Longitudinal Assessment of Bone Mineral Density in Women Living With and Without HIV Across Reproductive Phases.

BACKGROUND: Women living with HIV commonly experience low areal bone mineral density (BMD), but whether this is affected by low ovarian hormonal states (prolonged amenorrhea or menopause) is unknown. We compared rates of BMD loss between women living with HIV and HIV-negative control women and investigated its association with low ovarian hormonal states. SETTING: Women living with HIV were enrolled from Vancouver Canada and controls from 9 Canadian sites. METHODS: This longitudinal analysis included age-matched women living with HIV in the Children and Women: AntiRetrovirals and Markers of Aging cohort and controls in the population-based Canadian Multicentre Osteoporosis Study. Rate of change/year in BMD at the total hip and lumbar spine (L1-L4) between 3 and 5 years was compared between groups, adjusting for sociodemographic and clinical variables. RESULTS: Ninety-two women living with HIV (median [interquartile range] age: 49.5 [41.6-54.1] years and body mass index: 24.1 [20.7-30.8] kg/m 2 ) and 278 controls (age: 49.0 [43.0-55.0] years and body mass index: 25.8 [22.9-30.6] kg/m 2 ) were included. Total hip BMD loss was associated with HIV (ß: -0.003 [95% CI: -0.006 to -0.0001] g/cm 2 /yr), menopause (ß: -0.007 [-0.01 to -0.005] g/cm 2 /yr), and smoking (ß: -0.003 [-0.006 to -0.0002] g/cm 2 /yr); BMD gain was linked with higher body mass index (ß: 0.0002 [0.0007-0.0004] g/cm 2 /yr). Menopause was associated with losing L1-L4 BMD (ß: -0.01 [-0.01 to -0.006] g/cm 2 /yr). Amenorrhea was not associated with BMD loss. CONCLUSIONS: HIV and menopause negatively influenced total hip BMD. These data suggest women living with HIV require hip BMD monitoring as they age.

Global Prevalence of Chronic Pain in Women with HIV: A Systematic Review and Meta-analysis.

Chronic pain is common among people with human immunodeficiency virus (HIV) and detrimental to quality of life and overall health. It is often underdiagnosed, undertreated, and frankly dismissed in women with HIV, despite growing evidence that it is highly prevalent in this population. Thus, we conducted a systematic review and meta-analysis to estimate the global prevalence of chronic pain in women with HIV. The full protocol can be found on PROSPERO (identifier CRD42022301145). Of the 2984 references identified in our search, 36 were included in the systematic review and 35 in the meta-analysis. The prevalence of chronic pain was 31.2% (95% confidence interval [CI], 24.6%-38.7%; I2 = 98% [95% CI, 97%-99%]; P < .0001). In this global assessment, we found a high prevalence of chronic pain among women with HIV, underscoring the importance of understanding the etiology of chronic pain, identifying effective treatments, and conducting regular assessments in clinical practice.

Age at Natural Menopause in Women Living with HIV: A Cross-Sectional Study Comparing Self-Reported and Biochemical Data.

Early menopause (<45 years) has significant impacts on bone, cardiovascular, and cognitive health. Several studies have suggested earlier menopause for women living with HIV; however, the current literature is limited by reliance on self-report data. We determined age at menopause in women living with HIV and socio-demographically similar HIV-negative women based on both self-report of menopause status (no menses for ≥12 months) and biochemical confirmation (defined as above plus follicle-stimulating hormone level ≥ 25 IU/mL). Multivariable median regression models assessed factors associated with menopause age, controlling for relevant confounders. Overall, 91 women living with HIV and 98 HIV-negative women were categorized as menopausal by self-report, compared to 83 and 92 by biochemical confirmation. Age at menopause did not differ significantly between groups, whether based on self-report (median [IQR]: 49.0 [45.3 to 53.0] vs. 50.0 [46.0 to 53.0] years; p = 0.28) or biochemical confirmation (50.0 [46.0 to 53.0] vs. 51.0 [46.0 to 53.0] years; p = 0.54). In the multivariable model, no HIV-related or psychosocial variables were associated with earlier age at menopause (all p > 0.05). Overall, HIV status per se was not statistically associated with an earlier age at menopause, emphasizing the importance of comparing socio-demographically similar women in reproductive health and HIV research.

Vitamin D intakes among women living with and without HIV in Canada.

BACKGROUND: Patterns of vitamin D intake are relatively unexplored among women living with HIV, despite its importance for women's health. We compared vitamin D dietary and supplement intakes in women with HIV and population-based national controls and investigated barriers to intake. METHODS: In this case-control study, women with HIV in the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) cohort were matched with Canadian Multicentre Osteoporosis Study (CaMos) controls. Participants were queried for vitamin D in dairy consumption, supplementation/dosage, and sociodemographic variables. We assessed barriers to supplementation and factors associated with dietary intake by regression modelling. RESULTS: Ninety-five women living with HIV were age-matched to 284 controls. Women with HIV had lower income and bone mineral density and were more likely to smoke, take multiple medications and be non-white. Vitamin D dietary intake was lower in women living with HIV versus controls [0.76 vs. 1.79 µg/day; adjusted odds ratio (aOR) for greater than or equal to median intake 0.29 (0.12-0.61), p = 0.002], but any supplementation was higher [62.2% vs. 44.7%; aOR = 3.44 (95% CI: 1.16-11.00), p = 0.03]. Total vitamin D intake was similar between groups. Smoking was associated with no supplementation; non-white ethnicity and low income were related to lower dietary intake. CONCLUSIONS: Women living with HIV showed lower dietary vitamin D intake but higher supplementation rates, suggesting that care providers are promoting supplementation. Women living with HIV who smoke, have low incomes and are non-white may particularly benefit from targeted efforts to improve vitamin D intake.

Markers of ovarian reserve in women living with HIV: A systematic review.

BACKGROUND: Anti-Mullerian hormone (AMH) levels indicate ovarian reserve and are predictive of reproductive aging. Studies evaluating AMH levels in women with HIV have produced conflicting results, and reasons for inter-study differences have not been assessed. To understand reproductive aging in HIV, we conducted a systematic review of ovarian reserve among women with HIV. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, and CAB Direct for studies including AMH in reproductive-aged women with HIV. Two reviewers used the Newcastle-Ottawa scale to assess the quality of extracted data. RESULTS: Of the 315 reports screened, ten met the inclusion criteria. Studies were conducted across seven countries and included 3673 women with HIV and 2342 HIV-negative women in the comparison group. Ethnic distribution, combination antiretroviral therapy coverage, and viral load suppression varied considerably across studies. Nine of the ten reviewed studies reported lower unadjusted AMH levels in women with HIV than in those without HIV; however, in studies that adjusted for confounders (n = 4), only two showed an association between HIV and AMH. Low CD4 count and high viral load correlated with low AMH in the two largest studies. Other studies found that opioid use and elevated inflammatory markers were associated with low AMH. Study quality varied considerably, and many were of low quality (n = 6). CONCLUSION: Current evidence is inconclusive about the relationship between HIV and AMH, although studies suggest a trend toward lower AMH among women with HIV. Future studies that adjust for HIV-related factors, inflammatory markers, and substance use are needed in the era of contemporary HIV care to confirm the association between HIV and reduced ovarian reserve and establish its underlying cause.

Stressing the need for validated measures of cortisol in HIV research: A scoping review.

OBJECTIVES: People living with HIV experience numerous endocrine abnormalities and psychosocial stressors. However, interactions between HIV, cortisol levels, and health outcomes have not been well described among people living with HIV on effective therapy. Furthermore, methods for measuring cortisol are disparate across studies. We describe the literature reporting cortisol levels in people living with HIV, describe methods to measure cortisol, and explore how this relates to health outcomes. METHODS: We searched the PubMed database for articles published in the past 20 years regarding HIV and cortisol with ≥50% of participants on antiretroviral therapies. Articles included observational, case-control, cross-sectional, and randomized controlled trials analyzing cortisol by any method. Studies were excluded if abnormal cortisol was due to medications or other infections. Variables were extracted from selected studies and their quality was assessed using the Newcastle-Ottawa Scale. RESULTS: In total, 19 articles were selected and included, covering the prevalence of abnormal cortisol (n = 4), exercise (n = 4), metabolic syndrome and/or cardiovascular disease (n = 2), mental health and cognition (n = 9), and sex/gender (n = 6). Cortisol was measured in serum (n = 7), saliva (n = 8), urine (n = 2), and hair (n = 3) specimens. Comparisons between people with and without HIV were inconsistent, with some evidence that people with HIV have increased rates of hypocortisolism. Depression and cognitive decline may be associated with cortisol excess, whereas anxiety and metabolic disease may be related to low cortisol; more data are needed to confirm these relationships. CONCLUSIONS: Data on cortisol levels in the era of antiretroviral therapy remain sparse. Future studies should include controls without HIV, appropriately timed sample collection, and consideration of sex/gender and psychosocial factors.

British Columbia CARMA-CHIWOS Collaboration (BCC3): protocol for a community-collaborative cohort study examining healthy ageing with and for women living with HIV.

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 Children and Women: AntiRetroviral therapy and Markers of Aging-Canadian HIV Women's Sexual and Reproductive Health Cohort Study (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_HEAR_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.

Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity.

HIV-1 Nef enhances virion infectivity by counteracting host restriction factor SERINC5; however, the impact of natural Nef polymorphisms on this function is largely unknown. We characterize SERINC5 downregulation activity of 91 primary HIV-1 subtype B nef alleles, including isolates from 45 elite controllers and 46 chronic progressors. Controller-derived Nef clones display lower ability to downregulate SERINC5 (median 80% activity) compared with progressor-derived clones (median 96% activity) (p = 0.0005). We identify 18 Nef polymorphisms associated with differential function, including two CTL escape mutations that contribute to lower SERINC5 downregulation: K94E, driven by HLA-B∗08, and H116N, driven by the protective allele HLA-B∗57. HIV-1 strains encoding Nef K94E and/or H116N display lower infectivity and replication capacity in the presence of SERINC5. Our results demonstrate that natural polymorphisms in HIV-1 Nef can impair its ability to internalize SERINC5, indicating that variation in this recently described function may contribute to differences in viral pathogenesis.

Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection.

Sustained viremia after acute HIV infection is associated with profound CD4+ T cell loss and exhaustion of HIV-specific CD8+ T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer+) CD8+ T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8+ T cell activation. HIV-specific CD8+ T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (Tem) cells. Transcriptional analysis of tetramer+ CD8+ T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2, AXL, and SRC Early treatment also resulted in robust HIV-specific CD4+ T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4+ and CD8+ T cells, preserving key antiviral properties of these cells.