Boceprevir Added to Standard Hepatitis C Treatment Boosts Response Rate

Fran Lowry

August 10, 2010

August 10, 2010 — The addition of the direct-acting antiviral agent boceprevir to standard treatment with pegylated interferon and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection could double the sustained response rate vs that seen with standard treatment alone, according to a new study published Online First August 9 in The Lancet.

"Standard-of-care treatment of genotype 1 hepatitis C virus is pegylated interferon and ribavirin for 48 weeks, which results in sustained virological response (SVR) in about 40-50% of individuals," write Paul Y. Kwo, MD, from Indiana University School of Medicine in Indianapolis, and colleagues. "Those who achieve SVR can have long-term benefits with improvement in degrees of liver fibrosis, reduction in complications of chronic liver disease, and improved quality of life."

Boceprevir is a novel peptidomimetic NS3 protease inhibitor that forms a covalent reversible complex with the NS3 protease in vitro. It has shown potent antiviral activity in the hepatitis C virus replicon system and in patients who did not respond to peginterferon with or without ribavirin, the study authors explain.

The aim of this study, dubbed Serine Protease Inhibitor Therapy-1 (SPRINT-1), was to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin. The authors also sought to ascertain the possibility of using a lower dose of ribavirin in the second part of the study.

The open-label trial, which was done at 67 sites in the United States, Canada, and Europe, comprised a total of 520 treatment-naive patients with genotype 1 hepatitis C virus infection. It had 7 treatment groups. In the first part of the study, patients were randomly assigned to 1 of 5 treatments, as follows:

  • Peginterferon alfa-2b 1.5 µg/kg plus ribavirin 800 to 1400 mg per day for 48 weeks (PR48);

  • Peginterferon alfa-2b 1.5 µg/kg and ribavirin 800 to 1400 mg daily for 4 weeks followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg 3 times a day for 24 weeks (PRB24);

  • Peginterferon alfa-2b 1.5 µg/kg and ribavirin 800 to 1400 mg daily for 4 weeks followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg 3 times a day for 44 weeks (PRB44);

  • Peginterferon alfa-2b 1.5 µg/kg, ribavirin 800 to 1400 mg, and boceprevir 800 mg for 28 weeks (PRB28); and

  • Peginterferon alfa-2b 1.5 µg/kg, ribavirin 800 to 1400 mg, and boceprevir 800 mg 3 times a day for 48 weeks (PRB48).

The second part of the study, which explored the safety and efficacy of a lower dose of ribavirin, randomly assigned patients to receive either the PRB48 regimen as in part 1 (n = 16) or peginterferon alfa-2b 1.5 µg/kg with ribavirin 400 to 1000 mg, and boceprevir 800 mg 3 times a day for 48 weeks (low-dose PRB48, n = 59).

The primary endpoint was SVR at 24 weeks of treatment, and analysis was by intent-to-treat.

Study Results

The study found that all 4 boceprevir groups had higher rates of SVR vs the PR48 control group. The SVR rate was 54% (P = .013 vs control) for patients in the PRB28 group, 56% (P = .005 vs control) for the PR4/PRB24 group, 67% (P < .0001 vs control) for the PRB48 group, and 75% (P < .0001 vs control) for the PR4/PRB44 group. The SVR for the control group was 38%.

The study also found that low-dose ribavirin markedly reduced the effectiveness of the 3-drug combination. The SVR in the group receiving the low-dose ribavirin combination (low-dose PRB48) was 36%.

Boceprevir-based groups had higher rates of anemia (55% vs 34%) and distortion of their sense of taste (27% vs 9%) vs the control group. Rates of discontinuation because of adverse events were higher in the boceprevir groups, ranging from 9% to 19%, vs 8% for the control PR48 group.

Study Limitations

The open-label design and the fact that patients were stratified according to the presence or absence of cirrhosis are potential limitations of this study, the authors point out. Eligibility for the study required a liver biopsy to be taken within 5 years of entry. A patient who tested negative could therefore have gone on to have cirrhosis in the intervening years. Therefore, the study authors write, the promising results that were seen in patients with cirrhosis who received boceprevir need confirmation in larger trials that are in progress.

The study authors conclude: "Boceprevir, in combination with pegylated interferon and ribavirin, achieved high SVR rates with 28 weeks of therapy in most patients and is safe and effective for use up to 48 weeks in the few patients who benefit from longer duration of therapy. We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis."

Comment: A "Step Forward" but Drug Resistance and Other Concerns

In an accompanying comment, Laura Milazzo, MD, and Spinello Antinori, MD, from the University of Milan, Milan, Italy, write that the results of the study, "obtained in many patients, provide further evidence that adding a potent NS3 protease inhibitor to standard therapy substantially improved the proportion of sustained virological responses, although not to the desired proportion."

Drs. Milazzo and Antinori also write about their concerns about drug resistance. "In Kwo and co-workers' study, mutations conferring resistance to both boceprevir and telaprevir were identified in more than a quarter of samples from patients with viral breakthrough. Such resistance will be the biggest challenge in the future."

The editorialists also write that the results from the study give rise to several questions. Among them is whether direct-acting antiviral agents might eventually allow interferon-free and ribavirin-free regimens to treat hepatitis C virus infection.

"Major efforts in the near future will be aimed at redesigning the stopping rules for therapy of chronic hepatitis C and to further tailor antiviral strategies in the population infected with hepatitis C virus," they write in their concluding comments. "In this regard, the new NS3 protease inhibitors are a step forward."

Invited Comment: Study "Useful Addition" but Still Some Concerns

Invited to comment on this study by Medscape Medical News, Kapil Chopra, MD, clinical director of hepatology at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, said: "Clearly it is an important study with respect to widening our treatment options for the management of chronic hepatitis C genotype 1. It has been able to prove that the group of drugs that belong to the protease inhibitors and specifically targeted antiviral therapy, or direct-acting antiviral agents would be a useful addition to the management of this disease. However, the new agent was added to the existing standard therapy, hence the future at this time is still interferon based regimens."

Commenting on the design of the study, Dr. Chopra said that, although it was somewhat complicated for the reader, it was adequately powered to address the main question being posed. However, it was inadequately powered to draw firm conclusions about subgroups, such as blacks and patients with cirrhosis.

That lowering the dose of ribavirin was not effective is an important finding, Dr. Chopra noted. "It reinforces our understanding that using the higher dose of ribavirin leads to an improved SVR. On the other hand, using the higher dose of ribavirin in combination with the new drug, boceprevir, will also add to the toxicity of the combination."

He agreed with Drs. Milazzo and Antinori regarding their concern about the development of mutations with the use of boceprevir and also with another drug in its class, telaprevir. "The long-term significance of the development of mutations has not been addressed and we do not know the clinical importance," he said, adding that the practice of treating patients with hepatitis C virus infection "will need to be done only by experts in the field, with a view to stringent patient monitoring for compliance, as otherwise it could lead to development of mutations."

This study was funded by Merck. Dr. Kwo has disclosed various financial relationships with Schering-Plough, Merck, Vertex, Tibotec, Roche, Abbott, Bristol-Myers Squibb, Gilead, Idenix, Valeant, GlaxoSmithKline, Human Genome Sciences, Anadys, and Novartis. A complete description of disclosures of the other study authors is available in the orginal article. Drs. Milazzo, Antinori, and Chopra have disclosed no relevant financial relationships.

Lancet. Published online August 9, 2010.


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