HIV-seronegative Adults Research Articles

Subclinical Myocardial Fibrosis in South African Youth With HIV: Results From the CTAAC-Heart Study

Abstract Background Few data exist on myocardial fibrosis and inflammation in youth with HIV. Methods We performed cardiovascular magnetic resonance (CMR) on a cross section of South African youth: youth with perinatally acquired HIV (YPHIV) undergoing antiretroviral therapy (ART), youth with nonperinatally acquired HIV (YNPHIV) receiving ART, and youth without HIV. Quantile regression models were fit to assess the association between HIV status and CMR outcomes: subclinical fibrosis (late gadolinium enhancement [LGE] mass and fraction, native T1, extracellular volume) and inflammation (native T1, T2 mapping). Results Of 464 youth, 287 were YPHIV, 87 were YNPHIV, and 90 were HIV seronegative. The median age was 16 years (range, 11–24). LGE mass was higher in YPHIV and YNPHIV than in youth who were HIV seronegative (1.85 vs 2.00 vs 1.41 g, respectively), as was fraction (5.8% vs 6.4% vs 4.5%); native T1 was highest in YNPHIV. In adjusted analyses, when compared with youth with HIV seronegativity, YPHIV and YNPHIV exhibited higher LGE mass (β = 0.468, P = .001; β = 0.544, P = .002) and LGE fraction (β = 1.587, P < .001; β = 1.781, P < .001). CMR outcomes were similar between YPHIV and YNPHIV. Conclusions Despite ART use, YPHIV and YNPHIV appear to have higher subclinical myocardial fibrosis than youth who are HIV seronegative and healthy adults in South Africa and may benefit from early screening/monitoring for cardiovascular disease.

Association of first-line combination antiretroviral therapy with malaria among adult HIV-infected persons in Jos, Nigeria: a pilot cross sectional study

BackgroundMalaria and human immunodeficiency virus (HIV) infection coexist in significant numbers in some geographic areas including sub-Sahara Africa (SSA). HIV-infected patients are a World Health Organization (WHO) recognized high risk group for increased malaria morbidity. Majority of HIV-infected patients undertaking treatment in SSA are on WHO recognized first-line combination antiretroviral therapy (cART). Considering the immunity-enhancing capacity of antiretroviral therapies on people living with HIV, this study aimed to explore the association between first-line combination antiretroviral therapy (cART) with malaria parasitaemia and antigenaemia in adult HIV-infected persons and to determine the predictors of malaria antigenaemia in adult persons living with HIV.MethodsThe study was conducted at the AIDS Prevention Initiative in Nigeria (APIN) Centre, Jos University Teaching Hospital, Jos, Plateau State, from August 2018 to February 2019. Epi Info statistical tool was used to determine the sample size and power of the study. The study population consisted of three groups. The first group comprised first-line cART-experienced adult HIV-seropositive subjects, the second group comprised ARV-naïve HIV-seropositive adults and the third group comprised HIV-seronegative adults. For this pilot study, 60 persons were recruited into each group via convenience sampling. Malaria rapid diagnostic test (RDT) was performed according to manufacturer’s instruction for all the study participants using SD Bioline Malaria Ag P.f (HRP2/pLDH) (Standard Diagnostics, Hagal-Dong, Korea). All the study participants also had thick and thin blood film malaria microscopy. Data collected was processed and analyzed using the Stata statistical software version 15 (StataCorp, College Station, Texas). Chi square was used to test the association between malaria and first-line cART exposure. Univariate and multivariate analysis were also done to identify factors that were independently associated with malaria antigenaemia.ResultsA total of 180 persons participated in the study and involved 60 participants recruited in each of the three study groups. Overall, the predominant study participants were females (56.67%), traders (27.78%), secondary school leavers (43.33%) and urban dwellers (88.89%). Their mean age and standard deviation was 37.07 ± 11.53 years. Using malaria microscopy, the prevalence of malaria parasitaemia in ARV-naïve HIV-infected persons was 5% and 0% in the first-line cART-experienced HIV-infected persons as well as the HIV-negative persons. Malaria RDT result was positive in 7/60 (11.67%) of the first-line cART experienced HIV-infected participants, 6/60 (10%) of the ARV-naïve HIV-infected group and 1/60 (1.67%) of the HIV-negative group. Of the seven positive malaria RDT results in those on first-line cART, five persons were receiving zidovudine/lamivudine/nevirapine (AZT/3TC/NVP) while the remaining two were receiving tenofovir disoproxil fumarate/lamivudine/efavirenz (TDF/3TC/EFV), thus making an antigenaemia proportion of 16.67% and 6.67% respectively. Being an HIV-infected person on first-line cART (OR = 16.20, p = 0.04), having a headache (OR = 6.21, p = 0.03) and non-usage of window nets (OR = 3.74, p = 0.05) were found to be predictors of malaria antigenaemia.ConclusionMalaria parasite burden in HIV-infected persons on first-line cART is lower than that observed in ARV-naïve HIV-infected persons. Our study suggests that TDF/3TC/EFV may be associated with lower malaria antigenaemia when compared with AZT/3TC/NVP and can be considered an alternative first-line antiretroviral regimen in malaria-endemic regions.

Awareness and openness to the use of PrEP among a nationally representative sample of South African adults.

South Africa adopted for pre-exposure prophylaxis (PrEP) in 2016, becoming the first African country to do so. Yet to date, uptake has been underwhelming, only about 165,000 South Africans were reported to be on PrEP in mid-2021. Lack of awareness has been cited as a contributory factor for the low uptake, but this has never been examined using a nationally representative sample. we investigated this among a national sample of HIV seronegative adults. Data were from the 2017/2018 South African National HIV Prevalence, Incidence, Behaviour and Communication Survey. Awareness and openness to using PrEP were self-reported. Weighted percentages were calculated overall and by demographic characteristics. overall, only 3.2% of seronegative adults spontaneously reported PrEP as a way of preventing HIV. Overall, 69.6% were open to using PrEP, from 58.2% in Western Cape, to 78.5% Northern Cape. Openness was highest among the youngest age group (18-29 years, 78.3%) and lowest among the oldest (60+ years, 45.6%). Striking racial differences were observed with openness among Black Africans (75.4%) being 2.5 times higher than Whites (29.0%). Among women, openness was 64.7% among those currently pregnant, 80.4% among those pregnant in the past two years but not now, and 67.8% among those who were not pregnant in the past two years (χ(2)=134.2, p<0.001). Among males, openness was higher among those circumcised (75.6%) than uncircumcised (64.5%). planning for broad-scale implementation of PrEP within the South African context could build on knowledge gained from recent implementation and scale-up of relevant biomedical interventions (e.g. ART, voluntary medical male circumcision, and family planning).

Psychological grit moderates the relation between lifetime stressor exposure and functional outcomes among HIV-seropositive and HIV-seronegative adults.

The ability to maintain functional independence throughout the lifespan may be diminished among medically compromised and chronically stressed populations. People living with HIV are more likely to demonstrate functional impairment and report greater exposure to lifetime and chronic stressors than their seronegative counterparts. It is well-known that exposure to stressors and adversity is associated with functional impairment outcomes. However, to our knowledge, no studies have examined how protective factors such as psychological grit mitigate the negative effects of lifetime and chronic stressor exposure on functional impairment, and how this association differs by HIV-status. To address this issue, we studied associations between lifetime and chronic stressor exposure, grit, and functional impairment in 176 African American and non-Hispanic White HIV-seropositive (n=100) and HIV-seronegative (n=76) adults, aged 24-85 (M=57.28, SD=9.02). As hypothesised, HIV-seropositive status and lower grit, but not lifetime stressor exposure, were independently associated with more functional impairment. Moreover, there was a significant three-way interaction between HIV-status, grit, and lifetime stressor exposure, b=0.07, p=0.025, 95% CI [0.009, 0.135]. Specifically, lifetime stressor exposure was related to more functional impairment for HIV-seronegative-but not HIV-seropositive-adults who reported low levels of grit. These findings suggest that the protective effects of grit may differ across populations at risk for functional impairment.

Predictors of Loss to Follow-Up in an HIV Vaccine Preparedness Study in Masaka, Uganda.

Background: High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up (LTFU) in an HIV vaccine-preparedness study in Masaka, Uganda. Methods: Between July 2018 and March 2021, HIV sero-negative adults (18–45 years) at high risk of HIV infection were identified through HIV counselling and testing (HCT) from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria. Study procedures included collection of baseline socio-demographic data, quarterly HCT, and 6-monthly collection of sexual risk behaviour data. Retention strategies included collection of detailed locator data, short clinic visits (1–2 h), flexible reimbursement for transport costs, immediate (≤7 days) follow-up of missed visits via phone and/or home visits, and community engagement meetings. LTFU was defined as missing ≥2 sequential study visits. Poisson regression models were used to identify baseline factors associated with LTFU. Results: 672 participants were included in this analysis. Of these, 336 (50%) were female and 390 (58%) were ≤24 years. The median follow-up time was 11 months (range: 0–31 months). A total 214 (32%) participants were LTFU over 607.8 person-years of observation (PYO), a rate of 35.2/100 PYO. LTFU was higher in younger participants (18–24 years versus 35–45 years, adjusted rate ratio (aRR) = 1.29, 95% confidence interval (CI) 0.80–2.11), although this difference was not significant. Female sex (aRR = 2.07, 95% CI, 1.51–2.84), and recreational drug use (aRR = 1.61, 95% CI, 1.12–2.34) were significantly associated with increased LTFU. Engagement in transactional sex was associated with increased LTFU (aRR = 1.36, 95% CI, 0.97–1.90) but this difference was not significant. LTFU was higher in 2020–2021 (the period of COVID-19 restrictions) compared to 2018–2019 (aRR = 1.54, 1.17–2.03). Being Muslim or other (aRR = 0.68, 95% CI 0.47–0.97) and self-identification as a sex worker (aRR = 0.47, 95% CI, 0.31–0.72) were associated with reduced LTFU. Conclusion: We observed a high LTFU rate in this cohort. LTFU was highest among women, younger persons, recreational drug users, and persons who engage in transactional sex. Efforts to design retention strategies should focus on these subpopulations.

Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study.

BackgroundPeople infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity.Methods and findingsThis analysis comprises an observational cohort of 329 HIV–seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed.ConclusionsIn summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally.Trial registrationClinicalTrials.gov NCT04403880.

Socioeconomic Mobility and Psychological and Cognitive Functioning in a Diverse Sample of Adults With and Without HIV.

This cross-sectional study examined the effects of socioeconomic status (SES) mobility from childhood to adulthood on psychological and cognitive well-being in African American and non-Hispanic White HIV-positive (HIV+) and HIV-seronegative (HIV-) adults who are part of an ongoing study investigating psychosocial and neurobehavioral effects of HIV. Participants (N = 174, 24.1% female, 59.2% African American, 67.8% HIV+) were categorized into four groups (upward mobility, downward mobility, stable-not-poor, chronic-poverty) based on self-reported childhood and current community SES (which were correlated with objective measures of SES and proxies of childhood SES). SES groups were compared on self-report measures of psychological well-being, subjective executive functioning ratings, and performance across six cognitive domains. Primary analyses were stratified by HIV status. For the HIV+ group, SES mobility was associated with psychological well-being (chronic burden of stress: F(7,101) = 3.17, mean squared error [MSE] = 49.42, p = .030, η2 = 0.14; depressive symptoms: F(7,101) = 4.46, MSE = 70.49, p = .006,η2 = 0.14), subjective ratings of executive dysfunction (F(7,101) = 6.11, MSE = 114.29, p = .001,η2 = 0.18), and objective performance in executive functioning (F(9,99) = 3.22, MSE = 249.52, p = .030, η2 = 0.15) and learning (F(9,99) = 3.01, MSE = 220.52, p = .034, η2 = 0.13). In the control group, SES mobility was associated with chronic stress burden (F(5,49) = 4.677, p = .025, η2 = 0.15); however, no other relationships between SES mobility and outcomes of interest were observed (all p values > .20). In general, downward mobility and chronic poverty were associated with worse ratings across psychological well-being measures and cognitive performance. Findings within the HIV+ group are consistent with previous studies that report downward mobility to be associated with poor psychological outcomes. People living with HIV may be particularly vulnerable to the adverse effects of socioeconomic instability.

Increased Frequency of Memory CD4+ T-Cell Responses in Individuals With Previously Treated Extrapulmonary Tuberculosis.

Extrapulmonary TB (EPTB) occurs with increased frequency in persons with underlying immunodeficiency. Even after recovery from acute illness, differences in immune phenotype and activation persist. Studies defining characteristics of immune responses after recovery from extrapulmonary TB may provide insights into factors that increase TB risk. We performed two case-control studies (in the United States and Brazil) among HIV-seronegative adults with previous EPTB (n = 9; 25), previous pulmonary TB (n = 7; 25), latent M. tuberculosis (Mtb) infection (n = 11; 25), and uninfected TB contacts (n = 10; 25). We assessed the frequency of dual CD4+ interferon-γ and tumor necrosis factor-α responses after stimulation with overlapping Mtb peptides from ESAT-6 or CFP-10, or gamma-irradiated Mtb H37Rv, proliferative responses to Mtb antigens, T-regulatory cell (Treg) frequency and phenotype. In both study populations, individuals with prior EPTB had the highest frequency of intracellular cytokine-producing cells in response to Mtb antigens (p < 0.05; p <.0001). Persons with prior EPTB in Brazil had the highest levels of CD4 proliferation to Mtb antigens (p < 0.0001), and the highest expression of CD39 on Tregs (p < 0.0001). Individuals with treated EPTB maintained high frequencies of Mtb-specific memory responses and active Treg cells, suggesting that susceptibility to EPTB occurs despite the ability to develop and maintain enhanced adaptive immune responses.

The joint effect of aging and HIV infection on microstructure of white matter bundles.

Recent evidence suggests the aging process is accelerated by HIV. Degradation of white matter (WM) has been independently associated with HIV and healthy aging. Thus, WM may be vulnerable to joint effects of HIV and aging. Diffusion-weighted imaging (DWI) was conducted with HIV-seropositive (n = 72) and HIV-seronegative (n = 34) adults. DWI data underwent tractography, which was parcellated into 18 WM tracts of interest (TOIs). Functional Analysis of Diffusion Tensor Tract Statistics (FADTTS) regression was conducted assessing the joint effect of advanced age and HIV on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along TOI fibers. In addition to main effects of age and HIV on WM microstructure, the interactive effect of age and HIV was significantly related to lower FA and higher MD, AD, and RD across all TOIs. The location of findings was consistent with the clinical presentation of HIV-associated neurocognitive disorders. While older age is related to poorer WM microstructure, its detrimental effect on WM is stronger among HIV+ relative to HIV- individuals. Loss of WM integrity in the context of advancing age may place HIV+ individuals at increased risk for brain and cognitive compromise.

120. A Randomized Double-blind Trial Assessing the Efficacy of M72/AS01E Vaccine Against Pulmonary Tuberculosis Disease in Adults With Latent Mycobacterium tuberculosis Infection

BackgroundAn effective tuberculosis (TB) vaccine is urgently needed to support the End TB Strategy to reduce the number of new TB cases by 80% by 2030. M72/AS01E candidate vaccine is an adjuvanted recombinant fusion protein derived from Mycobacterium tuberculosis Mtb32A and Mtb39A proteins.MethodsWe conducted a randomized, double-blind, placebo-controlled phase 2b trial (NCT01755598) in Southern and Eastern Africa to assess M72/AS01E’s efficacy against bacteriologically confirmed pulmonary TB disease in HIV-seronegative (HIV–) adults aged 18–50 years infected with Mtb (defined by a positive IFN-γ release assay). Participants were randomized 1:1 to receive M72/AS01E or placebo at day D0 and D30. Reactogenicity, safety, immunogenicity were assessed, and incident TB disease measured from D30 postdose 2 up to ≥24 months for this analysis (follow-up ongoing up to 37 months). Efficacy against various TB disease case definitions (Figure 1) was estimated. Primary objective: efficacy against culture- or PCR-confirmed pulmonary TB disease in HIV– adults (case definition 1; success criterion: lower limit of 90% 2-sided CI >0%, power: 80%).ResultsDemographic characteristics were similar between M72/AS01E (1786) and placebo (1787) recipients. Efficacy against pulmonary TB disease case definition 1 was 54.0% (90% CI: 13.9, 75.4; P = 0.042); efficacy against other case definitions and a sensitivity analysis are shown in Figure 1. Leading solicited symptoms were pain, fatigue, and headache (Figure 2). In all recipients, unsolicited symptoms (D0–29) were more frequent after M72/AS01E (67.4%) than placebo (45.4%), mainly attributable to increased injection site reactions and flu-like symptoms. Serious adverse events (D0–month 7) incidences were similar between groups (M72/AS01E: 1.6%; placebo: 1.8%). During the study, 24 adults died (14 due to traumatic events); all deaths were unrelated to the trial.ConclusionM72/AS01E presents a clinically acceptable safety profile and significantly reduces bacteriologically confirmed pulmonary TB disease incidence in HIV– adults with latent Mtb infection. Funding. BMGF; Aeras; DFID UK; DGIS; AusAID; GlaxoSmithKline Biologicals SA.Disclosures O. Van Der Meeren, GSK: Employee and Shareholder, Salary. M. Hatherill, Aeras: Investigator, Research grant. R. J. Wilkinson, GSK: Grant Investigator, indirect funding. H. M. Ayles, GSK: Grant Investigator, Research grant. G. Henostroza, Aeras: Investigator, Grant recipient. M. A. Demoitié, GSK: owns stocks and is named inventor on patent applications relating to certain uses of M72/AS01E, Salary. T. Singh, GSK: Employee and Shareholder, Salary. E. J. Akite, GSK: Employee, Salary. A. K. Azam, GSK: Employee, Salary. A. Bollaerts, GSK: Employee, Salary. A. M. Ginsberg, GSK: Collaborator, Research support. BMGF: Grant Investigator, Grant recipient. UK DFID: Grant Investigator, Grant recipient. P. Gillard, GSK: Employee and Shareholder, Salary and stock. D. R. Tait, Aeras: Employee, Salary. GSK: Shareholder, Salary.

Associations Between Neighborhood Characteristics, Social Cohesion, and Perceived Sex Partner Risk and Non-Monogamy Among HIV-Seropositive and HIV-Seronegative Women in the Southern U.S.

Neighborhood social and physical factors shape sexual network characteristics in HIV-seronegative adults in the U.S. This multilevel analysis evaluated whether these relationships also exist in a predominantly HIV-seropositive cohort of women. This cross-sectional multilevel analysis included data from 734 women enrolled in the Women's Interagency HIV Study's sites in the U.S. South. Census tract-level contextual data captured socioeconomic disadvantage (e.g., tract poverty), number of alcohol outlets, and number of non-profits in the census tracts where women lived; participant-level data, including perceived neighborhood cohesion, were gathered via survey. We used hierarchical generalized linear models to evaluate relationships between tract characteristics and two outcomes: perceived main sex partner risk level (e.g., partner substance use) and perceived main sex partner non-monogamy. We tested whether these relationships varied by women's HIV status. Greater tract-level socioeconomic disadvantage was associated with greater sex partner risk (OR 1.29, 95% CI 1.06-1.58) among HIV-seropositive women and less partner non-monogamy among HIV-seronegative women (OR 0.69, 95% CI 0.51-0.92). Perceived neighborhood trust and cohesion was associated with lower partner risk (OR 0.83, 95% CI 0.69-1.00) for HIV-seropositive and HIV-seronegative women. The tract-level number of alcohol outlets and non-profits were not associated with partner risk characteristics. Neighborhood characteristics are associated with perceived sex partner risk and non-monogamy among women in the South; these relationships vary by HIV status. Future studies should examine causal relationships and explore the pathways through which neighborhoods influence partner selection and risk characteristics.

Neural response to working memory demand predicts neurocognitive deficits in HIV.

Human immunodeficiency virus (HIV) continues to have adverse effects on cognition and the brain in many infected people, despite a reduced incidence of HIV-associated dementia with combined antiretroviral therapy (cART). Working memory is often affected, along with attention, executive control, and cognitive processing speed. Verbal working memory (VWM) requires the interaction of each of the cognitive component processes along with a phonological loop for verbal repetition and rehearsal. HIV-related functional brain response abnormalities during VWM are evident in functional MRI (fMRI), though the neural substrate underlying these neurocognitive deficits is not well understood. The current study addressed this by comparing 24 HIV+ to 27 demographically matched HIV-seronegative (HIV-) adults with respect to fMRI activation on a VWM paradigm (n-back) relative to performance on two standardized tests of executive control, attention and processing speed (Stroop and Trail Making A-B). As expected, the HIV+ group had deficits on these neurocognitive tests compared to HIV- controls, and also differed in neural response on fMRI relative to neuropsychological performance. Reduced activation in VWM task-related brain regions on the 2-back was associated with Stroop interference deficits in HIV+ but not with either Trail Making A or B performance. Activation of the posterior cingulate cortex (PCC) of the default mode network during rest was associated with Hopkins Verbal Learning Test-2 (HVLT-2) learning in HIV+. These effects were not observed in the HIV- controls. Reduced dynamic range of neural response was also evident in HIV+ adults when activation on the 2-back condition was compared to the extent of activation of the default mode network during periods of rest. Neural dynamic range was associated with both Stroop and HVLT-2 performance. These findings provide evidence that HIV-associated alterations in neural activation induced by VWM demands and during rest differentially predict executive-attention and verbal learning deficits. That the Stroop, but not Trail Making was associated with VWM activation suggests that attentional regulation difficulties in suppressing interference and/or conflict regulation are a component of working memory deficits in HIV+ adults. Alterations in neural dynamic range may be a useful index of the impact of HIV on functional brain response and as a fMRI metric in predicting cognitive outcomes.

High prevalence of gastric intestinal metaplasia detected by confocal laser endomicroscopy in Zambian adults.

BackgroundConfocal laser endomicroscopy (CLE) may increase the detection of gastric premalignant lesions, and facilitate targeted biopsies for histology. The study aim was to analyse premalignant lesions in Zambian adults using CLE.MethodsUsing CLE and histology we analysed the antral mucosa for gastric premalignant lesions in asymptomatic adults living with HIV and in HIV seronegative adults. Fasting gastric pH and the presence of Helicobacter pylori (H. pylori) were also evaluated.ResultsWe enrolled 84 HIV seropositive participants (median age 43 years; 55 (65%) female), of whom 32 (38%) were anti-retroviral therapy (ART)-naïve. Also enrolled were 22 HIV seronegative controls (median age 39 years, 12 (55%) females). Hypochlorhydria was found in 48 (57%) HIV positive and 8 (38%) HIV negative controls (P = 0.14). Detection of gastric intestinal metaplasia (GIM) was higher (P = 0.007) using CLE (49, 54%) than histology (9, 9%) and, using CLE, GIM was similar between HIV positive (41, 60%) and negative groups (8, 36%; P = 0.08). Gastric luminal fluorescein leakage was significantly associated with the presence of GIM [OR 8.2; 95% CI 2.5–31, P<0.001].ConclusionCLE is useful for the detection of GIM, and luminal fluorescein leakage may represent a novel CLE marker for GIM. GIM is common in Zambian adults, and is highly prevalent irrespective of HIV infection or use of ART.

IP-10 Levels as an Accurate Screening Tool to Detect Acute HIV Infection in Resource-Limited Settings

Acute HIV infection (AHI) is the period prior to seroconversion characterized by high viral replication, hyper-transmission potential and commonly, non-specific febrile illness. AHI detection requires HIV-RNA viral load (VL) determination, which has very limited access in low-income countries due to restrictive costs and implementation constraints. We sought to identify a biomarker that could enable AHI diagnosis in scarce-resource settings, and to evaluate the feasibility of its implementation. HIV-seronegative adults presenting at the Manhiça District Hospital, Mozambique, with reported-fever were tested for VL. Plasma levels of 49 inflammatory biomarkers from AHI (n = 61) and non-HIV infected outpatients (n = 65) were determined by Luminex and ELISA. IP-10 demonstrated the best predictive power for AHI detection (AUC = 0.88 [95%CI 0.80–0.96]). A cut-off value of IP-10 ≥ 161.6 pg/mL provided a sensitivity of 95.5% (95%CI 85.5–99.5) and a specificity of 76.5% (95%CI 62.5–87.2). The implementation of an IP-10 screening test could avert from 21 to 84 new infections and save from US$176,609 to US$533,467 to the health system per 1,000 tested patients. We conclude that IP-10 is an accurate biomarker to screen febrile HIV-seronegative individuals for subsequent AHI diagnosis with VL. Such an algorithm is a cost-effective strategy to prevent disease progression and a substantial number of further HIV infections.

White matter hyperintensities correlate to cognition and fiber tract integrity in older adults with HIV.

Our aim was to examine the clinical relevance of white matter hyperintensities (WMH) in HIV. We used an automated approach to quantify WMH volume in HIV seropositive (HIV+; n=65) and HIV seronegative (HIV-; n=29) adults over age 60. We compared WMH volumes between HIV+ and HIV- groups in cross-sectional and multiple time-point analyses. We also assessed correlations between WMH volumes and cardiovascular, HIV severity, cognitive scores, and diffusion tensor imaging variables. Serostatus groups did not differ in WMH volume, but HIV+ participants had less cerebral white matter (mean: 470.95 [43.24] vs. 497.63 [49.42] mL, p=0.010). The distribution of WMH volume was skewed in HIV+ with a high proportion (23%) falling above the 95th percentile of WMH volume defined by the HIV- group. Serostatus groups had similar amount of WMH volume growth over time. Total WMH volume directly correlated with measures of hypertension and inversely correlated with measures of global cognition, particularly in executive functioning, and psychomotor speed. Greater WMH volume was associated with poorer brain integrity measured from diffusion tensor imaging (DTI) in the corpus callosum and sagittal stratum. In this group of HIV+ individuals over 60, WMH burden was associated with cardiovascular risk and both worse diffusion MRI and cognition. The median total burden did not differ by serostatus; however, a subset of HIV+ individuals had high WMH burden.

Elevated Markers of Vascular Remodeling and Arterial Stiffness Are Associated With Neurocognitive Function in Older HIV+ Adults on Suppressive Antiretroviral Therapy.

HIV is associated with elevated markers of vascular remodeling that may contribute to arterial fibrosis and stiffening and changes in pulse pressure (PP). These changes may, in turn, deleteriously affect autoregulation of cerebral blood flow and neurocognitive function. To evaluate these mechanisms, we studied markers of vascular remodeling, PP, and neurocognitive function among older (≥50 years of age) HIV-infected (HIV+, n = 72) and HIV-seronegative (HIV-, n = 36) adults. Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well-validated comprehensive battery. Three plasma biomarkers of vascular remodeling (ie, angiopoietin 2, Tie-2, and vascular endothelial growth factor, VEGF) were collected. HIV+ and HIV- participants had similar levels of plasma angiopoietin 2 (P = 0.48), Tie-2 (P = 0.27), VEGF (P = 0.18), and PP (P = 0.98). In a multivariable regression model, HIV interacted with Tie-2 (β = 0.41, P < 0.01) and VEGF (β = -0.43, P = 0.01) on neurocognitive function, such that lower Tie-2 and higher VEGF values were associated with worse neurocognitive function for HIV+ participants. Greater Tie-2 values were associated with increased PP (r = 0.31, P < 0.01). In turn, PP demonstrated a quadratic association with neurocognitive function (β = -0.33, P = 0.01), such that lower and higher, relative to mean sample, PP values were associated with worse neurocognitive function. These findings indicate that vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. Furthermore, HIV moderates the association between vascular remodeling and neurocognitive function but not the association between PP and neurocognitive function.

Swaziland HIV Incidence Measurement Survey (SHIMS): a prospective national cohort study

Swaziland has the highest national HIV prevalence worldwide. The Swaziland HIV Incidence Measurement Survey (SHIMS) provides the first national HIV incidence estimate based on prospectively observed HIV seroconversions. A two-stage survey sampling design was used to select a nationally representative sample of men and women aged 18-49 years from 14 891 households in 575 enumeration areas in Swaziland, who underwent household-based counselling and rapid HIV testing during 2011. All individuals aged 18-49 years who resided or had slept in the household the night before and were willing to undergo home-based HIV testing, answer demographic and behavioural questions in English or siSwati, and provide written informed consent were eligible for the study. We performed rapid HIV testing and assessed sociodemographic and behavioural characteristics with use of a questionnaire at baseline and, for HIV-seronegative individuals, 6 months later. We calculated HIV incidence with Poisson regression modelling as events per person-years × 100, and we assessed covariables as predictors with Cox proportional hazards modelling. Survey weighting was applied and all models used survey sampling methods. Between Dec 10, 2010, and June 25, 2011, 11 897 HIV-seronegative adults were enrolled in SHIMS and 11 232 (94%) were re-tested. Of these, 145 HIV seroconversions were observed, resulting in a weighted HIV incidence of 2·4% (95% CI 2·1-2·8). Incidence was nearly twice as high in women (3·1%; 95% CI 2·6-3·7) as in men (1·7%; 1·3-2·1, p<0·0001). Among men, partner's HIV-positive status (adjusted hazard ratio [aHR] 2·67, 1·06-6·82, p=0·040) or unknown serostatus (aHR 4·64, 2·32-9·27, p<0·0001) in the past 6 months predicted HIV seroconversion. Among women, significant predictors included not being married (aHR 2·90, 1·44-5·84, p=0·0030), having a spouse who lives elsewhere (aHR 2·66, 1·29-5·45, p=0·0078), and having a partner in the past 6 months with unknown HIV status (aHR 2·87, 1·44-5·84, p=0·0030). Swaziland has the highest national HIV incidence in the world. In high-prevalence countries, population-based incidence measures and programmes that further expand HIV testing and support disclosure of HIV status are needed. President's Emergency Plan for AIDS Relief (PEPFAR) by the Centers for Disease Control and Prevention.

Hearing loss among HIV-seropositive and HIV-seronegative men and women.

Age-related hearing loss affects quality of life. Data on hearing loss among aging human immunodeficiency virus-seropositive (HIV+) adults are limited. To evaluate pure-tone hearing thresholds among HIV+ and HIV-seronegative (HIV-) adults and to determine whether HIV disease variables and antiretroviral therapy are associated with pure-tone threshold levels. A total of 262 men (117 HIV+) from the Baltimore, Maryland/Washington, DC, site of the Multicenter AIDS Cohort Study and 134 women (105 HIV+) from the Washington, DC, site of the Women's Interagency HIV Study participated. Pure-tone air conduction thresholds were collected in a sound-treated room for each ear at frequencies from 250 through 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjustment for age, sex, race, and noise exposure history. Low-frequency pure-tone average (LPTA) at 250, 500, 1000, and 2000 Hz and high-frequency PTA (HPTA) at 3000, 4000, 6000, and 8000 Hz. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4⁺ and CD8⁺ T-cell counts, log10 plasma HIV RNA concentrations, receipt of AIDS diagnosis, and cumulative duration of antiretroviral therapy were included in the models for HIV+ participants only. HPTA and LPTA were significantly higher (18%: estimated ratio, 1.18 [95% CI, 1.02-1.36]; P = .02; and 12%: estimated ratio, 1.12 [95% CI, 1.00-1.26]; P = .05, respectively) for HIV+ participants compared with HIV- participants for the better ear. The direction of the effect was consistent across both the better and worse ears. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA. The HIV+ adults had significantly poorer lower-frequency and higher-frequency hearing than HIV- adults. High-frequency hearing loss is consistent with an accelerated aging (presbycusis); low-frequency hearing loss in middle age is unexpected. Because some vowels and consonants have predominantly low-frequency acoustic energy, poor low-frequency hearing may impair communication in HIV+ individuals.

A metabolic biosignature of early response to anti-tuberculosis treatment

BackgroundThe successful treatment of tuberculosis (TB) requires long-term multidrug chemotherapy. Clinical trials to evaluate new drugs and regimens for TB treatment are protracted due to the slow clearance of Mycobacterium tuberculosis (Mtb) infection and the lack of early biomarkers to predict treatment outcome. Advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. However, proof-of-concept of this approach has not been provided for a TB-early treatment response biosignature (TB-ETRB).MethodsUrine samples collected at baseline and during treatment from 48 Ugandan and 39 South African HIV-seronegative adults with pulmonary TB were divided into discovery and qualification sets, normalized to creatinine concentration, and analyzed by liquid chromatography-mass spectrometry to identify small molecule molecular features (MFs) in individual patient samples. A biosignature that distinguished baseline and 1 month treatment samples was selected by pairwise t-test using data from two discovery sample sets. Hierarchical clustering and repeated measures analysis were applied to additional sample data to down select molecular features that behaved consistently between the two clinical sites and these were evaluated by logistic regression analysis.ResultsAnalysis of discovery samples identified 45 MFs that significantly changed in abundance at one month of treatment. Down selection using an extended set of discovery samples and qualification samples confirmed 23 MFs that consistently changed in abundance between baseline and 1, 2 and 6 months of therapy, with 12 MFs achieving statistical significance (p < 0.05). Six MFs classified the baseline and 1 month samples with an error rate of 11.8%.ConclusionsThese results define a urine based TB-early treatment response biosignature (TB-ETRB) applicable to different parts of Africa, and provide proof-of-concept for further evaluation of this technology in monitoring clinical responses to TB therapy.

Seroepidemiology of hepatitis E virus infection in an urban population in Zambia: strong association with HIV and environmental enteropathy.

Background. Hepatitis E virus (HEV) infection causes major epidemics of infectious hepatitis, with high mortality rates in pregnant women. Recent reports indicate that HEV coinfections with human immunodeficiency virus (HIV) may have a more protracted course. However, the impact of HEV infections in communities heavily affected by HIV remains poorly studied. We set out to examine age-related seroprevalence in a community where we have previously carried out studies on environmental enteropathy.Methods. Blood samples from 194 children and 106 adults were examined for immunoglobulin G and immunoglobulin M antibodies for HEV. HEV data were correlated with HIV status and morphometric analysis of small intestinal biopsies.Results. Seroprevalence rose throughout childhood, from 8% in children aged 1–4 years, to 36% in children aged 10–14 years. In adults, the overall prevalence was 42%, with 28% in HIV-seronegative adults and 71% in HIV-seropositive adults (odds ratio, 6.2; 95% confidence interval, 2.2–18; P = .0001). In adults, villous height and crypt depth measurements showed that HEV seropositivity was associated with worse enteropathy (P = .05 and P = .005, respectively).Conclusions. HEV infection is common in Zambia. In adults it is strongly associated with HIV status, and also with environmental enteropathy.