Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQß1.

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-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 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-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 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-DQß1 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.

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

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.

Human Immunodeficiency Virus and Hepatitis C Virus Infection Testing Among Commercially Insured Persons Who Inject Drugs, United States, 2010-2017.

BACKGROUND: We assessed prevalence of testing for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection among persons who inject drugs (PWID). METHODS: Using a nationwide health insurance database for claims paid during 2010-2017, we identified PWID by using codes from the International Classification of Diseases, Current Procedural Terminology, and National Drug Codes directory. We then estimated the percentage of PWIDs tested for HIV or HCV within 1 year of an index encounter, and we used multivariate logistic regression models to assess demographic and clinical factors associated with testing. RESULTS: Of 844 242 PWIDs, 71 938 (8.5%) were tested for HIV and 65 188 (7.7%) were tested for HCV infections. Missed opportunities were independently associated with being male (odds ratios [ORs]: HIV, 0.50 [95% confidence interval {CI}, 0.49-0.50], P < .001; HCV, 0.66 [95% CI, 0.65-0.72], P < .001), rural residence (ORs: HIV, 0.67 [95% CI, 0.65-0.69], P < .001; HCV, 0.75 [95% CI, 0.73-0.77], P < .001), and receiving services for skin infections or endocarditis (adjusted ORs: HIV, 0.91 [95% CI, 0.87-0.95], P < .001; HCV, 0.90 [95% CI, 0.86-0.95], P < .001). CONCLUSIONS: Approximately 90% of presumed PWIDs missed opportunities for HIV or HCV testing, especially male rural residents with claims for skin infections or endocarditis, commonly associated with injection drug use.

Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection.

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.

Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

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.

Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013-2016.

Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States, causing substantial morbidity and mortality and costing billions of dollars annually. To update the estimated HCV prevalence among all adults aged ≥18 years in the United States, we analyzed 2013-2016 data from the National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of HCV in the noninstitutionalized civilian population and used a combination of literature reviews and population size estimation approaches to estimate the HCV prevalence and population sizes for four additional populations: incarcerated people, unsheltered homeless people, active-duty military personnel, and nursing home residents. We estimated that during 2013-2016 1.7% (95% confidence interval [CI], 1.4-2.0%) of all adults in the United States, approximately 4.1 (3.4-4.9) million persons, were HCV antibody-positive (indicating past or current infection) and that 1.0% (95% CI, 0.8-1.1%) of all adults, approximately 2.4 (2.0-2.8) million persons, were HCV RNA-positive (indicating current infection). This includes 3.7 million noninstitutionalized civilian adults in the United States with HCV antibodies and 2.1 million with HCV RNA and an estimated 0.38 million HCV antibody-positive persons and 0.25 million HCV RNA-positive persons not part of the 2013-2016 NHANES sampling frame. Conclusion: Over 2 million people in the United States had current HCV infection during 2013-2016; compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while RNA prevalence may have decreased, likely reflecting the combination of the opioid crisis, curative treatment for HCV infection, and mortality among the HCV-infected population; efforts on multiple fronts are needed to combat the evolving HCV epidemic, including increasing capacity for and access to HCV testing, linkage to care, and cure.

Prescription opioid injection among young people who inject drugs in New York City: a mixed-methods description and associations with hepatitis C virus infection and overdose.

AIM: Evidence is emerging that prescription opioid (PO) injection is associated with increased health risks. This mixed-methods study compares the mechanics of PO and heroin injection and examines the demographic and drug-related correlates of lifetime PO injection in a sample of young people who inject drugs (PWID) in New York City (NYC). METHODS: Qualitative analysis of 46 semi-structured interviews with young adult opioid users ages 18-32. Interview segments describing PO injection were analyzed for common themes. Quantitative analysis of structured interviews with 539 young adult opioid users ages 18-29 recruited via respondent-driven sampling (RDS). Analyses are based on the subsample of 353 participants (65%) who reported having ever injected drugs. All variables were assessed via self-report, except hepatitis C virus status, which was established via rapid antibody testing. RESULTS: Participants described injecting POs and reported that preparing abuse-deterrent pills for injection is especially cumbersome, requiring extended manipulation and large amounts of water. Injecting POs, in contrast to injecting heroin, requires repeated injections per injection episode. Among RDS-recruited participants, the majority of injectors reported injecting POs, sporadically (33%) or regularly (26%), but often infrequently (≤ 7 days/month). In separate multivariable analyses controlling for syringe- and cooker-sharing, ever injecting POs was a significant predictor of testing HCV antibody-positive (AOR = 2.97) and lifetime experience of non-fatal overdose (AOR = 2.51). Ever injecting POs was independently associated with lifetime homelessness (AOR = 2.93) and having grown up in a middle-income ($51,000-100,000/year vs. ≤ $50,000/year; AOR = 1.86) or a high-income household (> $100,000/year vs. ≤ $50,000/year; AOR = 2.54). CONCLUSIONS: Even in an urban environment like NYC with widespread heroin access, most young PWID have injected POs, although less frequently than heroin. PO injection involves practices that are known to increase risk for blood-borne viral infection (e.g., repeated injections) and predicted testing HCV-positive, as well as overdose. PO injection may also serve as a marker for a subgroup of PWID at elevated risk for multiple drug use-related comorbidities. Programs that provide prevention services to PWID need to tailor harm reduction measures and messaging to the specific practices and harms associated with the injection of POs.

Hepatitis D Viremia Among Injection Drug Users in San Francisco.

People who inject drugs (PWID) are commonly exposed to hepatitis B virus (HBV) and hepatitis D virus (HDV). We evaluated the prevalence of HDV viremia among hepatitis B surface antigen (HBsAg)-positive PWID (n = 73) using a new quantitative microarray antibody capture (Q-MAC) assay, HDV western blot, and HDV RNA. HDV Q-MAC performed well in this cohort: anti-HDV, 100% sensitivity and specificity; HDV viremia, 61.5% sensitivity and 100% specificity. Hepatitis D viremia was present in 35.6% of HBsAg-positive participants and was more common in those with resolved compared to chronic hepatitis C (5.1% vs 0.6%; adjusted odds ratio, 9.80; P < .0001).

Value of Comprehensive HCV Treatment among Vulnerable, High-Risk Populations.

OBJECTIVES: The objective of this study was to explore the trade-offs society and payers make when expanding treatment access to patients with chronic hepatitis C virus (HCV) infection in early stages of disease as well as to vulnerable, high-risk populations, such as people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM-HIV). METHODS: A discrete time Markov model simulated HCV progression and treatment over 20 years. Population cohorts were defined by behaviors that influence the risk of HCV exposure: PWID, MSM-HIV, an overlap cohort of individuals who are both PWID and MSM-HIV, and all other adults. Six different treatment scenarios were modeled, with varying degrees of access to treatment at different fibrosis stages and to different risk cohorts. Benefits were measured as quality-adjusted life-years and a $150,000/quality-adjusted life-year valuation was used to assess social benefits. RESULTS: Compared with limiting treatment to METAVIR fibrosis stages F3 or F4 and excluding PWID, expanding treatment to patients in all fibrosis stages and including PWID reduces cumulative new infections by 55% over a 20-year horizon and reduces the prevalence of HCV by 93%. We find that treating all HCV-infected individuals is cost saving and net social benefits are over $500 billion greater compared with limiting treatment. Including PWID in treatment access saves 12,900 to 41,200 lives. CONCLUSIONS: Increased access to treatment brings substantial value to society and over the long-term reduces costs for payers, as the benefits accrued from long-term reduction in prevalent and incident cases, mortality, and medical costs outweigh the cost of treatment.

Toward a more accurate estimate of the prevalence of hepatitis C in the United States.

UNLABELLED: Data from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) indicate that about 3.6 million people in the United States have antibodies to the hepatitis C virus, of whom 2.7 million are currently infected. NHANES, however, excludes several high-risk populations from its sampling frame, including people who are incarcerated, homeless, or hospitalized; nursing home residents; active-duty military personnel; and people living on Indian reservations. We undertook a systematic review of peer-reviewed literature and sought out unpublished presentations and data to estimate the prevalence of hepatitis C in these excluded populations and in turn improve the estimate of the number of people with hepatitis C in the United States. The available data do not support a precise result, but we estimated that 1.0 million (range 0.4 million-1.8 million) persons excluded from the NHANES sampling frame have hepatitis C virus antibody, including 500,000 incarcerated people, 220,000 homeless people, 120,000 people living on Indian reservations, and 75,000 people in hospitals. Most are men. An estimated 0.8 million (range 0.3 million-1.5 million) are currently infected. Several additional sources of underestimation, including nonresponse bias and the underrepresentation of other groups at increased risk of hepatitis C that are not excluded from the NHANES sampling frame, were not addressed in this study. CONCLUSION: The number of US residents who have been infected with hepatitis C is unknown but is probably at least 4.6 million (range 3.4 million-6.0 million), and of these, at least 3.5 million (range 2.5 million-4.7 million) are currently infected; additional sources of potential underestimation suggest that the true prevalence could well be higher.

Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance.

BACKGROUND & AIMS: Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. METHODS: We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach. RESULTS: Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048). CONCLUSION: IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.

Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus.

Interferon lambda 4 protein can be generated in IFNL4-ΔG carriers but not IFNL4-TT homozygotes. We studied 890 anti-hepatitis C virus (HCV)-positive participants in the Women's Interagency HIV Study. Among blacks (n = 555), HCV was more often cleared for those with genotype IFNL4-TT/TT (32.6%; odds ratio [OR], 3.59; P = 3.3 × 10(-5)) than IFNL4-TT/ΔG (11.3%; OR, 0.95; P = .86) or IFNL4-ΔG/ΔG (11.9%; referent). Pooling these data with published results in blacks (n = 1678), ORs were 3.84 (P = 8.6 × 10(-14)) for IFNL4-TT/TT and 1.44 (P = .03) IFNL4-TT/ΔG, and the area under the curve was 0.64 for IFNL4-ΔG genotype and 0.61 for rs12979860 (IL28B). IFNL4-ΔG is strongly associated with impaired spontaneous HCV clearance.

Hepatitis C screening: getting it right.

UNLABELLED: Hepatitis C is the most prevalent bloodborne viral disease in the United States and the deadliest. This year, the U.S. Preventive Services Task Force (USPSTF) will update its 2004 hepatitis C guideline, which recommends against screening asymptomatic adults for hepatitis C. This guideline has hampered public health efforts to encourage screening and identify and refer infected persons for care by declaring that such interventions were not supported by the evidence. A draft revision of the guideline, released on November 26, 2012, concludes that testing persons born between 1945 and 1965 probably has at least a small net benefit, but stops short of definitively recommending that this cohort be screened. This article examines the Task Force's process for writing its guidelines. It recommends that the Task Force adopt a balanced approach to evaluating the benefits and harms of screening; use the preponderance of the evidence as a standard for evaluating interventions that target serious public health problems; be transparent about the value judgments that go into its decisions; consider the wide variation in disease prevalence in diverse patient populations; and recommend screening asymptomatic adults for hepatitis C. CONCLUSION: By taking a broader view of the evidence, the Task Force can write new guidelines that will serve efforts to curb the hepatitis C epidemic, rather than frustrate them.

Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts.

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.

HCV RNA levels in a multiethnic cohort of injection drug users: human genetic, viral and demographic associations.

UNLABELLED: In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA. CONCLUSION: The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors.

Racial/ethnic differences in spontaneous HCV clearance in HIV infected and uninfected women.

BACKGROUND/AIMS: Among individuals without human immunodeficiency virus (HIV), African Americans have lower spontaneous clearance of hepatitis C virus (HCV) than Caucasians, and women have higher clearance than men. Few studies report racial/ethnic differences in acute HCV in HIV infected, or Hispanic women. We examined racial/ethnic differences in spontaneous HCV clearance in a population of HCV mono- and co-infected women. METHODS: We conducted a cross sectional study of HCV seropositive women (897 HIV infected and 168 HIV uninfected) followed in the US multicenter, NIH-funded Women's Interagency HIV Study (WIHS), to determine the association of race/ethnicity with spontaneous HCV clearance, as defined by undetectable HCV RNA at study entry. RESULTS: Among HIV and HCV seropositive women, 18.7 % were HCV RNA negative, 60.9 % were African American, 19.3 % Hispanic and 17.7 % Caucasian. HIV infected African American women were less likely to spontaneously clear HCV than Hispanic (OR 0.59, 95 % CI 0.38-0.93, p = 0.022) or Caucasian women (OR 0.57, 95 % CI 0.36-0.93, p = 0.023). Among HIV uninfected women, African Americans had less HCV clearance than Hispanics (OR 0.18, 95 % CI 0.07-0.48, p = 0.001) or Caucasians (OR 0.26, 95 % CI 0.09-0.79, p = 0.017). There were no significant differences in HCV clearance between Hispanics and Caucasians, among either HIV infected (OR 0.97, 95 % CI 0.57-1.66, p = 0.91) or uninfected (OR 1.45, 95 % CI 0.56-3.8, p = 0.45) women. CONCLUSIONS: African Americans were less likely to spontaneously clear HCV than Hispanics or Caucasians, regardless of HIV status. No significant differences in spontaneous HCV clearance were observed between Caucasian and Hispanic women. Future studies incorporating IL28B genotype may further explain these observed racial/ethnic differences in spontaneous HCV clearance.

Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion.

BACKGROUND: Hepatitis C virus (HCV) readily establishes chronic infection with exhaustion of HCV-specific T cells and escape from neutralizing antibodies. Spontaneous recovery from chronic infection is rare and has never to our knowledge been studied immunologically. METHODS: We prospectively studied, from prior to infection through >2 years of follow-up, cytokines, HCV-specific T cells, and antibodies, as well as viral sequence evolution in a white male who spontaneously cleared HCV genotype 1a after 65 weeks. RESULTS: Significant alanine aminotransferase and plasma cytokine elevation and broad HCV-specific T-cell responses did not result in HCV clearance in the acute phase. Frequency and effector function of HCV-specific T cells decreased thereafter, and HCV titers stabilized as is typical for the chronic phase. HCV clearance after 65 weeks followed the appearance of neutralizing antibodies at week 48 and was associated with reversal of HCV-specific T-cell exhaustion, as evidenced by reduced programmed death-1 (PD-1) expression and improved T-cell function. Clearance occurred without inflammation or superinfection with hepatitis B virus, human cytomegalovirus virus, influenza, and Epstein-Barr virus. CONCLUSIONS: T-cell exhaustion is reversible at least in the first 2 years of chronic HCV infection, and this reversion in conjunction with neutralizing antibodies may clear HCV. These findings are relevant for immunotherapy of chronic infections.