From the AGA Journals

All-oral simeprevir-sofosbuvir beat interferon-based regimen for HCV with compensated cirrhosis

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Cirrhosis better treated without ribavirin

At the time of sofosbuvir (SOF) and simeprevir (SMV) approval, efficacy results of the combinations assessed in this study were still limited, especially in patients with cirrhosis, GT-1a, and/or previous nonresponse. The recent study by Dr. Pearlman and his associates aims to give light to some of the questions

Dr. Xavier Forns

raised. In this open-label trial, 82 patients with GT-1a cirrhosis (61% null responders) were recruited. Patients were randomized 2:1 to either 12 weeks of all-oral SMV/SOF or to peginterferon (PEG)/ribavirin (RBV)/SOF. Fully 93% of patients given the all-oral regimen achieved SVR12, compared with 75% who received the interferon-containing regimen. SVR12 rates were higher in the SMV/SOF arm than in the PEG/RBV/SOF arm, independent of previous response (92% vs. 64% in null responders and 95% vs. 80% in naive patients). Moreover, virologic relapse was lower in the all-oral arm (12.5% vs. 8%; P = .009). These results, however, are based on a limited number of patients, particularly in the interferon-containing arm. In addition, the PEG used in this study was alfa-2b, which has not been studied in combination with SOF in clinical trials (its potential impact is thus unknown). One important point of the study is the lack of prognostic value of early viral kinetics: Rapid virologic response was not related to SVR12, which has been a hallmark in previous interferon-based regimens.

Regarding safety and tolerance, there were poorer self-reported outcomes and more side effects in the interferon group. The latter seems obvious because of

Dr. Sabela Lens

the well-known interferon profile, but RBV has been associated with higher rates of anemia in patients with cirrhosis undergoing interferon-free regimens. The use of SMV/SOF without RBV is certainly a crucial point of the study.

With the inherent limitations of the small number of patients, the study by Dr. Pearlman and his associates supports a greater efficacy and a better tolerance for a regimen combining SMV/SOF as compared to PEG/RBV/SOF in patients with GT-1a cirrhosis.

Dr. Sabela Lens and Dr. Xavier Forns are in the Liver Unit, Hospital Clínic Barcelona, IDIBAPS and CIBERehd, University of Barcelona. Dr. Lens has acted as an adviser for Janssen, MSD, and Gilead, and Dr. Forns has acted as an adviser for Janssen, Abbvie, and Gilead and has received unrestricted grant support from Janssen and MSD.



Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

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