Interferon Lambda Beats Interferon Alfa-2a for HCV Infection

Daniel M. Keller, PhD

April 11, 2011

April 11, 2011 (Berlin, Germany) — Pegylated interferon lambda (Peg-IFN lambda) showed virological responses superior to the standard of care, pegylated interferon alfa-2a (Peg-IFN alfa-2a), when tested in patients infected with hepatitis C virus (HCV) genotypes 1 or 4, researchers reported here at the European Association for the Study of the Liver 46th Annual Meeting. In addition, Peg-IFN lambda appeared to be better tolerated and safer. The virologic responses among patients infected with HCV genotype 2 or 3 were similar for the 2 forms of interferon.

As background, Stefan Zeuzem, MD, chief of the Department of Medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, explained that current therapies with Peg-IFN alfa are limited by hematologic toxicities, frequent adverse events, and suboptimal efficacy. Peg-IFN lambda might be a useful alternative for some patients. It shares functional similarities with the alfa interferons and uses the same intracellular signal transduction pathways. However, receptors for alfa interferons are widely distributed on many cell types, possibly contributing to adverse effects. Receptors for interferon lambda are expressed on hepatocytes, but expression is lower on hematologic cells and nonhepatocyte liver cells.

Dr. Zeuzem reported the interim results of an ongoing phase 2b trial comparing 3 doses of Peg-IFN lambda-1 (120, 180, and 240 μg) with Peg-IFN alfa-2a 180 μg, each combined with ribavirin, in treatment-naive patients with chronic HCV. Study participants were adults 18 to 70 years of age (mean age, 45 to 47 years) without cirrhosis. Approximately 60% were men, 82% to 87% were white, and mean body mass index was 26.8 to 27.3 kg/m2. About 80% had HCV genotype 1 or 4; the rest had genotype 2 or 3.

When Dr. Zeuzem showed his title slide, listing 48 authors, he said: "I can assure you that we have enrolled more patients than we have authors on this abstract." There were 526 patients in the study, and the vast majority of them had mild to moderate fibrosis.

Compared with Peg-IFN alfa-2a, Peg-IFN lambda-1 "showed more rapid and a slightly more profound antiviral activity over the first weeks of therapy in genotype 1 and 4 [infected patients] and [in genotype] 2 and 3 infected patients," Dr. Zeuzem said. "The cEVR [complete early viral response] rates, negativity at week 12, for genotype 1 and 4 infected patients . . . showed significantly enhanced virologic responses, from roughly 38% for Peg-interferon alfa-2a to levels of 55% to 56% with the various doses of Peg-interferon lambda." Genotypes 1 and 4 are the most difficult to eradicate with antiviral therapy. All the cEVR values for Peg-IFN lambda were significant, compared with the cEVR with Peg-IFN alfa-2a (P < .05).

For genotypes 2 and 3, the cEVR at 12 weeks was very similar across all dosages of Peg-IFN lambda (83% to 90%), and was similar for Pef-IFN alfa-2a (86%).

Peg-IFN lambda had a better adverse-effect profile than Peg-IFN alfa-2a. "There was no dose-dependency of the side effects for the 3 doses of interferon lambda," Dr. Zeuzem noted. "There were big differences, profound differences, in particular for the flu-like symptoms, which in some instances were 4 to 5 times higher with interferon alfa than with interferon lambda."

Flu-like symptoms occurred in 42.9% of patients receiving Peg-IFN alfa-2a but in only 9.7% to 12.5% of those receiving Peg-IFN lambda. Similarly, musculoskeletal symptoms affected 46.6% of the Peg-IFN alfa-2a group but only 14.2% to 18.0% of the Peg-IFN lambda group. Dr. Zeuzem said longer therapy and observations will be required to see if there is a difference in the neuropsychiatric adverse effects, such as depression and irritability, that have been associated with the 2 forms of interferon.

Fewer hematologic abnormalities occurred with Peg-IFN lambda, including anemia, neutropenia, and thrombocytopenia. Anemia necessitated ribavirin dose reductions for 12.8% of the Peg-IFN alfa-2a group but in no more than 2.3% of the patients in any of the 3 Peg-IFN lambda groups.

However, treatment-emergent liver-related laboratory abnormalities occurred more frequently with Peg-IFN lambda. "Treatment with Peg-interferon lambda had a higher rate of patients showing increased aminotransferase; this was particularly visible for patients receiving the 240 μg dose of interferon lambda. . . . but was not that prevalent in patients receiving only 120 or 180 μg" Dr. Zeuzem said.

The incidence of elevations in serum bilirubin level was highest at the 2 higher doses of Peg-IFN lambda, and especially at the highest dose (7.6% of patients with direct bilirubin above 1.2 mg/dL). Four adverse events of hyperbilirubinemia led to the discontinuation of treatment, after which time all the patients showed improvement.

Dr. Fabien Zoulim

Fabien Zoulim, MD, PhD, professor of medicine at Lyon University and medical director of the Liver Department at the Hôtel Dieu Hospital in Lyon, France, who was not involved in the study, cautioned that Dr. Zeuzem presented interim results of an ongoing trial. "We still have to be careful in terms of what would be the end of treatment response and sustained virologic response, and I think many of the questions from the audience were related to that," he said. "The virologic response rate seems to be very promising, especially in patients with genotypes 1 and 4, but we are still at an early stage of the trials." Dr. Zoulim noted that at this stage, the adverse-effect profile for interferon lambda, both in terms of flu-like syndrome and hematologic effects, looks promising.

Even though HCV genotypes 2 and 3 responded well to interferon alfa-2a, he suggested that a better adverse-effect profile (especially at the lower 2 doses) might make interferon lambda attractive for treating these patients.

Considering the alanine transaminase and bilirubin elevations at the highest dose, "we suspect that they may go for one of the lower doses," in Dr. Zoulim's estimation. The next steps are to see data on sustained virologic responses in the trial; those results will probably define the dose that will be used in the phase 3 trial.

Dr. Zoulim said if there are advantages for interferon lambda in terms of efficacy and tolerability, then "I think the future of interferon lambda will be in combination with the specific [small-molecule] inhibitors [in development]," he said.

Dr. Zeuzem disclosed relationships with Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, iTherX, Janssen, Merck, Novartis, Pharmasset, Roche, Santaris, Tibotec, and Vertex. Dr. Zoulim has disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) 46th Annual Meeting. Presented April 2, 2011.

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