Exploring the Anal Microbiome in HIV Positive and High-Risk HIV Negative Women.

This exploratory study sought to characterize the anal microbiome and explore associations among the anal microbiome, risk factors for anal cancer, and clinical factors. A pilot sample of 50 HIV infected and high-risk HIV negative women were recruited from the former Women's Interagency HIV Study. Microbiome characterization by 16S rRNA gene sequencing and datasets were analyzed using QIIME 2™. Composition of the anal microbiome and its associations with anal cancer risk factors and clinical factors were analyzed using linear decomposition model and permutational multivariate analysis of variance. Composition of the anal microbiome among HIV positive and high-risk negative women was dominated by Bacteroides, Prevotella, and Campylobacter. The overall taxonomic composition and microbial diversity of the anal microbiome did not significantly differ by HIV status. However, the abundance of Ruminococcus 1 belonging to the Rumincoccaceae family was associated with HIV status (q = .05). No anal cancer risk factors were associated with the anal microbiome composition. Clinical factors marginally associated with the anal microbiome composition included body mass index (BMI; p = .05) and hepatitis C virus (HCV; p = .05). Although HIV and risk factors for anal cancer were not associated with the composition of the anal microbiome in this pilot sample, other clinical factors such as BMI and HCV, may be worth further investigation in a larger study. Future research can build on these findings to explore the role of the microbiome and HIV comorbidities in women.

Self-Reported Sexually Transmitted Infections After Incarceration in Women with or at Risk for HIV in the United States, 2007-2017.

Background: U.S. women who have been incarcerated report high rates of sexual risk behavior and sexually transmitted infections (STIs). Materials and Methods: We estimated the effect of incarceration on the time to first incident STI in a multicenter cohort of U.S. women with or at risk for HIV. We used marginal structural models to compare time to first self-reported gonorrhea, chlamydia, or trichomonas infection for nonincarcerated women and incarcerated women. Covariates included demographic factors, HIV status, sex exchange, drug/alcohol use, and prior incarceration. Results: Three thousand hundred twenty-four women contributed a median of 4 at-risk years and experienced 213 first incident STI events. The crude incidence of STIs was 3.7 per 100 person-years for incarcerated women and 1.9 per 100 person-years for nonincarcerated women. The weighted hazard ratio for incident STIs was 4.05 (95% confidence interval: 1.61-10.19). Conclusion: Women with or at risk for HIV in the United States who have recently experienced incarceration may be at increased STI risk.

Incidence and Prevalence of Incarceration in a Longitudinal Cohort of Women at Risk for Human Immunodeficiency Virus in the United States, 2007-2017.

Background: To estimate the incidence, prevalence, frequency, and duration of incarceration and to identify risk factors for incarceration among women at risk for human immunodeficiency virus (HIV) in the United States. Methods: During semiannual study visits in a multicenter cohort study, 970 HIV sero-negative participants at risk for HIV were asked about their own incarceration (10/2007-09/2017) and incarceration of sexual partners (10/2013-09/2017). We used descriptive statistics and multivariable log-binomial regression to identify baseline predictors of incident incarceration. Results: Median follow-up time across the 970 participants was 5.5 years (IQR 3.5-9.5). Nearly half (n = 453, 46.7%) of participants were incarcerated during or before the study, and the incarceration rate was 5.5 per 100 person-years. In multivariable models, incident incarceration was associated with prior incarceration (RR 5.20, 95% CI: 3.23-8.41) and noninjection drug use (RR 1.57, 95% CI: 1.10-2.25). Conclusions: Incarceration is common for women at risk for HIV. Prevention interventions that address the complex interplay of drug use, sex exchange, and housing instability for women who have experienced incarceration have the potential to reach an important group of U.S. women at risk of HIV infection.

Incarceration and Number of Sexual Partners After Incarceration Among Vulnerable US Women, 2007-2017.

Objectives. To examine whether women's incarceration increases numbers of total and new sexual partners.Methods. US women with or at risk for HIV in a multicenter cohort study answered incarceration and sexual partner questions semiannually between 2007 and 2017. We used marginal structural models to compare total and new partners at visits not following incarceration with all visits following incarceration and visits immediately following incarceration. Covariates included demographics, HIV status, sex exchange, drug or alcohol use, and housing instability.Results. Of the 3180 participants, 155 were incarcerated. Women reported 2 partners, 3 or more partners, and new partners at 5.2%, 5.2%, and 9.3% of visits, respectively. Relative to visits not occurring after incarceration, odds ratios were 2.41 (95% confidence interval [CI] = 1.20, 4.85) for 2 partners, 2.03 (95% CI = 0.97, 4.26) for 3 or more partners, and 3.24 (95% CI = 1.69, 6.22) for new partners at visits immediately after incarceration. Odds ratios were similar for all visits following incarceration.Conclusions. Women had more total partners and new partners immediately and at all visits following incarceration after confounders and loss to follow-up had been taken into account.

Antiretroviral Therapy-Induced Bone Loss Is Durably Suppressed by a Single Dose of Zoledronic Acid in Treatment-Naive Persons with Human Immunodeficiency Virus Infection: A Phase IIB Trial.

BACKGROUND: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among persons with HIV (PWH). We previously showed long-acting antiresorptive zoledronic acid (ZOL) prevented ART-induced bone loss through 48 weeks of therapy and here investigate whether protection persisted. METHODS: We randomized 63 nonosteoporotic, treatment-naive adult PWH initiating ART to ZOL (5 mg) versus placebo in a double-blinded, placebo-controlled, phase IIb trial. Here we analyzed the long-term outcome data (144 weeks). Plasma bone turnover markers and bone mineral density (BMD) were quantified at weeks 0, 12, 24, 48, 96, and 144. Primary outcome was change in bone resorption marker C-terminal telopeptide of collagen (CTx). Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS: At 96 weeks, mean CTx was 62% lower with ZOL relative to placebo (n = 46; CTx = 0.123 vs 0.324 ng/mL; P < .001); at 144 weeks a 25% difference between arms was not statistically significant. At 48 weeks, lumbar spine BMD with ZOL was 11% higher than placebo (n = 60; P < .001) and remained 9-11% higher at 96 (n = 46) and 144 (n = 41; P < .001) weeks. 144 weeks after ZOL infusion, BMD did not change at the lumbar spine (P = .22) but declined at the hip (P = .04) and femoral neck (P = .02). CONCLUSIONS: A single dose of ZOL administered at ART initiation blunts bone resorption and BMD loss at key fracture-prone anatomical sites in treatment-naive PWH for 3 years. A multicenter randomized phase III clinical trial validating these results in a larger population is needed. CLINICAL TRIALS REGISTRATION: NCT01228318.

History of Incarceration Among Women with HIV: Impact on Prognosis and Mortality.

Objectives: To identify factors associated with incarceration among women and examine the relationship between incarceration and human immunodeficiency virus (HIV)-related outcomes. Materials and Methods: We analyzed longitudinal data from 3324 women (2372 with HIV and 952 uninfected) from 2007 to 2016 in the Women's Interagency HIV Study, a U.S. cohort of women with and without HIV. Lifetime history of incarceration before first study visit was used as the outcome and then as a predictor for HIV outcomes and mortality. Using multivariable models, we assessed associations between socio-demographic, behavioral, and clinical characteristics and incarceration, and between incarceration and HIV outcomes, including mortality. Results: Overall, 1256 (38%) of women reported ever being incarcerated. Women who had a history of drug use had a 44% greater prevalence of incarceration compared with those who did not use drugs. Sexual minority women and women who experienced physical and sexual abuse had a 47% and 28%, respectively, greater prevalence of incarceration than heterosexual women and those not abused. For the 862 women with HIV and a history of incarceration, having an incarceration history was independently associated with less viral suppression (adjusted prevalence ratios = 0.95; confidence intervals [CI]:0.90-1.00 p = 0.04) and higher likelihood of death (adjusted hazard ratios = 1.39; CI:1.04-1.86 p = 0.03). Conclusions: Incarceration is common in this cohort and may put women with HIV at increased odds of worse HIV outcomes and mortality than those without a history of incarceration. Addressing the intersecting epidemics of HIV, substance use, and incarceration by providing needed treatment and resources and avoiding criminalization may improve health outcomes in vulnerable women with HIV.

T-cell receptor activator of nuclear factor-κB ligand/osteoprotegerin imbalance is associated with HIV-induced bone loss in patients with higher CD4+ T-cell counts.

OBJECTIVE: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-κB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. DESIGN: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study. METHODS: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA. RESULTS: We demonstrate for the first time in-vivo human T-cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4 T-cell counts at least 200 cells/µl but not in those with lower counts. CONCLUSION: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4 T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss.

A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy-induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial.

BACKGROUND: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among HIV-infected individuals. ART-induced bone loss is most intense within the first 48 weeks of therapy, providing a window for prophylaxis with long-acting antiresorptives. METHODS: In a phase 2, double-blind, placebo-controlled trial, we randomized 63 nonosteoporotic, ART-naive adults with HIV initiating ART with atazanavir/ritonavir + tenofovir/emtricitabine to a single zoledronic acid (ZOL) infusion (5 mg) vs placebo to determine the efficacy of ZOL in mitigating ART-induced bone loss. Plasma bone turnover markers and bone mineral density (BMD) were performed at weeks 0, 12, 24, and 48 weeks. Primary outcome was change in C-terminal telopeptide of collagen at 24 weeks. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS: The ZOL arm had a 65% reduction in bone resorption relative to the placebo arm at 24 weeks (0.117 ng/mL vs 0.338 ng/mL; P < .001). This effect of ZOL occurred as early as 12 weeks (73% reduction; P < .001) and persisted through week 48 (57% reduction; P < .001). The ZOL arm had an 8% higher lumbar spine BMD at 12 weeks relative to the placebo arm (P = .003), and remained 11% higher at 24 and 48 weeks. Similar trends were observed in the hip and femoral neck. CONCLUSIONS: A single dose of ZOL administered at ART initiation prevented ART-induced bone loss through the first 48 weeks of ART, the period when ART-induced bone loss is most pronounced. Validation of these results in larger multicenter randomized clinical trials is warranted. CLINICAL TRIALS REGISTRATION: NCT01228318.

Mechanisms for the Negative Effects of Internalized HIV-Related Stigma on Antiretroviral Therapy Adherence in Women: The Mediating Roles of Social Isolation and Depression.

BACKGROUND: Internalization of HIV-related stigma may inhibit a person's ability to manage HIV disease through adherence to treatment regimens. Studies, mainly with white men, have suggested an association between internalized stigma and suboptimal adherence to antiretroviral therapy (ART). However, there is a scarcity of research with women of different racial/ethnic backgrounds and on mediating mechanisms in the association between internalized stigma and ART adherence. METHODS: The Women's Interagency HIV Study (WIHS) is a multicenter cohort study. Women living with HIV complete interviewer-administered questionnaires semiannually. Cross-sectional analyses for the current article included 1168 women on ART for whom data on medication adherence were available from their last study visit between April 2013 and March 2014, when the internalized stigma measure was initially introduced. RESULTS: The association between internalized stigma and self-reported suboptimal ART adherence was significant for those in racial/ethnic minority groups (AOR = 0.69, P = 0.009, 95% CI: 0.52 to 0.91), but not for non-Hispanic whites (AOR = 2.15, P = 0.19, 95% CI: 0.69 to 6.73). Depressive symptoms, loneliness, and low perceived social support mediated the association between internalized stigma and suboptimal adherence in the whole sample, as well as in the subsample of minority participants. In serial mediation models, internalized stigma predicted less-perceived social support (or higher loneliness), which in turn predicted more depressive symptoms, which in turn predicted suboptimal medication adherence. CONCLUSIONS: Findings suggest that interconnected psychosocial mechanisms affect ART adherence, and that improvements in adherence may require multifaceted interventions addressing both mental health and interpersonal factors, especially for minority women.

Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection.

HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.