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ObjectiveWe examined whether human mobility was associated with antiretroviral treatment adherence, measured via antiretroviral hair concentrations.DesignThis is a cross-sectional analysis of adults on antiretroviral treatment in East Africa at baseline in an observational cohort study.MethodsParticipants reported recent mobility (overnight travel) and histories of migration (changes of residence), including reasons, frequency/duration, and locations. Hair antiretroviral concentrations were analyzed using validated methods. We estimated associations between mobility and antiretroviral concentrations via linear regression adjusted for age, sex, region, years on treatment.ResultsAmong 383 participants, half were women and the median age was 40. Among men, 25% reported recent work-related mobility, 30% nonwork mobility, and 11% migrated in the past year (mostly across district boundaries); among women, 6 and 57% reported work-related and nonwork mobility, respectively, and 8% recently migrated (mostly within district). Those reporting work-related trips 2 nights or less had 72% higher hair antiretroviral levels (P = 0.02) than those who did not travel for work; in contrast, nonwork mobility (any duration, vs. none) was associated with 24% lower levels (P = 0.06). Intra-district migrations were associated with 59% lower antiretroviral levels than nonmigrants (P = 0.003) while inter-district migrations were not (27% higher, P = 0.40).ConclusionWe found that localized/intra-district migration and nonwork travel-more common among women-were associated with lower adherence, potentially reflecting care interruptions or staying with family/friends unaware of the participants' status. In contrast, short work-related trips-more common among men-were associated with higher adherence, perhaps reflecting higher income. Adherence interventions may require tailoring by sex and forms of mobility.

ObjectiveHIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently available metrics use liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitive antibody against tenofovir, the backbone of treatment and prevention, but conversion to a lateral flow assay (LFA) - analogous to a urine pregnancy test - is required for point-of-care testing. We describe the development of the first LFA to measure antiretroviral adherence in real-time.MethodsPrevious work in a directly observed therapy study of providing tenofovir disoproxil fumarate (TDF) to HIV-noninfected volunteers at various simulated adherence patterns defined the appropriate cut-off for the LFA (1500 ng tenofovir/ml urine). We developed the LFA using a sample pad for urine; a conjugate pad coated with TFV-specific antibodies conjugated to colloidal gold nanoparticles; a nitrocellulose membrane striped with tenofovir-antigen (test line) and a control line; with an absorbent pad to draw urine across the reaction membrane.ResultsWe tested 300 urine samples collected from the directly observed therapy study by this LFA and the gold-standard method of LC-MS/MS. The LFA demonstrated 97% specificity (95% CI 93-99%) and 99% sensitivity (94-100%) compared with LC-MS/MS. The LFA accurately classified 98% of patients who took a dose within 24 h as adherent.ConclusionWe describe the development and validation of the first point-of-care assay to measure short-term adherence to HIV prevention and treatment in routine settings. The assay is low-cost, easy-to-perform and measures the breakdown product (tenofovir) of both TDF and tenofovir alafenamide (TAF). This assay has the potential to improve HIV and PrEP outcomes worldwide by triggering differentiated service delivery with further study merited.

BackgroundAntiretroviral treatment (ART) adherence is often suboptimal in the perinatal period. We measured hair tenofovir (TFV) concentrations as a metric of adherence in postpartum women to understand patterns and predictors of adherence throughout this critical period. In addition, we examined the association between hair TFV concentrations and virologic outcomes.MethodsBetween 12/2012 and 09/2016, hair samples were collected longitudinally from delivery through breastfeeding from women on ART in the Promoting Maternal and Infant Survival Everywhere study (NCT01061151) in sub-Saharan Africa. Hair TFV levels were measured using validated methods. Using generalized estimating equations, we estimated the association between hair TFV levels and virologic suppression (

ObjectiveThe US preexposure prophylaxis (PrEP) Demonstration Project (U.S. Demo) evaluated MSM on PrEP postmarketing and found low seroconversion rates. The objective of this study is to examine hair levels as an adherence measure to PrEP.DesignUsing an 'opt-in' design, participants of PrEP Demo were invited to enroll into a substudy where hair was collected quarterly.MethodsTenofovir concentrations were measured in hair by liquid chromatography/tandem mass spectrometry. Hair levels consistent with ≥4 doses/week (protective in other studies) defined adequate adherence. Mixed effects multivariate logistic regression models examined factors associated with ≥4 doses/week. Separate mixed effects models evaluated the relationship between hair PrEP levels and changes in creatinine clearance (CrCl) over time.ResultsOverall, 58% of U.S. Demo participants enrolled into this opt-in study; reasons for nonparticipation included insufficient hair (61%) and concerns about hairstyle (27%). Hair and dried blood spots levels consistent with ≥4 doses/week were highly concordant (84%). Hair levels showed adequate adherence in 87% of 875 person-visits (among 280 participants). Factors associated with adequate adherence in multivariate models were amphetamine use [adjusted odds ratio (aOR) 2.59 (0.97-6.9, P 0.06)], condomless receptive anal sex [aOR 2.28 (1.19-4.40, P 0.01)], and stable housing [aOR 2.63 (1.03-6.67), P 0.04]. Hair levels of tenofovir showed a monotonic relationship with decline in CrCl (P 0.01 for trend).ConclusionIn this substudy of the U.S. PrEP demonstration project, hair and dried blood spots levels were highly concordant and hair concentrations demonstrated adequate adherence 87% of the time, with stable housing and high-risk behavior associated with higher adherence. Daily PrEP drug taking is associated with modest declines in CrCl.

BackgroundHIV latent infection can be established in vitro by treating resting CD4 T cells with chemokines that bind to chemokine receptors (CKR), CCR7, CXCR3, and CCR6, highly expressed on T cells.ObjectiveTo determine if CKR identify CD4 T cells enriched for HIV in HIV-infected individuals receiving suppressive antiretroviral therapy (ART).DesignA cross-sectional study of CKR expression and HIV persistence in blood from HIV-infected individuals on suppressive ART for more than 3 years (n = 48). A subset of 20 individuals underwent leukapheresis and sorting of specific CD4 T-cell subsets.MethodsWe used flow cytometry to quantify CCR5, CCR6, CXCR3, and CXCR5 expression on CD4 T cells. HIV persistence was quantified using real-time Polymerase Chain Reaction to detect total, integrated HIV DNA, 2-long terminal repeat circles and cell-associated unspliced (CA-US) HIV RNA in total CD4 T cells from blood or sorted T-cell subsets. Associations between CKR and HIV persistence in CD4 T cells in blood were determined using regression models and adjusted for current and nadir CD4 T-cell counts.ResultsThe frequency of cells harbouring integrated HIV DNA was inversely associated with current CD4 T-cell count and positively associated with CCR5+ CD4 T cells, CXCR3+CCR6+ and CXCR3+CCR6- expression on total memory CD4 T cells (P

ObjectiveCoinfection with hepatitis C virus (HCV) is a major cause of morbidity and mortality among individuals with HIV. Our objective was to assess the prognostic performance of noninvasive measures of liver fibrosis in predicting all-cause mortality in women with HIV/HCV coinfection.DesignWe studied HCV/HIV coinfected women enrolled in the prospective, multicenter Women's Interagency HIV Study. Aspartate aminotransferase to platelet ratio and FIB-4 were used to identify women without fibrosis at all visits and women who progressed to severe fibrosis.MethodsEnhanced liver fibrosis (ELF), which utilizes direct measures of fibrosis, hyaluronic acid, procollagen III aminoterminal peptide and tissue inhibitor of matrix metalloproteinase was performed.ResultsIncluded were 381 women with 2296 ELF measurements, with mean follow-up 8.3 ± 3.3 years. There were 134 deaths (60% with severe liver fibrosis). Receiver operator characteristic curves at fixed time windows prior to death or at end of follow-up showed that ELF was best at predicting mortality when tested within a year of death (area under the curve for ELF 0.85 vs. APRI 0.69, P

ObjectiveHair concentrations are a noninvasive measure of cumulative antiretroviral exposure and the strongest predictor of viral suppression in large cohorts of nonpregnant patients. We examined hair concentrations of antiretrovirals in relation to virologic outcomes in pregnant and breastfeeding women for the first time.Design and methodsThe Prevention of Malaria and HIV Disease in Tororo trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12-28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30-34 weeks gestation and 10-25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ≤400 copies/ml) at delivery and 24 weeks postpartum.ResultsAmong 325 women, median CD4 cell count was 366 cells/μl (interquartile range 270-488) at ART initiation. Mean self-reported 3-day adherence was greater than 97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, antiretroviral hair concentrations were the strongest predictor of viral suppression at delivery [efavirenz: adjusted odds ratio (aOR) 1.86 per doubling in concentration, 95% confidence interval (CI) 1.14-3.1, P = 0.013; lopinavir: aOR 1.90, 95% CI 1.33-2.7, P = 0.0004] and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22-2.7, P = 0.003; lopinavir: aOR 1.53, 95% CI 1.05-2.2, P = 0.026).ConclusionAntiretroviral hair concentrations represent an innovative tool that strongly predicts viral suppression among HIV-infected childbearing women during the critical periods of delivery and breastfeeding.

ObjectivesEvidence from the current era of combination antiretroviral therapy supports an association between HIV and cerebrovascular disease. In addition to traditional vascular risk factors, HIV-specific factors including immunodeficiency and viral replication may also predict stroke risk. The aim of this study was to determine the relationship between CD4(+) cell count, viral suppression and validated ischemic stroke outcomes.DesignA single-centre, case-control study.MethodsWe identified ischemic stroke cases in HIV-infected adults from an HIV clinic using International Classification of Diseases codes for cerebrovascular disease followed by validation of each case. Controls from the same HIV clinic were selected by incidence density sampling. Demographic and clinical data, including the most recent CD4(+) cell count and plasma HIV RNA concentration, were abstracted from hospital and HIV clinic electronic medical records. Matched conditional logistic regression models were used to evaluate the association between CD4(+) cell count, viral suppression and ischemic stroke.ResultsIn an adjusted model, viral suppression decreased the odds of ischemic stroke by a factor of 0.16 [95% confidence interval (95% CI) 0.05-0.50, P = 0.002]. This association, although attenuated [odds ratio (OR) 0.31, 95% CI 0.09-1.06, P = 0.062], remained after restricting the analysis to ischemic strokes due to true atherosclerotic mechanisms (i.e. excluding infection and malignancy-related strokes).ConclusionAchieving viral suppression may reduce ischemic stroke risk, including risk of atherosclerotic strokes, in HIV-infected individuals.

BackgroundHigher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/hepatitis C virus (HCV) coinfection are associated with abnormalities of lipoprotein subclasses is unknown.MethodsLipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM), Coronary Artery Risk Development in Young Adults (CARDIA), and Multi-Ethnic Study of Atherosclerosis (MESA) studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio.ResultsRelative to controls, small LDL levels were higher in HIV-monoinfected persons (+381 nmol/l, P

ObjectiveTenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world settings are unknown.DesignIntensive pharmacokinetic studies of tenofovir in a large, diverse cohort of HIV-infected women over 24 h at steady state were performed and factors that influenced exposure [assessed by areas under the concentration-time curves (AUCs)] identified.MethodsHIV-infected women (n = 101) on tenofovir-based therapy underwent intensive 24-h pharmacokinetic sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight, and BMI were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFRs) prior to starting tenofovir were estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using both creatinine and cystatin-C measures.ResultsThe median (range) of tenofovir AUCs was 3350 (1031-13 911) ng × h/ml. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, P = 0.002), increasing age (1.21-fold increase per decade, P = 0.0007), and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR