Testing for risk and protective trends in genetic analyses of HIV acquisition.
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ABSTRACT:
SUBMITTER: Mccarthy JM
PROVIDER: S-EPMC4441099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:The objective of this study is to understand how trends in HIV acquisition among youth can be influenced by change in HIV risk factors, social factors and prevention and treatment programmes. DESIGN:Trends in HIV incidence (per 1000 person-years), by sex and age group, were estimated using data from youth (15-24 years: n?=?22,164) in the Rakai Community Cohort Study. Trends in HIV incidence were compared with trends in previously identified HIV risk factors, social factors and programmes. METHODS:Poisson and linear regression were used to test for statistical significance and decomposition was used to calculate attribution of risk factors to HIV incidence. RESULTS:Substantial declines between 1999 and 2011 occurred in sexual experience, multiple partners and sexual concurrency among adolescents and young adults. HIV acquisition declined substantially (86%, P?=?0.006) among adolescent women (15-19 years) but not among men or young adult women. Changes in HIV incidence and risk behaviours coincided with increases in school enrolment, decline in adolescent marriage, availability of antiretroviral therapy (ART) and increases in male medical circumcision (MMC). Much of the decline in HIV incidence among adolescent women (71%) was attributable to reduced sexual experience; the decline in sexual experience was primarily attributable to increasing levels of school enrolment. CONCLUSION:Dramatic decreases in HIV incidence occurred among adolescent women in Rakai. Changes in school enrolment and sexual experience were primarily responsible for declining HIV acquisition over time among adolescent women. Given limited improvement among young men and young adult women, the need for effective HIV prevention for young people remains critical.
| S-EPMC6668715 | biostudies-literature
Project description:Youth aged 15-24 years in sub-Saharan Africa are at a high risk for HIV acquisition and urgently need HIV prevention interventions. HIV counselling and testing (HCT) is designed to promote HIV prevention. However the impact of HCT on HIV acquisition has never been assessed among youth. We assess the impact of HCT on HIV acquisition among South African youth.Data came from an annual HIV survey for persons aged 15 years and over, nested within a socio-demographic household surveillance in a geographically defined area of KwaZulu-Natal. Within this population, we used data from 2006 to 2011 to construct a cohort of HIV-uninfected youth aged 15-24 years.We compared youth who reported knowing their HIV status from HCT with those who reported not knowing their HIV status for time to HIV seroconversion using time-varying marginal structural Cox proportional hazards models.The cohort included 3959 HIV-uninfected youth, of whom 1167 (29%) reported HCT at baseline and an additional 1064 (27%) reported HCT during follow up. Youth experienced 248 seroconversions over 8536 person-years, an incidence rate of 2.91 per 100 person-years [95% confidence interval (CI) 2.56-3.28]. In crude analysis, HCT was not associated with HIV incidence (hazard ratio 1.02, 95% CI 0.79-1.31], but in marginal structural models weighted for risk factors, HCT was protective (hazard ratio 0.59, 95% CI 0.45-0.78).In this high-risk population, after accounting for differences in underlying HIV acquisition risk, HCT was associated with lower HIV incidence. HCT scale-up may have prevention benefits for HIV-uninfected youth.
| S-EPMC4028633 | biostudies-literature
Project description:The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from 5 human immunodeficiency virus type 1 (HIV-1) natural history cohorts. The hemizygous genotype had no effect on either acquisition of HIV-1 infection or progression to AIDS. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (odds ratio, 7.37; P= .024), progression to AIDS (relative hazard, 4.01; P=. 03), and viral set point (P= .04). These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1 acquisition and progression to AIDS and warrant further study.
| S-EPMC3690486 | biostudies-literature
Project description:In the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T (rs114945036). To investigate a role for this variant in HIV-1 acquisition in South Africans, we used the model of maternal-infant HIV-1 transmission. A nested case-control study was conducted of infants born to mothers living with HIV-1, comparing children with perinatally-acquired HIV-1 (cases, n = 176) to HIV-1-exposed uninfected children (controls, n = 349). All had received nevirapine for prevention of mother-to-child transmission. The FCGR2C copy number and expression variants (c.-386G>C, c.-120A>T c.169T>C, and c.798+1A>G) were determined using a multiplex ligation-dependent probe amplification assay and the c.134-96C>T genotype with Sanger sequencing. The copy number, genotype and allele carriage were compared between groups using univariate and multivariate logistic regression. The FCGR2C c.134-96C>T genotype distribution and copy number differed significantly between HIV-1 cases and exposed-uninfected controls (P = 0.002, P Bonf = 0.032 and P = 0.010, P Bonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, P Bonf = 0.016). Adjusting for birthweight and FCGR2C copy number, perinatal HIV-1 acquisition was associated with the c.134-96C>T (AOR = 1.89; 95% CI 1.25-2.87; P = 0.003, P Bonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, P Bonf = 0.016) minor alleles but not the promoter variant at position c.-386G>C. The c.134-96C>T variant was in strong linkage disequilibrium with the c.169C>T variant, but remained significantly associated with perinatal acquisition when adjusted for c.169C>T in multivariate analysis. In contrast to the protective effect observed in the Thai RV144 trial, we found the FCGR2C variant c.134-96T-allele associated with increased odds of perinatal HIV-1 acquisition in South African children. These findings, taken together with a similar deleterious association found with HIV-1 disease progression in South African adults, highlight the importance of elucidating the functional relevance of this variant in different populations and vaccination/disease contexts.
| S-EPMC8668943 | biostudies-literature
Project description:BackgroundMeasuring recent HIV infections from routine surveillance systems could allow timely and granular monitoring of HIV incidence patterns. We evaluated the relationship of two recent infection indicators with alternative denominators to true incidence patterns.MethodsWe used a mathematical model of HIV testing behaviours, calibrated to population-based surveys and HIV testing services programme data, to estimate the number of recent infections diagnosed annually from 2010 to 2019 in Côte d'Ivoire, Malawi, and Mozambique. We compared two different denominators to interpret recency data: those at risk of HIV acquisition (HIV-negative tests and recent infections) and all people testing HIV positive. Sex and age-specific longitudinal trends in both interpretations were then compared with modelled trends in HIV incidence, testing efforts and HIV positivity among HIV testing services clients.ResultsOver 2010-2019, the annual proportion of the eligible population tested increased in all countries, while positivity decreased. The proportion of recent infections among those at risk of HIV acquisition decreased, similar to declines in HIV incidence among adults (≥15 years old). Conversely, the proportion of recent infections among HIV-positive tests increased. The female-to-male ratio of the proportion testing recent among those at risk was closer to 1 than the true incidence sex ratio.ConclusionThe proportion of recent infections among those at risk of HIV acquisition is more indicative of HIV incidence than the proportion among HIV-positive tests. However, interpreting the observed patterns as surrogate measures for incidence patterns may still be confounded by different HIV testing rates between population groups or over time.
| S-EPMC8631145 | biostudies-literature
Project description:Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p?=?3.72?×?10-7, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p?=?1.88?×?10-6, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.
| S-EPMC5467143 | biostudies-literature
Project description:BackgroundWomen in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group.MethodsTwelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1β, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1β), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial.ResultsHIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3-7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines.ConclusionsElevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.
| S-EPMC4565995 | biostudies-literature
Project description:IntroductionTargeting most-at-risk individuals with HIV preventive interventions is cost-effective. We developed gender-specific indices to measure risk of HIV among sexually active individuals in Rakai, Uganda.MethodsWe used multivariable Cox proportional hazards models to estimate time-to-HIV infection associated with candidate predictors. Reduced models were determined using backward selection procedures with Akaike's information criterion (AIC) as the stopping rule. Model discrimination was determined using Harrell's concordance index (c index). Model calibration was determined graphically. Nomograms were used to present the final prediction models.ResultsWe used samples of 7,497 women and 5,783 men. 342 new infections occurred among females (incidence 1.11/100 person years,) and 225 among the males (incidence 1.00/100 person years). The final model for men included age, education, circumcision status, number of sexual partners, genital ulcer disease symptoms, alcohol use before sex, partner in high risk employment, community type, being unaware of a partner's HIV status and community HIV prevalence. The Model's optimism-corrected c index was 69.1 percent (95% CI = 0.66, 0.73). The final women's model included age, marital status, education, number of sex partners, new sex partner, alcohol consumption by self or partner before sex, concurrent sexual partners, being employed in a high-risk occupation, having genital ulcer disease symptoms, community HIV prevalence, and perceiving oneself or partner to be exposed to HIV. The models optimism-corrected c index was 0.67 (95% CI = 0.64, 0.70). Both models were well calibrated.ConclusionThese indices were discriminative and well calibrated. This provides proof-of-concept that population-based HIV risk indices can be developed. Further research to validate these indices for other populations is needed.
| S-EPMC3976261 | biostudies-literature
Project description:BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition.ResultsAmong 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV.ConclusionsLTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.
| S-EPMC9064099 | biostudies-literature
Project description:ObjectiveTo develop and validate an HIV risk assessment tool to predict HIV acquisition among African women.DesignData were analyzed from 3 randomized trials of biomedical HIV prevention interventions among African women (VOICE, HPTN 035, and FEM-PrEP).MethodsWe implemented standard methods for the development of clinical prediction rules to generate a risk-scoring tool to predict HIV acquisition over the course of 1 year. Performance of the score was assessed through internal and external validations.ResultsThe final risk score resulting from multivariable modeling included age, married/living with a partner, partner provides financial or material support, partner has other partners, alcohol use, detection of a curable sexually transmitted infection, and herpes simplex virus 2 serostatus. Point values for each factor ranged from 0 to 2, with a maximum possible total score of 11. Scores ≥5 were associated with HIV incidence >5 per 100 person-years and identified 91% of incident HIV infections from among only 64% of women. The area under the curve (AUC) for predictive ability of the score was 0.71 (95% confidence interval [CI]: 0.68 to 0.74), indicating good predictive ability. Risk score performance was generally similar with internal cross-validation (AUC = 0.69; 95% CI: 0.66 to 0.73) and external validation in HPTN 035 (AUC = 0.70; 95% CI: 0.65 to 0.75) and FEM-PrEP (AUC = 0.58; 95% CI: 0.51 to 0.65).ConclusionsA discrete set of characteristics that can be easily assessed in clinical and research settings was predictive of HIV acquisition over 1 year. The use of a validated risk score could improve efficiency of recruitment into HIV prevention research and inform scale-up of HIV prevention strategies in women at highest risk.
| S-EPMC4911322 | biostudies-literature