Association of IFNL3 and IFNL4 polymorphisms with liver‐related mortality in a multiracial cohort of HIV/HCV‐coinfected women

African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver‐related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV‐related outcomes, the impact of these variants on liver‐related mortality has not been investigated. We conducted a cohort study of HIV/HCV‐coinfected women followed in the multicentre, NIH‐funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN‐λ region were associated with liver‐related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver‐related death by race/ethnicity (ascertained by self‐report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver‐related deaths during up to 18 years of follow‐up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14–0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45–0.99, P = 0.047) were most strongly associated with liver‐related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16–1.04, P = 0.060 and HR 0.78, 95% CI 0.51–1.19, P = 0.25, respectively). African American women had persistently lower liver‐related death independent of IFN‐λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV‐coinfected women is not explained by genetic variation in the IFN‐λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver‐related mortality.     

Risk factors and algorithms to identify hepatitis C, hepatitis B, and HIV among Georgian tuberculosis patients.

OBJECTIVES: To determine prevalence, risk factors, and simple identification algorithms for HIV, hepatitis B, and hepatitis C co-infection; factors that may predispose for anti-tuberculosis therapy-induced hepatotoxicity. METHODS: We recruited 300 individuals at in-patient tuberculosis hospitals in three cities in Georgia, administered a behavioral questionnaire, and tested for antibody to HIV, hepatitis C (HCV), hepatitis B core antigen (anti-HBc), and the hepatitis B surface antigen (HBsAg). RESULTS: Of the individuals tested, 0.7% were HIV positive, 4.3% were HBsAg positive, 8.7% were anti-HBc positive, and 12.0% were HCV positive. In multivariable analysis, a history of blood transfusion, injection drug use, and prison were significant independent risk factors for HCV, while a history of blood transfusion, injection drug use, younger age at sexual debut, and a high number of sex partners were significant risk factors for HBV. Three-questionnaire item algorithms predicted HCV serostatus 74.1% of the time and HBV serostatus 85.2% of the time. CONCLUSIONS: Treatment of tuberculosis patients in resource-limited countries with concurrent epidemics of HCV, HBV, and HIV may be associated with significant hepatotoxicity. Serologic screening of tuberculosis patients for HBV, HCV, and HIV or using behavioral algorithms to identify patients in need of intensive monitoring during anti-tuberculosis therapy may reduce this risk.     

Application of a novel, rapid, and sensitive oligonucleotide ligation assay for detection of cancer-predicting mutations in the precore and basal core promoter of hepatitis B virus

Hepatocellular carcinoma (HCC) and cirrhosis are important causes of mortality worldwide. Persistent hepatitis B virus (HBV) infection is a major cause of these diseases. Double mutations in the basal core promoter (BCP) (A1762T and G1764A) and precore (pre-C) (G1896A) regions of the virus are associated with progression to HCC. The current study is aimed at developing a simple method for screening and detecting BCP and pre-C mutations in HBV carriers. We have developed and validated an oligonucleotide ligation assay (OLA) to detect point mutations in the HBV core gene. We have applied OLA methods to samples from HBV-infected carriers recruited from the Gambia Liver Cancer Study (GLCS) comprising asymptomatic HBsAg carriers, patients with cirrhosis, and patients with HCC. We observed an 89.3% and 95.8% concordance between the OLA and DNA sequencing for BCP and pre-C mutations, respectively. OLA detected the mutations in single-strain infections and in infections with mixtures of wild-type and mutant viruses under conditions where sequencing detected only the single dominant strains. BCP mutations were detected in 75.7% of patients with advanced liver disease (cirrhosis/HCC) compared to 47.6% of asymptomatic carriers, while pre-C mutations were detected in 34.5% of advanced liver disease patients and in 47.6% of asymptomatic HBsAg carriers. There was a significant association between the presence of BCP mutations and advanced liver disease. In conclusion, OLA is a simple, economical, and reliable assay for detection of pre-C and BCP mutations. Its application can lead to improvement in diagnosis and clinical care in regions where HBV is endemic.     

Prevalence of Hepatitis C, HIV, and Risk Behaviors for Blood-Borne Infections: A Population-Based Survey of the Adult Population of T'bilisi, Republic of Georgia

Injection drug use and associated hepatitis C virus (HCV) and HIV infections are on the rise in Russia and the republics of the former Soviet Union. While small targeted studies have found widespread drug use and disease among at-risk populations, there have been few attempts to comprehensively evaluate the extent of these epidemics in general post-Soviet societies. We conducted a two-stage cluster randomized survey of the entire adult population of T'bilisi, Republic of Georgia and assessed the burden of HCV, HIV, and risk behaviors for blood-borne infections in 2,000 study participants. Of the 2,000 surveyed individuals, 162 (8.1%) had injected illicit drugs during their lifetimes. Of the individuals who had injected illicit drugs, 138 (85.2%) reported sharing needles with injection partners. HCV was found in 134 (6.7%) of the total surveyed population, but in 114 (70.4%) of those who had injected illicit drugs. We found HIV in only three (0.2%) individuals, all of whom had injected illicit drugs. Injection drug use and high-risk injection practices are very common in Georgia and may be harbingers of a large burden of HCV-associated liver diseases and a potentially serious HIV epidemic in the years to come. Stvilia, Tsertsvadze, Sharvadze, and Aladashvili are with the Georgian AIDS and Clinical Immunology Research Center, T'bilisi, Republic of Georgia; Rio is with the Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Kuniholm and Nelson are with the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA; Nelson is with the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.     

Seroprevalence and distribution of Flaviviridae, Togaviridae, and Bunyaviridae arboviral infections in rural Cameroonian adults

Arboviruses from the families Flaviviridae, Togaviridae, and Bunyaviridae are suspected to cause widespread morbidity in sub-Saharan African populations, but little research been done to document the burden and distribution of these pathogens. We tested serum samples from 256 Cameroonian adults from nine rural villages for the presence of Dengue-2 (DEN-2), West Nile (WN), Yellow fever (YF), Chikungunya (CHIK), O'nyong-nyong (ONN), Sindbis (SIN), and Tahyna (TAH) infection using standard plaque-reduction neutralization tests (PRNT). Of these samples, 12.5% were DEN-2 positive, 6.6% were WN positive, 26.9% were YF positive, 46.5% were CHIK seropositive, 47.7% were ONN positive, 7.8% were SIN positive, and 36.3% were TAH positive. DEN-2, YF, and CHIK seroprevalence rates were lower among individuals living in dwellings with grass or thatched roofs versus corrugated tin and in villages isolated from urban centers. Seroprevalence rates of YF and CHIK increased with age. These results suggest that inter-epidemic arboviral infection is common in central African populations.     

Not all injection drug users are created equal: heterogeneity of HIV, hepatitis C virus, and hepatitis B virus infection in Georgia

Injection drug users (IDU) are widely believed to have accelerated the looming HIV/AIDS epidemic now faced by the Russian Federation and countries of the former Soviet Union. However, IDUs may be heterogeneous with regard to risk behaviors, and a subpopulation may be responsible for the majority of blood-borne pathogen transmission. We studied 926 adult injection drug users (IDU) from the cities of Tbilisi, Batumi, and Poti in Georgia, a small country in the Caucuses region between the Black and Caspian Seas, between 1997 and 1998. Study participants were administered a confidential questionnaire and were tested for antibody to HIV, hepatitis C virus (HCV), hepatitis B virus surface antigen (HBsAg), and hepatitis B core antibody (anti-HBc). Five (0.5%) individuals were positive for HIV; 539 (58.2%), for HCV; 67 (7.2%), for HBsAg; and 475, for (51.3%) anti-HBc. Surveyed individuals, 88.7%, reported sharing needles with others, and needle sharing with more than 10 other individuals versus no sharing was a highly significant predictor (OR: 278.12, 95% CI: 77.57, 997.20) of HCV seropositivity. In adjusted analysis, individuals who usually injected stolen medical/synthetic drugs had significantly lower odds of HCV (OR: 0.38, 95% CI: 0.22, 0.68) and HBV (OR: 0.58, 95% CI: 0.37, 0.90) than individuals most commonly injecting opium. Despite some limitations, these results suggest the presence of substantial heterogeneity between different injection drug-using groups in Georgia. Identification of high-risk IDU subpopulations is vital to efficiently target risk reduction programs and to prevent confounding by risk status in large HIV/AIDS behavioral intervention and vaccine trials.