Thursday, June 23, 2011

Adjunctive Telaprevir Boosts Response in Chronic HCV

By: MARY ANN MOON, Internal Medicine News Digital Network
Adding telaprevir to standard peginterferon-plus-ribavirin therapy markedly improves the sustained virologic response in patients with chronic hepatitis C infection, even in those who did not respond well to a previous course of standard treatment, according to two separate phase III clinical trials reported in the June 23 New England Journal of Medicine.

The addition of the HCV protease inhibitor allowed most patients to halve their duration of therapy, reducing total treatment time from 48 to 24 weeks, minimizing the therapy’s toxic effects, and decreasing the rate of treatment discontinuation.

In the first report, Dr. Stefan Zeuzem and his associates in the REALIZE study group assessed the benefit of adding telaprevir to the regimens of 662 patients from 17 countries who had previously shown no response (28%), a partial response (19%), or a relapse (53%) after standard peginterferon-plus-ribavirin therapy.
They also assessed whether using a 4-week lead-in phase of peginterferon plus ribavirin before the addition of telaprevir would reduce the emergence of protease-resistant variants, as had been suggested by a previous study using a different HCV protease inhibitor.

The rates of sustained virologic response proved to be significantly higher in subjects who received telaprevir, both with and without the lead-in period, than in those who did not. These rates were 64% without a lead-in period and 66% with a lead-in period, compared with only 17% in the control group, which received peginterferon plus ribavirin only.

Even patients who had previously shown a minimal response to earlier therapy showed a nearly sixfold increase in sustained virologic response when telaprevir was added to the regimen, the investigators said (N. Engl. J. Med. 2011;364:2417-28).

Telaprevir improved the rates of sustained virologic response across all subgroups of patients, regardless of their viral load at baseline or the presence and severity of liver fibrosis or cirrhosis, said Dr. Zeuzem of Johann Wolfgang Goethe University Hospital, Frankfurt, Germany, and his colleagues.
Telaprevir also raised the rate of adverse events, chiefly fatigue, pruritus, rash, nausea, anemia, and diarrhea. The number of grade 3 adverse events (mainly anemia, neutropenia, and leucopenia) also was increased with telaprevir (37%), compared with the control group (22%). The rate of adverse events leading to permanent discontinuation of the study drugs was 13% in subjects who received telaprevir, compared with 3% in the control group.

In the second report, Dr. Ira M. Jacobson and his associates in the ADVANCE study assessed the addition of telaprevir in 1,088 patients at 123 international sites. These study subjects had never received therapy for chronic HCV.

The objective was to adjust treatment guided by the patient’s response after 4 weeks. Earlier studies have shown "high rates of early viral suppression and low rates of relapse after cessation of telaprevir therapy, [suggesting] that therapy could potentially be shortened to 24 weeks in patients who have a rapid virologic response – that is, patients in whom HCV RNA is undetectable at week 4 of treatment," said Dr. Jacobson of Cornell University and the Center for the Study of Hepatitis C, both in New York, and his colleagues.
One group of subjects received telaprevir in addition to standard peginterferon-plus-ribavirin therapy for 12 weeks. If they showed a rapid virologic response at 4 and 12 weeks, telaprevir was withdrawn and standard therapy was continued for 12 more weeks, for a total of 24 weeks of treatment. If there was no rapid response, standard therapy was extended for the customary 36 weeks, for a total of 48 weeks of treatment.
A second group received telaprevir plus standard therapy for 8 weeks, followed by placebo plus standard therapy for 4 weeks; their response to treatment determined the same two alternative courses of therapy as in group 1. The control group received placebo plus standard therapy for 12 weeks, followed by standard therapy for 36 weeks, for the standard total of 48 weeks of therapy.

A total of 75% of group 1 and 69% of group 2 showed a rapid and sustained virologic response, allowing them to complete treatment in half the usual time. Relapse was "infrequent" in these patients, indicating that a total of 24 weeks of therapy is sufficient for rapid responders, Dr. Jacobson and his colleagues said (N. Engl. J. Med. 2011;364:2405-16).

In comparison, only 44% of the control group achieved a rapid and sustained virologic response.
The addition of telaprevir also substantially improved treatment response among patient groups who usually respond poorly to standard therapy, including those with fibrosis or cirrhosis, older patients, diabetics, and those with a high viral load at baseline. Telaprevir more than doubled treatment response among black patients, who typically show a very poor response to interferon that likely results from genetic factors, the researchers noted.

Both studies were funded by Tibotec and Vertex Pharmaceuticals, which both manufacture telaprevir. Dr. Zeuzem and Dr. Jacobson reported ties to Tibotec and Vertex, as well as to numerous other industry sources.

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