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Women living with HIV (WLWH) may be at higher risk for osteoporosis and fragility fractures. However, limited prospective data describe long-term trajectories of bone mineral density (BMD) in WLWH versus women without HIV. Thus, in this prospective study, we aimed to compare 10-year change in areal BMD (aBMD) between WLWH ( n  = 49; 36.8 ± 8.8 years; 96% pre/perimenopausal) and HIV-negative women (population-based controls; n  = 49; 41.9 ± 9.2 years; 80% pre/perimenopausal). In an exploratory analysis, we compared fracture history between WLWH and controls. Outcomes were lumbar spine (L 1 to L 4 ), total hip, and femoral neck aBMD at baseline and follow-up, which occurred at 13 and 10 years in WLWH and controls, respectively. We fit multivariable regression models to compare baseline and 10-year change in aBMD between groups, adjusting for osteoporosis risk factors. Within WLWH, we examined associations between aBMD and HIV-related factors, including combination antiretroviral therapy (cART) duration. WLWH were diagnosed 6.5 ± 3.7 years before baseline, 80% were on cART for 241 ± 142 weeks, and 49% had HIV plasma viral load <40 copies/mL. Before and after adjusting for osteoporosis risk factors, baseline and 10-year change in aBMD did not differ between WLWH and controls at any site. At baseline, more WLWH than controls reported a history of low-trauma fracture (30% versus 10%, p  < 0.05) and major osteoporotic fracture (17% versus 4%, p  < 0.05). During follow-up, the number of WLWH and controls with incident fragility fracture was not significantly different. Lifetime cART duration and tenofovir use were not associated with aBMD 10-year percent change. Higher CD4 count at baseline was positively associated with femoral neck aBMD 10-year percent change. Long-term aBMD change in this small WLWH cohort paralleled normal aging, with no evidence of influence from cART use; however, these results should be interpreted with caution given the small sample size. Larger cohort studies are needed to confirm these findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Understanding the true burden of tobacco smoking on adverse pregnancy outcomes is critical in generating appropriate interventions to improve outcomes. Self-reporting of human behaviour that is associated with stigma is associated with underreporting in general and may bias the impact of smoking in studies; however, self-reporting is frequently the most practical method of gleaning this information. The objective of this study was to evaluate concordance between self-reported smoking and concentrations of plasma cotinine, a biomarker of smoking, among participants enrolled in two related HIV cohorts. A total of 100 pregnant women (76 living with HIV [LWH] and 24 negative controls) in their third trimester, and 100 men and non-pregnant women (43 LWH and 57 negative controls) were included. Among all participants, 43 pregnant women (49% LWH and 25% negative controls) and 50 men and non-pregnant women (58% LWH and 44% negative controls) were self-reported smokers. The odds of discordance between self-reported smoking and cotinine levels were not significantly different between self-reported smokers and non-smokers, nor between pregnant women and others, but were significantly increased, regardless of self-reported status, among people LWH compared to negative controls. The overall concordance between plasma cotinine and self-reported data among all participants was 94% with a sensitivity and specificity of 90% and 96%, respectively. Taken together, these data demonstrate that participant surveying in a non-judgemental context can lead to accurate and robust self-report smoking data among both persons LWH and not, including in the context of pregnancy., (© 2023. The Author(s).)

Objectives: We sought to better understand factors associated with ovarian aging in women with HIV (WWH)., Design: HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, anti-Müllerian hormone (AMH), and HIV., Methods: We included WWH and HIV-negative women 12-50 years of age in the CARMA cohort with one or more study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analyzed in peak reproductive (<35 years) vs. late reproductive (≥35 years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and ΔAMH/year while adjusting for relevant confounders., Results: WWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women under 35 years of age and shorter LTL was associated with AMH levels below 2 ng/ml among women aged 35 years or older. Longitudinally, ΔAMH/year was largely related to initial AMH level among older women, and to age in younger women., Conclusions: Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counseling around pregnancy planning. In women aged 35 years or older, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Birth mode has been implicated as a major factor influencing neonatal gut microbiome development, and it has been assumed that lack of exposure to the maternal vaginal microbiome is responsible for gut dysbiosis among caesarean-delivered infants. Consequently, practices to correct dysbiotic gut microbiomes, such as vaginal seeding, have arisen while the effect of the maternal vaginal microbiome on that of the infant gut remains unknown. We conducted a longitudinal, prospective cohort study of 621 Canadian pregnant women and their newborn infants and collected pre-delivery maternal vaginal swabs and infant stool samples at 10-days and 3-months of life. Using cpn 60-based amplicon sequencing, we defined vaginal and stool microbiome profiles and evaluated the effect of maternal vaginal microbiome composition and various clinical variables on the development of the infant stool microbiome. Infant stool microbiomes showed significant differences in composition by delivery mode at 10-days postpartum; however, this effect could not be explained by maternal vaginal microbiome composition and was vastly reduced by 3 months. Vaginal microbiome clusters were distributed across infant stool clusters in proportion to their frequency in the overall maternal population, indicating independence of the two communities. Intrapartum antibiotic administration was identified as a confounder of infant stool microbiome differences and was associated with lower abundances of Escherichia coli , Bacteroides vulgatus , Bifidobacterium longum and Parabacteroides distasonis . Our findings demonstrate that maternal vaginal microbiome composition at delivery does not affect infant stool microbiome composition and development, suggesting that practices to amend infant stool microbiome composition focus factors other than maternal vaginal microbes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dos Santos, Pakzad, Albert, Elwood, Grabowska, Links, Hutcheon, Maan, Manges, Dumonceaux, Hodgson, Lyons, Mitchell-Foster, Gantt, Joseph, Van Schalkwyk, Hill and Money.)

Background: Multiple contraindications to combined hormonal contraceptives (CHC) use exist. The impact of these factors on contraceptive choice, particularly among women living with HIV (WLWH), is not well understood. We measured and compared the prevalence of contraceptive use and contraindications among WLWH and women not living with HIV (controls)., Methods: We examined cross-sectional survey and medical chart data from 83 WLWH and 62 controls, aged 16-49 and sexually active, from 2013-2017. We compared the age-adjusted prevalence and types of contraceptives used in the last month and the proportion of women with CHC contraindications, including drug interactions, medical comorbidities, and smoking at ≥ 35 years old. All WLWH received care at an interdisciplinary, women-centred HIV clinic., Results: Compared to controls, WLWH were older (median [IQR)] 39 [34-43] vs 31 [23-41] years; p = 0.003), had less post-secondary education (37% vs 73%; p < 0.001), and more often had household income < $15,000/year (49% vs 30%; p = 0.006). WLWH trended to higher contraceptive prevalence than controls (80% vs 63%; p = 0.06 adjusted for age). Overall hormonal contraceptive use was similar. However, despite controlling for age, WLWH used CHC less (4% vs 18%; p = 0.006) than controls, and had more frequently undergone tubal ligation (12% vs 2%; p = 0.03). WLWH also experienced more CHC contraindications (54% vs 13%; p = 0.0001), including smoking at ≥ 35 years old (30% vs 6%; p = 0.0003) or a CHC-related drug interaction (all antiretroviral related) (25% vs 0%; p = 0.0001)., Conclusions: WLWH attending our interdisciplinary clinic used hormonal contraception at similar rates as controls, though with different types. Differences may reflect different distributions of CHC contraindications. CHC contraindications present barriers to accessing the full range of contraceptive choices for WLWH. Guidelines and education for care providers and WLWH regarding contraceptive choices and drug interactions are needed, especially when care is provided without the benefit of an interdisciplinary women-centered healthcare team., (© 2021. The Author(s).)

Detection of bacterial DNA within meconium is often cited as evidence supporting in utero colonization. However, many studies fail to adequately control for contamination. We aimed to define the microbial content of meconium under properly controlled conditions. DNA was extracted from 141 meconium samples and subjected to cpn 60-based microbiome profiling, with controls to assess contamination throughout. Total bacterial loads of neonatal meconium, infant stool, and controls were compared by 16S rRNA quantitative PCR (qPCR). Viable bacteria within meconium were cultured, and isolate clonality was assessed by pulsed-field gel electrophoresis (PFGE). Meconium samples did not differ significantly from controls with respect to read numbers or taxonomic composition. Twenty (14%) outliers with markedly higher read numbers were collected significantly later after birth and appeared more like transitional stool than meconium. Total bacterial loads were significantly higher in stool than in meconium, which did not differ from that of sequencing controls, and correlated well with read numbers. Cultured isolates were most frequently identified as Staphylococcus epidermidis, Enterococcus faecalis, or Escherichia coli, with PFGE indicating high intraspecies diversity. Our findings highlight the importance of robust controls in studies of low microbial biomass samples and argue against meaningful bacterial colonization in utero . Given that meconium microbiome profiles could not be distinguished from sequencing controls, and that viable bacteria within meconium appeared uncommon and largely consistent with postnatal skin colonization, there does not appear to be a meconium microbiota. IMPORTANCE Much like the recent placental microbiome controversy, studies of neonatal meconium reporting bacterial communities within the fetal and neonatal gut imply that microbial colonization begins prior to birth. However, recent work has shown that placental microbiomes almost exclusively represent contamination from lab reagents and the environment. Here, we demonstrate that prior studies of neonatal meconium are impacted by the same issue, showing that the microbial content of meconium does not differ from negative controls that have never contained any biological material. Our culture findings similarly supported this notion and largely comprised bacteria normally associated with healthy skin. Overall, our work adds to the growing body of evidence against the in utero colonization hypothesis.

Introduction: Women living with HIV (WLWH) experience accelerated ageing and an increased risk of age-associated diseases earlier in life, compared with women without HIV. This is likely due to a combination of viral factors, gender differences, hormonal imbalance and psychosocial and structural conditions. This interdisciplinary cohort study aims to understand how biological, clinical and sociostructural determinants of health interact to modulate healthy ageing in WLWH., Methods and Analysis: The British Columbia C hildren and Women: A nti R etroviral therapy and M arkers of A ging- C anadian HI V W omen's Sexual and Reproductive Health Cohort S tudy (CARMA-CHIWOS) Collaboration (BCC3) study will enrol WLWH (n=350) and sociodemographically matched HIV-negative women (n=350) living in British Columbia. A subset of BCC3 participants will be past participants of CARMA, n≥1000 women and children living with and without HIV, 2008-2018 and/or CHIWOS, n=1422 WLWH, 2013-2018. Over two study visits, we will collect biological specimens for virus serologies, hormones and biological markers as well as administer a survey capturing demographic and sociostructural-behavioural factors. Sociodemographics, comorbidities, number and type of chronic/latent viral infections and hormonal irregularities will be compared between the two groups. Their association with biological markers and psychostructural and sociostructural factors will be investigated through multivariable regression and structural equation modelling. Retrospective longitudinal analyses will be conducted on data from past CARMA/CHIWOS participants. As BCC3 aims to follow participants as they age, this protocol will focus on the first study visits., Ethics and Dissemination: This study has been approved by the University of British Columbia Children's and Women's Research Ethics Board (H19-00896). Results will be shared in peer-reviewed journals, conferences and at community events as well as at www.hivhearme.ca and @HIV&#95;HEAR&#95;me. WLWH are involved in study design, survey creation, participant recruitment, data collection and knowledge translation. A Community Advisory Board will advise the research team throughout the study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Women living with HIV (WLWH) have higher rates of prolonged secondary amenorrhea (no flow for ≥1 year) than HIV-negative women. Both having amenorrhea and being HIV positive are associated with lower areal bone mineral density (BMD). However, their combined BMD effects remain unclear. Therefore, we investigated prolonged amenorrhea and BMD in WLWH and controls., Methods: This cross-sectional study enrolled WLWH and HIV-negative control women aged 19-68 years of similar backgrounds. We assessed BMD (Hologic; as age- and ethnicity-matched Z-scores) in the Children and women: AntiRetrovirals and Markers of Aging cohort. Participants were stratified by amenorrhea history defined as past/present lack of menses for ≥1 year at age 45 and younger and not because of surgery, breastfeeding, pregnancy, or hormonal contraception. Hip and spine Z-scores by amenorrhea/no amenorrhea used linear models with multivariable analysis for relationships within WLWH., Results: WLWH (N = 129) were similar to controls (N = 129) in age, body mass index, ethnicity, and substance use. Among WLWH, 21% experienced prolonged amenorrhea vs. 9% in controls. WLWH had significantly lower total hip (mean ± SD: -0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (-0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores than controls. Amenorrhea was independently associated with hip (P = 0.01) but not spine (P = 0.94) BMD by multivariable linear regression. WLWH with amenorrhea had lower hip Z-scores (-0.8 ± 0.9) than those without (-0.3 ± 0.8; P = 0.01). They also had higher rates of substance use, smoking, opioid therapy, hepatitis C coinfection, and lower CD4 nadir., Conclusions: WLWH had higher rates of prolonged amenorrhea and lower BMD than controls. WLWH with amenorrhea experienced lower hip BMD Z-scores than those without. Prolonged amenorrhea is an added osteoporosis risk in WLWH.

Objective: To investigate factors contributing to preterm birth (PTB), including cART use and clinical and social determinants of health, in women living with HIV (WLWH) from British Columbia, Canada., Design: Retrospective observational cohort., Methods: We investigated the effect of cART use and other clinical and demographic factors on spontaneous PTB (sPTB) rates (<37 weeks gestational age) among 631 singleton pregnancies between 1997 and 2018. Exposure to cART was modelled in comparison to no exposure, exposure in the first trimester, and between regimens. Differences in sPTB risk were estimated using time-dependent Cox's proportional hazards models., Results: Overall, the sPTB rate was 16%. Cumulative cART use was associated with lower risk of PTB (Wald test P = 0.02; hazard ratio = 0.98, 95% CI = 0.96-0.99) and specific cART regimens were not associated with increased risk of sPTB. Exposure in the first trimester was not associated with sPTB and for each week of cART exposure, the risk of sPTB decreased by 2%. In a multivariable model, HIV viral load and substance use remained associated with risk of sPTB, but not cART exposure., Conclusion: The sPTB rate among pregnant WLWH was more than three times higher than in the general population. However, sPTB was not related specifically to use of cART; in fact, cART appeared to reduce the risk of sPTB. Uncontrolled HIV replication and substance use were associated with increased risk of sPTB among pregnant WLWH. This emphasizes the important role of prenatal care, access to cART, and smoking cessation and harm reduction to reduce the risk of sPTB in WLWH.

Objective: To characterize comorbid disease and medication burden among women living with HIV (WLWH) in British Columbia (BC), Canada., Design: We examined baseline data from 267 WLWH and 276 HIV-negative women, aged at least 19 years, enrolled in the Children and Women: Antiretrovirals and Markers of Aging (CARMA) cohort., Methods: Self-reported demographic, medical condition, medication, vitamin, and substance exposure data were collected at baseline CARMA study visits. We considered conditions with appropriate concomitant medications to be 'treated'. Wilcoxon rank-sum and Fisher's exact tests compared continuous and categorical variables between WLWH and HIV-negative women. Number of diagnoses, prescribed medications (excluding HIV/antiretrovirals), vitamins, and prevalence of depression/anxiety/panic disorder were compared using negative binomial and logistic regressions for continuous and binary variables, respectively., Results: WLWH were younger [median, interquartile range (IQR) 39.9, 33.6-46.9 vs. 43.6, 31.8-54.6 years; P = 0.01], attained lower education (40.5 vs. 69.6% college/university; P < 0.001), and more often currently smoked tobacco (47.9 vs. 31.9%; P < 0.001) or had income less than $15 000/year (49.0 vs. 43.1%; P < 0.001). Although younger, and despite omitting HIV infection, WLWH had a greater number of diagnoses (incidence rate ratio, 95% confidence interval 1.58, 1.38-1.81; P < 0.001), and more depression/anxiety/panic disorder vs. controls (odds ratio, 95% CI 1.86, 1.22-2.83; P = 0.004). Our model predicts that with mean BMI (26.3), WLWH and HIV-negative peers would have two comorbid diagnoses by age 30 and 60, respectively., Conclusions: WLWH living in BC have more comorbid illness earlier in life than their HIV-negative peers, and have very high rates of depression/anxiety/panic disorder. Addressing mental health and comorbid conditions is essential to improving health outcomes among WLWH.

Background: HIV-mediated inflammation and immune activation can accelerate telomere attrition. In addition, antiretrovirals can inhibit telomerase, possibly shortening telomeres. We examined the longitudinal dynamics of leukocyte telomere length (LTL) during pregnancy in a unique cohort of women living with HIV (WLWH) treated with combination antiretroviral therapy (cART), and HIV-negative control women., Methods: Blood was collected at three visits during pregnancy, at 13-23, >23-30, and >30-40 weeks of gestation, and for WLWH only, at 6 weeks post-partum. LTL was measured by qPCR and both cross-sectional and longitudinal (MANOVA) models were used to examine possible predictors of LTL among participants who attended all three visits during pregnancy., Results: Among WLWH (n = 64) and HIV-negative women (n = 41), within participant LTL were correlated throughout pregnancy (p<0.001). LTL was shorter among WLWH at first visit, but this difference waned by the second visit. WLWH who discontinued cART post-partum experienced a decrease in LTL. Longitudinally, LTL was similar in both groups and increased as gestation progressed, a change that was more pronounced among women under 35 years. Among WLWH, both smoking throughout pregnancy (p = 0.04) and receiving a ritonavir-boosted protease inhibitor-based regimen (p = 0.03) were independently associated with shorter LTL., Conclusions: LTL increases as pregnancy progresses; the reasons for this are unknown but may relate to changes in blood volume, hormones, and/or cell subset distribution. While our observations need confirmation in an independent cohort, our data suggest that although some cART regimens may influence LTL, being on cART appears overall protective and that stopping cART post-partum may negatively impact LTL. The effect of smoking on LTL is clearly negative, stressing the importance of smoking cessation., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the birth rates of women living with HIV (WLWH) compared to the general population in British Columbia (BC), Canada., Methods: We retrospectively reviewed clinical and population level surveillance data from 1997 to 2015. Live birth rates from 1997 to 2015 among WLWH aged 15-49 years were compared with those of all BC women. Next, the number of live births among WLWH with a live birth between 1997-2012 and HIV-negative controls matched 1:3 by geocode were compared., Results: WLWH had a lower birth rate compared to all BC women [31.4 (95%CI, 28.6-34.3) vs. 40.0 (39.3-40.1)/1000 person years]. Stratified by age, WLWH aged 15-24 years had a higher birth rate while WLWH aged 25-49 years had a lower birth rate than BC women (p<0.01). Between 1997 and 2015, birth rates for both populations decreased among women aged 15-24 years, and increased among women aged 25-49 years, most strikingly among WLWH 35-49 years (p<0.01). When comparing WLWH with a live birth to HIV-negative geocode matched controls, WLWH aged 15-24 years (p = 0.03) and aged 25-34 years (p<0.01) had more live births than controls while WLWH aged 35-49 years did not (p = 0.06)., Conclusions: On a population level, WLWH have lower birth rates than the general population. However, this is not observed among WLWH who have ever given birth compared with matched controls, suggesting that sociodemographic factors may play an important role. WLWH are increasingly giving birth in their later reproductive years. Taken together, our data supports the integration of reproductive health and HIV care., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To assess and compare neurodevelopmental disorders in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children in British Columbia, Canada. To determine associations between these outcomes and in-utero exposure to antiretroviral drugs., Design: Retrospective controlled cohort study., Methods: Data were collected on 446 HEU children and 1323 HUU children (matched ∼1 : 3 for age, sex, and geocode) born between 1990 and 2012. Multivariable logistic regressions determined odds ratios of neurodevelopmental disorder diagnoses., Results: HEUs had three times higher odds of being born preterm (P < 0.0001), and a more than two-fold increase in odds for autism, disturbance of emotions, hyperkinetic syndrome, and developmental delay compared with matched HUUs (P < 0.02) in unadjusted analysis. This association was reduced [adjusted neurodevelopmental disorder odds ratio (AOR) = 1.67; 95% confidence interval: 1.12-2.48; P = 0.011] after adjusting for maternal substance use and/or smoking (children born after April 2000). Regardless of antiretroviral exposure type (i.e. none, treatment with one or multiple drug classes), HEUs had higher odds of any neurodevelopmental disorders compared with matched HUUs; however, there was no evidence suggesting any specific classes of antiretroviral drugs or exposure durations increased their likelihood of neurodevelopmental disorders., Conclusion: The results suggest no adverse associations between antiretroviral drugs and neurodevelopmental disorders within antiretroviral-exposed HEU children in our cohort. Prevalence of neurodevelopmental disorders is higher in HEUs; however, maternal substance use plays a role, as could other environmental factors not captured. These findings highlight a need for holistic support for pregnant women as well as careful developmental monitoring of HEUs past infancy, and access to early interventions, particularly among those born preterm and those exposed to addictive substances.

Background: Improving adherence to combined antiretroviral therapy (cART) can be challenging, especially among vulnerable populations living with HIV. Even where cART is available free of charge, social determinants of health act as barriers to optimal adherence rates. Patient-centered approaches exploiting mobile phone communications (mHealth) have been shown to improve adherence to cART and promote achievement of suppressed HIV plasma viral loads. However, data are scarce on the health care provider (HCP) time commitments and health care costs associated with such interventions. This knowledge is needed to inform policy and programmatic implementation., Objective: The purpose of this study was to approximate the resources required and to provide an estimate of the costs associated with running an mHealth intervention program to improve medication adherence in people living with HIV (PLWH)., Methods: This prospective study of HCP utilization and costs was embedded within a repeated measures effectiveness study of the WelTel short-message service (SMS) mHealth program. The study included 85 vulnerable, nonadherent PLWH in Vancouver, Canada, and resulted in improved medication adherence and HIV plasma viral load among participants. Study participants were provided mobile phones with unlimited texting (where required) and received weekly bidirectional text messages to inquire on their status for one year. A clinic nurse triaged and managed participants' responses, immediately logging all patient interactions by topic, HCP involvement, and time dedicated to addressing issues raised by participants. Interaction costs were determined in Canadian dollars based on HCP type, median salary within our health authority, and their time utilized as part of the intervention., Results: Participant-identified problems within text responses included health-related, social, and logistical issues. Taken together, management of problems required a median of 43 minutes (interquartile range, IQR 17-99) of HCP time per participant per year, for a median yearly cost of Can $36.72 (IQR 15.50-81.60) per participant who responded with at least one problem. The clinic nurse who monitored the texts solved or managed 65% of these issues, and the remaining were referred to a variety of other HCPs. The total intervention costs, including mobile phones, plans, and staffing were a median Can $347.74/highly vulnerable participant per year for all participants or Can $383.18/highly vulnerable participant per year for those who responded with at least one problem., Conclusions: Bidirectional mHealth programs improve HIV care and treatment outcomes for PLWH. Knowledge about the HCP cost associated, here less than Can $50/year, provides stakeholders and decision makers with information relevant to determining the feasibility and sustainability of mHealth programs in a real-world setting., Trial Registration: ClinicalTrials.gov NCT02603536; https://clinicaltrials.gov/ct2/show/NCT02603536 (Archived by WebCite at http://www.webcitation.org/70IYqKUjV)., (©Amber R Campbell, Karen Kinvig, Hélène CF Côté, Richard T Lester, Annie Q Qiu, Evelyn J Maan, Ariane Alimenti, Neora Pick, Melanie CM Murray. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 09.07.2018.)

With advances in combination antiretroviral therapy (cART), people living with HIV are now surviving to experience aging. Evidence suggests that individuals living with HIV are at greater risk for low bone mineral density (BMD), osteoporosis, and fractures. Better understanding of the pathophysiology of bone health in women living with HIV (WLWH) is important for treatment strategies. The goal of this study was to explore new biological factors linked to low BMD in WLWH. Standardized BMD measures of WLWH were compared to reference values from an unselected population of women from the same geographical region of the same age range. Linear regression analysis was used to assess relationships among health-related characteristics, cellular aging (measured by leukocyte telomere length; LTL), cART, and BMD of WLWH. WLWH ( n = 73; mean age 43 ± 9 years) had lower BMD Z -scores at the lumbar spine (LS) (mean difference = -0.39, p < 0.001) and total hip (TH) (-0.29, p = 0.012) relative to controls ( n = 290). WLWH between 50 and 60 years ( n = 17) had lower Z -scores at the LS ( p = 0.008) and TH ( p = 0.027) compared to controls ( n = 167). Among WLWH, LS BMD was significantly associated with LTL (R² = 0.09, p = 0.009) and BMI (R² = 0.06, p = 0.042). Spinal BMD was adversely affected in WLWH. Reduction of LTL was strongly associated with lower BMD and may relate to its pathophysiology and premature aging in WLWH., Competing Interests: N.P. is on the advisory board of Gilead, Merck, and VIIV. S.K. is Director of Scientific Innovation at Qu Biologics Inc. Other authors state they have no commercial or other conflicts of interests to declare. The funders had no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscripts, and in the decision to publish the results.

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort., Competing Interests: The authors declare no conflict of interest.

Objectives: To compare muscle power between youth who acquired HIV perinatally and HIV unexposed uninfected (HUU) youth., Methods: We assessed muscle power (relative to body mass, P max /mass), muscle force normalized to body weight (F max /BW), force efficiency, jump height (H max ) and velocity (V max ) during a single two-legged jump with hands on waist on a force platform (Leonardo) in HIV+ youth (n=35, 9-21 y). Thirty-three and 22 participants returned at 12- and 24-months, respectively. We compared age- and sex-specific z-scores in the HIV+ youth to those in HUU controls (n=716, 9-21 y) adjusting for height and muscle cross-sectional area (MCSA, by pQCT)., Results: At baseline, z-scores for Pmax/mass, F max /BW and V max were less than 1 standard deviation lower than HUU after adjusting for height and MCSA (p⟨0.05). P max /mass z-score was negatively associated with level of immunosuppression (p=0.013), but this relationship was not significant after adjusting for height and MCSA (p=0.07). Z-scores for all mechanography outcomes remained stable over time in HIV+ youth., Conclusion: Small deficits in muscle power were apparent in children and youth who acquired HIV perinatally, and the trajectory of muscle power did not change over two years. Further study is needed to identify effective strategies to improve dynamic muscle function in this population.

Background: Combination antiretroviral therapy (cART) as treatment for human immunodeficiency virus (HIV) infection is effective and available, but poor medication adherence limits benefits, particularly in vulnerable populations. In a Kenyan randomized controlled trial, a weekly text-messaging intervention (WelTel) improved cART adherence and HIV viral load (VL). Despite growing evidence for short message service (SMS) text-message interventions in HIV care, there is a paucity of data utilizing these interventions in marginalized or female cohorts., Objective: This study was undertaken to assess whether the standardized WelTel SMS text-message intervention applied to a vulnerable, predominantly female, population improved cART adherence and VL., Methods: We conducted a repeated measures study of the WelTel intervention in high-risk HIV-positive persons by measuring change in VL, CD4 count, and self-reported adherence 12 months before and 12 months after the WelTel intervention was introduced. Inclusion criteria included VL ≥200 copies/mL, indication for treatment, and meeting vulnerability criteria. Participants were given a mobile phone with unlimited texting (where required), and weekly check-in text messages were sent for one year from the WelTel computer platform. Clinical data were collected for control and intervention years. Participants were followed by a multidisciplinary team in a clinical setting. Outcomes were assessed using Wilcoxon signed ranks tests for change in CD4 and VL from control year to study end and mixed-effects logistic regressions for change in cART adherence and appointment attendance. A secondary analysis was conducted to assess the effect of response rate on the outcome by modeling final log 10 VL by number of responses while controlling for mean log 10 VL in the control year., Results: Eighty-five participants enrolled in the study, but 5 withdrew (final N=80). Participants were predominantly female (90%, 72/80) with a variety of vulnerabilities. Mean VL decreased from 1098 copies/mL in the control year to 439 copies/mL at study end (P=.004). Adherence to cART significantly improved (OR 1.14, IQR 1.10-1.18; P<.001), whereas appointment attendance decreased slightly with the intervention (OR 0.81, IQR 0.67-0.99; P=.03). A response was received for 46.57% (1753/3764) of messages sent and 9.62% (362/3764) of text messages sent were replied to with a problem. An outcome analysis examining relationship between reply rate and VL did not meet statistical significance (P=.07), but may be worthy of investigating further in a larger study., Conclusions: WelTel may be an effective tool for improving cART adherence and reducing VLs among high-risk, vulnerable HIV-positive persons., Trial Registration: Clinicaltrials.gov NCT02603536; https://clinicaltrials.gov/ct2/show/NCT02603536 (Archived by WebCite at http://www.webcitation.org/6qK57zCwv)., (©Elizabeth King, Karen Kinvig, Jonathan Steif, Annie Q Qiu, Evelyn J Maan, Arianne YK Albert, Neora Pick, Ariane Alimenti, Mary H Kestler, Deborah M Money, Richard T Lester, Melanie Caroline Margaret Murray. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 01.06.2017.)

Introduction: Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period., Methods: This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR., Results: Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001)., Conclusions: In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.

Background: Through implementation of combination antiretroviral therapy (cART) remarkable gains have been achieved in the management of HIV infection; nonetheless, the neurocognitive consequences of infection remain a pivotal concern in the cART era. Research has often employed norm-referenced neuropsychological scores, derived from healthy populations (excluding many seronegative individuals at high risk for HIV infection), to characterize impairments in predominately male HIV-infected populations., Methods: Using matched-group methodology, we assessed 81 HIV-seropositive (HIV+) women with established neuropsychological measures validated for detection of HIV-related impairments, as well as additional detailed tests of executive function and decision-making from the Cambridge Neuropsychological Test Automated Battery (CANTAB)., Results: On validated tests, the HIV+ women exhibited impairments that were limited to significantly slower information processing speed when compared with 45 HIV-seronegative (HIV-) women with very similar demographic backgrounds and illness comorbidities. Additionally, select executive impairments in shifting attention (i.e., reversal learning) and in decision-making quality were revealed in HIV+ participants. Modifiers of neurocognition in HIV-infected women included detectable HIV plasma viral load, active hepatitis C virus co-infection, and self-reported depression symptoms. In contrast, leukocyte telomere length (LTL), a marker of cellular aging, did not significantly differ between HIV+ and HIV- women, nor was LTL associated with overall neurocognition in the HIV+ group., Conclusions: The findings suggest that well-managed HIV infection may entail a more circumscribed neurocognitive deficit pattern than that reported in many norm-referenced studies, and that common comorbidities make a secondary contribution to HIV-related neurocognitive impairments.

Objectives: To determine if bone health is compromised in perinatally HIV-infected youth., Methods: We assessed BMC at the proximal femur, lumbar spine and total body using DXA in perinatally HIV-infected youth (n=31; 9-18y). Using pQCT, we assessed muscle CSA, total and cortical bone area, cortical BMD and thickness and strength strain index at the tibial shaft. Thirty and 18 participants returned at 12- and 24-months, respectively. We calculated age- and sex-specific z-scores for the HIV-infected youth using data from a healthy cohort (n=883; 9-18y)., Results: At baseline, height and MCSA were reduced in HIV-infected youth (-0.79 to -0.23, p<0.05). BMC z-scores adjusted for height and lean mass were lower than controls at all sites except the lumbar spine (-0.57 to -0.27, p<0.05). Bone area and strength z-scores were not different from zero after adjusting for tibial length and MCSA. In contrast, cortical BMD z-scores were greater in HIV-infected youth (0.46, p=0.011). Z-scores for all bone outcomes showed positive trends over time in HIV-infected youth., Conclusion: Although HIV infection may be associated with bone mass deficits during growth, bone geometry and strength appear adapted to muscle force. Further, deficits in bone mass may dissipate over time in this population.

Objectives: Nucleo(s/t)ide reverse transcriptase inhibitors given to HIV-infected pregnant women to prevent vertical transmission may adversely affect mitochondrial DNA (mtDNA). We hypothesized that HAART-exposed/HIV-uninfected infants may show higher blood mtDNA mutation burden than controls born to HIV-uninfected mothers., Methods: Blood was collected from in-utero HIV/HAART-exposed infants and controls, as well as from a subset of their mothers. The presence of mtDNA A→C/T→G (AC/TG) mutations was measured by cloning and sequencing D-loop PCR amplicons. Relationships with maternal characteristics were examined., Results: No significant difference was found between the percentage of HIV/HAART-exposed infants with AC/TG mutations (N = 15/57, 26.3%) and controls (N = 10/70, 14.3%) before (P = 0.090) or after controlling for covariates (P = 0.058), although a tendency was observed. However, significantly more HIV/HAART-exposed mothers (N = 18/42, 42.9%) harboured AC/TG mutations compared with controls (N = 7/39, 17.9%) before (P = 0.015) and after (P = 0.012) controlling for covariates. AC/TG mutations were more prevalent in HIV/HAART-exposed mothers than in their infants (N = 42, 42.9 vs. 23.8%, P = 0.033), however, this difference disappeared after controlling for covariates. No difference was seen between control mothers and their infants (N = 39, both 17.9%). In HIV/HAART-exposed mothers, only a detectable HIV plasma viral load near delivery predicted AC/TG mutations., Conclusion: Our results suggest that HIV and/or HAART exposure are associated with increased prevalence of AC/TG mtDNA mutations in mothers and show a similar tendency in infants exposed during pregnancy. As accumulation of mtDNA mutations has been linked with aging and age-associated diseases, this may raise concerns in the long term for HIV and HAART-exposed populations.

Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging., Methods: In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV-1-infected (HIV(+)) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV(-)) control children (n = 104) aged 0-19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV(+)/HEU children only, and c) HIV(+) children only., Results: After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV(+) group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007)., Conclusions: In this large study, group rates of LTL attrition were similar for HIV(+), HEU and HIV(-) children. No associations between children's LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.