Evidence For Contraceptive Options And HIV Outcomes Research Articles

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

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. 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. 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). 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.

Addressing missed visits to improve retention of young South African women in clinical trials

In clinical trials, a vital protocol requirement for participants is adherence to scheduled visits. A substantial number of missed visits and the resultant missing data could affect generalisability of the findings and undermine the scientific conclusions. We aimed to investigate the extent of and reasons for missed visits in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial in order to optimise recruitment and retention practices. Despite being a multi-country study, we investigated missed visits only at Setshaba Research Centre in Soshanguve, Tshwane, South Africa. Of 810 participants enrolled at Setshaba Research Centre, 94 (11.6%) participants missed visits and 231 missed visits were recorded. Of the 94 participants who missed visits, 53 (56.4%) missed at least two visits; 37 (39.4%) missed three or more visits, and of these, 32 (86.5%) missed at least two visits for the same reason. Overall, the main reasons for missed visits were: participant had to work (60; 26.0%), unable to contact participant (60; 26.0%), participant relocated (32; 13.9%), and participant travelled out of area (23; 10%). The large proportion of participants who missed two or more visits indicates that participants who miss a single visit are likely to miss even more, often for the same reason. Site staff need to be vigilant to detect any trends in missed visits early and innovative in developing personalised strategies to minimise missed visits and retain participants until completion of their scheduled visits. Significance: Despite trial site staff developing strategies to minimise missed visits, they will not be able to anticipate all scenarios. Participants’ work commitments, loss of contact with participants, and participants’ travel/relocation to distant areas were the main reasons for missing visits, and site staff need to consider the potential for these to arise during the course of the study when assessing potential participants at enrolment and at each follow-up visit. Case report forms designed for multi-country studies should be adapted to reflect the most likely reasons for missed visits for the local situation, so that trends in missed visits can be identified and addressed early.

Post-trial access to and use of pre-exposure prophylaxis in Durban, South Africa

BackgroundHIV endpoint-driven clinical trials increasingly provide oral pre-exposure prophylaxis (PrEP) as standard of prevention during the trial, however, among participants desiring to continue using PrEP at trial exit, little is known about post-trial PrEP access and continued use.MethodsWe conducted one-time, semi-structured, face-to-face, in-depth interviews with 13 women from Durban, South Africa, from November to December 2021. We interviewed women who initiated oral PrEP as part of the HIV prevention package during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial, elected to continue using PrEP at study exit, and were given a 3-month PrEP supply and referred to facilities for PrEP refills at the final trial visit. The interview guide probed for barriers and enablers to post-trial PrEP access, and current and future PrEP use. Interviews were audio-recorded and transcribed. Thematic analysis was facilitated using NVivo.ResultsOf the 13 women, six accessed oral PrEP post-trial exit, but five later discontinued. The remaining seven women did not access PrEP. Barriers to post-trial PrEP access and continued use included PrEP facilities having long queues, inconvenient operating hours, and being located far from women’s homes. Some women were unable to afford transport costs to collect PrEP. Two women reported visiting their local clinics and requesting PrEP but were informed that PrEP was unavailable at the clinic. Only one woman was still using PrEP at the time of the interview. She reported that the PrEP facility was located close to her home, staff were friendly, and PrEP education and counselling were provided. Most women not on PrEP reported wanting to use it again, particularly if barriers to access could be alleviated and PrEP was easily available at facilities.ConclusionsWe identified several barriers to post-trial PrEP access. Strategies to enhance PrEP access such as a reduction in waiting queues, convenient facility operating hours, and making PrEP more widely available and accessible are needed. It is also worth noting that oral PrEP access has expanded in South Africa from 2018 till now and this could improve access to PrEP for participants exiting trials who desire to continue PrEP.

Clinical outcomes of intrauterine device insertions by newly trained providers: The ECHO trial experience

ObjectivesTo assess the rates of failed insertion, expulsion, and perforation when intrauterine device (IUD) insertions were done by newly trained clinicians, and to examine factors that may affect these outcomes. Study designWe evaluated skill-based outcomes following IUD insertion at 12 African sites in a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial. Before trial initiation, we provided competency-based IUD training to clinicians and offered ongoing clinical support. We used Cox proportional hazards regression to examine factors associated with expulsion. ResultsAmong 2582 IUD acceptors who underwent first attempted IUD insertion, 141 experienced insertion failure (5.46%) and seven had uterine perforation (0.27%). Perforation was more common among breastfeeding women within three months postpartum (0.65%) compared with non-breastfeeding women (0.22%). We recorded 493 expulsions (15.5 per 100 person-years, 95% confidence interval [CI] 14.1─16.9): 383 partial and 110 complete. The risk of IUD expulsion was lower among women older than 24 years (aHR 0.63, 95% CI 0.50─0.78) and may be higher among nulliparous women. (aHR 1.65, 95% CI 0.97─2.82). Breastfeeding (aHR 0.94, 95% CI 0.72─1.22) had no significant effect on expulsion. IUD expulsion rate was highest during the first three months of the trial. ConclusionsIUD insertion failure and uterine perforation rates in our study were comparable to those reported in the literature. These results suggest that training, ongoing support, and opportunities to apply new skills were effective in ensuring good clinical outcomes for women receiving IUD insertion by newly trained providers. ImplicationsData from this study support recommendations to program managers, policymakers, and clinicians that IUDs can be inserted safely in resource-constrained settings when providers receive appropriate training and support.

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.

Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial.

Background:HIV 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.Methods:ECHO, 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.Results:Of 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).Conclusions:Over 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 number:NCT02550067.

High HIV incidence among young women in South Africa: Data from a large prospective study.

IntroductionSouth Africa has the highest national burden of HIV globally. Understanding drivers of HIV acquisition in recently completed, prospective studies in which HIV was an endpoint may help inform the strategy and investments in national HIV prevention efforts and guide the design of future HIV prevention trials. We assessed HIV incidence and correlates of incidence among women enrolled in ECHO (Evidence for Contraceptive Options and HIV Outcomes), a large, open-label randomized clinical trial that compared three highly effective. reversible methods of contraception and rates of HIV acquisition.MethodsDuring December 2015 to October 2018, ECHO followed sexually active, HIV-seronegative women, aged 16–35 years, seeking contraceptive services and willing to be randomized to one of three contraceptive methods (intramuscular depot medroxyprogesterone acetate, copper intrauterine device, or levonorgestrel implant) for 12–18 months at nine sites in South Africa. HIV incidence based on prospectively observed HIV seroconversion events. Cox proportional hazards regression models were used to define baseline cofactors related to incident HIV infection.Results5768 women were enrolled and contributed 7647 woman-years of follow-up. The median age was 23 years and 62.5% were ≤24 years. A total of 345 incident HIV infections occurred, an incidence of 4.51 per 100 woman-years (95%CI 4.05–5.01). Incidence was >3 per 100 woman-years at all sites. Age ≤24 years, baseline infection with sexually transmitted infections, BMI≤30, and having new or multiple partners in the three months prior to enrollment were associated with incident HIV.ConclusionsHIV incidence was high among South African women seeking contraceptive services. Integration of diagnostic management of sexually transmitted infections alongside delivery of HIV prevention options in health facilities providing contraception services are needed to mitigate ongoing risks of HIV acquisition for this vulnerable population.Clinical trial registrationClinicalTrials.gov, number NCT02550067 was the main Clinical Trial from which this secondary, non-randomized / observational analysis was derived with data limited to just South African sites.

High Levels of Pretreatment HIV-1 Drug Resistance Mutations Among South African Women Who Acquired HIV During a Prospective Study.

Pretreatment 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. HIV-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. We 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. The 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.

Effects of Depot Medroxyprogesterone Acetate Intramuscular Injection, Copper Intrauterine Device and Levonorgestrel Implant Contraception on Estradiol Levels: An Ancillary Study of the ECHO Randomized Trial

IntroductionHormonal contraception affects endogenous sex steroid levels. Robust evidence from randomized trials of the relative effects of different contraceptive methods is scarce. We compared the effects of three contraceptive methods on serum estradiol levels using data from women (18–35 years) requesting contraception in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial.MethodsWomen were randomly allocated to the depot medroxyprogesterone acetate intramuscular (DMPA-IM) injection, copper intrauterine device (IUD) or levonorgestrel (LNG) implant. In this sub-study, stored baseline and 6-month serum samples were analyzed in 401 participants from East London, South Africa (DMPA-IM: 131, IUD: 135 and LNG: 135).ResultsBaseline median (interquartile range, IQR) estradiol levels were similar between the three groups [DMPA-IM 229 (152–455), IUD 235 (168–426) and LNG 216 (153–419 pmol/L)]. At 6-months, median estradiol in the IUD group was unchanged (298 (163–467) pmol/L), whilst levels in the DMPA-IM and implant groups were significantly reduced from baseline. The median estradiol level in the DMPA-IM group [139 (97–193) pmol/L] was significantly lower than in both IUD (p < 0.0001) and implant (p = 0.005) groups; and level in the implant group [156 (112–250) pmol/L] was significantly lower than in the IUD group (p = 0.004).ConclusionsAt 6-months (DMPA-IM nadir), median estradiol with DMPA-IM was 53% lower and with the LNG implant, 48% lower than with the IUD. The greater reduction in estradiol levels with the DMPA-IM injection compared to the LNG implant and IUD has implications for the relative psychological, sexual as well as physiological side-effects of these contraceptive methods.ECHO Study RegistrationClinicalTrials.gov, identifier: NCT02550067.

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

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. 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. 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. We conclude that pre-contraceptive initiation immune profile modifies the effect of contraceptives on the FGT innate immune response.

Contraceptive method preference and reasons for contraceptive discontinuation among women randomized to intramuscular depot medroxyprogesterone acetate, a copper intrauterine device or a levonorgestrel implant: Findings from Durban, South Africa

ObjectivesThe use of intrauterine devices (IUDs) and contraceptive implants in South Africa is low with limited data on patterns of use and reasons for discontinuation. We describe contraceptive preferences and reasons for discontinuation among women enrolled in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial from one trial site. Study designECHO, conducted between 2015 and 2018, enrolled and randomized sexually active women, aged 16 to 35, and desiring contraception, to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (copper-IUD) or a levonorgestrel (LNG) implant; follow-up was 12 to 18 months. We interviewed 829 women at the Durban, South Africa trial site at ECHO Trial exit to ascertain contraceptive preferences at randomization. Reasons for randomized contraceptive discontinuation were collected at ECHO Trial exit and 6 months later. Data were analyzed descriptively. ResultsAt the final ECHO Trial visit, among women using their randomized contraceptive method (n = 757), 21% discontinued DMPA-IM, 20% discontinued LNG implant and 22% discontinued the copper-IUD. About a quarter from each group discontinued due to problems with bleeding. Among women continuing their randomized contraceptive at trial exit (n = 597), 25% discontinued DMPA-IM within 6 months of exiting the study, 8% discontinued LNG implant and 4% discontinued copper-IUD. A third of women reported wanting to be assigned DMPA-IM at randomization, 20% wanted the LNG implant and 18% the copper-IUD. ConclusionsDespite some women having preferences about which contraceptive they might be randomized to, discontinuation rates for all three methods at ECHO Trial exit and 6-month post-trial follow-up were low. ImplicationsDespite limited prior use of IUDs and implants among women enrolled in this study, and a desire by some women to not receive these methods at randomization, discontinuation rates remained low. The provision of quality contraceptive counselling and support may increase uptake and continued use of implants and IUDs.

How is Clinical Trial Reimbursement Money Spent? South African Trial Participants\u2019 Reported Reimbursement Spending Patterns and Perceptions of Appropriate Reimbursement Amounts

Reimbursement of participants in clinical trials is extensively debated. Guidance recommends that compensation should reflect time, inconvenience and reimbursement of expenses. This study describes how participants spend their reimbursement and perceptions of appropriate reimbursement amounts. This was a sub-study of the evidence for contraceptive options and HIV outcomes (ECHO) trial. Participants were from two sites in KwaZulu-Natal, South Africa. A mixed methods approach was used. 500 participants completed a questionnaire, and 32 participated in one of four focus group discussions (FGD). The majority (81%) used reimbursement for transport to the research site, followed by toiletry purchases (64%). Many described how reimbursement supplemented income, used to cover basic living costs. Some used money to buy luxury items and takeaway foods. The ideal reimbursement amount per visit ranged: ZAR150-ZAR340 (US$10–24). Reimbursement spending and perceptions are in line with local guidance. Reimbursement should consider risk minimization together with ensuring informed, voluntary decision making.

Integration of HIV Prevention With Sexual and Reproductive Health Services: Evidence for Contraceptive Options and HIV Outcomes Study Experience of Integrating Oral Pre-exposure HIV Prophylaxis in Family Planning Services in Lusaka, Zambia.

The WHO guideline on the integration of family planning (FP) and pre-exposure HIV prophylaxis (PrEP) to enhance the health of women and adolescent girls is reflected in the Zambia Consolidated Guidelines for Treatment and Prevention of HIV Infection, 2020. There is however a dearth of data on the integration of PrEP and FP in Zambia. We describe the integration of oral PrEP in FP services using the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study experience at Kamwala District Health Center in Lusaka, Zambia. The provision of oral PrEP at Kamwala started in October 2017, lasting for ~11 months, and utilized the model where initial processes to offer PrEP were on-site followed by off-site referral to laboratory and PrEP provider services. The characteristics of 658 women who enrolled in ECHO at Kamwala are representative of women accessing FP services in Lusaka. About 644 of the enrollees were offered oral PrEP. The proportion of women accepting PrEP was low at 1.08% and the proportion of study visits at which PrEP was requested was also low at 0.57%. Those who accepted PrEP were above 20 years old, married, with at least primary education, sexual behavior, and risk comparable to decliners. The ECHO study experience indicates that the setup and integration of oral PrEP and FP services are feasible in the setting. However, uptake of PrEP was very low. Possible contributory factors were as follows: (1) timing of introduction of PrEP midway in the study, (2) PrEP being a new intervention, (3) challenges of autonomy of young women to include a daily pill into their lives and anticipated challenges to adherence because of fear of adverse events, (4) possible underdetermined risk due to use of an unvalidated risk assessment tool and assessment by health care provider vs. self-assessment, and (5) extra layer of challenges to negotiate due to needing for off-site referrals. Following these findings, we conclude that further research through demonstration projects of integration of oral PrEP and FP may provide solutions to low uptake. This information is critical for scaling up of integration HIV prevention services and sexual and reproductive health (SRH) services.

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

ABSTRACT 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.

Weight change among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: Findings from a randomised, multicentre, open-label trial.

BackgroundThere is limited evidence on the impact of the use of progestin-only hormonal contraception (POC) on weight change. We conducted a secondary analysis of prospective weight change among women enrolled in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial.MethodsThe ECHO trial was conducted at 12 sites in eSwatini, Kenya, South Africa and Zambia between December 2015 and October 2018. HIV negative, women aged 16–35 years, desiring contraception, were randomised (1:1:1) to either 3-monthly intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant or copper intrauterine device (IUD). Follow-up was up to 18 months. Weight (kg) was measured at baseline and study exit. Analysis was performed as intention to treat (ITT) and time on continuous contraceptive use. The primary outcome of this secondary analysis is weight change from study enrolment to the final visit at study month 12–18. The ECHO trial is registered with ClinicalTrials.gov, NCT02550067.Findings7829 women were randomly assigned to DMPA-IM (n = 2609), copper IUD (n = 2607) or LNG implant (n = 2613). The ITT population included 7014 women 2293 DMPA-IM group, 2372 copper IUD group and 2349 LNG group) who were not lost to follow-up, pregnant on study, or missing weight data. The mean weight increased in all groups but was significantly different in magnitude: 3.5 kg (SD = 6.3), 2.4 kg (SD = 5.9) and 1.5 kg (SD = 5.7) in the DMPA-IM, LNG implant and copper IUD groups, respectively. Comparative differences between groups were (2.02 kg (95% CI, 1.68, 2.36, p < 0.001) for DMPA-IM versus copper IUD, 0.87 kg (0.53,1.20 p < 0.001) for LNG implant compared to copper IUD and 1.16 kg (0.82, 1.50, p < 0.001) for DMPA-IM compared with LNG implant. Results for continuous contraceptive use were similar.InterpretationWe found differences in weight gain between POC users compared to the non-hormonal copper IUD group over 12–18 months of use. Women using POCs should be counselled about this potential side effect when choosing a contraceptive method.

HIV, progestins, genital epithelial barrier function, and the burden of objectivity†.

Contributions from a diverse set of scientific disciplines will be needed to help individuals make fully informed decisions regarding contraceptive choices least likely to promote HIV susceptibility. This commentary recaps contrasting interpretations of results from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial, a study that compared HIV risk in women using the progestin-only injectable contraceptive depot medroxyprogesterone acetate (DMPA) vs. two other contraceptive choices. It also summarizes results from basic and translational research that establish biological plausibility for earlier clinical studies that identified enhanced HIV susceptibility in women using DMPA.

Integrating oral PrEP delivery among African women in a large HIV endpoint-driven clinical trial.

IntroductionGlobal 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.MethodsECHO 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.ResultsPrEP 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.ConclusionsThere 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.

Weight Change Among Women Using Intramuscular Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: Findings from a Randomised, Multicentre, Open-Label Trial

Background: There is limited evidence on the impact of the use of progestin-only hormonal contraception (POC) on weight change. We conducted a secondary analysis of prospective weight change among women enrolled in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial. Methods: The ECHO trial was conducted at 12 sites in eSwatini, Kenya, South Africa and Zambia. HIV negative, women aged 16-35 years, desiring contraception, were randomized (1:1:1) to either 3-monthly intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant or copper intrauterine device (IUD). Follow-up was up to 18 months. Weight (kgs) was measured at baseline and study exit. Analysis was performed as intention to treat (ITT) and time on continuous contraceptive use.  Findings: 7829 women were randomly assigned to DMPA-IM (n=2609), copper IUD (n=2607) or LNG implant (n=2613). The ITT population included 7014 women  2293 DMPA-IM group, 2372 copper IUD group and 2349 LNG group) who were not lost to follow-up, pregnant on study, or missing weight data.  The mean weight increased in all groups but was significantly different in magnitude: 3.5kg (SD=6.3), 2.4kg (SD=5.9) and 1.5kg (SD=5.7) in the DMPA-IM, LNG implant and copper IUD groups, respectively. Comparative differences between groups were (2.02 kg 95% CI, 1.68,2.36, p<0.001 ) for DMPA-IM versus copper IUD,  0.87kg (0.53,1.20 p<0.001)  for LNG implant compared to  copper IUD  and 1.16kg (0.82, 1.50, p<0.001) for DMPA-IM compared with LNG implant. Results for continuous contraceptive use were similar. Interpretation: We found differences in weight gain between POC users compared to the non-hormonal copper IUD group over  12-18 months of use.  Women using POCs should be counselled about this potential side effect when choosing a contraceptive method. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT02550067. Funding Statement: Bill & Melinda Gates Foundation, US Agency for International Development (USAID) and the President’s Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council, and UNFPA. Declaration of Interests: None to declare Ethics Approval Statement: Ethics review committees at each study site, FHI 360, and the World Health Organization (WHO) approved the study protocol. Women provided written informed consent in a language of their choice prior to the conduct of any study related procedures.

In the name of science: Ethical violations in the ECHO randomised trial

ABSTRACT It was in the 1990s, that the possibility of increased transmission of HIV with the use of injectable contraceptive Depo-Provera®, was first flagged in medical literature. This has posed a challenge for its use in countries, particularly in the African region, where the prevalence and transmission rate of HIV is high. In 2015, a randomised ‘clinical’ trial, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) was launched in four African countries to resolve the question whether the increased risk was causal. Contrary to expectations, the ECHO trial successfully recruited and randomised the specified number of girls/women participants. This paper argues that this was made possible by exercising undue influence, by using incentives, coercive language, and by concealing the real nature of the clinical trial during recruitment. The ECHO trial is unique in subjecting a group of healthy girls/women knowingly to a contraceptive drug with an intention not of finding out whether it is efficacious as a contraceptive, but to find out how risky or life-threatening its use could be. Thus, the ECHO trial has violated one of the central tenets of the Helsinki Declaration by privileging pursuit of knowledge over the interests of the girl/women trial participants from Africa.

Insights from outside BJOG

The undetectable = untransmittable (U = U) campaign was launched in 2016. It simply states that if an HIV-positive person is on antiretroviral therapy (ART) and has undetectable viral levels, they cannot sexually transmit the virus to others. The evidence for this statement is irrefutable and has been heralded in publications such as ‘U = U taking off in 2017’ (Lancet HIV 2017;4:e475) and now reiterated in JAMA (Eisinger et al. JAMA 2019;321:451–2). Both articles record the science – biomedical, behavioural and social – that underpins the attitudinal shifts that accompany the journals’ declarations. These findings will: The principles of U = U are: In South Africa, which has more HIV-positive citizens than any other country, the acceptance by the international community of U = U is wonderful news. It gives renewed hope in a country reeling from an ongoing epidemic and much in need of encouraging news regarding HIV. Also of interest to the 3 million South African women of childbearing age in the country who are HIV positive are the results of a modelling study that weighs up the risks of two antiretroviral drugs. Efavirenz (EFV) and dolutegravir (DTG) are amongst the most popular ART medications but there have been concerns about the teratogenic effects of DTG, which is the more effective in preventing HIV transmission and avoiding deaths from AIDS. This creates a dilemma for women wanting protection without danger, should they conceive (Hoffman and Mofenson Ann Intern Med 2019;170:658–659). The new calculations suggest that DTG will prove superior to EFV in terms of lives saved and transmissions avoided. This gives clinicians clear direction about how to advise young women despite the risk of neural tube defects to their offspring (Dugdale et al. Ann Intern Med 2019;170:614–25). Postmenopausal women who take hormone therapy are at greater risk of uterine prolapse than those not taking hormones. This appears to be the conclusion of a report from Finland where women having surgery for prolapse were investigated for their use of hormones and compared with women not having surgery (Rahkola-Soisalo et al. Menopause 2019;26:140–144). In this study, one-third (34%) of women undergoing surgical uterine removal for prolapse used menopausal hormone therapy. One-quarter (27%) of Finnish women in the general population (the control group) used hormones. For clarity: The authors of the study found this elevation of risk to be consistent, irrespective of the type of estrogen used or the type of accompanying progesterone prescribed. This included levonorgestrel-releasing intrauterine devices that give rise to very low levels of circulating progestins, leading to the conclusion that estrogens were responsible for the tendency to prolapse and the resultant need for repair surgery through their effects on collagen, metalloproteins, elastin, smooth muscle cells and fibroblasts in the pelvic floor. There is ongoing debate about when pregnancies that continue ‘past term’ should be delivered. Those that have co-morbidities are less contentious and require individual decision-making that take ‘non-chronological’ factors into account but pregnancies that are uncomplicated also deserve personal and shared discussion as to when induction of labour is indicated. Two recent publications add data to assist with clinical considerations. A trial in the Netherlands randomised low-risk women to either be induced at 41 weeks or 42 weeks should the pregnancy continue that far (Keulen et al. BMJ 2019;364:l344). The investigators had to approach 6000 women to recruit the 1800 needed for the study, which suggests that women have strongly held views about chronologically dictated induction, both for and against it. In the event, those allocated to be induced at 41 weeks were duly delivered as scheduled but many of those allocated to expectant management for the next week went into spontaneous labour. Ultimately the groups only differed in their median gestational age at delivery by 2 days. The results were that induction or waiting were similar for most of the outcomes, namely perinatal mortality, neonatal morbidity and maternal morbidity. There was a 1.4% increased risk of adverse perinatal outcomes in the expectant management cohort (3.1% versus 1.7%). An editorial commenting on the trial suggests the interpretation of the findings ‘should be viewed with caution’ and that they are ‘not sufficiently conclusive’ to change current practice (Kenyon et al. BMJ 2019;364:l681). Observational research from the USA provides information on large numbers of pregnancies of low-risk women having their first child (Chen et al. Obstet Gynecol 2019;133:729–37). Using datasets from 2010 onwards, the authors looked at the composite neonatal morbidity of over 3 million births at 39, 40 or 41 weeks of gestation. Taking 39-week deliveries as their baseline, they calculated neonatal morbidity risk ratios increased at 40 weeks to 1.22 (95% CI 1.19–1.25) and at 41 weeks to 1.53 (95% CI 1.49–1.58). Composite maternal morbidity also rose with later delivery and by similar risk ratios. The authors describe these increases as modest (Figure 1). Source: Chen et al. Obstet Gynecol 2019;133:729–37. Decisions to induce labour for reasons of gestational age carry implications for the mother, fetus, family, community and the allocation of resources. Induction policies, be they institutional or individual must be shared between the woman, her partner and those in charge of her care because of their impact on her experience of childbirth. With induction rates rising in countries with high socio-economic status (reaching 35% of nulliparous women in the UK), this aspect of obstetric care needs to be given wise thought as a widely used intervention that is based on policy is not personalised medicine. An article from Australia published in a sports journal poses the question of whether breast size affects how women participate in physical activity (Coltman et al. J Sci Med Sport 2019;22:324–29). It appears that it does, since the researchers found that if they divided volunteers’ breast sizes into small, medium, large and hypertrophic, there was a correlation between 3D scan breast volume and women's reported exercise history. The larger their breasts, the less their participation in vigorous-intensity physical activity. There was also an association between breast size and body mass index with more than 90% of women with large or hypertrophic breasts being overweight or obese. Those with larger breasts considered breast size to be an impediment to regular exercise, thus inhibiting their participation in activities that carry health benefits. Women face barriers of time, environment, safety and self-consciousness when reporting they cannot exercise and now it seems attention to breast size should be addressed when encouraging fitness through exercise. The issue encapsulates how one sustains health protective behaviours such as physical activity and healthy eating (Dunton JAMA 2018;320:639–40). Engaging with pro-active behaviours involves situational cues such as location, social context, mood, self-esteem plus family and collegial encouragement. Being sensitive to breast size and offering advice on garments, privacy for exercising and support groups may help. This field manual, produced by the various United Nations agencies and non-governmental organisations that make up the Inter-Agency Working Group on Reproductive Health in Crises (IAWG), is aimed at sexual and reproductive health co-ordinators and programme managers working in humanitarian settings. The manual provides evidence and practical examples regarding the application and adaptation of global sexual and reproductive health (SRH) or human rights standards in humanitarian settings. Chapter 2 outlines the fundamental principles of SRH programming in humanitarian settings including: work in respectful partnership, advance human rights and reproductive rights through sexual and reproductive health programming, ensure technical soundness, human rights and financial accountability, and share information and results. Chapter 3 discusses the humanitarian response to SRH needs at the onset of an emergency and outlines the Minimum Initial Service Package (MISP) for SRH, which is regarded as the minimum standard of care to be provided in humanitarian response. Comprehensive guidance, including at both community and health-service levels, is provided on contraception, abortion care, maternal and newborn health, gender-based violence, HIV and sexually transmitted infections. Practical programmatic examples are presented as are links to further reading and additional resources. This 2018 edition of the manual promotes the wider application of the guidance beyond refugee situations for the first time, to additionally include conflict zones and natural disasters. This high-impact practice brief focuses on promoting the engagement and mobilisation of communities in group dialogue and action to promote healthy sexual relationships, a finding that emerged from research investigating community group engagement (CGE) interventions to encourage healthy SRH behaviours. The CGE activities included mapping exercises, social network approaches, exploratory games, dramas, case studies, prioritisation exercises and coalition-building. The briefing discusses barriers, family and social changes and individual changes that can lead to changes in SRH behaviours. In terms of impact it is reported that community group engagement can improve both men's and women's SRH knowledge, improve women's decision-making power, influence change at the community, family and individual levels by building capacity within the community and that it is associated with higher levels of contraceptive use. A specific example is provided from Uganda and a number of implementation experience pointers are outlined. Three priority questions for future research are also highlighted with the technical advisory group recommending that CGE interventions be more thoroughly researched and evaluated to assess the potential impact. The World Health Organization (WHO) has recently published updated guidelines on the prevention of sexual transmission of Zika virus, superseding the interim guidelines published in September 2016. The updated guidelines are based on the growing amount of data and research evidence in the period since September 2016 and are aimed at policy makers and healthcare professionals. Recommendations focus on three main areas: individuals living in areas with ongoing transmission of Zika virus, individuals living in areas without ongoing transmission of Zika virus travelling to or from areas with ongoing Zika virus transmission and recommendations about safer sex. Specific guidance is provided for women or couples planning to conceive or having sex that could result in conception and for pregnant women and their sexual partners. The Johns Hopkins Center for Communication Programs has developed a new online resource aimed at health professionals looking after patients with HIV, family planning programme managers, advocates and journalists. The Results4informedchoice website was developed in response to previous research that indicated that women using progestogen-only injectable contraceptive methods may be at a higher risk of acquiring HIV and in response to the initiation of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, which began in 2015. The ECHO trial is investigating the comparative risk of HIV acquisition among women using one of three contraceptive methods: depomedroxyprogesterone acetate (DMPA) (injectable), levonorgestrel-releasing (LNG) implants and copper intrauterine devices (IUDs). The ECHO trial results are due to be published in July 2019. The website provides access to resources and tools to help professionals to counsel women and ensure they have all the information required to make an informed contraceptive choice. The resource library provides links to the ECHO trial publications, programme reports and research presentations. Key HIV and contraception data is provided for individual countries and communications materials for the media. Society of Obstetricians and Gynaecologists of Canada (SOGC) The following guidelines are now available at www.jogc.com No. 378-Placentophagy No. 379-Attendance at and Resources for Delivery of Optimal Maternity Care Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) The following guidelines are now available at www.ranzcog.edu.au Updated Guidance on Abortion, College Statement, Abortion (C-Gyn 17) Updated Guidance on Abortion, College Statement, Use of Mifepristone for medical abortion (C-Gyn 21) American College of Obstetricians and Gynecologists (ACOG) The following guideline is now available at www.acog.org Practice Advisory: Management of Pregnant and Reproductive-Aged Women during a Measles Outbreak Faculty of Sexual and Reproductive Healthcare (FSRH) The following guideline is now available at www.fsrh.org FSRH Clinical Guideline: Overweight, Obesity and Contraception Society for Maternal–Fetal Medicine (SMFM) The following guideline is now available at www.smfm.org SMFM Consult Series #48: Immediate Postpartum Long-acting Reversible Contraception for Women at High Risk for Medical Complications EP3466371 (A1) Neovaginal prosthesis. This patent application relates to the development of a prosthesis for temporary insertion between the bladder and rectum in a person who has undergone vaginoplasty to create a vagina or neovagina. The prosthesis has been specifically designed to avoid the need for skin grafts from the patient and involves only the prosthesis with an additional coating of biocompatible and biodegradable mesh. Acien AP, Oliva MMA, Sanchez LM, Martinez GJ, Acien Sanchez MI. 10 April 2019. WO2019060882 (A1) System for supporting clinical decision-making in reproductive endocrinology and infertility. This patent application discusses development of a computer system providing clinical decision-making support regarding patient treatment during ovarian stimulation cycles. The inventors state that the system aims to aid decision-making to ensure the highest likelihood of pregnancy whilst accounting for patient well-being, alternative approaches and the risks associated with infertility treatment. This application claims the benefit of US Provisional Application No. 62/562994, filed 25 September 2017. Letterie G, MacDonald A. 28 March 2019. US2019094229 (A1) Methods of diagnosing, classifying and treating endometrial cancer and precancer. This patent application proposes methods and kits for the detection, classification and treatment of endometrial cancer. Specifically, this involves the detection of a receptor mutation in fibroblast growth factor receptor 2 (FGFR2) in a biological sample containing endometrial cells, where the mutation is associated with FGFR2 receptor activation. The presence of one or more activation mutations in the FGFR2 is said to indicate a diagnosis of endometrial cancer or pre-cancer in the woman. This patent application is a continuation of US patent application Ser. No. 15/088,099, filed 31 March 2016 (published as US20160209417), which is a continuation of US patent application Ser. No. 13/973,614, filed 22 August 2013 (published as US20140057261), which is a continuation-in-part of US patent application Ser. No. 12/532,563 filed 11 November 2009 (published as US20100111944), which is a US National Stage Application of International Patent Application No. PCT/US2008/058065 filed 24 March 2008, which claims priority to US Provisional Application No. 60/896,884, filed 23 March 2007 and US Provisional Application No. 60/982,093, filed 23 October 2007. Pollock P, Goodfellow P. 28 March 2019. US2019085083 (A1) KLRG1 signalling therapy. This patent application relates to the reported discovery that killer cell lectin-like receptor G1 (KLRG1) can function as a co-inhibitory receptor and could be a target for immunotherapy such as cancer immunotherapy. Specifically, the patent outlines the administration of an effective amount of a killer cell lectin-like receptor G1 (KLRG1)/ligand binding agent to disrupt KLRG1 signalling and activate CD8+ cytotoxic T and/or NK cells, which could be used to treat cancers including breast cancer, ovarian cancer and metastatic breast cancer. Greenberg S, Gulla SV, Thompson KE. 21 March 2019. The government of El Salvador has reportedly recently commuted the prison sentences of three women who had previously been imprisoned after experiencing obstetric emergencies. Women in El Salvador who experience pregnancy-related emergencies such as miscarriage can be accused by the authorities of having an abortion and be imprisoned on charges of aggravated homicide. Source: www.reproductiverights.org The UN Committee on Economic, Social and Cultural Rights recently ruled that an Italian in vitro fertilisation (IVF) clinic had violated a woman's human rights as a result of the country's fertility laws, which led to an enforced pregnancy. The woman tried to withdraw consent to an embryo transfer during IVF treatment (as a result of the embryo being graded ‘average quality’ and therefore at greater risk of a miscarriage) but law 40/2004, which regulates assisted reproductive technologies, reportedly states that consent can only be withdrawn before fertilisation has occurred and the clinic threatened to sue her if she refused to go ahead with the transfer. Source: www.bionews.org.uk Clinicians keen to keep up-to-date regarding clinical studies that are currently recruiting may find the following informative.