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.


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:

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%.


"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:

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.


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."



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.