The Lancet, Early Online Publication, 9 August 2010
doi:10.1016/S0140-6736(10)60934-8
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Dr Paul Y Kwo MD a , Eric J Lawitz MD b, Jonathan McCone MD c, Prof Eugene R Schiff MD d, Prof John M Vierling MD e, David Pound MD f, Mitchell N Davis DO g, Joseph S Galati MD h, Stuart C Gordon MD i, Natarajan Ravendhran MD j, Prof Lorenzo Rossaro MD k, Frank H Anderson MD l, Prof Ira M Jacobson MD m, Raymond Rubin MD n, Kenneth Koury PhD o, Lisa D Pedicone PhD o, Clifford A Brass MD o, Eirum Chaudhri MD o, Janice K Albrecht PhD o
Summary
Background
Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.
Methods
In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 μg/kg plus ribavirin 800—1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400—1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670.
Findings
Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44—64], p=0·013 for PRB28; 58/103 [56%, 44—66], p=0·005 for PR4/PRB24; 69/103 [67%, 57—76], p<0·0001 for PRB48; and 77/103 [75%, 65—83], p<0·0001 for PR4/PRB44; vs 39/104 [38%, 28—48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.
Interpretation
In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone.
Funding
Merck.
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Adding Boceprevir to Standard Hepatitis C Treatment Could Double Response Rate
NEW YORK -- August 9, 2010 -- Fewer than half of patients given the standard hepatitis C virus (HCV) treatment for genotype 1 hepatitis C infection for 48 weeks achieve sustained virological response (SVR). But adding boceprevir to peginterferon and ribavirin can result in a near-doubling of the response rate, according to a study published early online and appearing in an upcoming edition of The Lancet.
Genotype 1 HCV remains the most difficult to treat with this standard regimen of pegylated interferon and ribavirin. In this 2-part study, Paul Y Kwo, MD, Indiana University School of Medicine, Indianapolis, Indiana, and colleagues aimed to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin, and to assess the possibility of using a lower dose of ribavirin.
In part 1 of the phase 2 trial, undertaken in 67 sites in the US, Canada, and Europe, 520 treatment-naive patients with genotype 1 HCV were randomly assigned to receive peginterferon alfa-2b 1.5 mcg/kg plus ribavirin 800 to 1400 mg daily for 48 weeks (PR48; n = 104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg TID for 24 weeks (PR4/PRB24; n = 103) or 44 weeks (PR4/PRB44; n = 103); or peginterferon alfa-2b, ribavirin, and boceprevir TID for 28 weeks (PRB28; n = 107) or 48 weeks (PRB48; n = 103).
In part two, 75 patients were randomly assigned to receive either PRB48 (n = 16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir TID for 48 weeks (low-dose PRB48; n = 59).
The primary endpoint was SVR 24 weeks after treatment.
The researchers found that patients in all 4 boceprevir groups had higher rates of SVR than did the control group (58/107 [54%] for PRB28; 58/103 [56%] for PR4/PRB24; 69/103 [67%] for PRB48; and 77/103 [75%] for PR4/PRB44; vs 39/104 [38%] for PR48 control).
Low-dose ribavirin markedly reduced the effectiveness of the 3-drug combination.
Boceprevir-based groups had higher rates of anaemia (55% vs 34%) and distortion of their sense of taste (27% vs 9%) than did the control group.
"The results of this phase 2 trial have shown that an optimum dose of boceprevir (800 mg three times a day), when added to the standard of care for treatment of chronic genotype 1 hepatitis C virus, significantly increased SVR in both 28-week and 48-week regimens compared with the control of peginterferon alfa-2b and ribavirin," the authors wrote.
"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," they continued. "We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis."
In a linked commentary, Laura Milazzo, MD, and Spinello Antinori, MD, University of Milan, Milan, Italy, said: "The emergence of drug-resistant virus needs to be addressed...The lesson learned from anti-HIV therapy indicates that complete viral suppression is required to prevent drug resistance. Hence new strategies must be established to explore the combinations of new drugs, improve adherence to treatment, improve pharmacokinetics (for example by boosting the new protease inhibitors with ritonavir to achieve higher plasma concentrations of active drug and to limit the pill burden), and develop resistance testing."
SOURCE: The Lancet
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