January 6, 2013

Hepatitis C Treated With Oral Nucleotide Inhibitor

Joe Barber Jr, PhD

Jan 03, 2013

Twelve weeks of sofosbuvir and ribavirin treatment may be sufficient for sustained antiviral activity in untreated and pretreated patients with hepatitis C virus (HCV) genotype 1, 2, or 3, according to the findings of an open-label, phase 2 trial.

Edward J. Gane, MD, from the New Zealand Liver Transplant Unit, Auckland City Hospital and the Gastroenterology Department, Christchurch Hospital, both in New Zealand, and colleagues published their findings in the January 3 issue of the New England Journal of Medicine.

"The results from this study confirm that sofosbuvir, an oral nucleotide analogue polymerase inhibitor, combined with ribavirin, is a very effective treatment in patients infected with both genotype 1 and non–genotype 1 HCV, without cirrhosis," Dr. Gane told Medscape Medical News by email. "This regimen is very well tolerated: all oral, short-duration (only 12 weeks), and without any significant drug interactions or specific toxicity."

In the study, the authors treated patients as follows: 4 groups of 10 previously untreated patients with HCV genotype 2 or 3 infection each received sofosbuvir plus ribavirin for 12 weeks, with 3 groups also receiving peginterferon alpha-2a for 4, 8 or 12 weeks (groups 1 - 4); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir alone for 12 weeks (group 5); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir plus peginterferon alpha-2a and ribavirin for 8 weeks (group 6); a group of 10 patients with HCV genotype 1 infection who did not respond to previous treatment and a group of 25 previously untreated patients with HCV genotype 1 infection both received sofosbuvir plus ribavirin for 12 weeks (groups 7 and 8).

Among the patients in groups 1 to 4, all 40 patients had undetectable HCV serum levels up to 48 weeks after treatment. In addition, all patients in group 6 had a sustained virologic response (SVR) at 12 weeks after the end of treatment and all 9 patients for whom data were available had an SVR at 24 weeks.

The authors excluded patients with positive tests for hepatitis B surface antigen, hepatitis B core immunoglobulin M antibodies, or HIV antibodies. In total, 6 (60%) of 10 patients in group 5 and 21 (84%) of 25 patients in group 8 had an SVR at 24 weeks after treatment, whereas only 1 (10%) of 10 patients in group 7 had an SVR.

Among the patients without SVRs at 24 weeks, deep sequencing revealed the presence of the S282T mutation in only 1 patient; no other mutations at conserved sites were identified.

No patient was forced to discontinue treatment because of adverse events. The most common adverse events included headache, fatigue, insomnia, and nausea.

Regarding hematologic events, sofosbuvir monotherapy was associated with modest (0.54 g/dL) decreases in hemoglobin levels. Patients who received peginterferon were more likely to experience hematologic abnormalities, and the degree of changes in hemoglobin levels was more severe among these patients.

Similarly, neutropenia and thrombocytopenia were only observed in patients who received interferon. No grade 3 or 4 elevations of bilirubin levels were observed, and only a single patient (in group 8) relapsed within 2 weeks after the end of treatment and displayed increased alanine aminotransferase levels.

Remaining Questions

In an email to Medscape Medical News, Dr. Gane identified several questions that remain to be addressed: "Will the excellent efficacy and tolerability in this phase 2 study be confirmed in the larger phase 3 studies, which contain patients with cirrhosis?" Dr Gane asked. "Which other antiviral agent should be combined with sofosbuvir to improve efficacy in treatment-experienced patients? Can such short-duration, all-oral therapy be administered in the community, thereby increasing treatment access?"

Donald M. Jensen, MD, director of the Center for Liver Diseases, the University of Chicago, Illinois, who was not involved in the study, noted that the treatment groups were small and fairly homogenous, thus requiring validation in larger, more representative cohorts. "We also need to know why prior interferon treatment failure predisposes to relapse but not on-treatment response and why this is more common in genotype 1a subjects (though few genotype 1b subjects were included in the present investigation)."

Dr. Jensen told Medscape Medical News by email: "Can this be overcome with longer treatment durations or combination with other antivirals? We also need to understand how ribavirin prevents relapse…a question that has plagued us for decades."

Ira M. Jacobsen, MD, chief of the Division of Gastroenterology and Hepatology from Cornell University in New York, also noted that the mechanism of ribavirin's role remains unclear. "Whether 12 weeks of sofosbuvir plus ribavirin will really provide 100% SVR rates in genotypes 2 and 3 remains to be answered by larger trials that are ongoing," Dr. Jacobson told Medscape Medical News by email. "Also unanswered is what will be required to achieve satisfactory SVR rates, preferably similar to naive patients, in nonresponders to previous peginterferon and ribavirin therapy. Optimization in genotype 1–naive patients is also a question."

The study was supported by Pharmasset and Gilead Sciences. Several coauthors are employed by Pharmasset, Chimerix, and/or Gilead. Dr. Gane's institution received funding from Pharmasset and Gilead, and he has received payment for board membership, lectures, and/or travel from Roche, Pharmasset, Gilead, Novartis, Janssen-Cilag, Tibotec, and Boehringer Ingelheim. One coauthor's institution received funding from Pharmasset and Gilead, and she received payment for advisory board membership and/or travel from Janssen-Cilag, Roche, and Gilead. Dr. Jensen has received grant funding from Abbott/AbbVie, Boehringer Ingelheim, BMS, Genentech/Roche, Gilead/Pharmasset, and Merck, and he serves as an advisor/consultant with Abbott/AbbVie, Astex, Biotica, Boehringer Ingelheim, BMS, Genentech/Roche, Gilead/Pharmasset, Merck, and Vertex. Dr. Jacobson has received grant funding from Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Pfizer, Roche/Genentech, Schering/Merck, Tibotec/Janssen, and Vertex, and he serves as a speaker and/or advisor/consultant with Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Roche/Genentech, Schering/Merck, Tibotec/Janssen, Enanta, Idenix, Kadmon, Presidio, and Vertex.

N Engl J Med. 2013;368:34-44. Abstract

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