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Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p value Meta = 1.24 × 10 -14 ) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p value Meta = 8.23 × 10 -11 ) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r 2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1 ∗ 03:01, and HLA-DRB1 ∗ 01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC 50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10 -38 ). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection., Competing Interests: Declaration of interests J.C.P. has received research grant support to her institution from Gilead Sciences, Merck, and Abbvie and has served on an advisory board for Gilead Sciences and Theratechnolgies. S.H.M. have received speaker fees from Gilead Sciences not related to this work. A.H.K. serves on the Data Monitoring Committee for Kintor Pharmaceutical., (Copyright © 2022. Published by Elsevier Inc.)

Background: Sexual transmission of hepatitis C virus (HCV) is uncommon, yet documented among men who have sex with men (MSM), primarily among those with human immunodeficiency virus (HIV)., Methods: In the HIV Prevention Trials Network 078 study (HPTN 078), which assessed an integrated strategy to achieve HIV viral suppression, 1305 MSM were screened across 4 geographically diverse US cities. At screening, demographic/behavioral/psychosocial questionnaires were completed, along with HIV and HCV testing. Multivariable logistic regression was used to evaluate associations with HCV antibody positivity., Results: Among the 1287 (99%) of the MSM with HCV antibody results, the median age was 41, 69% were black, 85% had a high school education or more, 35% were employed, 70% had HIV, and 21% had undergone substance use counseling. The median lifetime number of male sexual partners was 17 (interquartile range, 6-50), and 246 (19%) were HCV antibody positive. HCV antibody positivity was high in MSM with HIV (20%) and MSM without HIV (17%) (P = .12) and was higher in those receiving substance use counseling (36%) than in those who had not (15%) (P ≤ .01). Substance use counseling (odds ratio, 2.51; 95% confidence interval, 1.80-3.51) and unstable housing (2.16; 1.40-3.33) were associated with HCV antibody positivity., Conclusions: Nearly 1 in 5 MSM screened for HPTN 078 have been infected with HCV. The prevalence is high regardless of HIV status and is high even in those who did not undergo substance use counseling. In HIV burden networks, high HCV infection prevalence may occur in MSM without HIV. As implementation of preexposure prophylaxis expands and condom use declines, routine HCV counseling and screening among MSM are important., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors., Methods: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group., Results: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor., Conclusions: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Hepatitis C virus (HCV) infections in the United States occurred mostly among those born between 1945 and 1965. However, new infections continue to increase in recent years. To understand the changes in the prevalence and risk factors of HCV infection in different age and risk groups among men living with HIV, we performed a retrospective cross-sectional analyses of 1948 HIV-infected men at a multisite community health centre in urban/suburban and rural Maryland from 2003 through 2014. We used multivariate logistic regression to determine factors associated with HCV antibody (anti-HCV) positivity and restricted cubic spline method to model trends in anti-HCV prevalence over time. The overall anti-HCV prevalence was 24.2%. The annual prevalence declined in the full cohort, from 38% in 2003 to 24% in 2014, and among those ≥ 40 years old. However, the annual prevalence increased initially and then stabilized in the groups of men who were younger (<40 years old) or had injection-drug use and/or sex with men. Among the younger injection-drug users, the prevalence rose from 33% in 2003 to 79% in 2009 and then stabilized. The independent predictors for anti-HCV positivity differed between the men with and without injection-drug use and between those < 40 and ≥ 40 years old. Notably, a high prevalence of anti-HCV was observed among the younger, white injection-drug users residing in rural areas. Thus, the HCV epidemic continued unabated among high-risk individuals in this diverse population of HIV-infected men. The ongoing HCV transmission among young HIV-infected men poses a challenge en route to HCV eradication., (© 2020 John Wiley & Sons Ltd.)

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10 -04 ) and rs8099917 (P value = 5.5 × 10 -04 ). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10 -05 ). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10 -04 ). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) in hepatitis B virus (HBV) coinfection can result in HBV reactivation. In this issue of the JCI, Cheng and colleagues explored the role of interferon signaling in the complex interaction between HBV and HCV using cell lines, mouse models, and samples from people with coinfection. Notably, HCV enhanced interferon signaling, as measured by interferon-stimulated gene (ISG) expression, and decreased HBV transcription and replication. Blockade of interferon signaling reversed the effects on HBV replication. Further, pharmacologic inhibition of HCV replication in vitro and in coinfected humanized mice also reduced interferon signaling and, correspondingly, increased HBV replication. Intriguingly, baseline serum levels of the ISG CXCL10 predicted HBV reactivation in a cohort of coinfected people taking DAAs. Determining how interferon signaling silences HBV transcription and whether serum CXCL10 predicts HBV reactivation in a clinical setting are questions that warrant further investigation.

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8 + T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8 + T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease., Competing Interests: BD, LB, JL, CT, JA, GK, SK, SD, JG, BA No competing interests declared

Background & Aims: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry., Methods: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed., Results: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10 -50 ) and the MHC locus 6p21.32 (P = 1.15 × 10 -21 ). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10 -07 ). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants., Conclusions: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: Little is known about the cascade of hepatitis C care among HIV/hepatitis C virus (HCV)-coinfected patients in community-based clinics. Thus, we analysed our data from the interferon era to understand the barriers to HCV treatment, which may help improve getting patients into treatment in the direct-acting antivirals era., Design: Retrospective cohort study., Setting: Four HIV clinics of a multisite community health centre in the USA., Participants: 1935 HIV-infected men with >1 medical visit to the clinic between 2011 and 2013. Of them, 371 had chronic HCV and were included in the analysis for HCV care continuum during 2003-2014., Outcome Measures: HCV treatment initiation was designated as the primary outcome for analysis. Multivariate logistic regression was performed to identify factors associated with HCV treatment initiation., Results: Among the 371 coinfected men, 57 (15%) initiated HCV treatment. Entering care before 2008 (adjusted OR [aOR, 3.89; 95% CI, 1.95 to 7.78), higher educational attainment (aOR, 3.20; 95% CI, 1.59 to 6.44), HCV genotype 1 versus non-1 (aOR, 0.21; 95% CI, 0.07 to 0.65) and HIV suppression (aOR, 2.13; 95% CI, 1.12 to 4.06) independently predicted treatment initiation. Stratification by entering care before or after 2008 demonstrated that higher educational attainment was the only factor independently associated with treatment uptake in both periods (aOR, 2.79; 95% CI, 1.13 to 6.88 and aOR, 4.10; 95% CI, 1.34 to 12.50, pre- and post-2008, respectively). Additional associated factors in those entering before 2008 included HCV genotype 1 versus non-1 (aOR, 0.09; 95% CI, 0.01 to 0.54) and HIV suppression (aOR, 2.35; 95% CI, 1.04 to 5.33)., Conclusions: Some traditional barriers predicted HCV treatment initiation in those in care before 2008; however, the patients' level of educational attainment remained an important factor even towards the end of the interferon era. Further studies will need to determine whether educational attainment persists as an important determinant for initiating direct-acting antiviral therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confirmed two previously reported significant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fine-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe.

Background: Human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis B (HBV) and C (HCV) viruses are at increased risk of end-stage liver disease (ESLD). Whether modern antiretroviral therapy has reduced ESLD risk is unknown., Methods: Twelve clinical cohorts in the United States and Canada participating in the North American AIDS Cohort Collaboration on Research and Design validated ESLD events from 1996 to 2010. ESLD incidence rates and rate ratios according to hepatitis status adjusted for age, sex, race, cohort, time-updated CD4 cell count and HIV RNA were estimated in calendar periods corresponding to major changes in antiretroviral therapy: early (1996-2000), middle (2001-2005), and modern (2006-2010) eras., Results: Among 34 119 HIV-infected adults followed for 129 818 person-years, 380 incident ESLD outcomes occurred. ESLD incidence (per 1000 person-years) was highest in triply infected (11.57) followed by HBV- (8.72) and HCV- (6.10) coinfected vs 1.27 in HIV-monoinfected patients. Adjusted incidence rate ratios (95% confidence intervals) comparing the modern to the early antiretroviral era were 0.95 (.61-1.47) for HCV, 0.95 (.40-2.26) for HBV, and 1.52 (.46-5.02) for triply infected patients. Use of antiretrovirals dually activity against HBV increased over time. However, in the modern era, 35% of HBV-coinfected patients were not receiving tenofovir. There was little use of HCV therapy., Conclusions: Despite increasing use of antiretrovirals, no clear reduction in ESLD risk was observed over 15 years. Treatment with direct-acting antivirals for HCV and wider use of tenofovir-based regimens for HBV should be prioritized for coinfected patients., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Introduction: Liver disease related to hepatitis B (HBV) and hepatitis C (HCV) may temper the success of antiretroviral therapy (ART) in China. Limited data exist on their prevalence in HIV-positive Chinese. A multi-centre, cross-sectional study was carried out to determine the prevalence and disease characteristics of HBV and HCV co-infection in HIV-positive patients across 12 provinces., Methods: HIV-positive ART-naïve patients were recruited from two parent cohorts established during November 2008-January 2010 and August 2012-September 2014. Hepatitis B surface antigen (HBsAg), hepatitis B e antigen and HCV antibody (anti-HCV) status were retrieved from parent databases at the visit prior to ART initiation. HBV DNA was then determined in HBsAg+ patients. HCV RNA was quantified in anti-HCV+ patients. Aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 (FIB4) were calculated. Chi-square test, Kruskal-Wallis test and logistic regression were used for statistical analysis, as appropriate., Results: Of 1944 HIV-positive patients, 186 (9.5%) were HIV-HBV co-infected and 161 (8.3%) were HIV-HCV co-infected. The highest HIV-HBV prevalence (14.5%) was in Eastern China while the highest HIV-HCV prevalence was in the Central region (28.2%). HIV-HBV patients had lower median CD4 + T cell count (205 cells/μL) than either HIV monoinfected (242 cells/μL, P = 0.01) or HIV-HCV patients (274 cells/μL, P = 0.001). Moderate-to-significant liver disease was present in > 65% of the HIV-HCV, ~ 35% of the HIV-HBV and ~ 20% of the HIV monoinfected patients. Independent associations with moderate-to-significant liver disease based on APRI included HBV (Odds ratio, OR 2.37, P < 0.001), HCV (OR 9.64, P < 0.001), CD4 count ≤ 200 cells/μL (OR 2.55, P < 0.001) and age ≥ 30 years (OR 1.80, P = 0.001)., Conclusions: HBV and HCV prevalence is high in HIV-positive Chinese and differs by geographic region. HBV and HCV co-infection and HIV monoinfection are risks for moderate-to-significant liver disease. Only HIV-HBV is associated with greater HIV-related immunosuppression. Incorporating screening and management of hepatitis virus infections into Chinese HIV programmes is needed.

HIV increases the risk of liver disease as do two common coinfections, hepatitis B and C viruses (HBV and HCV). However, whether combination antiretroviral therapy (cART) reverses or exacerbates hepatic fibrosis remains unclear.This was an observational retrospective study. cART-naïve HIV-infected subjects without a history of substance abuse (including alcohol) had liver disease stage determined by aspartate aminotransferase-to-platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) before and 24 and 48 weeks after cART. All the data were retrieved from previously established cohorts. Values before and after cART were compared using Wilcoxon test for paired samples. Regression analyses were used to determine factors associated with moderate-to-severe liver disease.Of the 1105 HIV-infected subjects, 120 were HBV coinfected and 64 were HCV coinfected. About 20% of HIV monoinfected participants had APRI and FIB-4 scores consistent with moderate-to-significant fibrosis compared to ∼36% of HIV-HBV coinfected and 67% to 77% of HIV-HCV coinfected participants. In adjusted analyses compared with HIV monoinfection, HBV coinfection was associated with 1.18-fold higher APRI (P < 0.001) and a 1.12-fold higher FIB-4 (P = 0.007) prior to cART; while HCV coinfection was associated with 1.94-fold higher APRI (P < 0.001) and a 1.43-fold higher FIB-4 (P < 0.001). After 48 weeks of cART, both fibrosis scores decreased in all subjects; however, HCV coinfection was still associated with higher fibrosis scores at week 48 compared to HIV monoinfection.cART was associated with improvement in hepatic fibrosis scores in the majority of HIV-hepatitis coinfected and HIV-monoinfected Chinese participants.

Background: The probability of spontaneous hepatitis C virus (HCV) clearance ranges from 11% to 49%. Our previous cross-sectional study suggests that mode of acquisition explains some of this heterogeneity. We performed this prospective study to determine factors associated with spontaneous HCV clearance among men who have sex with men (MSM)., Methods: A mixture-cure model was used to evaluate the probability of spontaneous HCV clearance among 101 MSM in the Multicenter AIDS Cohort Study with acute HCV infection between 1984 and 2012., Results: Spontaneous HCV clearance occurred in 46% of MSM (49% in non-injection drug users [IDUs] and 23% in IDUs). In the multivariable analysis, age <30 years (clearance ratio [CR] = 2.43; 95% confidence interval [CI], 1.53-3.87) and being human immunodeficiency virus (HIV) uninfected (CR = 2.97; 95% CI, 1.98-4.46) were independently associated with spontaneous clearance. Among men aged ≥30 years, being HIV uninfected, not having unprotected anal intercourse, older age, and being on highly active antiretroviral therapy were independently associated with higher clearance. The interferon lambda rs12979860 single nucleotide polymorphism (SNP) was not associated with spontaneous clearance among the 88 MSM who were not active IDUs (CR = 0.74; 95% CI, .46-1.21 for CC vs CT/TT genotype)., Conclusions: The high probability of spontaneous HCV clearance together with the lack of an association between the rs12979860 SNP and spontaneous clearance among MSM who do not use injection drugs suggests that the immune mechanisms involved with a successful response to acute HCV differ by mode of virus acquisition. Understanding potential mechanistic differences could be important for HCV vaccine development., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Prospective characterization of hepatitis C virus (HCV) transmission in both human immunodeficiency virus (HIV)-infected and -uninfected men who have sex with men (MSM) over the entire HIV epidemic has not been comprehensively conducted., Methods: To determine the trends in and risk factors associated with incident HCV in MSM since 1984, 5310 HCV antibody (anti-HCV)-negative MSM in the Multicenter AIDS Cohort Study were prospectively followed during 1984-2011 for anti-HCV seroconversion., Results: During 55 343 person-years (PYs) of follow-up, there were 115 incident HCV infections (incidence rate, 2.08/1000 PYs) scattered throughout the study period. In a multivariable analysis with time-varying covariates, older age (incidence rate ratio [IRR], 1.40/10 years, P < .001), enrollment in the later (2001-2003) recruitment period (IRR, 3.80, P = .001), HIV infection (IRR, 5.98, P < .001), drinking >13 alcoholic drinks per week (IRR, 1.68, P < .001), hepatitis B surface antigen positivity (IRR, 1.68, P < .001), syphilis (IRR, 2.95, P < .001), and unprotected receptive anal intercourse with >1 male partner (IRR, 3.37, P < .001) were independently associated with incident HCV. Among HIV-infected subjects, every 100 cell/mm(3) increase in CD4 count was associated with a 7% (P = .002) decrease in the HCV incidence rate up to a CD4 count of 500 cells/mm(3), whereas there was no association with highly active antiretroviral therapy., Conclusions: The spread of HCV among both HIV-infected and -uninfected MSM in the United States has been ongoing since the beginning of the HIV epidemic. In HIV-infected men with <500 CD4(+) T cells, the HCV incidence rate was inversely proportional to CD4 T-cell count.

Unlabelled: Chinese translation, Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood., Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection., Design: 2-stage, genome-wide association study., Setting: 13 international multicenter study sites., Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence)., Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs)., Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015)., Limitation: Epigenetic effects were not studied., Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.

Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8-6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.

Treatment-induced control and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFN-λ3 up-regulates interferon-stimulated genes, similar to IFN-α and IFN-β but via a different receptor. There is also evidence that IFN-λ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated IFN-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFN-λ3, the clinical implications of the genetic association, and areas of future research., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high-resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multiracial cohort of U.S. women with a high prevalence of HCV and HIV. Our primary analyses evaluated associations between 12 HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1-2.6), B*5701 (PR=2.0; 95% CI = 1.0-3.1), B*5703 (PR = 1.7; 95% CI = 1.0-2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0-3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), whereas DRB1*0301 (PR = 0.4; 95% CI = 0.2-0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2-11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (N = 838), but no significant relationships were observed., Conclusion: HLA genotype influences the host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance because they were a priori hypothesized.

Human genetic variation is a determinant of recovery from acute hepatitis C virus (HCV) infection; however, to date, single-nucleotide polymorphisms (SNPs) in only a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune response genes are important for HCV clearance, by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK (version 1.05) and Haploview (version 4.1) software packages were used to perform association, permutation, and haplotype analyses stratified by African American and European American race. Of the 1536 SNPs tested, 1426 (92.8%) were successfully genotyped. In African Americans, we identified 18 SNPs located in 11 gene regions that were associated with HCV infection outcome (empirical P value, < .01). In European Americans, there were 20 SNPs located in 8 gene regions associated with HCV infection outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1, and IL18BP) contained SNPs for which the empirical P value was <.01 in both of the race groups. In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified 4 gene regions that are likely candidates for a role in HCV clearance or persistence in both African Americans and European Americans.

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Human genome variations explain some of the heterogeneity in the immune response to antigenic stimuli. Such differences in response to hepatitis C virus (HCV) antigens can account for the ability of the immune response to clear HCV after an acute infection or to develop more rapidly progressive liver disease. Several studies have examined polymorphisms in several candidate immune-response genes for their relation to these HCV outcomes. Results of some of these studies complement knowledge gained from immunology studies, and others offer new insights into HCV biology. This review summarizes published studies on variation in immune-response genes and HCV outcomes.

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-alpha-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.01, odds ratio (OR) = 2.66 [corrected] (confidence interval 1.3-5.6)[corrected]]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-gamma promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.

Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.

: The utility of longitudinal AST-to-platelet ratio index (APRI), a surrogate for hepatic fibrosis, is unknown. We compared APRI up to 9 years before liver-related death among 57 cases of viral hepatitis-infected men (91% HIV+) to matched controls. APRI was stable among controls but, among cases, increased 4.6%/year from 9 to 3 years predeath (P = 0.10) and 30%/year during the 3 years predeath (P

BackgroundHepatitis C virus (HCV) infection may increase the risk of cardiovascular disease (CVD). We evaluated the association of chronic HCV infection and coronary atherosclerosis among participants in the Multicenter AIDS Cohort Study.MethodsWe assessed 994 men with or without human immunodeficiency virus (HIV) infection (87 of whom had chronic HCV infection) for coronary plaque, using noncontrast coronary computed tomography (CT); 755 also underwent CT angiography. We then evaluated the associations of chronic HCV infection and HIV infection with measures of plaque prevalence, extent, and stenosis.ResultsAfter adjustment for demographic characteristics, HIV serostatus, behaviors, and CVD risk factors, chronic HCV infection was significantly associated with a higher prevalence of coronary artery calcium (prevalence ratio, 1.29; 95% confidence interval [CI], 1.02-1.63), any plaque (prevalence ratio, 1.26; 95% CI, 1.09-1.45), and noncalcified plaque (prevalence ratio, 1.42; 95% CI, 1.16-1.75). Chronic HCV infection and HIV infection were independently associated with the prevalence of any plaque and of noncalcified plaque, but there was no evidence of a synergistic effect due to HIV/HCV coinfection. The prevalences of coronary artery calcium, any plaque, noncalcified plaque, a mixture of noncalcified and calcified plaque, and calcified plaque were significantly higher among men with an HCV RNA load of ≥2 × 10(6) IU/mL, compared with findings among men without chronic HCV infection.ConclusionsChronic HCV infection is associated with subclinical CVD, suggesting that vigilant assessments of cardiovascular risk are warranted for HCV-infected individuals. Future research should determine whether HCV infection duration or HCV treatment influence coronary plaque development.

Background: People with HIV are disproportionately coinfected with hepatitis C virus (HCV) and experience accelerated liver-related mortality. Direct-acting antivirals (DAAs) yield high sustained virologic response (SVR) rates, but uptake is suboptimal. This study characterizes the DAA-era HCV treatment cascade and barriers among US men and women with or at risk for HIV.Methods: We constructed HCV treatment cascades using the Women's Interagency HIV Study (women, 6 visits, 2015-2018, n = 2447) and Multicenter AIDS Cohort Study (men, 1 visit, 2015-2018, n = 2221). Cascades included treatment-eligible individuals (ie, HCV RNA-positive or reported DAAs). Surveys captured self-reported clinical (eg, CD4), patient (eg, missed visits), system (eg, appointment access), and financial/insurance barriers.Results: Of 323/92 (women/men) treatment eligible, most had HIV (77%/70%); 69%/63% were black. HIV-positive women were more likely to attain cascade outcomes than HIV-negative women (39% vs 23% initiated, 21% vs 12% SVR); similar discrepancies were noted for men. Black men and substance users were treated less often. Women initiating treatment (vs not) reported fewer patient barriers (14%/33%). Among men not treated, clinical barriers were prevalent (53%).Conclusions: HIV care may facilitate HCV treatment linkage and barrier navigation. HIV-negative individuals, black men, and substance users may need additional support.Clinical Trials Registration: NCT00000797 (Women's Interagency HIV Study); NCT00046280 (Multicenter AIDS Cohort Study). [ABSTRACT FROM AUTHOR]

Background The cost of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) prompted many payers to restrict treatment to patients who met non–evidence-based criteria. These restrictions have implications for survival of people with HCV, especially for people with human immunodeficiency virus (HIV)/HCV coinfection who are at high risk for liver disease progression. The goal of this work was to estimate the effects of DAA access policies on 10-year all-cause mortality among people with HIV. Methods The study population included 3056 adults with HIV in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study from 1 October 1994 through 30 September 2015. We used the parametric g-formula to estimate 10-year all-cause mortality under DAA access policies that included treating (i) all people with HCV; (ii) only people with suppressed HIV; (iii) only people with severe fibrosis; and (iv) only people with HIV suppression and severe fibrosis. Results The 10-year risk difference of treating all coinfected persons with DAAs compared with no treatment was –3.7% (95% confidence interval [CI], –9.1% to.6%). Treating only those with suppressed HIV and severe fibrosis yielded a risk difference of –1.1% (95% CI, –2.8% to.6%), with 51% (95% CI, 38%–59%) of coinfected persons receiving DAAs. Treating a random selection of 51% of coinfected persons at baseline decreased the risk by 1.9% (95% CI, –4.7% to.3%). Conclusions Restrictive DAA access policies may decrease survival compared to treating similar proportions of people with HIV/HCV coinfection with DAAs at random. These findings suggest that lives could be saved by thoughtfully revising access policies. [ABSTRACT FROM AUTHOR]

Background Persons living with human immunodeficiency virus (HIV; PLwH) are commonly co-infected with hepatitis C virus (HCV). Most co-infected individuals can achieve a sustained HCV virologic response after treatment with direct-acting antivirals (DAA). However, the effect of HCV co-infection and DAA treatment on mortality after initiating antiretroviral therapy (ART) is unknown for PLwH. Methods We analyzed data from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Participants included those who had prevalent HIV or seroconverted during follow-up; all were antiretroviral-naive and acquired immunodeficiency syndrome (AIDS)-free prior to their first visit after 1 October 1994. The follow-up lasted 10 years or until 30 September 2015. We used parametric g-computation to estimate the effects of HCV infection and DAA treatment on mortality had participants initiated ART at study entry. Results Of the 3056 eligible participants, 58% were female and 18% had HCV. The estimated 10-year all-cause mortality risk in the scenario in which no PLwH had HCV was 10.4% (95% confidence interval [CI] 6.0–18.0%). The 10-year mortality risk difference for HCV infection was 4.3% (95% CI 0.4–8.9%) and the risk ratio was 1.4 (95% CI 1.0–1.9). The risk difference for DAA treatment was -3.8% (95% CI -9.2–0.9%) and the risk ratio was 0.8 (95% CI 0.6–1.1). Conclusions HCV co-infection remains an important risk factor for mortality among PLwH after initiating ART according to modern guidelines, and DAAs are effective at reducing mortality in this population. HCV prevention and treatment interventions should be prioritized to reduce mortality among PLwH. [ABSTRACT FROM AUTHOR]

The isolated hepatitis B core antibody (anti-HBc) pattern was generally stable, associated with human immunodeficiency virus and hepatitis C virus infection, and most commonly transitioned to or from a pattern of past infection. The isolated anti-HBc pattern likely represents resolved hepatitis B virus infection with low or undetected anti-HBs.Background. The significance of hepatitis B core antibody (anti-HBc) without hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is unclear.Methods. This cohort study included men enrolled in the Multicenter AIDS Cohort to determine clinical and laboratory predictors of isolated anti-HBc.Results. A total of 2286 subjects (51% human immunodeficiency virus [HIV]–infected) were followed over 3.9 years. Overall, 16.9% (387) had at least 1 visit with isolated anti-HBc. The isolated anti-HBc pattern was stable 84% of the time, and transitioned to or from a pattern of past infection (anti-HBc and anti-HBs). Isolated anti-HBc was associated with HIV infection (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.73–2.79) and hepatitis C virus (HCV; OR, 4.21; 95% CI; 2.99–5.91). The HCV association was stronger for chronic HCV infection (OR, 6.76; 95% CI, 5.08–8.99) than for cleared HCV (OR, 3.03; 95% CI, 1.83–5.03). HIV infection, chronic HCV, and cleared HCV infection all remained associated with isolated anti-HBc in multivariable models (OR, 1.74; 95% CI, 1.33–2.29; OR, 6.24; 95% CI, 4.62–8.42; and OR, 2.77; 95% CI, 1.65–4.66, respectively). Among HIV-infected subjects, highly active antiretroviral therapy was negatively associated (OR, 0.79; 95% CI, .66–.95) with isolated anti-HBc.Conclusions. Isolated anti-HBc is associated with HIV and HCV coinfection, especially active HCV replication, and most commonly occurs as a transition to or from the pattern of natural immunity (anti-HBc and anti-HBs). The isolated anti-HBc pattern likely represents resolved HBV infection with low or undetected anti-HBs. [ABSTRACT FROM AUTHOR]

The effect of hepatitis C virus (HCV) on antiretroviral therapy (ART) response in patients in sub-Saharan Africa is unknown. We studied 1431 HIV-infected ART initiators in Jos, Nigeria, of whom 6% were HCV coinfected. A similar proportion of HIV/HCV-coinfected and HIV-monoinfected patients achieved HIV RNA <400 copies per milliliter after 24 and 48 weeks of ART (P > 0.05). Hepatotoxicity was uncommon (0.8% and 0.33% at 24 and 48 weeks, respectively) but was more common in the HIV/HCV-coinfected group at 24 (adjusted odds ratio = 19.3; 95% confidence interval: 4.41 to 84.4) and 48 weeks (adjusted odds ratio = 56.7; 95% confidence interval: 5.03 to 636.92). HCV did not significantly impact ART response in this Nigerian cohort. [ABSTRACT FROM AUTHOR]

The article examines studies on the development of liver disease in human immunodeficiency virus (HIV)-infected and HIV-negative older people. High active antiretroviral therapy (HAART) is said to have resulted to increased longevity among HIV-infected patients aged more than 50 years old. HAART also contribute to a rise in the number of new infections such as liver infection in older people. The association between aging and increased risk of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections is discussed. Also discussed is the incidence of alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) and hepatocellular cancer in older people.

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-γ gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received lFN-α-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-γ promoter region next to the binding motif of heat shock transcription factor (HSF), -764G. was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-γ promoter SNP-764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients. [ABSTRACT FROM AUTHOR]