Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B)

• Published in: Journal of hepatology Vol. 64; no. 5; pp. 1011 - 1019
• Main Authors: Chan, Henry L.Y., Ahn, Sang Hoon, Chang, Ting-Tsung, Peng, Cheng-Yuan, Wong, David, Coffin, Carla S., Lim, Seng Gee, Chen, Pei-Jer, Janssen, Harry L.A., Marcellin, Patrick, Serfaty, Lawrence, Zeuzem, Stefan, Cohen, David, Critelli, Linda, Xu, Dong, Wind-Rotolo, Megan, Cooney, Elizabeth
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2016
• Subjects: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Gastroenterology and Hepatology; Hepatitis B e Antigens - immunology; Hepatitis B virus - immunology; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - virology; Human; Humans; Immunomodulatory therapy; Interleukins - administration & dosage; Male; Polyethylene Glycols - administration & dosage; Time Factors; Treatment Outcome; Viral hepatitis; LLOQ; 80% CIs; qHBsAg; pegIFN-alfa; qHBeAg; alfa; mITT; IFN; lambda; Viral hepatitis; SNP; ULN; Immunomodulatory therapy; TLR; ISG; Human; Hgb; AE; HBeAg; HBsAg; HBsAb; NA; LLOD; SAE; HBeAb; CHB; NK; CHC; quantitative hepatitis B e antigen; single nucleotide polymorphism; 80% confidence intervals; natural killer; hepatitis B e antibody; lower limit of quantification; quantitative hepatitis B surface antigen; chronic hepatitis B; nucleos(t)ide analogue; chronic hepatitis C; adverse event; lower limit of detection; modified intent-to-treat; hemoglobin; peginterferon alfa-2a; peginterferon lambda-1a; serious adverse event; HBeAg-positive; HBsAg-positive; interferon; hepatitis B surface antibody; pegylated interferon alfa; upper limit of normal; toll-like receptor; IFN-stimulated gene
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2015.12.018

Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection. Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180μg) or peginterferon alfa-2a (alfa) for 48weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >−15%. Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound −24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4–12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise. On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762.