EASL 2009: Boceprevir Achieves Highest Cure Rate Ever Against Hepatitis C in SPRINT-1

Becky McCall

April 27, 2009

April 27, 2009 (Copenhagen, Denmark) — Boceprevir, an investigational oral hepatitis C virus (HCV) protease inhibitor, in combination with peginterferon alfa-2b and ribavirin, significantly increases the sustained viral response (SVR) rate in patients with HCV genotype 1, according to a study presented here at the European Association for the Study of the Liver 44th Annual Meeting.

The findings are the final results of the phase 2 HCV Serine Protease Inhibitor Therapy (SPRINT)-1 study, which evaluated boceprevir (800 mg 3 times a day) in 3 treatment regimens: 4 weeks of peginterferon alfa-2b (1.5 μg/kg once weekly) plus ribavirin (800 to 1400 mg daily by weight) followed by the addition of boceprevir (800 mg 3 times a day) for either 24 weeks or 44 weeks; boceprevir in combination with peginterferon alfa-2b plus ribavirin at the doses above for either 28 or 48 weeks (triple-combination therapy); and peginterferon alfa-2b plus low-dose ribavirin (400 to1000 mg/day) and boceprevir for 48 weeks.

The primary end point of the study was SVR, defined as undetectable levels of virus, after 24 weeks of follow-up in the 595 chronic HCV genotype 1 patients who had not received treatment previously. Worldwide, these patients are the most difficult to treat, and it is the most common form of HCV in the United States, with more than 3 million individuals infected.

Lead investigator Paul Kwo, MD, associate professor of medicine at the School of Medicine, University of Indiana, in Indianapolis, explained that the study incorporated some difficult-to-treat subgroups. A total of "90% of the SPRINT-1 patients had a high viral level, 6% to 9 % of patients were cirrhotic, and 14% to 17% % were African American — another difficult-to-treat population." In total, 77% of patients were enrolled in the United States; the remainder were from Canada and Europe.

In part 1 of the study, control subjects were treated with peginterferon alfa-2b (1.5 μg/kg once weekly) and ribavirin (800 to 1400 mg daily by weight) alone for 48 weeks. In part 2, subjects receiving boceprevir in combination with peginterferon alfa-2b and low-dose ribavirin for 48 weeks were compared with control subjects receiving boceprevir in combination with peginterferon alfa-2b and standard-dose ribavirin for 48 weeks.

At 28 weeks, 56% of patients (58 of 103) achieved an SVR rate in the peginterferon alfa-2b and ribavirin lead-in followed by boceprevir. However, at 48 weeks, the peginterferon alfa-2b and ribavirin lead-in followed by boceprevir achieved an SVR rate of 75% (77 of 103), representing a near doubling of the 38% SVR rate (39 of 104) for patients in the control group (P < .0001).

Dr. Kwo explained that this result was landmark. "To date, for a trial of this size, this is the highest cure rate or SVR ever reported in the HCV genotype 1 population," he said.

Low-dose ribavirin was intended to minimize anemia, a common adverse effect of ribavirin treatment (and boceprevir). "To try to minimize these effects, ribavirin was given at a low dose. The strategy was to modestly reduce the ribavirin dose by 400 mg to see if we might reduce anemia while maintaining viral response rates, but this clearly did not work," Dr. Kwo told Medscape Gastroenterology.

Anemia was reported as an adverse event by half of the patients who received boceprevir and by one third of the patients taking the combination of peginterferon alfa-2b plus ribavirin at the standard doses. The low-dose ribavirin patients did report less anemia, with just one quarter reporting it as an adverse event. Patients with anemia were given erythropoietin, which was taken by 49% to 51% of patients taking boceprevir and 26% of patients taking the peginterferon alfa-2b plus ribavirin combination.

SPRINT-1 shows that boceprevir therapy can be tailored to the needs of individual patients and their response rates. "If the viral decline is sharp [and] becomes undetected in the first 4 weeks of boceprevir, which occurred in two thirds of patients (week 8 of total treatment), then the cure rates are between 82% and 94%, respectively, in the 28- and 48-week treatment groups, suggesting that the majority of patients treated with boceprevir will be treated for 28 weeks, Dr. Kwo pointed out. "But if the patient is a slow responder due to low interferon sensitivity or other reasons . . . and you clear the virus between weeks 4 and 12 of boceprevir, then continuing on for 48 weeks maximizes your chance of cure."

He illustrated this in cirrhotic patients who are very difficult to treat. Dr. explained that "50% of cirrhotic patients achieved SVR on the boceprevir combination, which is higher than the 40% rate for noncirrhotic patients on standard therapy."

Dr. Kwo concluded that larger studies with adequate statistical power need to be conducted to confirm these findings.

Commenting on boceprevir and other promising new compounds, Heiner Wedemeyer, MD, from the German Liver Foundation, explained to Medscape Gastroenterology that it is becoming increasingly important to monitor patient responses and to individualize treatment to patient needs. "We need . . . to shorten treatment durations as much as possible by actively measuring viral load so we know when a patient becomes virus-negative. This concept is starting to be introduced into the development of new compounds like boceprevir."

Dr. Wedemeyer also added that identifying the best responders early during treatment will help avoid unnecessarily initiating these patients on a new compound, saving costs and unnecessary treatment. However, "suboptimal treatment in patients not responding to interferon can also be avoided, thus preventing the development of resistance against boceprevir," he added.

The study was funded by Schering-Plough. Dr. Kwo has received grants from Schering-Plough, Vertex, Merck, Roche, GlaxoSmithKline, Onyx, and Novartis. Dr. Wedemeyer has disclosed no relevant financial relationships.

European Association for the Study of the Liver 44th Annual Meeting: Abstract 4. Presented April 23, 2009.

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