IL-28B Polymorphisms and the Response to Antiviral Therapy in HCV Genotype 2 and 3 Varies by Ethnicity

A Meta-Analysis

A. S. Rangnekar; R. J. Fontana


J Viral Hepat. 2013;20(6):377-384. 

In This Article

Materials and Methods

Literature Search

A search of the MEDLINE, PUBMED and EMBASE computer databases was performed of manuscripts published between January 2000 and January 2012, using the text words IL-28B, IL28B, IL28 and interleukin 28. Additional electronic and manual searches of abstracts presented at the American Association for the Study of Liver Diseases and American Gastroenterological Association meetings were undertaken from 2007 to 2012. Finally, consultation with expert hepatologists and recursive manual searches of references from published studies were performed.

Study Selection Criteria

Criteria for study inclusion were as follows: (i) published studies of IL-28B genotyping in adults with HCV genotype 2 or 3 infection; (ii) treatment with pegIFN and ribavirin and (iii) a reported outcome of SVR. All published studies were included regardless of sample size, but studies published solely as abstracts were excluded due to a lack of extractable data for SVR stratified by IL-28B genotype. The following exclusion criteria were applied: (i) human immunodeficiency virus (HIV) co-infection, (ii) prior liver transplantation, (iii) use of DAAs and (iv) use of IL-28B SNPs other than rs12979860 or rs8099917. After reviewing all citations identified in the literature search, two investigators (AS, RF) independently applied these selection criteria and extracted data. Any disagreements were resolved by consensus.

Data Extraction

All eligible studies were reviewed in an independent and duplicate manner by both investigators (AS, RF). For each study, the following data were collected: (i) Study: year, location, design, publication status; (ii) Patient factors: number, mean age, baseline serum aspartate aminotransferase (AST), baseline alanine aminotransferase (ALT), body mass index (BMI) and percentage with diabetes mellitus, male gender, treatment naïve and HIV co-infection; (iii) HCV factors: HCV genotype, baseline HCV RNA level, number of patients achieving RVR and SVR; (iv) Treatment factors: duration of pegIFN and ribavirin, type of pegIFN, dose reduction of antiviral medications, use of growth factors; and (v) IL-28B: IL-28B SNP tested and number with each IL-28B genotype who achieved RVR and SVR. Discrepancies in data extraction were resolved by discussion between the investigators.

IL-28B Testing

The two IL-28B SNPs reported in the individual studies were rs12979860 and rs8099917. The favourable genotype for rs12979860 is CC, while the unfavourable genotypes are CT and TT. The favourable genotype for rs8099917 is TT, while the unfavourable genotypes are TG and GG.

Primary Outcome

The primary outcome measure was achievement of SVR after pegIFN and ribavirin treatment, defined as undetectable serum HCV RNA by polymerase chain reaction (PCR) testing 24 weeks after treatment.

Secondary Outcome

A secondary outcome measure was achievement of RVR with pegIFN and ribavirin treatment, defined as an undetectable serum HCV RNA at week 4.

Quality Assessment

Study quality was assessed using an 8-item scoring system based on previously validated tools that focused on study design, population homogeneity and potential study biases.[8,9] High quality was defined by a score of ≥6 (Table 2).

Statistical Analysis

The estimate of effect was a pooled odds ratio (OR) determined using the DerSimonian and Laird method for a random effects model. Study heterogeneity was assessed by the I 2 test, with I 2 > 50% suggesting substantial heterogeneity. Publication bias was assessed through the Harbord and Peters tests. Influence analysis was performed to determine whether a single study exerted undue influence. Data from the included studies were analysed separately by patient race. Sensitivity and subgroup analyses were performed based on treatment algorithm, prior treatment and study quality score. All statistics were computed using STATA 11.0 (StataCorp LP, College Station, TX, USA).