Maria Pyra

Effectiveness of hormonal contraception in HIV-infected women using antiretroviral therapy

Objective:The objective of this study is to assess whether antiretroviral therapy (ART) may diminish the effectiveness of hormonal contraceptive methods. Methods:Using data from 5153 HIV-infected women followed prospectively for 1–3 years in three HIV prevention studies in Africa, we compared incident pregnancy rates by contraceptive method (implant, injectable, oral or none) and ART use. Multivariable Cox regression models were used to determine adjusted hazard ratios (aHRs) and test interactions between each method and ART use. Results:During follow-up, 9% of women ever used implants, 40% used injectables and 14% used oral contraceptives; 31% of women ever used ART, mostly nevirapine (75% of ART users) or efavirenz-based (15%). Among women not using contraception, pregnancy rates were 13.2 and 22.5 per 100 women-years for those on and not on ART, respectively. Implants greatly reduced the incidence of pregnancy among both women on ART [aHR 0.06, 95% confidence interval (95% CI) 0.01–0.45] and not on ART (aHR 0.05, 95% CI 0.02–0.11). Injectables (aHR 0.18 on ART and aHR 0.20 not on ART) and oral contraceptives (aHR 0.37 on ART and aHR 0.36 not on ART) also reduced pregnancy risk, though by lesser degrees. ART use did not significantly diminish contraceptive effectiveness, although all methods showed nonstatistically significant reduced effectiveness when concurrently using efavirenz. Conclusion:Hormonal contraceptive methods are highly effective in reducing pregnancy risk in HIV-infected women, including those concurrently using ART. Studies of potential interactions between ART and contraceptives should evaluate real-world effectiveness of contraceptive methods; in this study, implants were the most effective method to prevent pregnancy, even during ART use.

Sexual minority women and depressive symptoms throughout adulthood

OBJECTIVES We examined the associations between depressive symptoms and sexual identity and behavior among women with or at risk for HIV. METHODS We analyzed longitudinal data from 1811 participants in the Womens Interagency HIV Study (WIHS) from 1994 to 2013 in Brooklyn and the Bronx, New York; Chicago, Illinois; Washington, DC; and Los Angeles and San Francisco, California, by comparing depressive symptoms by baseline sexual identity and ongoing sexual behavior. We controlled for age, socioeconomic status, violence history, and substance use. RESULTS In separate analyses, bisexual women and women who reported having sex with both men and women during follow-up had higher unadjusted odds of depressive symptoms compared with heterosexuals and women who reported only having male sexual partners (adjusted odd ratio [AOR] = 1.36; 95% confidence interval [CI]  = 1.10, 1.69 and AOR = 1.21; 95% CI = 1.06, 1.37, respectively). Age was a significant effect modifier in multivariable analysis; sexual minority women had increased odds of depressive symptoms in early adulthood, but they did not have these odds at midlife. Odds of depressive symptoms were lower among some sexual minority women at older ages. CONCLUSIONS Patterns of depressive symptoms over the life course of sexual minority women with or at risk for HIV might differ from heterosexual women and from patterns observed in the general aging population.

Sexual Minority Status and Violence Among HIV Infected and At-Risk Women

ABSTRACTIMPORTANCESexual minority women with and at-risk for human immunodeficiency virus (HIV) may face increased risks of violence.OBJECTIVETo understand the relationship between sexual minority status and violence; and how high-risk sex and substance use mediate that relationship among women with and at-risk for HIV.DESIGN & PARTICIPANTSLongitudinal study of 1,235 HIV infected and 508 uninfected women of the Womens Interagency HIV Study (WIHS) cohort, from New York City, NY, Chicago, IL, Washington D.C., and San Francisco, CA, 1994–2012.MAIN MEASURESPrimary exposures are sexual identity (heterosexual, bisexual, lesbian/gay) and sexual behavior (male, female, or male & female partners). Primary outcomes are sexual abuse, intimate partner violence (IPV) and physical violence; high-risk sex and substance use were examined as mediators.KEY RESULTSBisexual women were at increased odds for sexual abuse [aOR 1.56 (1.00, 2.44)], IPV [aOR 1.50 (1.08, 2.09)], and physical violence [aOR 1.77 (1.33, 2.37)] compared to heterosexual women. In a separate analysis, women who reported sex with men and women (WSMW) had increased odds for sexual abuse [aOR 1.65 (0.99, 2.77], IPV [aOR 1.50 (1.09, 2.06)] and physical violence [aOR 2.24 (1.69, 2.98)] compared to women having sex only with men (WSM). Using indirect effects, multiple sex partners, cocaine and marijuana were significant mediators for most forms of abuse. Transactional sex was only a mediator for bisexual women. Women who reported sex only with women (WSW) had lower odds of sexual abuse [aOR 0.23 (0.06, 0.89)] and physical violence [aOR 0.42 (0.21, 0.85)] compared to WSM.CONCLUSIONSWomen who identify as bisexual or report both male and female sex partners are most vulnerable to violence; multiple recent sex partners, transactional sex and some types of substance use mediate this relationship. Acknowledging sexual identity and behavior, while addressing substance use and high-risk sex in clinical and psychosocial settings, may help reduce violence exposure among women with and at-risk for HIV.

Effect of Pregnancy on Response to Antiretroviral Therapy in HIV-Infected African Women

Background: While most recent evidence does not support a role for pregnancy in accelerating HIV disease progression, very little information is available on the effects of incident pregnancy in response to antiretroviral therapy (ART). Hormonal, immune, and behavioral changes during pregnancy may influence response to ART. We sought to explore the effects of incident pregnancy (after ART initiation) on virologic, immunologic, and clinical response to ART. Methods: Data were collected from HIV-infected women participating in 3 prospective studies (Partners in Prevention Herpes simplex virus/HIV Transmission Study, Couples Observational Study, and Partners Preexposure Prophylaxis Study) from 7 countries in Africa from 2004 to 2012. Women were included in this analysis if they were ⩽45 years of age, were started on ART during the study and were not pregnant at ART initiation. Pregnancy was treated as a time-dependent exposure variable covering the duration of pregnancy, including all pregnancies occurring after ART initiation. Virologic failure was defined as a viral load (VL) greater than 400 copies per milliliter ≥6 months after ART initiation and viral suppression was defined as VL ⩽400 copies per milliliter. Multivariable Cox proportional hazards models were used to assess the association between pregnancy and time to viral suppression, virologic failure, World Health Organization clinical stage III/IV, and death. Linear mixed-effects models were used to assess the association between pregnancy and CD4+ count and VL. All analyses were adjusted for confounders, including pre-ART CD4+ count and plasma VL. Results: A total of 1041 women were followed, contributing 1196.1 person-years of follow-up. Median CD4+ count before ART initiation was 276 cells per cubic millimeter (interquartile range, 209–375); median pre-ART VL was 17,511 copies per milliliter (interquartile range, 2480–69,286). One hundred ten women became pregnant after ART initiation. Pregnancy was not associated with time to viral suppression (adjusted hazard ratio [aHR], 1.20, 95% confidence interval [CI]: 0.82 to 1.77), time to virologic failure (aHR, 0.67, 95% CI: 0.37 to 1.22), time to World Health Organization clinical stage III or IV (aHR, 0.79, 95% CI: 0.19 to 3.30), or time to death (aHR, 2.04, 95% CI: 0.25 to 16.8). Incident pregnancy was associated with an adjusted mean decrease in CD4+ T-cell count of 47.3 cells per cubic millimeter (P < 0.001), but not with difference in VL (P = 0.06). Conclusions: For HIV-infected women on ART, incident pregnancy does not affect virologic control or clinical HIV disease progression. A modest decrease in CD4+ T-cell count could be due to physiologic effects of pregnancy.

HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis

ABSTRACT Although nonhuman primate studies have shown that simian immunodeficiency virus/simian-human immunodeficiency virus (SIV/SHIV) exposure during preexposure prophylaxis (PrEP) with oral tenofovir can induce SIV immunity without productive infection, this has not been documented in humans. We evaluated cervicovaginal IgA in Partners PrEP Study participants using a subtype C primary isolate and found that women on PrEP had IgA with higher average human immunodeficiency virus type 1 (HIV-1)-neutralizing magnitude than women on placebo (33% versus 7%; P = 0.008). Using a cutoff of ≥90% HIV-1 neutralization, 19% of women on-PrEP had HIV-1-neutralizing IgA compared to 0% of women on placebo (P = 0.09). We also estimated HIV-1 exposure and found that the proportion of women with HIV-1-neutralizing IgA was associated with the level of HIV-1 exposure (P = 0.04). Taken together, our data suggest that PrEP and high levels of exposure to HIV may each enhance mucosal HIV-1-specific humoral immune responses in sexually exposed but HIV-1-uninfected individuals. IMPORTANCE Although there is not yet an effective HIV-1 vaccine, PrEP for at-risk HIV-1-uninfected individuals is a highly efficacious intervention to prevent HIV-1 acquisition and is currently being recommended by the CDC and WHO for all individuals at high risk of HIV-1 acquisition. We previously demonstrated that PrEP use does not enhance peripheral blood HIV-1-specific T-cell responses in HIV-exposed individuals. Here, we evaluate for cervicovaginal HIV-neutralizing IgA responses in genital mucosal secretions of HIV-exposed women, which is likely a more relevant site than peripheral blood for observation of potentially protective immune events occurring in response to sexual HIV-1 exposure for various periods. Furthermore, we assess for host response in the context of longitudinal quantification of HIV-1 exposure. We report that HIV-neutralizing IgA is significantly correlated with higher HIV-1 exposure and, furthermore, that there are more women with HIV-1-neutralizing IgA in the on-PrEP group than in the placebo group.

Concordance of self-reported hormonal contraceptive use and presence of exogenous hormones in serum among African women

OBJECTIVES Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV. STUDY DESIGN We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography-mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use. RESULTS Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had ≥1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status. CONCLUSION Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health outcomes. IMPLICATIONS Research studies investigating associations between hormonal contraceptive use and HIV should consider validating self-reported use by objective measures; because both overreporting and underreporting of use occur, potential misclassification based on self-report could lead to biased results in directions that cannot be easily predicted.

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.

Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS

OBJECTIVE The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) and apply this method to human serum samples. STUDY DESIGN We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. We analyzed serum collected from women self-reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). RESULTS Limits of quantitation were 0.010ng/mL for E2, EE2 and P4; 0.020ng/mL for ENG, LNG and MPA; and 0.040ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%-108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. CONCLUSIONS We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. IMPLICATIONS This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing.

Prevalence, Magnitude, and Correlates of HIV-1 Genital Shedding in Women on Antiretroviral Therapy

Background Genital human immunodeficiency virus (HIV) RNA shedding can continue despite HIV being undetectable in blood, and can be associated with transmission. Methods We included African women on antiretroviral therapy (ART). Linear and generalized linear mixed models were used to compare the magnitude and prevalence of genital shedding, respectively, by time since ART initiation. Multivariable logistic regression with generalized estimating equations was used to assess predictors of genital shedding among women with undetectable plasma viral load (VL). Results Among 1114 women, 5.8% of visits with undetectable plasma VL and 23.6% of visits with detectable VL had genital shedding. The proportion of visits with genital shedding decreased with time since ART initiation but the magnitude of shedding remained unchanged when plasma VL was undetectable (P = .032). Prevalence of shedding did not vary by time since ART initiation when plasma VL was detectable (P = .195), though the magnitude of shedding significantly increased (P = .04). Predictors of genital shedding were HIV disease stage, antiretroviral regimen, and genital ulcers or cervical tenderness. Discussion In addition to ART, reducing immune activation through prevention and treatment of HIV-related conditions and genital tract infections may decrease the risk of HIV-1 shedding and potential transmission.

Correction for Lund et al., HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis.

Volume 90, no. 21, p. 9855-9861, 2016, https://doi.org/10.1128/JVI.01482-16. Page 9858, Fig. 1: Treatment Group colors are incorrect in the key at the bottom of the figure. Colors indicating Placebo, Post-PrEP, and On PreP groups should be blue, yellow, and green, respectively.