A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C

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Abstract

Background

A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection.

Methods

Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR.

Results

A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm.

Conclusions

In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.

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Most cited references 13

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IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

Sergei V. Kotenko, Grant Gallagher, Vitaliy V Baurin … (2003)

We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.

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Boceprevir for untreated chronic HCV genotype 1 infection.

Fred Poordad, Jonathan McCone, Bruce Bacon … (2011)

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

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IL-28, IL-29 and their class II cytokine receptor IL-28R.

Paul Sheppard, Wayne Kindsvogel, Wenfeng Xu … (2003)

Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and an orphan class II receptor chain, designated IL-28Ralpha. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.

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Author and article information

Contributors

Chien-Wei Su: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 17 October 2016

Publication date Collection: 2016

Volume: 11

Issue: 10

Electronic Location Identifier: e0164563

Affiliations

[1 ]Department of Infectious Diseases and Hepatology, Medical University of Bialystock, Bialystock, Poland

[2 ]Bon Secours Liver Institute of Virginia, Richmond, Virginia, United States of America

[3 ]Department of Gastroenterology and Hepatology, University Hospital Donostia, San Sebastián, Spain

[4 ]Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

[5 ]Department of Higher Level General Medicine, Russian State Medical University, Moscow, Russia

[6 ]Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut, United States of America

Taipei Veterans General Hospital, TAIWAN

Author notes

Competing Interests: Grants were provided by Bristol-Myers Squib, Achillion, AbbVie, Gilead, Beckman-Colter, Beohringer-Ingelheim, Conatus, CymaBay, Galectin, Immuron, Intercept, Lumena, NGMBio. The authors of this manuscript are also employed by Bristol-Myers Squib (S. S., K. R., Y. D.).

Conceived and designed the experiments: SS YD.
Performed the experiments: RF MS JA HC IN.
Analyzed the data: RF MS JA HC IN KR SS.
Contributed reagents/materials/analysis tools: YD KR SS.
Wrote the paper: RF MS JA HC IN YD KR SS.

* E-mail: subasree@ 123456sbcglobal.net

Article

Publisher ID: PONE-D-16-12779

DOI: 10.1371/journal.pone.0164563

PMC ID: 5066958

PubMed ID: 27749900

SO-VID: 7f8a3530-f6fb-40b3-8ff7-9f577ec7bb59

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 March 2016

Date accepted : 2 September 2016

Page count

Figures: 1, Tables: 4, Pages: 12

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;

Bristol-Myers Squibb (the sponsor) designed the study in collaboration with the academic investigators (Robert Flisiak, Mitchell Shiffman, Juan Arenas, Hugo Cheinquer, and Igor Nikitin), conducted the study, collected study data, and performed statistical analyses. The sponsor, together with all authors, interpreted the data and drafted the manuscript with the assistance of a medical writer funded by the sponsor. Authors employed by the sponsor (Yuping Dong, Khurram Rana, and Subasree Srinivasan), in concert with all other authors, approved the final manuscript and made the decision to submit the manuscript for publication.

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Data Availability All relevant data are within the paper and its Supporting Information files.

A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C

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Abstract

Background

Methods

Results

Conclusions

Related collections

PLOS Climate

Most cited references 13

IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

Boceprevir for untreated chronic HCV genotype 1 infection.

IL-28, IL-29 and their class II cytokine receptor IL-28R.

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