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BackgroundInfancy is an important developmental period when the microbiome is shaped. We hypothesized that earlier antiretroviral therapy (ART) initiation would attenuate HIV effects on microbiota in the mouth.MethodsOral swabs were collected from 477 children with HIV (CWH) and 123 children without (controls) at two sites in Johannesburg, South Africa. CWH had started ART less than 3 years of age; 63% less than 6 months of age. Most were well controlled on ART at median age 11 years when the swab was collected. Controls were age-matched and recruited from the same communities. Sequencing of V4 amplicon of 16S rRNA was done. Differences in microbial diversity and relative abundances of taxa were compared between the groups.ResultsCWH had lower alpha diversity than controls. Genus-level abundances of Granulicatella, Streptococcus, and Gemella were greater and Neisseria and Haemophilus less abundant among CWH than controls. Associations were stronger among boys. Associations were not attenuated with earlier ART initiation. Shifts in genus-level taxa abundances in CWH relative to controls were most marked in children on lopinavir/ritonavir regimens, with fewer shifts seen if on efavirenz ART regimens.ConclusionA distinct profile of less diverse oral bacterial taxa was observed in school-aged CWH on ART compared with uninfected controls suggesting modulation of microbiota in the mouth by HIV and/or its treatments. Earlier ART initiation was not associated with microbiota profile. Proximal factors, including current ART regimen, were associated with contemporaneous profile of oral microbiota and may have masked associations with distal factors such as age at ART initiation.

ObjectiveWe tested whether bone-related extracellular vesicle phenotypes changed after initiating antiretroviral therapy (ART) and determined whether changes in levels of extracellular vesicles correlated with changes in bone mineral density (BMD).DesignExtracellular vesicle phenotypes were measured in blinded serum samples from 15 adults with HIV at baseline, 1, 3, 6 and 12 months after ART initiation. Not all samples were available at each time point so we averaged early (TP1, 1-3 months) and late (TP2, 6-12 months) time points.MethodsExtracellular vesicles were stained for osteocalcin (OC), RANKL (CD254), RANK (CD265), M-CSF (macrophage colony stimulating factor), and CD34. Serum OC, procollagen type I N-terminal propeptide (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were also measured.ResultsBMD significantly decreased from baseline to 12 months. Levels of OC+EVs, serum OC, serum P1NP, and CTx were significantly higher at early and late time points compared with baseline. Increases in EVs expressing OC, RANKL, RANK, and CD34 from baseline to TP1 were associated with decreases in total hip BMD from baseline to 12 months. Change in serum OC, P1NP, and CTx from baseline to TP1 or TP2 did not correlate with change in BMD.ConclusionEarly changes in extracellular vesicles expressing markers of bone activity were associated with total hip bone loss 12 months after ART initiation. These data suggest that serum extracellular vesicles may serve as novel biomarkers of bone remodeling. Future studies are required to determine if extracellular vesicles contribute to the effects of ART on changes in bone turnover markers and BMD.

ObjectivesHIV and hepatitis C virus (HCV) have been associated with cardiovascular disease (CVD), but it is unclear whether HIV and HCV are also associated with peripheral artery disease (PAD). We examined the association of HIV, HCV, and traditional CVD risk factors with PAD in the Women's Interagency HIV Study, a multicenter US cohort.MethodsIn this cross-sectional study, ankle-brachial index was estimated using Doppler ultrasound and manual sphygmomanometer in 1899 participants aged more than 40 years with HIV/HCV coinfection, HCV or HIV monoinfection, or neither infection. Multivariable logistic regression was used to estimate the odds of PAD (ankle-brachial index ≤0.9) after controlling for demographic, behavioral, and CVD risk factors.ResultsOver two-thirds were African-American, median age was 50 years, and PAD prevalence was 7.7% with little difference by infection status. After multivariable adjustment, neither HIV nor HCV infection was associated with greater odds of PAD. Factors associated with PAD included older age [adjusted odds ratio (aOR): 2.01 for age 61-70 vs. 40-50 years; 95% confidence interval (CI): 1.04, 3.87], Black race (aOR: 2.30; 95% CI: 1.15, 4.63), smoking (aOR: 1.27 per 10-pack-year increment; 95% CI: 1.09, 1.48), and higher SBP (aOR: 1.14 per 10 mmHg; 95% CI: 1.01, 1.28).ConclusionThe high PAD prevalence in this nationally representative cohort of women with or at risk for HIV is on par with general population studies in individuals a decade older than our study's median age. HIV and HCV infection are not associated with greater PAD risk relative to uninfected women with similar risk factors. Modifiable traditional CVD risk factors may be important early intervention targets in women with and at risk for HIV.

As of July 2021, >180 million persons worldwide were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and remain in the convalescent phase (1). Long-term implications for male fertility [...]

ObjectivesWe compared skeletal microarchitecture using trabecular bone score (TBS) and evaluated relationships between change in TBS and lumbar spine (LS) bone mineral density (BMD) in women with and without HIV.MethodsDual-energy X-ray absorptiometry was performed on 319 women with HIV and 118 without HIV in the Women's Interagency HIV Study at baseline and 2 and 5 years, to measure regional BMD and lean and fat mass. TBS was extracted from LS dual-energy X-ray absorptiometry images and examined continuously and categorically [normal (≥1.35), intermediate (1.20-1.35), or degraded (≤1.20) microarchitecture]. Pearson correlation and linear regression examined associations of TBS with regional BMD at baseline and over time.ResultsWomen with HIV were older (43 vs. 37 years), more likely to be postmenopausal (27% vs. 4%), have lower baseline total fat mass, trunk fat, and leg fat than uninfected women, degraded microarchitecture (27% vs. 9%, P = 0.001), and lower baseline mean TBS (1.3 ± 0.1 vs. 1.4 ± 0.1, P < 0.001). After adjusting for age, race, menopause status, and body mass index, TBS remained lower in women with HIV (P < 0.0001). Annual change in TBS correlated with LS BMD change among women with HIV (r = 0.36, P < 0.0001) and without HIV (r = 0.26, P = 0.02); however, mean % annual TBS change did not differ by HIV status (-1.0%/yr ± 2.9% for HIV+ vs. -0.8%/yr ± 1.7% for HIV-, P = 0.42).ConclusionsWomen with HIV have worse bone microarchitecture than uninfected women, but annual percent change in LS BMD or TBS was similar. Use of TBS as an adjunct to BMD to improve prediction of fragility fractures in women with HIV merits further study.

ObjectivesA fracture risk assessment tool (FRAX) using clinical risk factors (CRFs) alone underestimates fracture risk in HIV-infected men. Our objective was to determine whether accuracy of FRAX would be improved by considering HIV as a cause of secondary osteoporosis, and further improved with addition of dual-energy X-ray absorptiometry parameters in HIV-infected women.DesignSubgroup analysis of Women's Interagency HIV Study.MethodsWe included 1148 women (900 HIV-infected and 248 uninfected) over age 40 with data to approximate FRAX CRFs and 10-year observational data for incident fragility fractures; 181 (20%) HIV-infected women had dual-energy X-ray absorptiometry data. Accuracy of FRAX was evaluated by the observed/estimated ratios of fracture in four models: CRFs alone; CRFs with HIV included as a cause of secondary osteoporosis; CRFs and femoral neck bone mineral density (FN BMD); and CRFs, FN BMD and trabecular bone score.ResultsFRAX using CRFs were less accurate in HIV-infected than uninfected women for major osteoporotic (observed/estimated ratio: 5.05 vs. 3.26, P

ObjectiveThe aim of this study was to determine the associations between visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) mass with homeostatic model assessment-insulin resistance (HOMA-IR) and incidence of diabetes mellitus in women with and without HIV infection.DesignCross-sectional design for associations between abdominal fat and HOMA-IR; longitudinal design for associations between abdominal fat and incident diabetes.MethodsWe assessed associations between dual X-ray absorptiometry scan-derived VAT and SAT with HOMA-IR in a subsample from the Women's Interagency HIV Study (n = 226 with and n = 100 without HIV) using linear regression. We evaluated associations of VAT, SAT and HOMA-IR with incident diabetes mellitus using Cox proportional hazards models.ResultsVAT mass was positively associated with log HOMA-IR in fully adjusted linear regression models stratified by HIV serostatus, including adjustment for SAT. During median follow-up of 10.6 years, incidence of diabetes was 1.63 [95% confidence interval (95% CI) 1.15-2.31] and 1.32 [95% CI 0.77-2.28] cases per 100 person-years in women with and without HIV (P = 0.52). In a fully adjusted model, baseline VAT (hazard ratio 2.64 per kg; 95% CI 1.14-6.12; P = 0.023) and SAT (hazard ratio 1.34 per kg; 95% CI 0.73-2.45; P = 0.35) were associated with incident diabetes, but the latter was not statistically significant.ConclusionVAT mass was independently associated with HOMA-IR in women with and without HIV and was independently associated with future development of diabetes.

ObjectiveTo characterize the oral bacterial microbiome in HIV-infected participants at baseline and after 24 weeks of EFV/FTC/TDF.DesignThirty-five participants co-enrolled in two AIDS Clinical Trials Group (ACTG) studies, A5272 and A5280, with paired saliva samples and complete data sets were assessed.MethodsPaired saliva samples were evaluated for bacterial microbiome using 16S rDNA PCR followed by Illumina sequencing. Diversity and differential abundance was compared between groups. A random forest classification scheme was used to determine the contribution of parameters in classifying participants' CD4+ T-cell count.ResultsBacterial communities demonstrated considerable variability both within participants and between timepoints, although they became more similar after 24 weeks of ART. At baseline, both the number of taxa detected and the average alpha diversity were variable between participants, but did not differ significantly based on CD4+ cell count, viral load or other factors. After 24 weeks of ART samples obtained from participants with persistently low CD4+ T-cell counts had significantly higher bacterial richness and diversity. Several differentially abundant taxa, including Porphyromonas species associated with periodontal disease, were identified, which discriminated between baseline and posttreatment samples. Analysis demonstrated that although inflammatory markers are important in untreated disease, the salivary microbiome may play an important role in CD4+ T-cell count recovery after ART.ConclusionShifts in the oral microbiome after ART initiation are complex, and may play an important role in immune function and inflammatory disease.

BackgroundData on associations between abdominal fat depot mass and subclinical atherosclerosis are limited, especially in women with HIV.MethodsWe assessed cross-sectional associations of dual X-ray absorptiometry scan-derived estimates of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) with 3 measures of subclinical carotid artery atherosclerosis-carotid artery stiffness (Young's modulus of elasticity), presence of carotid artery lesions, and carotid artery intima-media thickness-in a subsample of participants in the Women's Interagency HIV Study. Statistical models adjusted for demographic variables, HIV serostatus, behavioral variables, and cardiovascular risk factors.ResultsThere were 244 women with and 99 without HIV infection (median age 42, 62% black). VAT mass (but not SAT) was associated with greater carotid artery stiffness in a fully adjusted linear regression model, including adjustment for SAT (β = 11.3 log 10·N·m per kg VAT, 95% confidence interval: 1.0 to 21.7). Greater SAT mass was associated with lower odds of having a carotid artery lesion in a fully adjusted model, including adjustment for VAT [adjusted odds ratio, 0.49 per kg of SAT (0.25 to 0.94)]. Neither VAT nor SAT was associated with carotid artery intima-media thickness. The VAT/SAT ratio was not statistically associated with any of the outcomes after covariate adjustment.ConclusionsIn our cross-sectional study of women, the majority of whom had HIV, greater VAT mass was associated with increased carotid artery stiffness, whereas greater SAT mass was associated with a reduced odds of prevalent carotid artery lesions.

BackgroundAlthough fracture rates are higher in HIV+ than HIV- women, whether HIV infection increases risk of falls is unclear. We determined the longitudinal occurrence and risk factors for falls in the Women's Interagency HIV Study (WIHS), and explored associations with cognitive complaints.MethodsRecent (prior 6 months) self-reported falls were collected in 1,816 (1,250 HIV+; 566 HIV-) women over 24 months. Generalized estimating equation models using stepwise selection determined odds of any fall (versus none).ResultsHIV+ women were older than HIV- women (median 49 versus 47 years; P=0.0004), more likely to report neuropathy (20% versus 16%; P=0.023), and had greater central nervous system (CNS) medication use. At least one fall was reported in 41% HIV+ versus 42% HIV- women, including ≥2 falls in 25% HIV+ and 24% HIV- (overall P=0.30). Cognitive complaints were associated with falls among HIV+ (odds ratio [OR] 2.38; 95% CI 1.83, 3.09) and HIV- women (OR 3.43; 95% CI 2.37, 4.97); in adjusted models, cognitive complaints remained significant only in HIV- women (adjusted [aOR] 2.26; 95% CI 1.46, 3.48). Factors associated with any fall in adjusted analyses included: depressive symptoms and neuropathy (both HIV+ and HIV-); age, marijuana use, multiple CNS medications, and HCV infection (HIV+ only); and cognitive complaints, quality of life, hypertension and obesity (HIV- only).ConclusionsMiddle-aged HIV+ and HIV- women had similar fall rates. Among HIV+ women, factors affecting cognition such as age, depressive symptoms, marijuana use and multiple CNS medications were important predictors of falls, however, cognitive complaints were not.

ObjectivesObesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are proinflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur.MethodsThe Veterans Aging Cohort Study survey cohort is a prospective, observational study of predominantly male HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were body mass index ≥ 18.5 kg/m and biomarker measurement. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed.ResultsData were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels significantly lower in obese/HIV+ compared with nonobese/uninfected (P

BackgroundHIV infection is associated with low bone mineral density (BMD) and alterations in adipokines, which may mediate the relationship between fat and bone.ObjectiveTo evaluate the relationship of adiponectin and leptin with BMD in HIV-infected and uninfected women.MethodsWe measured BMD over 5 years at the lumbar spine, total hip (TH), and femoral neck (FN) using dual-energy X-ray absorptiometry in 318 HIV-infected and 122 HIV-uninfected participants of the multicenter Women's Interagency HIV Study (WIHS). Total adiponectin and leptin were assayed on stored sera. Multivariable linear mixed models assessed the effects of adipokines and HIV status on BMD.ResultsHIV-infected women had higher adiponectin (median 6.2 vs. 5.6 μg/mL,) but lower leptin (11.7 vs. 19.8 ng/mL) levels at baseline (both P < 0.05) compared with HIV-uninfected women. HIV infection was associated with lower BMD at the lumbar spine (-0.074 g/cm), FN (-0.049 g/cm), and TH (-0.047 g/cm) (all P < 0.05) after adjusting for demographic, behavioral, and metabolic factors. HIV infection remained associated with lower BMD at each site, with little change in the effect sizes after additional adjustment for adiponectin or leptin. Among HIV-infected women, higher adiponectin was associated with lower TH BMD (-0.025 g/cm per 10-fold increase, P = 0.035), whereas higher leptin was associated with higher BMD at FN (+0.027 g/cm per 10-fold increase, P = 0.005) and TH (+0.019 g/cm, P = 0.028). After multivariable adjustment, the adipokines showed little association with BMD at any site (P > 0.8 for adiponectin; P > 0.2 for leptin).ConclusionsAlterations in serum adiponectin and leptin do not explain low BMD in HIV-infected women.

Objectives: People living with HIV (PLWH) have been shown to have lower bone density at the spine, hip, and radius. However, whether a similar bone phenotype is seen in craniofacial bones is not known. The goal of this study was to evaluate the bone microarchitecture of the mandibular condyle in PLWH. Methods: We recruited 212 participants, which included 88 HIV‐negative participants and 124 PLWH on combination antiretroviral therapy with virological suppression from a single academic center. Each participant filled out a validated temporomandibular disorder (TMD) pain screening questionnaire and had cone beam computed tomography (CBCT) of their mandibular condyles. Qualitative radiographic evidence of temporomandibular joint disorders‐osteoarthritis (TMJD‐OA) assessment and quantitative microarchitecture analysis of their mandibular condylar bones were conducted. Results: There was no statistically significant difference in either self‐reported TMD or in radiographic evidence of TMJD‐OA in PLWH compared with HIV‐negative controls. Linear regression analysis revealed that positive HIV status remained significantly associated with increased trabecular thickness, decreased cortical porosity, and increased cortical bone volume fraction after adjusting for race, diabetes, sex, and age. Conclusion: PLWH have increased mandibular condylar trabecular bone thickness and cortical bone volume fraction compared with HIV‐negative controls. [ABSTRACT FROM AUTHOR]

BackgroundWe previously reported that fracture incidence rates did not differ by HIV status among predominantly premenopausal Women's Interagency HIV Study participants. We now conduct a follow-up study with 5 additional observation years to further characterize fracture risk associated with HIV infection in women as they age.MethodsWe measured time to first new fracture at any site in 2375 (1713 HIV-infected and 662 HIV-uninfected) Women's Interagency HIV Study participants, with median 10-year follow-up. Fractures were self-reported semiannually. Proportional hazards models assessed predictors of incident fracture.ResultsAt index visit, HIV-infected women were older [median age of 40 years (IQR: 34-46) vs. 35 (27-43), P < 0.0001] and more likely to be postmenopausal, hepatitis C virus infected, and weigh less than HIV-uninfected women. Among HIV-infected women, mean CD4 count was 480 cells per microliter and 63% were taking highly active antiretroviral therapy. Unadjusted incidence rates of any fracture were higher in HIV-infected than in HIV-uninfected women [2.19/100 person-years (py) vs. 1.54/100 py, P = 0.002]. In multivariate models, HIV status, older age, white (vs. black) race, prior fracture, history of cocaine use, and history of injection drug use were significant predictors of incident fracture. Among HIV-infected women, age, white race, prior fracture, smoking, and prior AIDS were predictors of new fracture.ConclusionsMiddle-aged HIV-infected women had a higher adjusted fracture rate than HIV-uninfected women. Cocaine use and injection drug use were also associated with a greater risk of incident fracture. Further research is needed to understand whether the risk of fracture associated with cocaine use relates to increased rate of falls or direct effects on bone metabolism.

BackgroundMetabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24).MethodsTreatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression.ResultsAnalyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1).ConclusionsRaltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation.Clinical trials registrationNCT 00811954.