Phase 1b Study of Pegylated Interferon Lambda 1 With or Without Ribavirin in Patients with Chronic Genotype 1 Hepatitis C Virus Infection†

Abstract

Interferon lambda 1 (IFN-k1) is a type III IFN that produces intracellular responses similar to those of IFN-a but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-k) at 1.5 or 3.0 lg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-a-based treatment. Part 2 evaluated weekly doses of PEG-IFN-k ranging from 0.5 to 2.25 lg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-k at 1.5 lg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-k dose levels (from 0.5 to 3.0 lg/kg). Two of seven treatmentnaive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-k. Most DLT occurred in patients with high PEG-IFN-k exposure. Conclusion: Weekly PEG-IFN-k with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;52:822-832) T he World Health Organization estimates that 180 million people worldwide (3% of the world population) are infected with hepatitis C virus (HCV), and 130 million of these are chronic HCV carriers. 1 Chronic HCV infection is responsible for 50% to 76% of all liver cancer cases, two-thirds of all liver transplants in the developed world, and considerable morbidity and mortality. Identifying effective treatments for chronic HCV infection is therefore a global health priority. 1

Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation

“…37 The potential role of newer treatments (including direct-acting anti-virals and newer forms of interferon) in the treatment of chronic HCV is still being evaluated, but the data currently available for interferon-lamba 1 suggest there may be fewer neuropsychiatric complications resulting from its use compared to IFN-a. 38 Development of depression is the commonest reason for HCV treatment discontinuation. 36 A recent study found that up to 10% of patients treated for HCV with pegylated interferon and ribavirin had to prematurely withdraw from treatment, and the majority (65%) of these patients had developed features of major depression [as defined by total score >35 points on the Major Depression Inventory (MDI)].…”

Hepatitis C pharmacogenetics: State of the art in 2010

“…Supporting this hypothesis are results from an open-label study of PEG-IFN-k1 (IL29) in patients with genotype 1 HCV, in which weekly dosing had antiviral activity and was well tolerated. 19 However, larger, blinded studies are needed to further evaluate the safety and efficacy of lambda IFNs.…”

Discovery of critical host factor, IL‐28B, associated with response to hepatitis C virus treatment

“…29 As described above, HCV replication is inhibited by the antiviral effects of IFN-l. A pegylated IFN-l1 has already been tried against chronic hepatitis C in phase 2 trials. 30,31 Interestingly, impressive antiviral effects (at least as good as with PegIFN-a) were observed but with fewer and less severe side effects. 31 The expression pattern of IFN-l receptor is restricted in specific tissues.…”