Polymorphism in the human major histocompatibility complex and early viral decline during treatment of chronic hepatitis C

Abstract

The dynamics of the viral decline immediately after the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response. Considerable interindividual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in the immune response to viral infections. We examined whether carriage of specific human MHC alleles are associated with the rate of the early viral decline. Longitudinal viral level data (baseline and days 1, 2, 7, 14, and 28 of treatment), medium resolution MHC genotyping, and random coefficients models were used to examine associations between MHC class I and class II allele carriage and the dynamics of the viral decline in 180 African-Americans (AAs) and 194 Caucasian Americans (CAs) with genotype-1 HCV infection over the first 28 days of treatment with peginterferon alpha2a plus ribavirin. Baseline viral levels were similar by race, irrespective of allele carriage. However, the rate of change in the viral decline was associated with both allele and race. Among the four subgroups defined by race and specific allele, the fastest rates of decline were observed (in terms of estimated mean viral declines log(10) IU/ml during the first four weeks) in CA noncarriers for A*03 (2.75; P = 0.018), in CA carriers for Cw*03 (2.99; P = 0.046), and in CA noncarriers for DQA1*04 (2.66; P = 0.018) or DQB1*0402 (2.65; P = 0.018). MHC alleles are associated with the viral decline during the first 28 days of peginterferon therapy.

FIG. 1.

Average viral levels (based on imputed and observed viral levels) in the cohort overall before and after transformation. (A) Viral levels before transformation of the time variable (time is expressed as days); (B) viral levels after transformation of time (time is expressed as weeks) utilizing a square-root transformation. Dark circles indicate the mean viral levels (in log₁₀ IU/ml) at each time point. Vertical bars depict the 95% confidence intervals (mean ± 1.96 [standard error of the mean]). Solid lines represent the estimated linear relationship based on general linear models. A slightly better linear relationship can be seen between mean viral level and time in panel B than in panel A.

FIG. 2.

The predicted mean decline of HCV viral levels by allele carriage and race. The vertical axis presents log₁₀-transformed predicted mean viral levels from the random coefficients model, while the horizontal axis presents time. The time variable was expressed as days. In addition, predicted baseline viral levels along with the rates of viral change, are provided below each figure by race and the carriage of each of the alleles over time (with a √week transformation). (A) DQA1*04; (B) DQB1*0402; (C) A*03; (D) Cw*03.