Trimethoprim-Sulfamethoxazole Plus Azithromycin to Prevent Malaria and Sexually Transmitted Infections in Pregnant Women With HIV (PREMISE): A Randomized, Double-Masked, Placebo-Controlled, Phase IIB Clinical Trial.

Background: This trial tested the effectiveness of a novel regimen to prevent malaria and sexually transmitted infections (STIs) among pregnant women with HIV in Cameroon. Our hypothesis was that the addition of azithromycin (AZ) to standard daily trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis would reduce malaria and STI infection rates at delivery. Methods: Pregnant women with HIV at gestational age <28 weeks were randomized to adjunctive monthly oral AZ 1 g daily or placebo for 3 days and both groups received daily standard oral TMP-SMX through delivery. Primary outcomes were (1) positive peripheral malaria infection by microscopy or polymerase chain reaction and (2) composite bacterial genital STI (Chlamydia trachomatis, Neisseria gonorrhoeae, or syphilis) at delivery. Relative risk and 95% confidence intervals were estimated using 2 × 2 tables with significance as P < .05. Results: Pregnant women with HIV (n = 308) were enrolled between March 2018 and August 2020: 155 women were randomized to TMP-SMX-AZ and 153 women to TMP-SMX-placebo. Groups were similar at baseline and loss to follow up was 3.2%. There was no difference in the proportion with malaria (16.3% in TMP-SMX-AZ vs 13.2% in TMP-SMX; relative risk, 1.24 [95% confidence interval, .71-2.16]) or STI at delivery (4.2% in TMP-SMX-AZ vs 5.8% in TMP-SMX; relative risk, 0.72 [95% confidence interval, .26-2.03]). Adverse birth outcomes were not significantly different, albeit lower in the TMP-SMX-AZ arm (preterm delivery 6.7% vs 10.7% [P = .3]; low birthweight 3.4% vs 5.4% [P = .6]). Conclusions: The addition of monthly azithromycin to daily TMP-SMX prophylaxis in pregnant women living with HIV in Cameroon did not reduce the risk of malaria or bacterial STI at delivery.

Urgent Need to Understand and Prevent Gonococcal Infection: From the Laboratory to Real-World Context.

Neisseria gonorrhoeae is widespread globally. Primary prevention is unsuccessful and antimicrobial resistance threatens optimal management. There is no specific vaccine and natural infection studies show that N. gonorrhoeae can avoid and suppress immune responses. In addition to extensive variation in expression and specificity of many gonococcal surface antigens, it induces a robust inflammatory response through the Th17 pathway with a large influx of neutrophils and inflammatory cytokines but evades macrophages. The Th1- and Th2-mediated response is suppressed, resulting in low, short-lived antibody titers. Real-world evidence suggests that gonorrhea cases are reduced among recipients of N. meningitidis group B vaccines containing outer membrane vesicles (OMV). Although the first randomized trial of an OMV-containing MenB vaccine against N. gonorrhoeae infection did not show statistically significant vaccine efficacy, ongoing trials might shed further light. Several candidate vaccine antigens for a gonococcal-specific vaccine are being evaluated preclinically but only one has reached clinical trials.

HIV Preexposure Prophylaxis With Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women.

Importance: Emtricitabine and tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP) is highly effective in cisgender men who have sex with men (MSM) when adherence is high (>4 doses/week). Real-world effectiveness and adherence with F/TDF for PrEP in cisgender women is less well characterized. Objective: To characterize the effectiveness of F/TDF for PrEP and its relationship with adherence in cisgender women. Design, Setting, and Participants: Data were pooled from 11 F/TDF PrEP postapproval studies conducted in 6 countries that included 6296 cisgender women aged 15 to 69 years conducted from 2012 to 2020. HIV incidence was evaluated according to adherence level measured objectively (tenofovir diphosphate concentration in dried blood spots or tenofovir concentration in plasma; n = 288) and subjectively (electronic pill cap monitoring, pill counts, self-report, and study-reported adherence scale; n = 2954) using group-based trajectory modeling. Exposures: F/TDF prescribed orally once a day. HIV incidence was analyzed in subgroups based on adherence trajectory. Main Outcomes and Measures: HIV incidence. Results: Of the 6296 participants, 46% were from Kenya, 28% were from South Africa, 21% were from India, 2.9% were from Uganda, 1.6% were from Botswana, and 0.8% were from the US. The mean (SD) age at PrEP initiation across all studies was 25 (7) years, with 61% of participants being younger than 25 years. The overall HIV incidence was 0.72 per 100 person-years (95% CI, 0.51-1.01; 32 incident HIV diagnoses among 6296 participants). Four distinct groups of adherence trajectories were identified: consistently daily (7 doses/week), consistently high (4-6 doses/week), high but declining (from a mean of 4-6 doses/week and then declining), and consistently low (less than 2 doses/week). None of the 498 women with consistently daily adherence acquired HIV. Only 1 of the 658 women with consistently high adherence acquired HIV (incidence rate, 0.13/100 person-years [95% CI, 0.02-0.92]). The incidence rate was 0.49 per 100 person-years (95% CI, 0.22-1.08) in the high but declining adherence group (n = 1166) and 1.27 per 100 person-years (95% CI, 0.53-3.04) in the consistently low adherence group (n = 632). Conclusions and Relevance: In a pooled analysis of 11 postapproval studies of F/TDF for PrEP among cisgender women, overall HIV incidence was 0.72 per 100 person-years; individuals with consistently daily or consistently high adherence (4-6 doses/week) to PrEP experienced very low HIV incidence.

Sexually Transmitted Infection Prevalence, Partner Notification, and Human Immunodeficiency Virus Risk Perception in a Cohort of Women Completing Sexually Transmitted Infection Screening as Part of a Safer Conception Study.

BACKGROUND: Integrating sexually transmitted infection (STI) and preexposure prophylaxis (PrEP) care may optimize sexual and reproductive health. METHODS: We nested an STI substudy within a human immunodeficiency virus (HIV) prevention cohort (parent study) of 18- to 35-year-old women from South Africa, planning pregnancy with a partner with HIV or of unknown serostatus. Parent-study women completed annual surveys regarding HIV-risk perceptions and were offered oral PrEP. Preexposure prophylaxis initiators completed quarterly plasma tenofovir (TFV) testing. Substudy women completed STI screening at enrollment, 6 months, onset of pregnancy, and in the third trimester via examination, vaginal swabs tested via PCR for Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis , Mycoplasma genitalium , and blood tested for Treponema pallidum . Follow-up was 6 months. Women with STIs were treated, offered partner notification (PN) cards, and surveyed regarding PN practices. We describe STI prevalence and incidence, and model factors associated with prevalent infection. Sexually transmitted infection substudy and parent study-only participants were matched on age and number of days on study to assess HIV-risk perception scores between the 2 groups and the proportion with detectable TFV. RESULTS: Among 50 substudy participants, 15 (30%) had prevalent STI. All 13 completing follow-up reported PN. Most did not prefer assisted PN. Mean HIV risk perception scores and proportion with detected plasma TFV were similar across groups. CONCLUSIONS: High STI prevalence supports the importance of laboratory screening to optimize sexual health for women planning pregnancy. Rates of self-reported PN are reassuring; low interest in assisted PN suggests the need for alternative approaches. Enhanced STI care did not affect HIV-risk perception or PrEP adherence, however both were relatively high in this cohort.

"Just the Stigma Associated with PrEP Makes You Feel Like It's HIV Itself": Exploring PrEP Stigma, Skepticism, and Medical Mistrust Among Black Cisgender Women in Urban and Rural Counties in the U.S. Deep South.

Despite its effectiveness in HIV prevention, PrEP use among Black women is suboptimal. Notably in the Deep South, Black women have the lowest PrEP uptake rates among all US regions. To increase PrEP engagement, research suggests the implementation of structural and social interventions particular to the needs of Black women. The state of Alabama is of priority to federal HIV prevention initiatives; therefore, this study conducted focus groups among 47 cis-gender Black women in rural and urban Alabama counties, with the highest statewide HIV incidence rates, to understand perceptions of PrEP and decision-making processes. Deductive coding analysis was conducted and themes were finalized based on consensus among the two coders. Four themes were identified. Findings show stigma undergirds Alabaman Black women's decisions to engage in PrEP care. Moreover, women reported stigma stifled community-level education about PrEP. Despite these experiences, education was regarded as a strategy to decrease stigma and PrEP skepticism, the latter of which emerged as a prominent theme. Medical mistrust and healthcare engagement were the other emergent themes influencing participation in PrEP care. To ensure PrEP efforts meet the needs of Black cisgender women in Alabama counties, interventions must address longstanding stigma, increase educational initiatives, and ensure interventions consider women's experiences with medical mistrust and health care engagement.

Experiences and attitudes towards Menstrual Suppression among Women with Bacterial vaginosis Randomised to Continuous Use of NuvaRing in Kenya.

Background: The contraceptive vaginal ring (NuvaRing), one of the Multipurpose Prevention Technologies (MPT) products, is effective in preventing unintended pregnancies and may contribute to reducing the frequency of Bacterial Vaginosis (BV), which is a risk factor for HIV acquisition, transmission, and shedding among women. NuvaRing may cause irregular menstruation, including menstrual suppression, which may influence women's decision on product choice, use, and acceptability. In this prospective cohort study, we assessed women's experiences with menstruation suppression following continued NuvaRing use. Methods: A total of 18 in-depth interviews were conducted using a semi-structured interview guide among purposively selected women with BV in Thika, Kenya, aged 18-40 years, who used NuvaRing continuously. All women received counseling on possibility of menstrual suppression following continuous NuvaRing use. Audio recordings were transcribed verbatim and thematically analyzed. Results: Participants who expected and were aware that menstrual suppression was a possible side effect of Nuvaring accepted its benefits, and expressed acceptance and desire to continue using NuvaRing. Participants who had not anticipated menstrual suppression expressed anxiety and fear, with some expressing desire to continue using NuvaRing but worried about unintended negative consequences. The ability to perform daily activities uninterrupted, reduced expenses on sanitary supplies, enhanced sexual pleasure and relationships, and absence of menstrual pain were benefits of menstrual suppression. Although all participants received counseling on menstrual suppression, some expressed anxiety over the possibility of unintended pregnancy. As a result, they frequented medical facilities for health check-ups and pregnancy tests, and some used combined oral contraceptives to induce menses. Conclusion: Understanding perceptions regarding menstrual suppression is crucial in offering targeted and comprehensive counseling to improve women's understanding of menstruation suppression to influence acceptance and use of NuvaRing. Additionally, improved male involvement in reproductive health concerns and women's autonomy in discussing reproductive health issues with partners is essential.

The Association Between Heterosexual anal Intercourse and HIV Acquisition in Three Prospective Cohorts of Women.

The extent to which receptive anal intercourse (RAI) increases the HIV acquisition risk of women compared to receptive vaginal intercourse (RVI) is poorly understood. We evaluated RAI practice over time and its association with HIV incidence during three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline, 16% (RV 217), 18% (VOICE) of women reported RAI in the past 3 months and 27% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. HIV incidence in the three cohorts was positively associated with reporting RAI at baseline, albeit not always significantly. The adjusted hazard rate ratios for potential confounders (aHR) were 1.1 (95% Confidence interval: 0.8-1.5) for VOICE and 3.3 (1.6-6.8) for RV 217, whereas the ratio of cumulative HIV incidence by RAI practice was 1.9 (0.6-6.0) for HVTN 907. For VOICE, the estimated magnitude of association increased slightly when using a time-varying RAI exposure definition (aHR = 1.2; 0.9-1.6), and for women reporting RAI at every follow-up survey (aHR = 2.0 (1.3-3.1)), though not for women reporting higher RAI frequency (> 30% acts being RAI vs. no RAI in the past 3 months; aHR = 0.7 (0.4-1.1)). Findings indicated precise estimation of the RAI/HIV association, following multiple RVI/RAI exposures, is sensitive to RAI exposure definition, which remain imperfectly measured. Information on RAI practices, RAI/RVI frequency, and condom use should be more systematically and precisely recorded and reported in studies looking at sexual behaviors and HIV seroconversions; standardized measures would aid comparability across geographies and over time.

An Ulcer by Any Other Name: Non-herpes and Non-syphilis Ulcerative Sexually Transmitted Infections.

The myriad presentations of ulcerative sexually transmitted infections, other than genital herpes and syphilis, challenge even the most astute clinician given the considerable overlap in clinical presentation and lack of widely available diagnostic resources, such as nucleic acid testing, to confirm the diagnosis. Even so, case prevalence is relatively low, and incidence of chancroid and granuloma inguinale are declining. These diseases still cause substantial morbidity and increased chance for HIV acquisition, and with the recent advent of mpox as a cause, it remains imperative to identify and treat accurately.

Genital Herpes Simplex Virus Type 2 Suppression With Valacyclovir Is Not Associated With Changes in Nugent Score or Absolute Abundance of Key Vaginal Bacteria.

Background: In women, genital herpes simplex virus type 2 (HSV-2) infection is associated with increased risk for recurrent bacterial vaginosis (BV), but causal relationships are unclear. Methods: Women with a self-reported history of BV and HSV-2 seropositivity self-collected vaginal and anogenital swabs for 2 nonconsecutive 28-day periods, in the absence or presence of valacyclovir suppressive therapy (500 mg daily). HSV polymerase chain reaction was performed on anogenital swabs; vaginal swabs were used for assessment of BV by Nugent score and quantification of vaginal microbiota. Days with BV, defined by Nugent score ≥7, were compared during the observational period and valacyclovir treatment. Results: Forty-one women collected swabs for a median of 28 days (range, 20-32 days) each study period. The HSV-2 shedding rate decreased from 109 of 1126 days (9.7%) presuppression to 6 of 1125 days (0.05%) during valacyclovir (rate ratio [RR], 0.06 [95% confidence interval {CI}, .02-.13]). BV occurred on 343 of 1103 days (31.1%) during observation and 302 of 1091 days (27.7%) during valacyclovir (RR, 0.90 [95% CI, .68-1.20]). The median per-person Nugent score was 3.8 during observation and 4.0 during valacyclovir. Average log10 concentrations of vaginal bacterial species did not change significantly during valacyclovir treatment. Conclusions: Short-term HSV-2 suppression with valacyclovir did not significantly affect the Nugent score or the vaginal microbiome despite potent suppression of HSV-2 shedding.

High PrEP uptake and objective longitudinal adherence among HIV-exposed women with personal or partner plans for pregnancy in rural Uganda: A cohort study.

BACKGROUND: In Uganda, fertility rates and adult HIV prevalence are high, and many women conceive with partners living with HIV. Pre-exposure prophylaxis (PrEP) reduces HIV acquisition for women and, therefore, infants. We developed the Healthy Families-PrEP intervention to support PrEP use as part of HIV prevention during periconception and pregnancy periods. We conducted a longitudinal cohort study to evaluate oral PrEP use among women participating in the intervention. METHODS AND FINDINGS: We enrolled HIV-negative women with plans for pregnancy with a partner living, or thought to be living, with HIV (2017 to 2020) to evaluate PrEP use among women participating in the Healthy Families-PrEP intervention. Quarterly study visits through 9 months included HIV and pregnancy testing and HIV prevention counseling. PrEP was provided in electronic pillboxes, providing the primary adherence measure ("high" adherence when pillbox was opened ≥80% of days). Enrollment questionnaires assessed factors associated with PrEP use. Plasma tenofovir (TFV) and intraerythrocytic TFV-diphosphate (TFV-DP) concentrations were determined quarterly for women who acquired HIV and a randomly selected subset of those who did not; concentrations TFV ≥40 ng/mL and TFV-DP ≥600 fmol/punch were categorized as "high." Women who became pregnant were initially exited from the cohort by design; from March 2019, women with incident pregnancy remained in the study with quarterly follow-up until pregnancy outcome. Primary outcomes included (1) PrEP uptake (proportion who initiated PrEP); and (2) PrEP adherence (proportion of days with pillbox openings during the first 3 months following PrEP initiation). We used univariable and multivariable-adjusted linear regression to evaluate baseline predictors selected based on our conceptual framework of mean adherence over 3 months. We also assessed mean monthly adherence over 9 months of follow-up and during pregnancy. We enrolled 131 women with mean age 28.7 years (95% CI: 27.8 to 29.5). Ninety-seven (74%) reported a partner with HIV and 79 (60%) reported condomless sex. Most women (N = 118; 90%) initiated PrEP. Mean electronic adherence during the 3 months following initiation was 87% (95% CI: 83%, 90%). No covariates were associated with 3-month pill-taking behavior. Concentrations of plasma TFV and TFV-DP were high among 66% and 47%, 56% and 41%, and 45% and 45% at months 3, 6, and 9, respectively. We observed 53 pregnancies among 131 women (1-year cumulative incidence 53% [95% CI: 43%, 62%]) and 1 HIV-seroconversion in a non-pregnant woman. Mean pillcap adherence for PrEP users with pregnancy follow-up (N = 17) was 98% (95% CI: 97%, 99%). Study design limitations include lack of a control group. CONCLUSIONS: Women in Uganda with PrEP indications and planning for pregnancy chose to use PrEP. By electronic pillcap, most were able to sustain high adherence to daily oral PrEP prior to and during pregnancy. Differences in adherence measures highlight challenges with adherence assessment; serial measures of TFV-DP in whole blood suggest 41% to 47% of women took sufficient periconception PrEP to prevent HIV. These data suggest that women planning for and with pregnancy should be prioritized for PrEP implementation, particularly in settings with high fertility rates and generalized HIV epidemics. Future iterations of this work should compare the outcomes to current standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03832530 https://clinicaltrials.gov/ct2/show/NCT03832530?term=lynn+matthews&cond=hiv&cntry=UG&draw=2&rank=1.

'I still desire to have a child': a qualitative analysis of intersectional HIV- and childlessness-related stigma in rural southwestern Uganda.

This study explored the intersecting forms of stigma experienced by HIV-serodifferent couples with unmet reproductive goals in rural Uganda. The parent mixed-methods study, which included 131 HIV-exposed women with plans for pregnancy, offered comprehensive HIV prevention counselling and care over a nine-month period. In-depth interviews were conducted with 37 women and seven male partners to explore care experiences and the use of safer conception strategies. This secondary analysis explored how challenges conceiving informed pregnancy plans and HIV prevention behaviours. The following themes were developed (1) partnership conflicts arise from HIV- and infertility-related forms of stigma, contributing to gender-based violence, partnership dissolution and the pursuit of new partners; (2) cultural and gender norms pressure men and women to conceive and maintain partnerships, which is complicated by the stigma directed towards serodifferent couples; (3) frustration with low partner participation in safer conception strategies led to the decreased use of these methods of HIV prevention; (4) health care provider support promotes continued hope of conception and helps overcome stigma. In HIV-affected partnerships, these intersecting forms of stigma may impact HIV prevention. Seeking to fulfil their reproductive needs, partners may increase HIV transmission opportunities as they engage in condomless sex with additional partners and decrease adherence to prevention strategies. Future research programmes should consider the integration of fertility counselling with reproductive and sexual health care.

Prevention of Neisseria gonorrhoeae With Meningococcal B Vaccine: A Matched Cohort Study in Southern California.

BACKGROUND: Neisseria gonorrhoeae is acquiring increasing resistance to available oral antibiotics, and current screening and treatment approaches have not decreased gonorrhea incidence. Although a gonorrhea-specific vaccine does not exist, N. gonorrhoeae shares much of its genome with Neisseria meningitidis, notably critical antigenic determinants including outer membrane vesicles (OMV). Prior observational studies have suggested that OMV-based meningococcal serogroup B vaccines confer protection against gonorrhea. METHODS: We conducted a matched cohort study from 2016 to 2020 to examine the association of OMV-containing recombinant meningococcal serogroup B vaccine (4CMenB) with gonorrhea infection among teens and young adults at Kaiser Permanente Southern California. Recipients of 4CMenB were matched in a ratio of 1:4 to recipients of non-OMV-containing polysaccharide-conjugate vaccine targeting serotypes A, C, W, and Y (MenACWY) who had not received 4CMenB and were followed for incident gonorrhea. We used Cox proportional hazards regression to compare gonorrhea rates among recipients of 4CMenB vs MenACWY, adjusting for potential confounders. We conducted the same analysis with chlamydia as a negative control outcome. RESULTS: The study included 6641 recipients of 4CMenB matched to 26 471 recipients of MenACWY. During follow-up, gonorrhea incidence rates per 1000 person-years (95% confidence intervals [CIs]) were 2.0 (1.3-2.8) for recipients of 4CMenB and 5.2 (4.6-5.8) for recipients of MenACWY. In adjusted analyses, gonorrhea rates were 46% lower among recipients of 4CMenB vs MenACWY (hazard ratio [HR], 0.54; 95% CI, .34-.86), but chlamydia rates were similar between vaccine groups (HR, 0.98; 95% CI, .82-1.17). CONCLUSIONS: These results suggest cross-protection of 4CMenB against gonorrhea, supporting the potential for vaccination strategies to prevent gonorrhea.

Infections caused by Clostridium perfringens and Paeniclostridium sordellii after unsafe abortion.

After the legalisation of abortion in the USA in 1973, the risk of infectious morbidity and mortality from this procedure notably decreased. With increasingly restrictive legislation targeting access to safe abortion services, reviewing infectious complications of unsafe pregnancy termination is crucial, particularly the diagnosis and management of life-threatening clostridial (and related anaerobic bacterial) infections that can complicate unsafe abortion. This Review deals with two especially devastating infections that are well-documented causes of septic abortion: the anaerobic, spore-forming pathogens Clostridium perfringens and Paeniclostridium sordellii. We seek to familiarise the reader with these bacteria, the clinical syndromes they can cause (with a focus on toxic shock syndrome), and provide a review of diagnosis and treatment options.

Attitudes Toward Menstrual Suppression Among Cyclic and Continuous Contraceptive Vaginal Ring Users in Kenya.

Objective: Multipurpose prevention technologies (MPTs) are developmental dual-purpose options that would provide women with a contraceptive as well as a prevention modality aimed at sexually transmitted infections. The contraceptive vaginal ring (CVR) has many properties that makes it an ideal MPT candidate. The objective of this study is to understand women's attitudes towards menstrual suppression, a potential side effect of using a CVR, and how to address these attitudes for MPT vaginal rings in development. Materials and methods: We analyzed data derived from a subset of cohort study participants (n=45) in Thika, Kenya between January 2016- December 2018. The primary study enrolled 121 women 18-40 years with bacterial vaginosis and randomized them to cyclic or continuous CVR use for eight months. During the 6-month follow-up, a questionnaire eliciting attitudes towards menstrual suppression was administered. Responses to the menstrual suppression questionnaire between participants in the cyclic and continuous CVR use groups were compared. Likert-scale responses were summed to create a menstrual suppression attitude summary score, and a hierarchical cluster analysis was conducted to identify similarities in response patterns among all participants. Results: Totally 81.8% of continuous CVR users believed that one was less likely to get pregnant after using hormonal medication to suppress menses, compared to 47.8% of cyclic CVR users (P=0.02), and were more worried it would cause long-term health effects (86.4% vs 60.9%, p = 0.05). The menstrual suppression attitude summary score ranged from 8 to 42, with lower scores indicating negative attitudes. The summary score identified three distinct clusters. When asked if menstrual suppression effects long-term health; 100% of Cluster 3 was worried compared to 80.8% of Cluster 2 and 46.2% of Cluster 1 (p = 0.03). The average summary score among Cluster 3 (Mean = 14.8, SD = 4.6) was lower (p < 0.001) and women were more worried about discomfort during sex (p=0.05) as well as their sexual partners feeling the ring (p=0.02). Conclusion: Women are more likely to have negative attitudes if they believe menstrual suppression hinders future reproductive health. Education on cycle control and fertility could mitigate negative attitudes and improve uptake of CVRs.