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Background People with HIV have higher risk of hepatocellular carcinoma than the general population, partly because of higher prevalence of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Methods We calculated standardized incidence ratios for hepatocellular carcinoma in people with HIV by comparing rates from people with HIV in the HIV/AIDS Cancer Match Study, a population-based HIV and cancer registry linkage, to those in the general population. We used multivariable Poisson regression to estimate adjusted incidence rate ratios among people with HIV and linked the Texas HIV registry with medical claims data to estimate adjusted odds ratios (AORs) of HBV and HCV in hepatocellular carcinoma patients with logistic regression. Results Compared with the general population, hepatocellular carcinoma rates in people with HIV were elevated 2.79-fold (n = 1736; 95% confidence interval [CI] = 2.66 to 2.92). Hepatocellular carcinoma rates decreased statistically significantly from 2001-2004 to 2015-2019 (P  < .001). Compared with men who have sex with men, hepatocellular carcinoma risk was elevated 4.28-fold among men who injected drugs (95% CI = 3.72 to 4.93) and 1.83-fold among women who injected drugs (95% CI = 1.49 to 2.26). In Texas, 146 hepatocellular carcinoma cases among people with HIV were linked to claims data: 25% HBV positive, 59% HCV positive, and 13% coinfected with HBV and HCV. Compared with men who had sex with men, people who inject drugs had 82% decreased odds of HBV (AOR = 0.18, 95% CI = 0.05 to 0.63) and 2 times the odds of HCV (AOR = 20.4, 95% CI = 3.32 to 125.3). Conclusions During 2001-2019, hepatocellular carcinoma risk declined among people with HIV, though rates remain statistically significantly elevated compared with the general population, particularly among people who inject drugs. Prevention and treatment of HBV/HCV are needed to reduce hepatocellular carcinoma risk among people with HIV. [ABSTRACT FROM AUTHOR]

Background IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984–1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,.76–1.11]), cytomegalovirus infection (0.94 [.71–1.24]), herpes simplex virus infection (1.37 [.68–2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown.Methods: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype.Results: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status.Conclusions: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients. [ABSTRACT FROM AUTHOR]

An editorial is presented on the COVID-19 a respiratory illness caused by a novel coronavirus has first identified in the Hubei province of China in December 2019 and has spread worldwide. Topics icnlude the investigators found that although these 2 coronaviruses have similar cell tropism, and the viral replication being much more efficient for SARS-CoV-2 than SARSCoV.

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). [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on genetic associations of HLA-B57 allele group and interferon lambda 4 (IFNL4)–ΔG/TT genotype with CD4 T-cell decline in women's human immunodeficiency virus (HIV) controllers. Topics discussed include the identification of HIV controller phenotype, the HIV progression phenotype, and the African American women on whom the study was conducted.

Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α–free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α–free DAA therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and v2 tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28Bgenotype with HCV clearancemay improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association. [ABSTRACT FROM AUTHOR]

Background: 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) exposure has been demonstrated to cause liver tumors in laboratory rodents. DDT's persistent metabolite and environmental degradation product, 1,1-dichioro-2,2-bis(p-chlorophenyl)ethylene (DDE), has also been associated with liver tumors in laboratory animals. Whether DDT and DDE are associated with hepatocarcinogenesis in humans is not clear. Methods: We carried out a nested case-control study among the participants of the Nutritional Intervention Trials in Linxian, China. The case group included 168 individuals who developed liver cancer during the trials, and the control group included 385 individuals frequency-matched on age and sex who were alive and well at the end of the study. Serum concentrations of DDT and DDE were measured by gas chromatography-mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable analysis. Results: In multivariable-adjusted models, the risk of developing liver cancer increased with increased serum DDT concentration (OR for quintile 1 versus quintile 5 = 3.8, 95% CI = 1.7 to 8.6, Ptrend = .0024). In contrast, there was no statistically significant association between liver cancer and serum DDE concentration. The association between high serum DDT concentration and liver cancer was stronger among individuals with DDE concentrations below the median value (odds ratio for tertile 3 versus tertile 1 = 3.55, 95% CI = 1.45 to 8.74) than those with concentrations above the median (OR = 1.70, 95% CI = 0.97 to 2.98). A calculation of crude liver cancer risk found that there would be 26 liver cancers per 100000 persons per year in the lowest quintile of DDT exposure versus 46 liver cancers per 100000 persons per year in the highest quintile of DDT exposure. Conclusions: DDT may be a risk factor for liver cancer, particularly among persons with lower DDE concentrations. Risk may be particularly increased among persons exposed directly to DDT (resulting in a higher ratio of DDT to DDE) or, alternatively, risk may be associated with individual ability to metabolize DDT to DDE. [ABSTRACT FROM AUTHOR]

Background: CC-chemokine receptor 5 (CCR5) is a co-receptor for human immunodeficiency virus type 1 (HIV-1) infection. Homozygosity for a 32–base pair (bp) deletion (Δ32) in the CCR5 gene confers resistance to HIV-1. Previous studies found an increased prevalence of hypertension among CCR5-Δ32 homozygotes and among carriers of a polymorphism (CCR2-64I) found on the gene that codes a closely related chemokine receptor. The present study was carried out to verify these associations. Methods: Subjects in this cross-sectional study were selected from the Global Repository at Genomics Collaborative, which includes patients and healthy control subjects enrolled at multiple clinical sites in the United States and other nations. The current study includes 2842 subjects with hypertension and 2893 nonhypertensive control subjects from white populations in the United States and Poland. Case and control subjects were frequency matched by age, gender, and birthplace. All subjects were genotyped for CCR5-Δ32 and CCR2-64I polymorphisms by established Taqman assays. Results: The CCR5-Δ32 genotype was not found to be associated with hypertension (CCR5-Δ32 heterozygosity: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.87 to 1.14; CCR5-Δ32 homozygosity: OR 1.07, 95% CI 0.68 to 1.67) among these subjects. There was also no association between CCR2-64I genotype and hypertension (CCR2-64I heterozygosity: OR 0.96, 95% CI 0.83 to 1.10; CCR2-64I homozygosity: OR 1.18, 95% CI 0.73 to 1.92). These results changed little after adjustment for potential confounding variables. Conclusion: The results of the present study, which is much larger than previously published studies, provide no evidence that either CCR5-Δ32 or CCR2-64I is associated with hypertension. [Copyright &y& Elsevier]

A polymorphism, 3179G/T, in the promoter of the interferon (IFN)-γ gene (IFNG) confers differential tumor necrosis factor-α (TNF-α) inducibility to the IFNG promoter. The rarer allele, 3179T, but not 3179G, is inducible by TNF-α. We investigated the effects of IFNG 3179G/T on AIDS pathogenesis. In 298 African American human immunodeficiency virus (HIV)-1 seroconverters, the IFNG 3179G/T genotype was associated with accelerated progression to CD4<200 and AIDS-1993, a finding suggesting that IFNG 3179T is a risk factor for AIDS progression, as measured by CD4 cell count. It is possible that increased IFN-γ production induced by TNF-α when 3179T is present causes CD4 cell depletion by apoptosis. [ABSTRACT FROM AUTHOR]

SEN viruses (SENVs) are newly discovered bloodborne viruses that may play a role in liver disease. SENV strain prevalence was examined in a race/ethnicity-stratified sample of 531 injection drug users (IDUs) from the San Francisco Bay area. Weighted prevalences were as follows: SENV-A, 45.7%; SENV-C/H, 35.6%; and SENV-D, 10.3%. Infection was associated with a longer duration of injection drug use. SENV-A was more common in black subjects (adjusted odds ratio [OR[SUBa]], 4.37; 95% confidence interval [CI], 2.65-7.21) and Hispanic subjects (OR[SUBa], 2.30; 95% CI, 1.38-3.85) than in white and non-Hispanic subjects, and the pattern) was similar for SENV-C/H. For SENV-D, prevalence was similar in black and white subjects, but lower in Hispanic subjects; infection was less common among women than men (OR[SUBa], 0.32; 95% CI, 0.15-0.71) and more common among men with at least 1 recent male sex partner than among heterosexual men (OR[SUBa], 7.05; 95% CI, 2.62-18.95). SENV strains are common among San Francisco Bay area IDUs, and prevalence varies demographically within this group. [ABSTRACT FROM AUTHOR]

The association between injection drug use and human herpesvirus 8 (HHV-8) was examined to investigate bloodborne transmission of the virus. In all, 1905 injection drug users (IDUs) enrolled in a cross-sectional study were tested for K8.1 antibodies to HHV-8 lytic antigen. Logistic regression was used to adjust for demographic and sexual behavior variables. HHV-8 seroprevalence was 10% among women, 10% among heterosexual men, and 23% among men who have sex with men. In adjusted analyses, HHV-8 seroprevalence increased with longer duration of injection drug use for each of these groups (P = .01, P = .03, and P = .049 for trend, respectively). HHV-8 infection is relatively common among IDUs in San Francisco, and longer duration of injection drug use is associated with an increase in the risk of HHV-8 infection that is not explained by sexual behavior or demographic differences. These results are consistent with the occurrence of bloodborne transmission of HHV-8 among IDUs. [ABSTRACT FROM AUTHOR]

The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis. [ABSTRACT FROM PUBLISHER]

The article presents a commentary on a study which conducted a meta-analysis of individual participants' data (MIPD) with time-to-event analyses in the field of genetic epidemiology. The study has found that the MIPD offers many advantages over a meta-analysis of the published literature, including inclusion of extended databases from published studies, inclusion of data from unpublished studies and better time-to-event analyses. A disadvantage of an MIPD is the inability for published data to be made available for synthesis.

Risk factors for postcoital bleeding were examined in 475 women who were enrolled in a study of heterosexual transmission of human immunodeficiency virus (HIV). In bivariate analyses, history of sexually transmitted diseases (STDs; P = .03), HIV infection (P = .008), and dyspareunia or pain during intercourse (P = .0001) were significant risk factors. In multivariate analysis, the two latter factors remained significant (for HIV, odds ratio [OR] = 2.1, P = .02,95% confidence interval [CI] = 1.1–4.0; for dyspareunia, OR = 3.5, P < .001, 95% CI = 1.8–6.6), as did the interaction term of STD history and heavy smoking (OR = 2.4, P = .02, 95% CI = 1.2–5.0). Pain during intercourse was the strongest predictor of postcoital bleeding but may be part of the same phenomenon. Similarly, because this study relied on cross-sectional data, the direction of the causal pathway linking HIV to postcoital bleeding cannot be established. However, these data suggest that smoking, a modifiable risk factor, may increase risk of postcoital bleeding and contribute to susceptibility for HIV and other STDs. [ABSTRACT FROM PUBLISHER]

Kaposi's sarcoma (KS)—associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8) may play an etiologic role in the pathogenesis of KS. In an attempt to assess KSHV/HHV-8 infection, an ELISA was developed using an 18-amino acid peptide from a putative minor capsid protein of KSHV/HHV—8 conjugated to bovine serum albumin. Overall, sera from human immunodeficiency virus type 1 (HIV-l)—positive patients with KS had a higher reactivity in the assay than did sera from HIV-1—positive patients without KS (P = .018). Of 35 HIV-1—positive patients with KS, 60% were antibody positive, compared with 27% of 33 HIV-1—positive patients without KS. Of 30 healthy blood donors, 20% were antibody positive. The ELISA responses did not correlate with antibody titers to Epstein-Barr virus. Given the homology and antigenic relatedness between KSHV/HHV-8 and Epstein-Barr virus, serologic assays involving unique KSHV/HHV-8 peptides may prove to be valuable in defining the epidemiology and clinical expression of this virus. [ABSTRACT FROM PUBLISHER]

Cholangiocarcinomas are topographically categorized as intrahepatic or extrahepatic by the International Classification of Diseases for Oncology (ICD-O). Although hilar cholangiocarcinomas (Klatskin tumors) are extrahepatic cholangiocarcinomas, the second edition of the ICD-O (ICD-O-2) assigned them a histology code 8162/3, Klatskin, which was cross-referenced to intrahepatic cholangiocarcinoma. Recent studies in the United States that included this code (8162/3, Klatskin) with intrahepatic cholangiocarcinoma reported an increasing incidence of intrahepatic cholangiocarcinoma and a decreasing incidence of extrahepatic cholangiocarcinoma. To investigate the impact of this misclassification on site-specific cholangiocarcinoma incidence rates, we calculated annual percent changes (APCs) with data from the Surveillance, Epidemiology, and End Results (SEER) program using a Poisson regression model that was age-adjusted to the year 2000 U.S. population. All statistical tests were two-sided. During 1992—2000, when SEER used ICD-O-2, 1710 intrahepatic cholangiocarcinomas, 1371 extrahepatic cholangiocarcinomas, and 269 hilar cholangiocarcinomas identified by code 8162/3, Klatskin were diagnosed. Ninety-one percent (246 of 269) of the hilar cholangiocarcinomas were incorrectly coded as intrahepatic cholangiocarcinomas, resulting in an overestimation of intrahepatic cholangiocarcinoma incidence by 13% and underestimation of extrahepatic cholangiocarcinomas incidence by 15%. However, even after the exclusion of tumors that were coded to the histology code 8162/3, Klatskin, age-adjusted annual intrahepatic cholangiocarcinoma incidence increased during this period (APC = 4%, 95% confidence interval = 2% to 6%, P<.001). [ABSTRACT FROM AUTHOR]

The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Subgroup Differences in Response to 8 Weeks of Ledipasvir/Sofosbuvir for Chronic Hepatitis C" by K.V. Kowdley.

A response by T. M. Welzel, K. A. McGlynn, A. W. Hsing, T. R. O'Brien and R. M. Pfeiffer to a letter to the editor about their article "Impact of Classification of Hilar Cholangiocarcinomas (Klatskin Tumors) on Incidence of Intra- and Extrahepatic Cholangiocarcinoma in the United States " in the 2006 issue is presented.

Treatment of hepatitis C virus (HCV) infection with ledipasvir/sofosbuvir promises tremendous benefits, but high cost may impede implementation of this regimen. Subgroups with excellent response to 8 weeks of treatment might respond to a shorter course. In ION-3, 423 previously untreated HCV genotype 1-infected patients without cirrhosis had outcome data after receiving ledipasvir/sofosbuvir for 8 weeks. After reanalyzing published ION-3 data, we found that sustained virologic response (SVR) rates varied significantly by gender (P = .002) and rs12979860 genotype (Ptrend = .03), exceeding 98% in women and rs12979860-CC individuals. The very high SVR rates in these subgroups suggest that these factors might be considered in selecting patients to receive 8 weeks of ledipasvir/sofosbuvir and support shorter trials of this regimen in selected patients. [ABSTRACT FROM PUBLISHER]

Examines the risk of heterosexual transmission of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) on men with hemophilia. Use of immunoblot assay in detecting plasma antibodies; Measurement of HIV RNA level; Correlation between HIV and HCV positivity.