Female Sex and IL28B, a Synergism for Spontaneous Viral Clearance in Hepatitis C Virus (HCV) Seroconverters from a Community-Based Cohort

Abstract

Background & AimsSince acute hepatitis C virus (HCV) infection is often asymptomatic, it is difficult to examine the rate and determinants of spontaneous clearance. Consequently, these studies are subject to bias, which can potentially lead to biased rates of viral clearance and risk estimates. We evaluated determinants of spontaneous HCV clearance among HCV seroconverters identified in a unique community-based cohort.MethodsSubjects were 106 drug users with documented dates of HCV seroconversion from the Amsterdam Cohort Study. Logistic regression was used to examine sociodemographic, behavioral, clinical, viral and host determinants, measured around acute infection, of HCV clearance.ResultsThe spontaneous viral clearance rate was 33.0% (95% confidence interval (CI) 24.2–42.8). In univariate analyses female sex and fever were significantly associated with spontaneous clearance. The favorable genotypes for rs12979860 (CC) and rs8099917 (TT) were associated with spontaneous clearance, although borderline significant. In multivariate analysis, females with the favorable genotype for rs12979860 (CC) had an increased odds to spontaneously clear HCV infection (adjustedOR 6.62, 95% 2.69–26.13), whereas females with the unfavorable genotype were as likely as men with the favorable and unfavorable genotype to clear HCV. Chronic Hepatitis B infection and absence of HIV coinfection around HCV seroconversion also favor HCV clearance.ConclusionsThis study shows that co-infection with HIV and HBV and genetic variation in the IL28B region play an important role in spontaneous clearance of HCV. Our findings suggest a possible synergistic interaction between female sex and IL28B in spontaneous clearance of HCV.

Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection—the InC3Study

“…This is particularly notable because, by definition, all participants with reinfection have already cleared 1 HCV infection and therefore would be expected to have a greater tendency toward spontaneous clearance a priori. In the context of primary clearance, similar findings have been reported with respect to female sex [1,22] and IFNL4 genotype [24,25] predicting clearance independently and in combination [15,23], including within the InC 3 study population [15]. The IFNL4 gene region encodes the interferon λ3 protein and is involved in viral control, although the precise mechanism remains unknown.…”

“…It is possible that female sex influences HCV clearance through a mechanism related to general sex-based differences in immunity [34,35]; however, the pathways by which these differences affect HCV control require elucidation. Further research is required to assess whether the combined effect of IFNL4 genotype and sex on primary clearance and reclearance is simply the product of the 2 independent effects or whether there is a synergistic effect [15,23]. The importance of sex and IFNL4 genotype in both primary HCV infection and reinfection suggests that these factors have a crucial role in long-term protection from persistent HCV infection.…”

“…Potential interactions between study site-categorized as the Baltimore Before and After Acute Study of Hepatitis (BBAASH; the study contributing largest number of reinfection events) versus other sites-and hypothesized predictors were evaluated. Hypothesized predictors were determined a priori on the basis of established predictors of primary clearance, including age [21], sex [1,15,22,23], IFNL4 genotype (SNP rs12979860; CC vs CT/TT) [24][25][26], the combined effect of sex and IFNL4 genotype (female rs12979860 CC vs others) [15,23], HCV genotype during reinfection (genotype 1 vs non-genotype 1) [15,27], and reinfection with the same versus a different HCV genotype from that in the primary infection. It was hypothesized that participants reinfected with the same HCV genotype would have a greater propensity toward reclearance [28,29].…”

X-Chromosome Complement and Estrogen Receptor Signaling Independently Contribute to the Enhanced TLR7-Mediated IFN-α Production of Plasmacytoid Dendritic Cells from Women

“…Our data support the notion that the X-chromosome complement, together with sex hormones, may act in concert to confer elevated production of type I IFNs by pDCs in response to TLR7 ligands, thereby contributing to the enhanced TLR7-mediated response of pDCs from women. This finding might have broader implications for our understanding of the pathogenesis of RNA virus-mediated infectious diseases, such as HIV-1 infection and chronic hepatitis C, for which sexbased differences have been reported (35,45). …”

Rapid diagnostic HCV antibody assays

“…Whereas rapid assays provide information about anti-HCV immunoglobulin G which is a marker of active as well as resolved infection, NATs provide direct evidence of active HCV infection. This is an important distinction because between 15% and 33% of patients spontaneously clear the virus [25] resulting in an antibody-positive/NAT-negative result. Furthermore, HCV-infected patients who achieve sustained virological response after antiviral therapy will also demonstrate the same antibody-positive/NAT-negative profile.…”