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Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.
Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).
In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.
The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).
Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.
At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.
Having cirrhosis reduced the regimen’s SVR rate to 80%.
The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).
Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.
In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.
Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.
In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.
Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.
Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.
"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."
Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).
The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.
The rapid change in the landscape for treating hepatitis C virus infection and the speed of drug development in the field – in the case of sofosbuvir, only a 3-year interval separates the publications of the chemical discovery of the protease inhibitor and its clinical data – may have negatively affected the design of clinical trials in the field.
For example, only one of the two studies conducted by Dr. Lawitz was a randomized controlled trial, and while the Food and Drug Administration has approved an endpoint of an SVR at 12 weeks (rather than the previously approved 24 weeks) for use in HCV trials, there is a small percentage (4%-6%) of patients with relapse of disease 12-24 weeks after treatment with sofosbuvir despite having an SVR. Although viral breakthrough does not appear to happen with sofosbuvir and did not occur in any of these patients, they somehow still relapsed despite meeting the trial’s definition for SVR; the reasons for relapse remain unknown.
However, these concerns may be outweighed by the sofosbuvir regimen’s low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drug .
Dr. Joost P.H. Drenth is in the department of gastroenterology and hepatology at Radboud University Nijmegen (the Netherlands) Medical Center. He disclosed previous grants from Gilead Sciences, maker of sofosbuvir, and other pharmaceutical companies. His comments are derived from his editorial accompanying the sofosbuvir studies (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMe1303818]).
The rapid change in the landscape for treating hepatitis C virus infection and the speed of drug development in the field – in the case of sofosbuvir, only a 3-year interval separates the publications of the chemical discovery of the protease inhibitor and its clinical data – may have negatively affected the design of clinical trials in the field.
For example, only one of the two studies conducted by Dr. Lawitz was a randomized controlled trial, and while the Food and Drug Administration has approved an endpoint of an SVR at 12 weeks (rather than the previously approved 24 weeks) for use in HCV trials, there is a small percentage (4%-6%) of patients with relapse of disease 12-24 weeks after treatment with sofosbuvir despite having an SVR. Although viral breakthrough does not appear to happen with sofosbuvir and did not occur in any of these patients, they somehow still relapsed despite meeting the trial’s definition for SVR; the reasons for relapse remain unknown.
However, these concerns may be outweighed by the sofosbuvir regimen’s low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drug .
Dr. Joost P.H. Drenth is in the department of gastroenterology and hepatology at Radboud University Nijmegen (the Netherlands) Medical Center. He disclosed previous grants from Gilead Sciences, maker of sofosbuvir, and other pharmaceutical companies. His comments are derived from his editorial accompanying the sofosbuvir studies (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMe1303818]).
The rapid change in the landscape for treating hepatitis C virus infection and the speed of drug development in the field – in the case of sofosbuvir, only a 3-year interval separates the publications of the chemical discovery of the protease inhibitor and its clinical data – may have negatively affected the design of clinical trials in the field.
For example, only one of the two studies conducted by Dr. Lawitz was a randomized controlled trial, and while the Food and Drug Administration has approved an endpoint of an SVR at 12 weeks (rather than the previously approved 24 weeks) for use in HCV trials, there is a small percentage (4%-6%) of patients with relapse of disease 12-24 weeks after treatment with sofosbuvir despite having an SVR. Although viral breakthrough does not appear to happen with sofosbuvir and did not occur in any of these patients, they somehow still relapsed despite meeting the trial’s definition for SVR; the reasons for relapse remain unknown.
However, these concerns may be outweighed by the sofosbuvir regimen’s low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drug .
Dr. Joost P.H. Drenth is in the department of gastroenterology and hepatology at Radboud University Nijmegen (the Netherlands) Medical Center. He disclosed previous grants from Gilead Sciences, maker of sofosbuvir, and other pharmaceutical companies. His comments are derived from his editorial accompanying the sofosbuvir studies (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMe1303818]).
Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.
Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).
In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.
The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).
Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.
At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.
Having cirrhosis reduced the regimen’s SVR rate to 80%.
The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).
Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.
In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.
Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.
In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.
Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.
Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.
"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."
Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).
The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.
Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.
Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).
In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.
The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).
Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.
At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.
Having cirrhosis reduced the regimen’s SVR rate to 80%.
The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).
Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.
In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.
Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.
In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.
Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.
Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.
"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."
Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).
The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: A regimen containing sofosbuvir gave 90% of patients with genotype 1 or 4 HCV infection an SVR at 12 weeks, whereas genotype 2 and 3 patients had a 12-week SVR rate of 67%.
Data source: Two phase III studies (one single-group, open-label study and one randomized, open-label, active-control trial) of more than 1,000 patients
Disclosures: The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.