Post-randomization Differences in Condomless Vaginal Sex Among Women Randomized to Intramuscular Depot Medroxyprogesterone Acetate Injections, a Copper Intrauterine Device or a Levonorgestrel Implant in the ECHO Trial.

The Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial found no substantial difference in HIV acquisition risk between women randomised to injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. We evaluated post-randomization sexual behavior using an objective marker of condomless vaginal sex in a subset of participants. We conducted a sub-study among 458 ECHO participants at three sites (Cape Town, Johannesburg, Kisumu) to evaluate the frequency of condomless vaginal sex, measured by prostate specific antigen (PSA) detection in vaginal swabs, collected at the month 6 and final visit and the concordance of self-reported condomless vaginal sex with PSA detection, by randomized arm. We compared PSA detection frequency and concordance of PSA and self-reported condomless vaginal sex, by randomized group using Cochran-Mantel-Haenszel tests and adjusted generalized logistic growth curve models. PSA was detected less frequently in the DMPA-IM (16%), compared to the Cu-IUD (21%) and LNG implant (24%) groups, although results were not statistically significant in the unadjusted model when accounting for pre-specified multiple-testing criteria. There were significant differences in PSA detection between the DMPA-IM and LNG-implant groups (odds ratio 0.61 (95% CI 0.40, 0.94) in the adjusted model. There was moderate discordance between self-reported condomless vaginal sex and detection of PSA that was similar across randomized groups. These data suggest that women randomized to Cu-IUD and LNG implant may have had condomless sex more frequently than women randomized to DMPA-IM. The discordance between detectable PSA and self-reported sexual behaviour has important implications for design of future HIV prevention studies.

ART initiation among women newly diagnosed with HIV in a contraceptive trial in sub-Saharan Africa.

Current guidelines recommend starting antiretroviral therapy (ART) as soon as possible after HIV diagnosis to reduce morbidity, mortality and onward HIV transmission. We examined factors influencing ART initiation by women who seroconverted during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. ECHO, conducted between 2015 and 2018, enrolled HIV-negative, sexually active women, aged 16-35 years, from four African countries. Follow-up was 12-18 months, with quarterly HIV testing. Women with incident HIV infection received extensive counselling by trial staff and referral to local facilities for HIV care. Of 304 women with ≥90 days follow-up time since HIV diagnosis, 186(61.2%) initiated ART within 90 days, 69(22.7%) initiated after 90 days, and 49(16.1%) had not initiated by the end of the study. There were no statistically significant differences in characteristics among women who initiated ART ≤90 days versus those who did not. Frequent reasons for delayed or non-initiation of ART included not feeling ready to start ART and being newly diagnosed. In a large clinical trial, ART initiation was modest within 90 days of HIV diagnosis and grew to 84% with longer observation. Despite extensive counselling on the importance of early ART initiation, personal barriers delayed some women from starting ART.

What's Sex Got to Do With It? Understanding Potential Confounding and Exposure Misclassification in Mechanistic Sexually Transmitted Infection Research.

We conducted a prospective study of 13 heterosexual couples to understand the impact of recent condomless vaginal sex on vaginal immune marker measurement and potential exposure misclassification due to the presence of semen. All immune markers were detectable in semen and concentrations of vaginal immune markers varied by sex recency.

Sexually transmitted infections among women randomised to depot medroxyprogesterone acetate, a copper intrauterine device or a levonorgestrel implant.

OBJECTIVES: Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods. METHODS: We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16-35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression. RESULTS: At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group (PR 0.83, 95% CI 0.72 to 0.95). Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups (PR 0.67, 95% CI 0.52 to 0.87). CONCLUSIONS: The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use.

Recent Advances and New Challenges in Cisgender Women's Gynecologic and Obstetric Health in the Context of HIV.

Although rates of human immunodeficiency virus (HIV) have declined globally over the past 10 years, United Nations Programme on HIV/AIDS estimates 1.7 million new infections occurred in 2019, with cisgender women (cis women) and girls accounting for 48%. Acquired immune deficiency syndrome-related illnesses are the leading global cause of mortality in cis women aged 15 to 49, and in many sub-Saharan Africa countries, young women face substantially higher HIV risk than their male counterparts. Drivers of this increased risk include sexual and reproductive health characteristics unique to cis women. This review discusses the role of sexually transmitted infections, contraception and pregnancy in HIV risk, and biomedical HIV prevention technologies available and in development.

Inflammatory cytokine biomarkers of asymptomatic sexually transmitted infections and vaginal dysbiosis: a multicentre validation study.

OBJECTIVES: Vaginal dysbiosis and STIs are important drivers of the HIV epidemic and reproductive complications. These conditions remain prevalent, partly because most cases are asymptomatic. We have shown that inflammatory cytokines interleukin (IL)-1α, IL-1ß and interferon-γ-induced protein (IP)-10 are biomarkers for detecting asymptomatic STIs and vaginal dysbiosis (bacterial vaginosis (BV) or intermediate microbiota). This study aimed to validate the performance of these biomarkers in African women recruited regardless of symptoms. METHODS: IL-1α, IL-1ß and IP-10 were measured in menstrual cup secretions, endocervical, lateral vaginal wall and vulvovaginal swabs from 550 women from Pretoria, Soweto and Cape Town, South Africa and Bondo, Kenya using Luminex and ELISA. STIs were assessed by PCR, BV by Nugent scoring and vaginal microbiota by 16S rRNA sequencing. RESULTS: Across four study populations and four types of genital specimens, the performance of IL-1α, IL-1ß and IP-10 for identification of women with STIs, BV or intermediate microbiota was consistent. Of the genital samples assessed, biomarkers measured in lateral vaginal wall swabs performed best, correctly classifying 76%(95% CI 70% to 81%) of women according to STI, BV or intermediate microbiota status (sensitivity 77%, specificity 71%) and were more accurate than clinical symptoms (sensitivity 41%, specificity 57%) (p=0.0003). Women incorrectly classified as STI/BV positive using the biomarkers had more abundant dysbiosis-associated bacteria, including Prevotella bivia and Gardnerella sp, detected by 16S rRNA sequencing, but not Nugent scoring. Including vaginal pH with the cytokine biomarkers improved the accuracy of the test (82% (95% CI 75% to 88%) correctly classified), although pH alone had poor specificity (61%). CONCLUSIONS: An inexpensive, point-of-care screening test including IL-1α, IL-1ß and IP-10 (and potentially pH) could be used in resource-limited settings to identify women with asymptomatic STIs and dysbiosis. These women could then be referred for aetiological testing, followed by specific treatment.

Preexposure prophylaxis for HIV infection among African women.

BACKGROUND: Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety. RESULTS: HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. CONCLUSIONS: Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).

Intermediate vaginal flora and bacterial vaginosis are associated with the same factors: findings from an exploratory analysis among female sex workers in Africa and India.

OBJECTIVES: Several recent studies suggest that intermediate vaginal flora (IVF) is associated with similar adverse health outcomes as bacterial vaginosis (BV). Yet, it is still unknown if IVF and BV share the same correlates. We conducted a cross-sectional and exploratory analysis of data from women screened prior to enrolment in a microbicide trial to estimate BV and IVF prevalence and examine their respective correlates. METHODS: Participants were interviewed, examined and provided blood and genital samples for the diagnosis of IVF and BV (using Nugent score) and other reproductive tract infections. Polytomous logistic regressions were used in estimating respective ORs of IVF and BV, in relation to each potential risk factor. RESULTS: Among 1367 women, BV and IVF prevalences were 47.6% (95% CI 45.0% to 50.3%) and 19.2% (95% CI 17.1% to 21.2%), respectively. Multivariate polytomous analysis of IVF and BV showed that they were generally associated with the same factors. The respective adjusted ORs were for HIV 1.98 (95% CI 1.37 to 2.86) and 1.62 (95% CI 1.20 to 2.20) (p=0.2248), for gonorrhoea 1.25 (95% CI 0.64 to 2.4) and 2.01 (95% CI 1.19 to 3.49) (p=0.0906), for trichomoniasis 3.26 (95% CI 1.71 to 6.31) and 2.39 (95% CI 1.37 to 4.33) (p=0.2630), for candidiasis 0.52 (95% CI 0.36 to 0.75) and 0.59 (95% CI 0.44 to 0.78) (p=0.5288), and for hormonal contraception 0.65 (95% CI 0.40 to 1.04) and 0.62 (95% CI 0.43 to 0.90) (p=0.8819). In addition, the association between vaginal flora abnormalities and factors such as younger age, HIV, gonorrhoea trichomoniasis and candidiasis were modified by the study site (all p for interaction ≤0.05). CONCLUSIONS: IVF has almost the same correlates as BV. The relationship between some factors and vaginal flora abnormalities may be site-specific.

True and false positive HIV point of care test results in a prospective multinational study of at-risk African women: implications for large-scale repeat HIV testing in HIV prevention programs.

BACKGROUND: Accurate HIV point of care testing is the cornerstone of prevention and treatment efforts globally, though false (both negative and positive) results are expected to occur. SETTING: We assessed the spectrum of true and false positive HIV results in a large prospective study of HIV incidence in African women using three contraceptive methods tested longitudinally in Eswatini, Kenya, South Africa, and Zambia. METHODS: HIV serologic testing was conducted quarterly using two parallel rapid HIV tests. When one or both tests were positive, additional confirmatory testing was conducted, including HIV enzyme immunoassay (EIA) and ribonucleic acid (RNA). RESULTS: 7730 women contributed 48,234 visits: true positive results occurred at 412 visits (0.9%) and false positives at 96 visits (0.2%). Of 412 women with HIV seroconversion, 10 had discordant (i.e., one negative and one positive) rapid tests and 13 had undetectable HIV RNA levels. Of 62 women with false positive rapid HIV results, most had discordant rapid testing but six (9.7%) had dually-positive rapid results and four (6.5%) had false positive or indeterminate EIA results. The positive predictive value of dual positive rapid results was 98.3%. CONCLUSION: Although the majority of rapid test results were accurate, false positive results were expected and occurred in this population of initially HIV seronegative individuals tested repeatedly and prospectively. When HIV infection occurred, not all cases had textbook laboratory results. Our findings highlight the importance of confirmatory testing, particularly for individuals undergoing repeat testing and in settings where the point prevalence is expected to be low.

Behavioural and medical predictors of bacterial vaginosis recurrence among female sex workers: longitudinal analysis from a randomized controlled trial.

BACKGROUND: Data on risk factors of recurrent bacterial vaginosis (RBV) are still scarce. We used data from female sex workers (FSW) participating in a randomized controlled microbicide trial to examine predictors of BV recurrence. METHODS: Trial's participants with at least an episode of BV which was treated and/or followed by a negative BV result and at least one subsequent visit offering BV testing were included in the analysis. Behavioural and medical data were collected monthly while laboratory testing for STI and genital tract infections were performed quarterly. The Andersen-Gill proportional hazards model was used to determine predictors of BV recurrence both in bivariate and multivariate analyses. RESULTS: 440 women were included and the incidence rate for RBV was 20.8 recurrences/100 person-months (95% confidence interval (CI) =18.1-23.4). In the multivariate analysis controlling for the study site, recent vaginal cleansing as reported at baseline with adjusted hazard-ratio (aHR)=1.30, 95% CI = 1.02-1.64 increased the risk of BV recurrence, whereas consistent condom use (CCU) with the primary partner (aHR=0.68, 95% CI=0.49-0.93) and vaginal candidiasis (aHR=0.70, 95% CI=0.53-0.93), both treated as time-dependent variables, were associated with decreased risk of RBV. CONCLUSION: This study confirms the importance of counselling high-risk women with RBV about the adverse effects of vaginal cleansing and the protective effects of condom use with all types of partners for the prevention of sexually transmitted infections, including BV. More prospective studies on risk factors of BV recurrence are warranted. TRIAL REGISTRATION: Trial registration: NCT00153777.

Prevalence and incidence of sexually transmitted infections among South African women initiating injectable and long-acting contraceptives.

BACKGROUND: South Africa is among the countries with the highest prevalence of sexually transmitted infections (STIs), including Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). In 2017, there were an estimated 6 million new CT, 4.5 million NG and 71 000 Treponema pallidum infections among South African men and women of reproductive age. METHODS: We evaluated STI prevalence and incidence and associated risk factors in 162 women aged 18-33 years old, residing in eThekwini and Tshwane, South Africa who were part of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. Women were randomised to use depot medroxyprogesterone acetate (n = 53), copper intrauterine device (n = 51), or levonorgestrel (n = 58) implant. Lateral vaginal wall swab samples were collected prior to contraceptive initiation and at months one and three following contraceptive initiation for STI testing. RESULTS: There were no significant differences in STI incidence and prevalence across contraceptive groups. At baseline, 40% had active STIs (CT, NG, Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) or herpes simplex virus-2 shedding across all age groups- 18-21 years (46%), 22-25 years (42%) and 26-33 years (29%). The incidence of STIs during follow-up was exceptionally high (107.9/100 women-years [wy]), with younger women (18-21 years) more likely to acquire CT (75.9/100 wy) compared to 26-33 year olds (17.4/100 wy; p = 0.049). TV incidence was higher in the 26-33 year old group (82.7/100 wy) compared to the 18-21 year olds (8.4/100 wy; p = 0.01). CONCLUSIONS: Although the study participants received extensive counselling on the importance of condom use, this study highlights the high prevalence and incidence of STIs in South African women, especially amongst young women, emphasising the need for better STI screening and management strategies.

Intermediate vaginal flora is associated with HIV prevalence as strongly as bacterial vaginosis in a cross-sectional study of participants screened for a randomised controlled trial.

OBJECTIVE: The authors analysed data from female sex workers screened prior to participation in a microbicide trial to examine the association between prevalent vaginal flora abnormalities and HIV infection, with special emphasis on the role of the intermediate vaginal flora (IVF) in this association. METHODS: Data from the Kampala, Cotonou, Chennai and Mudhol/Jamkhandi sites were analysed. Participants were interviewed and provided blood for HIV and syphilis antibody testing, genital samples for the diagnosis of vaginal flora abnormalities (using Nugent score) and other reproductive tract infections. Log-binomial regression was used to estimate the HIV prevalence ratio (PR) in relation to IVF and bacterial vaginosis (BV). RESULTS: Among 1367 women, BV, IVF and HIV prevalences were 47.6% (95% CI=45.0% to 50.3%), 19.2% (95% CI=17.1% to 21.2%) and 27.0% (95% CI=24.6% to 29.3%), respectively. In multivariate analysis, adjusting for study site, age, years of education, occupation, female sterilisation, oral sex, past history of sexually transmitted infection, gonorrhoea and candidiasis, IVF was significantly associated with HIV infection with a PR similar to that of BV (adjusted PR=1.56 (95% CI=1.22 to 1.98) and 1.48 (95% CI=1.20 to 1.84), respectively). CONCLUSIONS: Though the cross-sectional design of the study precludes directional interpretation of the findings, the data do suggest that IVF may be as important as BV in HIV acquisition. The authors recommend prospective research to better understand the association between IVF and HIV acquisition.

Return to ovulation after Sayana Press is injected every 4 months for one year: Empirical and pharmacokinetic/pharmacodynamic modeling results.

Objective: To characterize return to ovulation after injecting Sayana Press (104 mg/0.65 mL medroxyprogesterone acetate [MPA] in the Uniject device) every 4 months for 1 year of treatment. Study design: We followed a subset of women for return to ovulation in a trial that demonstrated Sayana Press remains highly effective when the subcutaneous reinjection interval is extended from 3 to 4 months. We measured serum progesterone in weeks 38 to 42 and 46 to 50 after a final (third) injection and used a concentration ≥4.7 ng/mL as a surrogate for ovulation. We also performed pharmacokinetic and pharmacodynamic modeling to predict differences in MPA accumulation and return to ovulation had - contrary to fact - injections been given every 3 months. Results: Ten of 19 women (53%; 95% confidence interval: 29-76) ovulated within 50 weeks of their last injection. We predicted that typical 12-month trough MPA concentrations are 34% lower (0.46 vs 0.69 ng/mL) and the median time from last dose to ovulation is 1.1 months shorter (13.1 vs 14.2 months) when injections are given every four months for 1 year. Conclusion: Extending the Sayana Press reinjection interval from 3 to 4 months leads to less drug accumulation, without a noticeable loss in efficacy. Although the Sayana Press patient leaflet specifies that over 80% of women desiring pregnancy will conceive within a year of stopping the method (independent of treatment duration), our empirical and modeling results indicate women should anticipate waiting a year or more for fertility to return after repeat dosing, with a somewhat shorter delay were the reinjection interval extended to four months. Implications: Providers should counsel women regarding the distinct possibility that return to fertility will take a year or longer following repeat use of Sayana Press. Extending the dosing interval from 3 to 4 months would result in approximately a 1-month shorter delay, without any appreciable reduction in contraceptive efficacy.

Acceptability of the contraceptive Sayana® Press when injected every four months: Results from a twelve-month trial in Brazil, Chile and the Dominican Republic.

OBJECTIVE: We assessed the acceptability of subcutaneous depot-medroxyprogesterone acetate 104 mg (Sayana® Press) when injected every 4 months for 12 months. STUDY DESIGN: We assessed acceptability using questionnaires within a clinical trial to evaluate contraceptive effectiveness of Sayana® Press when the reinjection interval was extended from 3 to 4 months. We enrolled 750 women aged 18 to 35 years and at risk of pregnancy at 3 centers in Brazil, Chile, and the Dominican Republic who agreed to use Sayana® Press every 4 months for 12 months. Acceptability outcomes included responses to questions about perception of bleeding patterns and side effects, likes, and dislikes about the regimen. We descriptively compared outcomes across study centers and between those who completed the study and those who discontinued early. RESULTS: Across the 3 centers, participants differed in age, marital status, years of schooling, and race. At the final visit, 90% reported being satisfied with Sayana® Press and 75% reported preferring to use this contraceptive every 4 months. The most common reasons women liked using Sayana® Press were for its duration of effectiveness, followed by amenorrhea. The most common dislike, when a reason was identified, was its effect on uterine bleeding, including amenorrhea reported by some participants. We also observed center-level differences in the proportion of women who liked amenorrhea. CONCLUSIONS: Satisfaction with Sayana® Press injected every 4 months was high across the 3 demographically diverse Latin-American centers. However, participants had varied feelings towards contraceptive-induced amenorrhea. IMPLICATIONS: We found that Sayana® Press when injected every 4 months was highly acceptable among women in 3 Latin American settings despite differences in their feelings toward contraceptive-induced amenorrhea. Our results suggest that there will be interest in using this method every 4 months if introduced into these settings.

Contraceptive effectiveness, pharmacokinetics, and safety of Sayana® Press when injected every four months: a multicenter phase 3 trial.

BACKGROUND: Sayana Press® is a 3-monthly contraceptive injection approved by regulatory agencies in more than 40 countries worldwide. Existing effectiveness and pharmacokinetics (PK) data suggest that high contraceptive efficacy may be maintained if the reinjection interval of Sayana Press is extended from 3 to 4 months. METHODS: We conducted a phase 3 trial at three sites in the Dominican Republic, Brazil, and Chile from September 2017 through April 2020. We enrolled 750 women at risk of pregnancy who agreed to use Sayana Press off-label every 4 months (3 treatment cycles) for 12 months. The effectiveness cohort included 710 participants randomized equally to receive injections in the abdomen or thigh. Forty additional participants received injections in the back of the upper arm for comparative PK analyses. The primary outcome was pregnancy, defined by a positive urine pregnancy test confirmed by ultrasound and/or serum human chorionic gonadotropin. Secondary outcomes included PK, safety, and acceptability. Laboratory and trial Sponsor staff were blind to injection site. This study is registered with ClinicalTrials.gov, number NCT03154125. FINDINGS: There were no pregnancies during follow-up; the Pearl Index during 629.3 woman-years (WY) of follow-up in the primary effectiveness analysis was 0.00 (95% CI 0.00, 0.59). Pharmacokinetic profiles differed by injection site, with higher geometric mean (GM) medroxyprogesterone acetate concentrations for the abdomen than the thigh and arm. At month 8, significantly higher GM concentrations were observed in the abdomen and the thigh as compared to the arm, as well as at month 12 in the abdomen as compared to the arm. Injection site reactions were reported by 10.7% of participants. INTERPRETATION: Both pregnancy and PK results confirm that Sayana Press is a highly effective contraceptive method when administered every 4 months. These findings may inform modification of the dosing schedule, or duration of the grace period for reinjection, or both, to reduce overall drug exposure while maintaining contraceptive efficacy. FUNDING: This work is made possible by the generous support of the American people through the U.S. Agency for International Development (USAID), provided to FHI 360 through Cooperative Agreement AID-OAA-A-15-00,045, and a grant from the Gates Foundation. The contents are the responsibility of FHI 360 and do not necessarily reflect the views of USAID, the United States Government, or the Gates Foundation, nor does any mention of trade names, commercial products, or organizations imply endorsement by FHI 360, USAID, the United States Government, or the Gates Foundation.

Genital inflammatory status and the innate immune response to contraceptive initiation.

PROBLEM: Data on the effects of contraceptives on female genital tract (FGT) immune mediators are inconsistent, possibly in part due to pre-existing conditions that influence immune mediator changes in response to contraceptive initiation. METHODS: This study included 161 South African women randomised to injectable depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD), or levonorgestrel (LNG) implant in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. We measured thirteen cytokines and antimicrobial peptides previously associated with HIV acquisition in vaginal swabs using Luminex and ELISA, before, and at 1 and 3 months after contraceptive initiation. Women were grouped according to an overall baseline inflammatory profile. We evaluated modification of the relationships between contraceptives and immune mediators by baseline inflammation, demographic, and clinical factors. RESULTS: Overall, LNG implant and copper IUD initiation were associated with increases in inflammatory cytokines, while no changes were observed following DMPA-IM initiation. However, when stratifying by baseline inflammatory profile, women with low baseline inflammation in all groups experienced significant increases in inflammatory cytokines, while those with a high baseline inflammatory profile experienced no change or decreases in inflammatory cytokines. CONCLUSION: We conclude that pre-contraceptive initiation immune profile modifies the effect of contraceptives on the FGT innate immune response.

Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission.

BACKGROUND: Women make up more than 50% of adults living with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa. Thus, female-initiated HIV prevention methods are urgently needed. METHODS: We performed a randomized, double-blind, placebo-controlled trial of cellulose sulfate, an HIV-entry inhibitor formulated as a vaginal gel, involving women at high risk for HIV infection at three African and two Indian sites. The primary end point was newly acquired infection with HIV type 1 or 2. The secondary end point was newly acquired gonococcal or chlamydial infection. The primary analysis was based on a log-rank test of no difference in the distribution of time to HIV infection, stratified according to site. RESULTS: A total of 1398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P=0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.02 [corrected]; P=0.05 [corrected]) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P=0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08). CONCLUSIONS: Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition. (ClinicalTrials.gov number, NCT00153777; and Current Controlled Trials number, ISRCTN95638385.)

Age-Specific Risk Scores Do Not Improve HIV-1 Prediction Among Women in South Africa.

BACKGROUND: HIV-1 risk scoring tools could help target provision of prevention modalities such as pre-exposure prophylaxis. Recent research suggests that risk scores for women aged 18-45 may not predict risk well among young women aged 18-24. We evaluated the predictive performance of age-specific risk scores compared with the existing non-age-specific VOICE risk score, developed for women aged 18-45. METHODS: We conducted a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes Trial to develop and internally validate HIV-1 risk scores for women aged 18-24 and 25-35 in South Africa. Candidate predictors included baseline demographic, clinical, behavioral, and contextual characteristics readily available in clinical settings. The VOICE risk score was applied to women aged 18-35. We evaluated predictive performance of each risk score by area under the receiver operating characteristic curve (AUC). RESULTS: Predictive performance of all risk scores was moderate, with AUC (95% confidence interval) of 0.64 (0.60 to 0.67) among women aged 18-24, 0.68 (0.62 to 0.73) among those aged 25-35, and 0.61 (0.58 to 0.65) for the VOICE risk score applied to women aged 18-35; The AUC was similar in internal validation. Among women aged 18-24, HIV-1 incidence was high even at low risk scores, at 3.9 per 100 person-years (95% confidence interval: 3.2 to 4.7). CONCLUSIONS: All risk scores were moderately predictive of HIV-1 acquisition, and age-specific risk scores performed only marginally better than the VOICE non-age-specific risk score. Approaches for targeted pre-exposure prophylaxis provision to women in South Africa may require more extensive data than are currently available to improve prediction.

Contraceptive use and the risk of sexually transmitted infection: systematic review and current perspectives.

PURPOSE: Evidence on the association between contraceptive use and risk of sexually transmitted infections (STIs) and bacterial vaginosis (BV) is lacking, with few prospective studies. We systematically reviewed the last 10 years' evidence on the association between contraception and STI/BV, building on the most recent systematic reviews published in 2006 and 2009. METHODS: We searched the MEDLINE and POPLINE databases for peer-reviewed articles p ublished between January 1, 2008 and January 31, 2018 reporting prospective studies that assessed the association between contraceptive use and incident STI and/or incident or recurrent BV. RESULTS: We identified 33 articles that evaluated combined oral contraceptives (COC), depot medroxyprogesterone acetate (DMPA), the copper intrauterine device (Cu-IUD), the levonorgestrel intrauterine system (LNG-IUS) and other methods. The strength of the evidence for many specific contraceptive method/STI associations is limited by few prospective studies with comparably defined exposures and outcomes. Available data suggest no association of COCs and Neisseria gonorrhoeae, Trichomonas vaginalis, HSV-2 or syphilis, and mixed evidence on the association with HPV, Chlamydia trachomatis, and BV. For DMPA, none of the studies identified found an association with N. gonorrhoeae or syphilis, and data on C. trachomatis, T. vaginalis, HPV and BV were mixed. Two large studies showed a highly clinically significant increased risk of HSV-2 infection with DMPA use. Data on the effect of Cu-IUD and the LNG-IUS on the acquisition of C. trachomatis, N. gonorrhoeae and T. vaginalis are sparse, and data on HPV and BV are mixed. CONCLUSION: Few data are available from prospective studies, including randomized trials, to draw strong conclusions about the relationships between contraceptive methods and specific STIs. The overall evidence on the association between contraceptive use and STI/BV risk is limited by the lack of any randomized trials, few published prospective studies designed to analyze these associations, wide variability in exposure definitions and comparator groups, potential for confounding due to inaccurate sexual behavior data, differential confounder adjustment and differences in study populations and sizes. Despite these limitations, new evidence is supportive of a significantly increased risk of HSV-2 infection among DMPA users which warrants additional research to better understand this association.

A Longitudinal Assessment of Cervical Inflammation and Immunity Associated with HIV-1 Infection, Hormonal Contraception, and Pregnancy.

Hormonal contraception (HC), particularly injectable depot-medroxyprogesterone acetate (DMPA), has been associated with increased HIV acquisition and higher levels of cervical regulated upon activation, normal T-cell expressed, and secreted (RANTES), also associated with HIV seroconversion. Longitudinal changes in cervical immunity associated with DMPA and combined oral contraceptives (COCs) have not been studied. Cervical samples from 216 HIV seroconverters in Uganda and Zimbabwe with matched samples from 727 HIV-uninfected controls were collected at two quarterly visits before (t - 2, t - 1), at (t0), and two visits following (t + 1, t + 2) HIV seroconversion and corresponding visits for HIV-negative controls. We measured 10 biomarkers of inflammation and immunity and used generalized linear models to estimate and compare biomarker levels across HIV status, contraceptive, and pregnancy groups. Biomarkers remained relatively stable across visits for controls, while in HIV-infected women cervical immunity started to change before seroconversion with RANTES and BD-2 increased and secretory leukocyte protease inhibitor (SLPI) decreased at t - 1 and continued to change at t0 with ICAM-1 up and IL-8 down and with more biomarkers after seroconversion (IL-1ß, IL-6, MIP-3α, VEGF, and IL-1RA down and IL-1RA:IL-1ß ratio up). In multivariable analyses, seroconverters had higher BD-2 at t - 1, higher RANTES and lower SLPI from t - 1 through t + 2, and lower IL-8 and IL-1RA at and/or after seroconversion compared to nonseroconverters. Compared to non-HC users, DMPA users had higher RANTES at all visits and lower BD-2 at t - 2 through t0, while COC users and pregnant women had higher IL-8 and SLPI at all visits; COC users also had lower BD-2 preseroconversion; pregnant women had lower RANTES at t0 - t + 2. Longitudinal patterns of cervical immunity differ between HIV seroconverters and HIV-negative women; seroconverters demonstrate increased RANTES and decreased SLPI starting before and continuing postseroconversion. Furthermore, these patterns are differentially regulated by DMPA, COC, and pregnancy.