Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3

Daniel M. Keller, PhD

April 27, 2012

April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.

Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.

Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.

At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log10 IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.

Lambda Effective With Fewer Adverse Events

Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.

HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.

With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.

Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.

Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).

However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).

There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.

Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.

It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).

There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.

"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.

In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.

Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."

Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.


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