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BackgroundPostpartum haemorrhage (PPH) is the leading cause of global maternal deaths, accounting for 30-50% of maternal deaths in sub-Saharan Africa. Most PPH-related deaths are preventable with timely detection and initiation of care, which may be facilitated by using a clinical care bundle. We explore influences on current PPH detection and management and on the future implementation of a new PPH bundle (E-MOTIVE) in low-resource, high-burden settings.MethodsSemi-structured qualitative interviews based on the Theoretical Domains Framework were conducted with 45 healthcare providers across nine hospitals in Nigeria, Kenya and South Africa, to identify barriers and enablers to current PPH detection and management and future implementation of a new PPH care bundle. Data were analysed using thematic and framework analysis. The Behaviour Change Wheel was used to identify potential interventions to address identified barriers and enablers.ResultsInfluences on current PPH detection and management fell under 12 domains: Environmental Context and Resources (drug and staff shortages), Skills (limited in-service training), Knowledge (variable understanding of the recommended practice), Behaviour Regulation (limited quality improvement culture), Beliefs about Consequences (drawbacks from inaccurate detection), Emotion (stress from the unpredictability of PPH), Social Influence (teamwork), Memory, Attention and Decision-making (limited guideline use), Social/Professional Role and Identity (role clarity), Beliefs about Capabilities (confidence in managing PPH), Reinforcement (disciplinary procedures) and Goals (PPH as a priority). Influences on bundle uptake included: Beliefs about Consequences (perceived benefits of new blood loss measurement tool), Environmental Context and Resources (high cost of drugs and new tools), Memory, Attention and Decision-making (concerns about whether bundle fits current practice), Knowledge (not understanding 'bundled' approach), Social Influence (acceptance by women and staff) and Intention (limited acceptance of 'bundled' approach over existing practice). These influences were consistent across countries. Proposed interventions included: Education, Training, Modelling (core and new skills), Enablement (monitoring uptake), Persuasion (leadership role) and Environmental Restructuring (PPH emergency trolley/kit).ConclusionsA wide range of individual, socio-cultural and environmental barriers and enablers to improving PPH detection and management exist in these settings. We identified a range of interventions that could improve PPH care and the implementation of new care bundles in this context.Trial registrationClinicalTrials.gov : NCT04341662.

BackgroundPretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial.MethodsHIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database.ResultsWe sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs.ConclusionsThe high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.

BackgroundHIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial.MethodsECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification.ResultsOf 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83).ConclusionsOver a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end.Clinical trial numberNCT02550067.

BackgroundPostpartum haemorrhage (PPH) is the leading cause of maternal death globally. Most PPH deaths can be avoided with timely detection and management; however, critical challenges persist. A multi-country cluster-randomised trial (E-MOTIVE) will introduce a clinical care bundle for early detection and first-response PPH management in hospital settings. This formative qualitative study aimed to explore healthcare providers' knowledge and practices of PPH detection and management after vaginal birth, to inform design and implementation of E-MOTIVE.MethodsBetween July 2020-June 2021, semi-structured qualitative interviews were conducted with 45 maternity healthcare providers (midwives, nurses, doctors, managers) of nine hospitals in Kenya, Nigeria, and South Africa. A thematic analysis approach was used.ResultsFour key themes were identified, which varied across contexts: in-service training on emergency obstetric care; limited knowledge about PPH; current approaches to PPH detection; and current PPH management and associated challenges. PPH was recognised as an emergency but understanding of PPH varied. Early PPH detection was limited by the subjective nature of visual estimation of blood loss. Lack of expertise on PPH detection and using visual estimation can result in delays in initiation of PPH management. Shortages of trained staff and essential resources, and late inter-hospital referrals were common barriers to PPH management.ConclusionThere are critical needs to address context-specific barriers to early and timely detection and management of PPH in hospital settings. These findings will be used to develop evidence-informed implementation strategies, such as improved in-service training, and objective measurement of blood loss, which are key components of the E-MOTIVE trial (Trial registration: ClinicalTrials.gov: NCT04341662).

HIV acquisition risk with norethisterone (NET) enanthate (NET-EN) is reportedly less than for depo-medroxyprogesterone acetate intramuscular (DMPA-IM). We investigated the effects of these progestin-only injectable contraceptives on serum testosterone and sex hormone binding globulin (SHBG) levels, since these may play a role in sexual behavior and HIV acquisition. The open-label WHICH clinical trial, conducted at two sites in South Africa from 2018–2019, randomized HIV-negative women aged 18–40 years to 150 mg DMPA-IM 12-weekly (n = 262) or 200 mg NET-EN 8-weekly (n = 259). We measured testosterone by UHPLC-MS/MS and SHBG by immunoassay in matched pairs of serum samples collected at baseline (D0) and at peak serum progestin levels at 25 weeks post initiation (25W) (n = 214–218 pairs). Both contraceptives substantially decreased, from D0 to 25W, the total testosterone [DMPA-IM D0 0.560, 25W 0.423 nmol/L, -24.3% (p < 0.0001); NET-EN D0 0.551, 25W 0.253 nmol/L, -54.1%, (p < 0.0001)], SHBG [DMPA-IM D0 45.0, 25W 32.7 nmol/L, -29.8% (p < 0.0001); NET-EN D0 50.2, 25W 17.6 nmol/L, -65.1% (p < 0.0001)], and calculated free testosterone levels [DMPA-IM D0 6.87, 25W 5.38 pmol/L, -17.2% (p = 0.0371); NET-EN D0 6.00, 25W 3.70, -40.0% (p < 0.0001)]. After adjusting for change from D0, the total testosterone, SHBG and calculated free testosterone levels were significantly higher for DMPA-IM than NET-EN (64.9%, p < 0.0001; 101.2%, p < 0.0001; and 38.0%, p = 0.0120, respectively). The substantial and differential decrease in testosterone and SHBG levels does not explain our previous finding of no detected decrease in risky sexual behavior or sexual function for DMPA-IM or NET-EN users from D0 to 25W. Medroxyprogesterone (MPA) and NET are androgenic and are both present in molar excess over testosterone and SHBG concentrations at 25W. Any within or between contraceptive group androgenic effects on behavior in the brain are likely dominated by the androgenic activities of MPA and NET and not by the decreased endogenous testosterone levels. The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976). [ABSTRACT FROM AUTHOR]

Background: Contraceptive use has complex effects on sexual behaviour and mood, including those related to reduced concerns about unintended pregnancy, direct hormonal effects and effects on endogenous sex hormones. We set out to obtain robust evidence on the relative effects of three contraceptive methods on sex behaviours, which is important for guiding contraceptive choice and future contraceptive developments. Methods: This is a secondary analysis of data from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial in which 7,829 HIV-uninfected women from 12 sites in Eswatini, Kenya, South Africa and Zambia seeking contraception were randomly assigned to intramuscular depot-medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. Data collected for 12 to 18 months using 3-monthly behavioural questionnaires that relied on recall from the preceding 3 months, were used to estimate relative risk of post-baseline sex behaviours, as well as sexual desire and menstrual bleeding between randomized groups using modified Poisson regression. Results: We observed small but generally consistent effects wherein DMPA-IM users reported lower prevalence of specified high risk sexual behaviours than implant users than Cu-IUD users (the '>' and '<' symbols indicate statistically significant differences): multiple sex partners 3.6% < 4.8% < 6.2% respectively; new sex partner 3.0% < 4.0% <5.3%; coital acts 16.45, 16.65, 17.12 (DMPA-IM < Cu-IUD); unprotected sex 65% < 68%, 70%; unprotected sex past 7 days 33% <36%, 37%; sex during vaginal bleeding 7.1%, 7.1% < 8.9%; no sex acts 4.1%, 3.8%, 3.4% (DMPA-IM > Cu-IUD); partner has sex with others 10% < 11%, 11%. The one exception was having any sex partner 96.5%, 96.9% < 97.4% (DMPA-IM < Cu-IUD). Decrease in sexual desire was reported by 1.6% > 1.1% >0.5%; amenorrhoea by 49% > 41% >12% and regular menstrual pattern by 26% <35% < 87% respectively. Conclusions: These findings suggest that women assigned to DMPA-IM may have a modest decrease in libido and sexual activity relative to the implant, and the implant relative to the Cu-IUD. We found more menstrual disturbance with DMPA-IM than with the implant (and as expected, both more than the Cu-IUD). These findings are important for informing the contraceptive choices of women and policymakers and highlight the need for robust comparison of the effects of other contraceptive methods as well. [ABSTRACT FROM AUTHOR]

Background: Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods. Methods: In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months. Results: We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p < 0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference − 22.98, p < 0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference − 50.04, p < 0.001 and than DMPA (mean percentage difference − 39.45, p < 0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001). Conclusions: This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study. ECHO trial registration: ClinicalTrials.gov, number NCT02550067 15/09/2015. Plain English summary: Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns. [ABSTRACT FROM AUTHOR]

: Introduction: Global guidelines emphasize the ethical obligation of investigators to help participants in HIV‐endpoint trials reduce HIV risk by offering an optimal HIV prevention package. Oral pre‐exposure prophylaxis (PrEP) has increasingly become part of state‐of‐the‐art HIV prevention. Here we describe the process of integrating oral PrEP delivery into the HIV prevention package of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. Methods: ECHO was an open‐label randomized clinical trial that compared HIV incidence among women randomized to one of three effective contraceptives. In total, 7830 women aged 16 to 35 years from 12 sites in four African countries (Eswatini, Kenya, South Africa and Zambia) were enrolled and followed for 12 to 18 months, from 2015 to 2018. Part‐way through the course of the trial, oral PrEP was provided to study participants either off‐site via referral or on site via trained trial staff. PrEP uptake was compared between different contraceptive users using Chi‐squared tests or t‐tests. HIV seroincidence rates were compared between participants who never versus ever initiated PrEP using exact Poisson regression. Results: PrEP access in ECHO began through public availability in Kenya in May 2017 and was available at all sites by June 2018. When PrEP became available, 3626 (46.3%) eligible women were still in follow‐up in the study, and of these, 622 (17.2%) initiated PrEP. Women initiating PrEP were slightly older; more likely to be unmarried, not living with their partner, having multiple partners; and less likely to be earning their own income and receiving financial support from partners (all p < 0.05). PrEP initiation did not differ across study randomized groups (p = 0.7). Two‐thirds of PrEP users were continuing PrEP at study exit. Conclusions: There is a need for improved HIV prevention services in clinical trials with HIV endpoints, especially trials among African women. PrEP as a component of a comprehensive HIV prevention package provided to women in a large clinical trial is practical and feasible. Provision of PrEP within clinical trials with HIV outcomes should be standard of prevention., Introduction Within the context of clinical trials in which incident HIV infection is a primary study outcome, global guidelines emphasize an ethical imperative to assist participants reduce HIV risk by [...]