Novel Hep C Treatment Excludes Peginterferon Alfa

Therapy with a novel nonnucleoside polymerase inhibitor, in combination with a protease inhibitor and ribavirin, achieved a 100% virologic response rate at 29 days among patients with hepatitis C genotype 1, Dr. Stefan Zeuzem and colleagues reported in the December issue of Gastroenterology.

Moreover, this novel alternative to the standard peginterferon alfa regimen was safe, with no serious adverse events, and was highly tolerable, the investigators said.

"This indicates that HCV [hepatitis C virus] can be eradicated in chronically infected patients with a PegIFN-free DAA [direct-acting antiviral agent] combination regimen," the authors wrote.

Dr. Zeuzem, of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues studied 34 adult patients (mean age 51 years) who were naive to interferon, PegIFN, ribavirin, or any DAA for acute or chronic hepatitis C infection.

All patients had plasma HCV RNA levels of at least 100,000 IU/mL at screening and did not have cirrhosis.

Patients with hepatitis B virus, human immunodeficiency virus, previous or ongoing rash or photosensitivity, decompensated liver disease, or hyperbilirubinemia greater than 1.5 times the upper limit of normal were excluded.

Participants were randomized in a 1:1 fashion to receive a thrice-daily 400-mg or 600-mg dose of BI 207127, "an orally bioavailable, reversible, thumb pocket 1 nonnucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro," according to the authors (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.08.051]).

"This indicates that HCV can be eradicated in chronically infected patients with a PegIFN-free DAA combination regimen."

All participants also received BI 201335, "a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT-1a/1b subtypes," wrote the authors, at a dose of 120 mg per day, as well as daily weight-dosed ribavirin, all taken with food, for 4 weeks.

"Drug-resistance studies in cell culture demonstrate that BI 201335 and BI 207127 have different resistance profiles, and previous observations using NS3/4A protease inhibitors and NS5B thumb pocket 1 NNI compounds demonstrate that 2-drug combinations profoundly reduce the selection of drug-resistant variants," explained Dr. Zeuzem.

The researchers found that in the cohort taking the larger, 600-mg doses of the polymerase inhibitor BI 207127, virologic response rates (defined as plasma HCV RNA levels of less than 25 IU/mL) were 18%, 82%, 100%, and 100% at days 8, 15, 22, and 29, respectively.

Slightly less impressive results were seen in the 400-mg group, with rates of 27%, 47%, 67%, and 73% at days 8, 15, 22, and 29 respectively.

Also in the 400-mg cohort, "higher response rates were observed in genotype 1b infected patients, compared with genotype 1a infected patients," wrote the authors, whereas results in the 600 mg group were not contingent on sub-genotypes.

"Most patients in the 600 mg TID [three times a day] dose group even had undetectable HCV RNA at days 22 and 29 (53% and 71%, respectively), while these rates did not exceed 20% in the 400 mg TID dose group," added the investigators.

Looking at safety and tolerability, Dr. Zeuzem and colleagues noted that most patients in both dosing cohorts complained of mild diarrhea, nausea, and vomiting.

Additionally, at the 600-mg dose, 42% developed mild rashes or photosensitivities, they said, and four patients developed "transient and very mild paresthesias of very different localizations."

"However, there were no severe AEs [adverse events], serious AEs or AE-related premature treatment discontinuations within the 4-week study period."

The "crucial next step," according to the investigators, will be achievement of longer-term SVR on the novel peginterferon-free regimen.

"Moreover, eliminating not only PegIFN but also RBV [ribavirin] from future HCV treatment would undoubtedly improve tolerability and would potentially allow for the treatment of patients with RBV contraindications," they added.

Indeed, at the time of this study’s publication, a phase 2b study was ongoing.

Dr. Zeuzem, along with several of his coinvestigators, disclosed financial and consulting relationships with multiple pharmaceutical companies, including the makers of the novel drugs used in this study, Boehringer Ingelheim. Boehringer Ingelheim also funded editorial assistance provided for this article.

Therapy with a novel nonnucleoside polymerase inhibitor, in combination with a protease inhibitor and ribavirin, achieved a 100% virologic response rate at 29 days among patients with hepatitis C genotype 1, Dr. Stefan Zeuzem and colleagues reported in the December issue of Gastroenterology.

Moreover, this novel alternative to the standard peginterferon alfa regimen was safe, with no serious adverse events, and was highly tolerable, the investigators said.

"This indicates that HCV [hepatitis C virus] can be eradicated in chronically infected patients with a PegIFN-free DAA [direct-acting antiviral agent] combination regimen," the authors wrote.

Dr. Zeuzem, of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues studied 34 adult patients (mean age 51 years) who were naive to interferon, PegIFN, ribavirin, or any DAA for acute or chronic hepatitis C infection.

All patients had plasma HCV RNA levels of at least 100,000 IU/mL at screening and did not have cirrhosis.

Patients with hepatitis B virus, human immunodeficiency virus, previous or ongoing rash or photosensitivity, decompensated liver disease, or hyperbilirubinemia greater than 1.5 times the upper limit of normal were excluded.

Participants were randomized in a 1:1 fashion to receive a thrice-daily 400-mg or 600-mg dose of BI 207127, "an orally bioavailable, reversible, thumb pocket 1 nonnucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro," according to the authors (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.08.051]).

"This indicates that HCV can be eradicated in chronically infected patients with a PegIFN-free DAA combination regimen."

All participants also received BI 201335, "a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT-1a/1b subtypes," wrote the authors, at a dose of 120 mg per day, as well as daily weight-dosed ribavirin, all taken with food, for 4 weeks.

"Drug-resistance studies in cell culture demonstrate that BI 201335 and BI 207127 have different resistance profiles, and previous observations using NS3/4A protease inhibitors and NS5B thumb pocket 1 NNI compounds demonstrate that 2-drug combinations profoundly reduce the selection of drug-resistant variants," explained Dr. Zeuzem.

The researchers found that in the cohort taking the larger, 600-mg doses of the polymerase inhibitor BI 207127, virologic response rates (defined as plasma HCV RNA levels of less than 25 IU/mL) were 18%, 82%, 100%, and 100% at days 8, 15, 22, and 29, respectively.

Slightly less impressive results were seen in the 400-mg group, with rates of 27%, 47%, 67%, and 73% at days 8, 15, 22, and 29 respectively.

Also in the 400-mg cohort, "higher response rates were observed in genotype 1b infected patients, compared with genotype 1a infected patients," wrote the authors, whereas results in the 600 mg group were not contingent on sub-genotypes.

"Most patients in the 600 mg TID [three times a day] dose group even had undetectable HCV RNA at days 22 and 29 (53% and 71%, respectively), while these rates did not exceed 20% in the 400 mg TID dose group," added the investigators.

Looking at safety and tolerability, Dr. Zeuzem and colleagues noted that most patients in both dosing cohorts complained of mild diarrhea, nausea, and vomiting.

Additionally, at the 600-mg dose, 42% developed mild rashes or photosensitivities, they said, and four patients developed "transient and very mild paresthesias of very different localizations."

"However, there were no severe AEs [adverse events], serious AEs or AE-related premature treatment discontinuations within the 4-week study period."

The "crucial next step," according to the investigators, will be achievement of longer-term SVR on the novel peginterferon-free regimen.

"Moreover, eliminating not only PegIFN but also RBV [ribavirin] from future HCV treatment would undoubtedly improve tolerability and would potentially allow for the treatment of patients with RBV contraindications," they added.

Indeed, at the time of this study’s publication, a phase 2b study was ongoing.

Dr. Zeuzem, along with several of his coinvestigators, disclosed financial and consulting relationships with multiple pharmaceutical companies, including the makers of the novel drugs used in this study, Boehringer Ingelheim. Boehringer Ingelheim also funded editorial assistance provided for this article.

Therapy with a novel nonnucleoside polymerase inhibitor, in combination with a protease inhibitor and ribavirin, achieved a 100% virologic response rate at 29 days among patients with hepatitis C genotype 1, Dr. Stefan Zeuzem and colleagues reported in the December issue of Gastroenterology.

Moreover, this novel alternative to the standard peginterferon alfa regimen was safe, with no serious adverse events, and was highly tolerable, the investigators said.

"This indicates that HCV [hepatitis C virus] can be eradicated in chronically infected patients with a PegIFN-free DAA [direct-acting antiviral agent] combination regimen," the authors wrote.

Dr. Zeuzem, of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues studied 34 adult patients (mean age 51 years) who were naive to interferon, PegIFN, ribavirin, or any DAA for acute or chronic hepatitis C infection.

All patients had plasma HCV RNA levels of at least 100,000 IU/mL at screening and did not have cirrhosis.

Patients with hepatitis B virus, human immunodeficiency virus, previous or ongoing rash or photosensitivity, decompensated liver disease, or hyperbilirubinemia greater than 1.5 times the upper limit of normal were excluded.

Participants were randomized in a 1:1 fashion to receive a thrice-daily 400-mg or 600-mg dose of BI 207127, "an orally bioavailable, reversible, thumb pocket 1 nonnucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro," according to the authors (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.08.051]).

"This indicates that HCV can be eradicated in chronically infected patients with a PegIFN-free DAA combination regimen."

All participants also received BI 201335, "a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT-1a/1b subtypes," wrote the authors, at a dose of 120 mg per day, as well as daily weight-dosed ribavirin, all taken with food, for 4 weeks.

"Drug-resistance studies in cell culture demonstrate that BI 201335 and BI 207127 have different resistance profiles, and previous observations using NS3/4A protease inhibitors and NS5B thumb pocket 1 NNI compounds demonstrate that 2-drug combinations profoundly reduce the selection of drug-resistant variants," explained Dr. Zeuzem.

The researchers found that in the cohort taking the larger, 600-mg doses of the polymerase inhibitor BI 207127, virologic response rates (defined as plasma HCV RNA levels of less than 25 IU/mL) were 18%, 82%, 100%, and 100% at days 8, 15, 22, and 29, respectively.

Slightly less impressive results were seen in the 400-mg group, with rates of 27%, 47%, 67%, and 73% at days 8, 15, 22, and 29 respectively.

Also in the 400-mg cohort, "higher response rates were observed in genotype 1b infected patients, compared with genotype 1a infected patients," wrote the authors, whereas results in the 600 mg group were not contingent on sub-genotypes.

"Most patients in the 600 mg TID [three times a day] dose group even had undetectable HCV RNA at days 22 and 29 (53% and 71%, respectively), while these rates did not exceed 20% in the 400 mg TID dose group," added the investigators.

Looking at safety and tolerability, Dr. Zeuzem and colleagues noted that most patients in both dosing cohorts complained of mild diarrhea, nausea, and vomiting.

Additionally, at the 600-mg dose, 42% developed mild rashes or photosensitivities, they said, and four patients developed "transient and very mild paresthesias of very different localizations."

"However, there were no severe AEs [adverse events], serious AEs or AE-related premature treatment discontinuations within the 4-week study period."

The "crucial next step," according to the investigators, will be achievement of longer-term SVR on the novel peginterferon-free regimen.

"Moreover, eliminating not only PegIFN but also RBV [ribavirin] from future HCV treatment would undoubtedly improve tolerability and would potentially allow for the treatment of patients with RBV contraindications," they added.

Indeed, at the time of this study’s publication, a phase 2b study was ongoing.

Dr. Zeuzem, along with several of his coinvestigators, disclosed financial and consulting relationships with multiple pharmaceutical companies, including the makers of the novel drugs used in this study, Boehringer Ingelheim. Boehringer Ingelheim also funded editorial assistance provided for this article.