By Michael Smith, North American Correspondent, MedPage Today
Published: August 08, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
An investigational protease inhibitor aimed at blocking hepatitis C replication can double the response rate compared with standard care, researchers said.
In an open-label randomized phase II trial, adding the compound -- boceprevir -- to standard therapy in various combinations increased the so-called sustained virological response compared with a control group who got only standard care, according to Paul Kwo, MD, of the Indiana University School of Medicine in Indianapolis, and colleagues.
But the response rate was doubled when patients were first treated with four weeks of standard therapy -- peginterferon alfa-2b and ribavirin -- before boceprevir was added for another 44 weeks, they reported online in The Lancet.
The current standard therapy for hepatitis C aims to stimulate the immune system in general without specific interference in viral replication. For patients with the difficult-to-treat genotype 1 of the virus, the therapy yields a sustained virological response in between 40% and 50% of patients.
In contrast, boceprevir (and a second drug, telaprevir, being investigated separately) blocks the action of the NS3 protease enzyme of hepatitis C, directly preventing viral replication. Early results of this trial were reported last year. (See Sustained Response Seen with New Hepatitis C Drug)
The researchers tested various drug combinations and treatment schedules in 520 treatment-naive patients with genotype 1 virus. They were randomly assigned to get:
•A control standard therapy of peginterferon alfa-2b plus ribavirin for 48 weeks
•Standard care for four weeks, then standard care plus boceprevir (at 800 milligrams three times a day) for 24 weeks
•Standard care for four weeks, then standard care plus boceprevir (at the same dosage) for 44 weeks
•Standard care and boceprevir for 28 weeks
•Standard care and boceprevir for 48 weeks
In a second part of the study, 75 patients were randomly assigned to get 48 weeks of the triple combination or a 48-week variant in which the ribavirin dose was reduced from 800 to 1,400 milligrams daily to 400 to 1,000 milligrams.
All of the combinations that included boceprevir did better than standard therapy, the researchers reported, with sustained virological response rates ranging from 54% to 75%, compared with 39% for patients in the control arm.
The 75% response rate occurred in the patients who got standard care for four weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir for 44 weeks. The difference from the control arm was significant at P<0.0001.
Next best was a 67% response rate seen in patients who got all three drugs for 48 weeks. The difference from the control arm was also significant at P<0.0001.
In the second part of the trial, the low-dose ribavirin combination yielded a response rate of 36% and was associated with a high rate of both viral breakthrough (caused by resistance mutations) and relapse, the researchers wrote.
In both parts of the study, they reported, boceprevir-based groups had higher rates of anemia and dysgeusia (altered sense of taste) than did the control group -- 55% versus 34% and 27% versus 9%, respectively.
The new NS3 protease inhibitors are a step forward in the treatment of hepatitis C, according to Laura Milazzo, MD, and Spinello Antinori, MD, both of the University of Milan.
Writing in an accompanying editorial, they said the results of the study suggest that adding boceprevir to the standard treatment substantially improves outcomes, "although not to the desired proportion."
But, they added, the emergence of resistance is an issue that needs to be addressed. "Such resistance will be the biggest challenge in the future," they wrote.
Lessons from the HIV pandemic, they commented, demonstrate that only complete suppression of viral replication can prevent drug resistance, so that new strategies are needed to explore combinations of drugs, improve adherence, improve the pharmacokinetics of the drugs, and develop resistance testing.
Limitations of the study included its open-label design (although the authors noted that the endpoints were hepatitis C RNA levels which were blinded laboratory measurements) and classification of patients as with or without cirrhosis based on liver biopsy, which could have been as much as five years old.
The study was supported by Merck.
Kwo reported financial links with Schering-Plough/Merck, Vertex, Tibotec, Roche, Abbott, Bristol-Myers Squibb, Gilead, Idenix, Valeant, Novartis, Anadys, GlaxoSmithKline, and Human Genome Sciences. Several other authors reported financial links with Schering-Plough/Merck, as well as with a range of other pharmaceutical companies.
The editorialists declared they had no competing interests.
Primary source: The Lancet
Source reference:
Kwo PY, et al "Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)60934-8.
Additional source: The Lancet
Source reference:
Milazzo L, Antinori S "STAT-C: a full revolution or just a step forward?" Lancet 2010; DOI: 10.1016/S0140-6736(10)61056-2.
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