San Diego—Patients infected with hepatitis C virus (HCV) who reduced their daily ribavirin dose during telaprevir-based triple therapy did not significantly decrease their odds for achieving a sustained virologic response (SVR), according to a study presented at the 2012 Digestive Disease Week meeting (abstract 594).


After analyzing data from several previously published Phase III trials, the investigators found that ribavirin dose reduction, to 600 mg per day or less, had no substantial effect on SVR rates. The results do not suggest that telaprevir can or should be used without ribavirin; rather, they indicate that in cases where a patient is experiencing significant negative side effects from ribavirin, the dosage can be cut back in accordance with the package label without major consequence for SVR rates.
“In treatment-naive patients, the timing, duration and degree of ribavirin dose reduction did not substantially affect SVR achievements with a telaprevir-based regimen,” said study co-author Stuart K. Roberts, MD, of the Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia.

“This study gives us some degree of confidence that we can reduce ribavirin. We saw good results even with the 400 and 200 [mg per day] patients, and still maintained high SVR rates.”
Since telaprevir obtained the FDA’s go-ahead in May 2011, clinicians have struggled with how to manage patients who develop anemia, the key side effect associated with this protease inhibitor. In initial trials, hemoglobin values of 10 g/dL or less were observed in 36% of patients and of 8.5 g/dL or less in 14% of patients who received telaprevir combination treatment compared with 17% and 5%, respectively, with peginterferon (peg/IFN)-α and ribavirin alone. Although reducing the dose of ribavirin can ameliorate anemia, researchers did not know if and how a ribavirin decrease would influence SVR.

The current findings help clarify this question. Dr. Roberts and colleagues examined data from three Phase III studies of telaprevir: REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes), ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) and ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir). The ADVANCE and ILLUMINATE studies included treatment-naive patients with HCV genotype 1 who received 12 weeks of telaprevir with 24 or 48 weeks of peg/IFNα-2a/ribavirin. The REALIZE study consisted of treatment-experienced patients who received 12 weeks of telaprevir with 48 weeks of peg/IFNα-2a/ribavirin.

Analysis showed that half of treatment-naive patients (446 of 885) had their ribavirin dose reduced at least once, and of these, 90% had a reduction to 600 mg or less per day. (Ribavirin is typically given in 1,000 or 1,200 mg per day doses, depending on a patient’s weight.)

The researchers found that patients who received telaprevir achieved high SVR rates, regardless of ribavirin dosage. In the telaprevir-treated population, SVR was achieved in 74% of patients who received 600 mg of ribavirin or less per day, 75% of those who received 800 to 1,000 mg per day and 79% of those who did not receive a reduced dose. In the placebo group, SVR rates were much lower: 42%, 54% and 46%, respectively. Also, patients receiving placebo and peg/IFN-ribavirin were significantly less likely to reduce their ribavirin intake; only 18% of patients in the placebo group had a ribavirin dose reduction.

The study also showed that treatment-experienced patients were less likely to require ribavirin dose reduction than treatment-naive patients, but still had more dose modifications than patients in the placebo group. SVR rates were lower among treatment-experienced than in treatment-naive patients, and varied based on past experience. Prior partial responders and prior null responders, particularly, had reduced SVR rates ranging from 0% to 50%. Although the small sample size of previously treated patients limited interpretation of the data, the results suggest that there was minimal effect of ribavirin dose reduction on SVR among treatment-experienced patients, the investigators said.

This study answers very two important questions for clinicians, said Paul Pockros, MD, director of the Liver Disease Center, Scripps Clinic, La Jolla, Calif., who was not involved in the research.

“People always ask about ribavirin dose reduction—does it matter? The second question we ask is, ‘Should the dose be increased after the anemia is recovered?’ The dose reduction data suggest it doesn’t make any difference, and that ribavirin does not need to be increased.”

The package insert for telaprevir calls for physicians to use the labeled ribavirin dose-modification guidelines to manage anemia.


Investigators involved with the study reported the following disclosures: advisory committees/review panels for Abbott Laboratories, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck & Co., Onyx Pharmaceuticals, Pharmasset, Roche/Genentech, Tibotec, Vertex Pharmaceuticals and Wyeth Pharmaceuticals.