A closer look at hepatitis C clearance in HIV controllers.

Abstract

It is with great interest that we read the paper titled ‘Human leukocyte antigen B*57 does not fully explain hepatitis C clearance in HIV controllers’ that was recently published in AIDS[1]. The authors of this very interesting cross-sectional study reported that several genetic markers including HLA B*57, HLA Cw*04 and IL28B do not explain the association between HIV controller status and hepatitis C virus (HCV) clearance that they observed in the Study of the Consequences of Protease Inhibitor Era (SCOPE) cohort. In light of the results from our recently published study of HCV prevalence and clearance in a cohort of nearly 7000 MSM enrolled in the Multicenter AIDS Cohort Study (MACS) [2], there are several aspects of the study by Asher et al.[1] that deserve further consideration. One important finding from our study was that several participant characteristics were differentially associated with HCV clearance by presumed mode of acquisition [2]. For example, we found that the magnitude of the association between the IL28B (rs12979860) C/C genotype and HCV clearance was significantly higher among MSM with a history of IDU than among MSM who most likely acquired HCV via sexual exposure (clearance ratios 4.16 and 1.71, respectively; P = 0.03). Given this difference by IDU history, one wonders whether the effects of HLA B*57, HLA Cw*04, IL28B and/or HIV controller status might differ between those with versus without a history of IDU in the SCOPE cohort. On the basis of the numbers reported by Asher et al.[1] in Table 1, their study cohort included nearly equal numbers of individuals with (n = 137) and without (n = 142) a history of IDU, which provides a sufficiently large sample for testing this hypothesis. Asher et al.[1] also reported that HCV clearance was similar among men and women and concluded that ‘there is no clear explanation for why men were equally likely to clear their HCV infection as women in this cohort’. Our study in the MACS might provide an insight into this observation. We found that HCV clearance was significantly higher among non-IDU MSM (34.5%) than among IDU MSM (11.5%) (P < 0.001) [2]. Consequently, mode of HCV acquisition might confound the comparison of HCV clearance between men and women in the SCOPE cohort if, for instance, women were more likely to have been infected with HCV via IDU while men were more likely to have been infected via sexual contact. This possibility is supported by the authors’ statement that HIV-positive MSM is ‘a group well represented within the SCOPE cohort’[1]. Our final two comments about the study by Asher et al.[1] concern their multivariable analysis. First, in the last paragraph of the Results section, the authors report that HIV controller status and IL28B genotype were the only two factors found to be independently associated with HCV clearance. IL28B genotype, however, was not reported in Table 4; thus, it is not clear whether Table 4 accurately portrays the results from their final multiple regression model. Second, the authors note that HIV controller status was not associated with HCV clearance in their univariate analysis even though this association was found to be statistically significant in the multiple regression analysis. Assuming that the results in Table 4 are accurate, the reason for these apparently discrepant findings is clear. An interaction term for HIV controller status by HLA B*57 was forced into the model even though it was not statistically significant (P = 0.21). With this interaction term in the model, the HCV clearance difference between HIV controllers and noncontrollers [adjusted clearance ratio (ACR) 1.78] that the authors highlight in their discussion represents this comparison restricted to individuals without HLA B*57. In contrast, the interaction term demonstrates that HIV controllers with HLA B*57 were less likely to clear HCV (ACR 0.52). The univariate analysis effectively combined these two ACRs, resulting in the nonsignificant association between HIV controller status and HCV clearance. It is indeed intriguing that the HIV controller effect was qualitatively different between those with versus without HLA B*57. Unfortunately, the authors provided no discussion about the cause or implication of their finding that HIV controllers were more likely to clear HCV only if they were HLA B*57 negative. In summary, there is mounting evidence that the factors associated with spontaneous HCV clearance may differ by mode of acquisition, and these differences suggest that the mechanisms involved with spontaneous HCV clearance might also differ by mode of acquisition. Future research should examine whether any association observed between HIV controller status and HCV clearance differs by IDU status. Acknowledgements Financial support was provided by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute [grant numbers UO1 AI35042 and UM1 AI35043]. Conflicts of interest We have no conflicts to disclose.