepatitis C genotype 1 in real-world use, which to date has included some of the patients most urgently in need of treatment at the dawn of the interferon-free era, according to a pair of presentations at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting last week in Boston. Sofosbuvir plus ribavirin alone is highly effective for people with genotype 2.

The advent of direct-acting antivirals (DAAs) that target different steps of the hepatitis C virus (HCV) lifecycle has brought about a revolution in treatment. While these drugs can improve effectiveness and shorten treatment duration when added to interferon-based therapy, many patients and providers have held out for all-oral regimens that avoid interferon and its difficult side effects.

Researchers with the HCV-TARGET Study Group and the TRIO Health network presented findings on real-world use of currently approved new DAAs suitable for use in all-oral regimens. (The first-generation HCV protease inhibitors boceprevir [Victrelis] and telaprevir [Incivek] must be used with interferon.)

Gilead Sciences' nucleotide HCV polymerase inhibitor sofosbuvir is among the most effective of these new drugs. While sofosbuvir plus ribavirin alone works well for people with easier-to-treat HCV genotype 2, those with harder-to-treat genotypes including 1 or 3 may need to add interferon or other DAAs.

Janssen's next-generation HCV protease inhibitor simeprevir was approved around the same time as sofosbuvir in late 2013. These drugs were not initially indicated for combined use and this regimen has not been through Phase 3 trials. However, the Phase 2 COSMOS trial showed that sofosbuvir plus simeprevir taken with or without ribavirin for 12 weeks curedmore than 90% of previously untreated and treatment-experienced genotype 1 patients with or without cirrhosis. 

Guidelines developed by both American experts and European specialists recommend sofosbuvir plus simeprevir for people with HCV genotype 1 who are unwilling or unable to take interferon, and this combination this month received supplemental approval from the U.S. Food and Drug Administration. But the recent approval of Gilead's sofosbuvir/ledipasvir coformulation (Harvoni) offers an at least equally effective and less expensive option for genotype 1 patients.

HCV-TARGET

In an oral abstract session devoted to currently approved HCV therapies, Donald Jensen from the University of Chicago Medical Center presented findings on the real-world experience of people undergoing treatment with sofosbuvir-containing regimens in HCV-TARGET, a consortium of more than 50 academic and community medical centers in the U.S., Canada, and Germany.

A total of 2330 people with hepatitis C consented to be included in HCV-TARGET, and of these 2063 started treatment. Nearly two-thirds were men, 76% were white, 12% were black, and the average age was 58 years; 2% were coinfected with HIV. About half were previously untreated for hepatitis C and half were treatment-experienced, including 18% who did not respond to a prior course of triple therapy with first-generation protease inhibitors.

Given the high cost of sofosbuvir and simeprevir, and the various restrictions on their availability and insurance coverage, experts recommend that people with advanced liver disease be prioritized for treatment, and that was reflected in this population. Nearly half (48%) had liver cirrhosis, 43% had a history of decompensation, and 34% had a MELD score >10. 10% had liver cancer and 11% had received a liver transplant. Overall, people who used sofosbuvir plus simeprevir were sicker than those who used sofosbuvir with pegylated interferon/ribavirin or with ribavirin alone.

Treatment was administered according to local standards of care, and patients and providers chose which regimens to use:

• Sofosbuvir plus simeprevir (n=784);
• Sofosbuvir plus ribavirin alone (n=667);
• Sofosbuvir plus pegylated interferon/ribavirin (n=384);
• Sofosbuvir/simeprevir/ribavirin (n=228).

Treatment distribution varied by HCV genotype. Among people with genotype 1, 53% used sofosbuvir plus simeprevir, 23% used sofosbuvir plus pegylated interferon/ribavirin, 15% used sofosbuvir/simeprevir/ribavirin and 9% used sofosbuvir with ribavirin alone. Almost everyone (99%) with genotype 2 received sofosbuvir with ribavirin alone. Genotype 3 is more difficult to treat but simeprevir is not effective against it, so 92% of these patients also used sofosbuvir with ribavirin alone.

Nelson reported sustained virological response rates for patients who had reached week 4 after completion of treatment (SVR4). While SVR4 is generally reflective of outcomes at 12 weeks post-treatment (SVR12), it is too soon to declare a cure as relapse may still occur. Among the subset of patients with both SVR4 and SVR12 results available (n=259), concordance or agreement was 94%-98%.

Results

• Overall, 78% of participants completed therapy and 18% were still on treatment. Only 3% stopped treatment prematurely, mostly due to adverse events (2.1%), which was not more likely to occur among people taking interferon.
• Early discontinuation due to lack of efficacy (0.4%), loss to follow-up (0.3%), or death (0.6%) was rare.
• Among evaluable genotype 1 patients treated with sofosbuvir plus pegylated interferon/ribavirin (n=164), the SVR4 rate was 85% (90% for non-cirrhotics vs 70% for cirrhotics).
• Among genotype 1 patients using sofosbuvir plus simeprevir with or without ribavirin (n=303), the SVR4 rate was 89% (92% for non-cirrhotics vs 87% for cirrhotics vs 75% for those with prior decompensation).
• Further breaking down the genotype 1 population who used sofosbuvir plus simeprevir, SVR4 rates were 86% for people with HCV subtype 1a and 95% for those with easier-to-treat subtype 1b.
• Among evaluable patients with prior treatment failure (n=54), the SVR4 rate was 81% (85% for non-cirrhotics vs 79% for cirrhotics).
• Among genotype 2 patients treated with sofosbuvir plus ribavirin (n=187), the SVR4 rate was 90% (91% for non-cirrhotics vs 88% for cirrhotics).
• Genotype 3 patients were not included in this report because most received longer treatment and were still undergoing follow-up for sustained response.
• In a minimally adjusted multivariate analysis, predictors of sustained response to sofosbuvir plus simeprevir with or without ribavirin included HCV subtype 1a, prior liver decompensation, lower baseline albumin level (a marker of poor liver function), and prior treatment failure using triple therapy.
• Across all patient subgroups using sofosbuvir plus simeprevir -- including the most difficult to treat genotype 1a cirrhotics -- adding ribavirin did not significantly increase response rates compared to sofosbuvir plus simeprevir alone.
• Overall, sofosbuvir-containing regimens were generally safe and well-tolerated. Serious adverse events were uncommon across all regimens (2.9% to 7.9%).
• The most frequent side effects were fatigue, headache and nausea.
• Flu-like symptoms were more common in the pegylated interferon arm, while anemia was reported more often among patients taking ribavirin.

"There was a high percentage of 'off-label' use of sofosbuvir/simeprevir," and real world data were "generally consistent" with Phase 2-3 clinical trial data, the researchers concluded.

Adverse event rates for all-oral regimens were "much lower" than those with pegylated interferon, they added, with the lowest frequency observed for interferon-free and ribavirin-free regimens.

TRIO Network

Douglas Dieterich from Mt Sinai Medical Center in New York City presented outcomes among hepatitis C patients people treated with sofosbuvir-based regimens in the TRIO Health network, which collects prescription data from U.S. academic and community medical centers, primarily in the northeast and Midwest.

The network obtained data from a total of 1211 hepatitis C patients seen by 231 providers at 150 practices (31 academic and 119 community sites). This analysis focused on 955 patients taking 12-week regimens:

• Sofosbuvir plus pegylated interferon/ribavirin (n=384);
• Sofosbuvir plus simeprevir, with or without ribavirin (n=320);
• Sofosbuvir plus ribavirin alone (n=227).

About 60% were men, most were white, 16% were black, and the average age was 57 years. Dieterich noted that the population had a lower proportion of men and more African-Americans than typical hepatitis C drug trials. Nearly three-quarters had HCV genotype 1, 22% had genotype 2, and about 5% had genotypes 3-6.

Nearly one-third had liver cirrhosis. About 40% were treatment-experienced, of whom two-thirds were relapsers or partial responders and one-third were prior null responders; 20% had previously been treated with HCV protease inhibitors. People taking sofosbuvir plus simeprevir were more likely to have cirrhosis and to be treatment-experienced.

Most genotype 2 patients (89%) received sofosbuvir plus ribavirin alone, while people with genotype 1 usually also included either pegylated interferon or simeprevir. Dieterich noted that many providers stopped using ribavirin with sofosbuvir plus simeprevir after the COSMOS results presented at this year's International Liver Congress showed that it did not significantly improve cure rates but did add side effects.

Results

• Among the 955 treated patients, most (92%) completed therapy, 44 discontinued treatment early, 25 were lost to follow-up, 9 died, and 1 received a liver transplant.
• Overall, 79% of participants achieved SVR12 in an intent-to-treat analysis of patients with sufficient follow-up time (n=822), rising to 88% in an as-treated or per-protocol analysis of patients who completed the full course of treatment (n=743).
• Among genotype 1 patients, intent-to-treat cure rates were 82% (90% per protocol) with sofosbuvir plus simeprevir with or without ribavirin, 77% (85% per protocol) with sofosbuvir plus pegylated interferon/ribavirin, and just 50% (78% per protocol) with sofosbuvir plus ribavirin alone.
• Focusing on the treatment-naive genotype 1 group, intent-to-treat SVR12 rates were about the same for people with HCV subtypes 1a and 1b who used sofosbuvir plus pegylated interferon/ribavirin (81% vs 82%), but 1b patients did better on sofosbuvir plus simeprevir (80% vs 92%).
• Similarly, people with and without cirrhosis had the same cure rate using sofosbuvir plus pegylated interferon/ribavirin (81%), but non-cirrhotics were more likely than cirrhotics to be cured with sofosbuvir plus simeprevir (88% vs 75%).
• Looking at the treatment-experienced genotype 1 group, intent-to-treat SVR12 rates did not differ between people with HCV 1a and 1b, regardless of regimen.
• Here, non-cirrhotics did better than people with cirrhosis whether they used sofosbuvir plus pegylated interferon/ribavirin (76% vs 62%) or sofosbuvir plus simeprevir (87% vs 76%).
• Turning to people with genotype 2, the intent-to-treat SVR12 rate using sofosbuvir plus ribavirin was 84% (90% per protocol).
• Intent-to-treat cure rates were 89% for both treatment-naive and treatment-experienced people without cirrhosis, falling to 65% for treatment-naive and 75% for treatment-experienced patients cirrhotics.
• Two-thirds (67%) of the 22 patients with genotype 4, 5, or 6 treated with sofosbuvir plus pegylated interferon/ribavirin were cured.
• There were not genotype 3 patients to analyze (n=7).
• Again, treatment was generally safe and well-tolerated.
• 6 people (2.0%) taking sofosbuvir plus pegylated interferon/ribavirin and 4 people (1.4%) taking sofosbuvir plus simeprevir stopped therapy early due to adverse events.

In this large, real-life population, SVR12 rates for 12-week regimens were "comparable to data reported in clinical trials," the researchers concluded, and "cirrhosis is the most important predictor of response."

Dieterich added that the cure rates seen in this real-world analysis were "much higher than I had predicted."

11/21/14

References

DM Jensen, JG O'Leary, PJ Pockros, et al. Safety and Efficacy of Sofosbuvir-Containing Regimens for Hepatitis C: Real-World Experience in a Diverse, Longitudinal Observational Cohort. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 45.

D Dieterich, BR Bacon, SL Flamm, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 46.