Kerry Murphy

Research Gaps in Defining the Biological Link between HIV Risk and Hormonal Contraception

Epidemiologic data suggest an association between depot medroxyprogesterone acetate (DMPA), a progesterone‐based hormonal contraceptive, and increased risk of HIV acquisition and transmission. DMPA is highly effective and is among the most commonly used form of hormonal contraception in areas of high HIV prevalence. Thus, defining the biological mechanisms that contribute to the potential negative synergy between DMPA and HIV is key and may facilitate the identification of alternative contraceptive strategies. Proposed mechanisms include thinning or disruption of the cervicovaginal epithelial barrier, induction of mucosal inflammation, interference with innate and adaptive soluble and cellular immune responses, and/or alterations in the vaginal microbiome. DMPA may also indirectly increase the risk of HIV by promoting genital herpes or other sexually transmitted infections. However, there is a paucity of rigorous in vitro, animal model and clinical data to support these potential mechanisms highlighting the need for future research.

Understanding the disparity: Predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity

Background:Stark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of 3 primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities. Methods:Using data from HIV-infected women participating in the Womens Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) after suppression (HIV RNA < 80 copies/mL) on highly active antiretroviral therapy. We identified predictors of virologic failure using discrete time survival analysis and calculated racial/ethnic-specific population-attributable fractions (PAFs). Results:Of 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and white women had significantly lower hazards of virologic failure than African American women [Hispanic hazard ratio, (HR) = 0.8, 95% confidence interval: (0.6 to 0.9); white HR = 0.7 (0.5 to 0.9)]. The PAF of virologic failure associated with low income was higher in Hispanic [adjusted hazard ratios (aHR) = 2.2 (0.7 to 6.5), PAF = 49%] and African American women [aHR = 1.8 (1.1 to 3.2), PAF = 38%] than among white women [aHR = 1.4 (0.6 to 3.4), PAF = 16%]. Lack of health insurance compared with public health insurance was associated with virologic failure only among Hispanic [aHR = 2.0 (0.9 to 4.6), PAF = 22%] and white women [aHR = 1.9 (0.7 to 5.1), PAF = 13%]. By contrast, depressive symptoms were associated with virologic failure only among African-American women [aHR = 1.6 (1.2 to 2.2), PAF = 17%]. Conclusions:In this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression.

Association of self-reported race with AIDS death in continuous HAART users in a cohort of HIV-infected women in the United States

Objective:To assess the association of race with clinical outcomes in HIV-positive women on continuous HAART. Design:Prospective study that enrolled women from 1994 to 1995 and 2001 to 2002. Setting:Womens Interagency HIV Study, a community-based cohort in five US cities. Participants:One thousand, four hundred and seventy-one HIV-positive continuous HAART users. Main outcome measures:Times to AIDS and non-AIDS death and incident AIDS-defining illness (ADI) after HAART initiation. Results:In adjusted analyses, black vs. white women had higher rates of AIDS death [adjusted hazard ratio (aHR) 2.14, 95% confidence interval (CI) 1.30, 3.50; P = 0.003] and incident ADI (aHR 1.58, 95% CI 1.08, 2.32; P = 0.02), but not non-AIDS death (aHR 0.91, 95% CI 0.59, 1.39; P = 0.65). Cumulative AIDS death incidence at 10 years was 17.3 and 8.3% for black and white women, respectively. Other significant independent pre-HAART predictors of AIDS death included peak viral load (aHR 1.70 per log10, 95% CI 1.34, 2.16; P < 0.001), nadir CD4+ cell count (aHR 0.65 per 100 cells/&mgr;l, 95% CI 0.56, 0.76; P < 0.001), depressive symptoms by Center for Epidemiology Studies Depression score at least 16 (aHR 2.10, 95% CI 1.51, 2.92; P < 0.001), hepatitis C virus infection (aHR 1.57, 95% CI 1.02, 2.40; P = 0.04), and HIV acquisition via transfusion (aHR 2.33, 95% CI 1.21, 4.49; P = 0.01). In models with time-updated HAART adherence, association of race with AIDS death remained statistically significant (aHR 3.09, 95% CI 1.38, 6.93; P = 0.006). Conclusion:In continuous HAART-using women, black women more rapidly died from AIDS or experienced incident ADI than their white counterparts after adjusting for confounders. Future studies examining behavioral and biologic factors in these women may further the understanding of HAART prognosis.

Use of antimüllerian hormone to predict the menopausal transition in HIV-infected women

BACKGROUND: HIV infection has been associated with early menopausal onset, which may have adverse long‐term health consequences. Antimüllerian hormone, a biomarker of ovarian reserve and gonadal aging, is reduced in HIV‐infected women. OBJECTIVE: We sought to assess the relationship of antimüllerian hormone to age of menopause onset in HIV‐infected women. STUDY DESIGN: We used antimüllerian hormone levels measured in plasma in 2461 HIV‐infected participants from the Womens Interagency HIV Study to model the age at final menstrual period. Multivariable normal mixture models for censored data were used to identify factors associated with age at final menstrual period. RESULTS: Higher antimüllerian hormone at age 40 years was associated with later age at final menstrual period, even after multivariable adjustment for smoking, CD4 cell count, plasma HIV RNA, hepatitis C infection, and history of clinical AIDS. Each doubling of antimüllerian hormone was associated with a 1.5‐year increase in the age at final menstrual period. Median age at final menstrual period ranged from 45 years for those in the 10th percentile of antimüllerian hormone to 52 years for those in the 90th percentile. Other factors independently associated with earlier age at final menstrual period included smoking, hepatitis C infection, higher HIV RNA levels, and history of clinical AIDS. CONCLUSION: Antimüllerian hormone is highly predictive of age at final menstrual period in HIV‐infected women. Measuring antimüllerian hormone in HIV‐infected women may enable clinicians to predict risk of early menopause, and potentially implement individualized treatment plans to prevent menopause‐related comorbidities and to aid in interpretation of symptoms.

The Interplay of Host Immunity, Environment and the Risk of Bacterial Vaginosis and Associated Reproductive Health Outcomes

Bacterial vaginosis (BV) is one of the most common causes of vaginal symptoms in US women, but its causal mechanism has not yet been defined. BV is more prevalent in women who are immunosuppressed, and several risk factors for the development of BV are associated with lower quantities of immune mediators in vaginal fluid. In contrast, the poor reproductive health outcomes associated with BV, such as preterm birth and human immunodeficiency virus type 1 acquisition, are associated with increased levels of proinflammatory immune mediators in the genital tract. In this article, we discuss how variations in the host immune profile and environmental effects on host immunity may influence the risk of BV, as well as the risk of complications associated with BV.

Levels of Genital Tract Defensins and Cytokines Differ between HIV-Uninfected US and African Women

To explore the impact of race and geographic region on biomarkers of HIV risk and vaginal health, differences in soluble immune mediators were measured in US versus African and US white versus US black women at enrollment into a phase 2 microbicide trial.

Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women

Sexual violence is associated with increased risk of HIV acquisition/transmission in women. Forced sex can result in physical trauma to the reproductive tract as well as severe psychological distress. However, immuno-biological mechanisms linking sexual violence and HIV susceptibility are incompletely understood. Using the Women’s Interagency HIV Study repository, a total of 77 women were selected to form 4 groups, stratified by HIV serostatus, in the following categories: 1) no sexual abuse history and low depressive symptom score (below clinically significant cut-off, scores <16) (Control); 2) no sexual abuse history but high depressive symptom score, ≥16 (Depression); 3) chronic sexual abuse exposure and low depressive symptom score (Abuse); 4) chronic sexual abuse exposure and high depressive symptom score (Abuse+Depression). Inflammation-associated cytokines/chemokines/proteases (TNF-α, IL-6, IL-1α, IL-1β, TGF-β MIP-3α, IP-10, MCP-1, Cathepsin B), anti-inflammatory/anti-HIV mediators (Secretory leukocyte protease inhibitor (SLPI), Elafin, beta defensin 2 (HBD2), alpha defensins (HNP 1–3), Thrombospondin (TSP-1), Serpin A1, A5, Cystatin A, B), and wound-healing mediators (Gro-α, VEGF, PDGF, EGF, FGF, IGF), were measured in cervical-vaginal lavage (CVL) using ELISA. Linear regression was used to model association of biomarkers with depression and abuse as predictor variables; the interaction between depression and abuse was also tested. Anti-HIV activity in CVL was tested using TZM-bl indicator cell line. In HIV-uninfected women, median levels of IL-6 (p = 0.04), IL-1α (p<0.01), TGF-β (p = 0.01), IP-10 (p = <0.01), PDGF (p<0.01) and FGF (p<0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased IL-1α (p<0.01), MIP-3α (p = 0.04), IP-10 (p<0.01), Serpin B1 (p = 0.01), FGF (p = 0.04) and decreased TGF-β (p<0.01), MCP-1 (p = 0.02), PDGF (p<0.01). Further, there was evidence of significant interactions between chronic sexual abuse and current depression for IL-1α, IP-10, Serpin A1, Cystatin B, and FGF. In HIV-infected women, median levels of TNF-α (p<0.01), IL-6 (p = 0.05), MIP-3α (p<0.01), and MCP-1 (p = 0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased MCP-1 (p = 0.03), Gro-α (p = 0.01) and decreased TNF-α (p<0.01), IL-1α (p = 0.02), MIP-3α (p<0.01) and Cathepsin B (p = 0.03). Current depressive symptoms were associated with significantly decreased MIP-3α (p<0.01). There was evidence of significant interactions between chronic sexual abuse and current depression for MCP-1 and FGF. No significant differences were observed in anti-HIV activity among all eight groups. Heat-map analyses revealed distinct immune network patterns, particularly in the Abuse groups for both HIV-infected and uninfected women. Our data indicates a complex relationship between chronic sexual abuse exposure, depressive symptoms, and FRT immune mediators that are also affected by HIV status. Association of chronic sexual abuse with increase in inflammation-associated cytokine/chemokine expression, along with impaired wound-healing associated growth-factors can create a microenvironment that can facilitate HIV infection. Evaluation of longitudinal changes in exposures and biomarkers are needed to untangle the immuno-biological mechanisms that may put women who endure life-long sexual abuse at increased risk for HIV.

Correlates of Bacterial Vaginosis Over Long-Term Follow-Up: Impact of HIV Infection

Abstract Correlates of bacterial vaginosis (BV) are poorly understood, especially in HIV infection. In a cohort study, HIV-seropositive and comparison seronegative women were assessed every 6 months during 1994–2015. BV was considered present when three of four Amsel criteria were met. Behavioral characteristics were assessed using structured interviews. Multivariable logistic regression used generalized estimating equation models to determine factors associated with BV. Cumulative incidence of BV over time was assessed using the log-rank test. Among 3,730 women (964 HIV seronegative and 2,766 HIV seropositive) contributing 70,970 visits, BV was diagnosed at 2,586 (14.0%) visits by HIV-seronegative women and 6,224 (11.9%) visits by HIV-seropositive women (p < .0001). The cumulative incidence of BV was 530/964 (55.0%) in HIV-seronegative women and 1,287/2,766 (46.5%) in seropositive women (p < .0001). In adjusted analyses, factors associated with BV were younger age, ethnicity, lower income, less education...

Correlates of bacterial vaginosis over long-term follow-up: Impact of human immunodeficiency virus infection

Correlates of bacterial vaginosis (BV) are poorly understood, especially in HIV infection. In a cohort study, HIV-seropositive and comparison seronegative women were assessed every 6 months during 1994-2015. BV was considered present when three of four Amsel criteria were met. Behavioral characteristics were assessed using structured interviews. Multivariable logistic regression used generalized estimating equation models to determine factors associated with BV. Cumulative incidence of BV over time was assessed using the log-rank test. Among 3,730 women (964 HIV seronegative and 2,766 HIV seropositive) contributing 70,970 visits, BV was diagnosed at 2,586 (14.0%) visits by HIV-seronegative women and 6,224 (11.9%) visits by HIV-seropositive women (p < .0001). The cumulative incidence of BV was 530/964 (55.0%) in HIV-seronegative women and 1,287/2,766 (46.5%) in seropositive women (p < .0001). In adjusted analyses, factors associated with BV were younger age, ethnicity, lower income, less education, recruitment site, recruitment in the 2001-2002 cohort, heavier drinking, current smoking, depression, and sex with a male partner; both hormonal contraception and menopause were negatively associated with BV. Of 533 women with prevalent BV, 228 (42.8%) recurred within a year, while persistent BV was found in 12.8% of participants; neither proportion differed by HIV serostatus. Time trends in the proportion of women with BV at any single visit were not identified. BV is common among women with and at risk for HIV, but HIV infection does not predispose to BV, which is associated instead with behavioral and cultural factors.