Systematic review: Safety of surgical male circumcision in context of HIV prevention public health programmes.

Background: Since the recommendation of voluntary medical male circumcision (VMMC) to reduce the risk of heterosexually acquired HIV, a number of adolescent boys and men in 15 priority countries in Africa have been circumcised. Our primary goal was to identify the incidence of adverse events (AEs) associated with VMMC and to assess the safety profile among adolescent boys 10 - 14 years. Methods: We searched the databases MEDLINE and Embase, WHO, and conference abstracts from 2005 to 2019. The incidence of AEs was estimated by type of AE, size of study and age. Results: We retained 40 studies. Severe and moderate AEs overall were estimated at 0.30 per 100 VMMC clients with wide variability per study type. A higher rate was noted in small and moderate scale programmes and device method research studies compared with larger scale programmes. There was a limited number of studies reporting AEs among younger adolescent boys and they had higher infection-related AEs than those aged 20 years and older. Case studies noted rare AEs such as necrotizing fasciitis, tetanus, and glans injury. Conclusions: AE rates were comparable to those from the randomized controlled trials (RCTs) that led to recommendations and implementation of VMMC in high HIV burden countries, despite being implemented in low resource settings. Clients over time have increasingly included adolescents under the age of 15 years. Studies suggest potentially higher risks in this age group. As VMMC services are sustained, patient safety surveillance systems and promoting a patient safety culture are crucial to identify and mitigate potential harms from medical male circumcision.

Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies.

Background: Human immunodeficiency virus (HIV)-infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified. Methods: Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" were used to estimate the relative contribution of risk factors to overall mortality. Results: Cumulative incidence of death was 5.5% (95% confidence interval, 5.1-5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months. Conclusions: Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates.

Patterns of HIV Care Clinic Attendance and Adherence to Antiretroviral Therapy Among Pregnant and Breastfeeding Women Living With HIV in the Context of Option B+ in Zimbabwe.

BACKGROUND: Consistent use of antiretroviral therapy (ART) during pregnancy and breastfeeding reduces the likelihood of mother-to-child HIV transmission. All pregnant and breastfeeding women living with HIV in Zimbabwe are offered ART with same-day initiation regardless of CD4 count (Option B+). We investigated patterns of clinic attendance and adherence to ART among HIV-infected pregnant women in Zimbabwe. METHODS: The Evidence for Elimination cluster-randomized trial evaluating point-of-care CD4 testing included 1150 HIV-infected ART-naive women attending antenatal care between January 2014 and June 2015. Thirty-two primary care facilities were randomized between 2 arms. In this secondary analysis of Evidence for Elimination data collected from routine clinic records, we classified women by number of pills dispensed, and estimated adherence from the ratio of pills to days since ART initiation (Medication Possession Ratio, adherent if ≥95%) or the period when they stopped receiving medication. RESULTS: Two-thirds (67.7%) were still receiving medication 1 year after initiation; less than half of the cohort (39.1%) were adherent. Younger women, newly diagnosed with HIV, and/or first presenting to antenatal care in their third trimester were more likely to drop from care or be nonadherent 360 days after ART initiation. CONCLUSION: Adherence to ART is suboptimal particularly among young, newly diagnosed, and/or late presenting patients. Interventions that target these groups, as well as provide additional support to all women who are newly diagnosed, may improve Option B+ ART care. More information is needed about the barriers to ART care among late presenters and teenagers.

Innovative Methods of Male Circumcision for HIV Prevention-Getting the Right Evidence.

World Health Organization recommends that countries with hyperendemic and generalized HIV epidemics implement voluntary medical male circumcision programs for HIV prevention. Innovative methods of male circumcision including devices have the potential to simplify the procedure, reduce time and cost, increase client acceptability, enhance safety, and expand the numbers of providers who may perform circumcision. We describe work led by World Health Organization and supported by global partners to define a pathway for the evaluation of efficacy and safety of male circumcision devices, to set priority criteria, and to establish a process to guide the use of devices in publicly funded voluntary medical male circumcision programs for HIV prevention. A device classification scheme, an expert Technical Advisory Group on Innovations in Male Circumcision, and a formal prequalification program have also guided considerations on safe use of devices. A rigorous approach was deemed appropriate given the intervention is for use among healthy men for public health purposes. The pathway and processes led to coordinated research, better standardization in research outcomes, and guidance that informed the research, introduction and implementation phases. The lessons learnt from this case study can inform evaluation and use of future public health innovations.

Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A.

OBJECTIVES: To compare rates of unintended pregnancy, method continuation and reasons for removal among women using the 52-mg levonorgestrel (daily release 20 microg) intrauterine device (LNG-IUD) or the copper T 380 A IUD (TCu380A). STUDY DESIGN: This was an open-label 7-year randomized controlled trial in 20 centres, 11 of which in China. Data on 1884 women with interval insertion of the LNG-IUD and 1871 of the TCu380A were analysed using life tables with 30-day intervals and Cox proportional hazards models. RESULTS: The cumulative 7-year pregnancy rate of the LNG-IUD was 0.5 (standard error 0.2) per 100, significantly lower than 2.5 (0.4) per 100 of the TCu380A, cumulative method discontinuation rates at 7 years were 70.6 (1.2) and 40.8 (1.3) per 100, respectively. Dominant reasons for discontinuing the LNG-IUD were amenorrhea (26.1 [1.3] per 100) and reduced bleeding (12.5 [1.1] per 100), particularly in Chinese women and, for the TCu380A, increased bleeding (9.9 [0.9] per 100), especially among non-Chinese women. Removal rates for pain were similar for the two intrauterine devices (IUDs). Cumulative rates of removal for symptoms compatible with hormonal side effects were 5.7 (0.7) and 0.4 (0.2) per 100 for the LNG-IUD and TCu380A, respectively, and cumulative losses to follow-up at 7 years were 26.0 (1.4) and 36.9 (1.3) per 100, respectively. CONCLUSION: The LNG-IUD and the TCu380A have very high contraceptive efficacy, with the LNG-IUD significantly higher than the TCu380A. Overall rates of IUD removals were higher among LNG-IUD users than TCu380A users. Removals for amenorrhea appeared culturally associated. IMPLICATIONS: The 52-mg LNG-IUD and the TCu380A have very high contraceptive efficacy through 7 years. As an IUD, the unique side effects of the LNG-IUD are reduced bleeding, amenorrhea and symptoms compatible with hormonal contraceptives.

WHO guidance grounded in a comprehensive approach to sexual and reproductive health and human rights: topical pre-exposure prophylaxis.

INTRODUCTION: Two new microbicide products based on topical (vaginal) application of antiretroviral drugs - 1% tenofovir gel and the dapivirine ring - are currently in late-stage clinical testing, and results on their safety and effectiveness are expected to become available in early 2015. WHO guidelines on the use of topical pre-exposure prophylaxis (topical PrEP) are important in order to ensure that these new prevention products are optimally used. DISCUSSION: Given that these new topical PrEP products are designed to be woman initiated and will likely be delivered in reproductive health settings, it is important to ensure that the guidance be framed in the context of comprehensive sexual and reproductive health and human rights. In addition to the safety and effectiveness data resulting from clinical trials, and the regulatory approval required for new products, the WHO normative guidelines on the use of topical PrEP will be essential for rapid roll-out in countries. CONCLUSIONS: Human rights standards and principles provide a framework for the provision of woman-initiated HIV prevention products. These include addressing issues related to the gender inequities which are linked to the provision of HIV-prevention, treatment and care for young girls and women. Effective programming for women and girls must therefore be based on understanding the local, social and community contexts of the AIDS epidemic in the country, and adapting HIV strategies and programmes accordingly. Such a framework therefore is needed not only to ensure optimal uptake of these new products by women and girls but also to address sociocultural barriers to women's and girls' access to these products.

Preparing for microbicide introduction, rollout, and sustained access.

Two topical vaginal microbicide candidates for HIV prevention are at an advanced stage of clinical testing, with efficacy results from three clinical trials expected within the next 2 years. Therefore, preparations for introducing and ensuring access to these products in the event that they are proven safe and effective now require increased attention. Microbicides are expected to fill an important global public health need for HIV prevention options for women. They have been developed almost exclusively with public and private funding through academic and nongovernmental institutions and minimal involvement of commercial pharmaceutical partners. Efficient and rapid introduction of a new public health technology requires a broad range of expertise and collaborations, some of which are new to the microbicide field as products are at last completing late-stage pivotal licensure studies. Strong leadership, political commitment, and considerable financial investments will be required to ensure successful distribution as well as uptake and continued access to this new product class. This paper highlights work conducted since 2000 by scientists, advocates, and public health officials to prepare for microbicide introduction, and discusses some of the needed actions to ensure that products will become readily accessible to the women who need them.

Voluntary medical male circumcision: an HIV prevention priority for PEPFAR.

As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the President's Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenya's Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods-such as medical devices that remove the foreskin without injected anesthesia and/or sutures-are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all.

Voluntary medical male circumcision: a framework analysis of policy and program implementation in eastern and southern Africa.

BACKGROUND: Following confirmation of the effectiveness of voluntary medical male circumcision (VMMC) for HIV prevention, the World Health Organization and the Joint United Nations Programme on HIV/AIDS issued recommendations in 2007. Less than 5 y later, priority countries are at different stages of program scale-up. This paper analyzes the progress towards the scale-up of VMMC programs. It analyzes the adoption of VMMC as an additional HIV prevention strategy and explores the factors may have expedited or hindered the adoption of policies and initial program implementation in priority countries to date. METHODS AND FINDINGS: VMMCs performed in priority countries between 2008 and 2010 were recorded and used to classify countries into five adopter categories according to the Diffusion of Innovations framework. The main predictors of VMMC program adoption were determined and factors influencing subsequent scale-up explored. By the end of 2010, over 550,000 VMMCs had been performed, representing approximately 3% of the target coverage level in priority countries. The "early adopter" countries developed national VMMC policies and initiated VMMC program implementation soon after the release of the WHO recommendations. However, based on modeling using the Decision Makers' Program Planning Tool (DMPPT), only Kenya appears to be on track towards achievement of the DMPPT-estimated 80% coverage goal by 2015, having already achieved 61.5% of the DMPPT target. None of the other countries appear to be on track to achieve their targets. Potential predicators of early adoption of male circumcision programs include having a VMMC focal person, establishing a national policy, having an operational strategy, and the establishment of a pilot program. CONCLUSIONS: Early adoption of VMMC policies did not necessarily result in rapid program scale-up. A key lesson is the importance of not only being ready to adopt a new intervention but also ensuring that factors critical to supporting and accelerating scale-up are incorporated into the program. The most successful program had country ownership and sustained leadership to translate research into a national policy and program. Please see later in the article for the Editors' Summary.

Assessing menopausal status in women aged 40 - 49 using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraception.

BACKGROUND: Determining symptoms of menopause in older users of hormonal injectable contraceptives may be challenging, owing to method-induced amenorrhoea, suppression of follicle-stimulating hormone (FSH) and vasomotor symptoms. OBJECTIVE: To investigate menopausal symptoms in women aged 40 - 49 using injectable contraceptives depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) or combined oral contraceptives (COCs), compared with non-users of hormonal contraception. METHODS: Women using DMPA (N = 127), NET-EN (N = 102), COCs (N = 106) and 161 non-hormonal contraceptive user controls were recruited. Baseline visit serum FSH was measured and information was collected on vasomotor symptoms and menstrual regularity. RESULTS: There was no difference in reporting of vasomotor symptoms between the groups. There was no evidence of a difference in FSH level between non-users (mean FSH 26.7 IU/ml, SD 28.7) and DMPA users (mean FSH 23.1 IU/ml, SD 27.8) (p = 0.64). However, the NET-EN (mean FSH 11.0 IU/ml, SD 10.9) (p = 0.003) and COC groups (mean FSH 12.5 IU/ml, SD 18.7) (p = 0.001) had significantly lower FSH levels compared with the non-user group. CONCLUSION: The lower FSH levels found in the NET-EN and COC users compared with controls may indicate a greater degree of suppression of FSH levels in these two methods, compared with DMPA. Measuring FSH levels may therefore be informative of menopausal status in DMPA users but not in NET-EN or COC users. Vasomotor symptoms may assist in assessing menopausal status in DMPA, NET-EN and COC users.

Female genital mutilation and obstetric outcome: WHO collaborative prospective study in six African countries.

BACKGROUND: Reliable evidence about the effect of female genital mutilation (FGM) on obstetric outcome is scarce. This study examines the effect of different types of FGM on obstetric outcome. METHODS: 28 393 women attending for singleton delivery between November, 2001, and March, 2003, at 28 obstetric centres in Burkina Faso, Ghana, Kenya, Nigeria, Senegal, and Sudan were examined before delivery to ascertain whether or not they had undergone FGM, and were classified according to the WHO system: FGM I, removal of the prepuce or clitoris, or both; FGM II, removal of clitoris and labia minora; and FGM III, removal of part or all of the external genitalia with stitching or narrowing of the vaginal opening. Prospective information on demographic, health, and reproductive factors was gathered. Participants and their infants were followed up until maternal discharge from hospital. FINDINGS: Compared with women without FGM, the adjusted relative risks of certain obstetric complications were, in women with FGM I, II, and III, respectively: caesarean section 1.03 (95% CI 0.88-1.21), 1.29 (1.09-1.52), 1.31 (1.01-1.70); postpartum haemorrhage 1.03 (0.87-1.21), 1.21 (1.01-1.43), 1.69 (1.34-2.12); extended maternal hospital stay 1.15 (0.97-1.35), 1.51 (1.29-1.76), 1.98 (1.54-2.54); infant resuscitation 1.11 (0.95-1.28), 1.28 (1.10-1.49), 1.66 (1.31-2.10), stillbirth or early neonatal death 1.15 (0.94-1.41), 1.32 (1.08-1.62), 1.55 (1.12-2.16), and low birthweight 0.94 (0.82-1.07), 1.03 (0.89-1.18), 0.91 (0.74-1.11). Parity did not significantly affect these relative risks. FGM is estimated to lead to an extra one to two perinatal deaths per 100 deliveries. INTERPRETATION: Women with FGM are significantly more likely than those without FGM to have adverse obstetric outcomes. Risks seem to be greater with more extensive FGM.

Detection of raised FSH levels among older women using depomedroxyprogesterone acetate and norethisterone enanthate.

The objective of this study was to investigate whether follicle-stimulating hormone (FSH) levels can be used reliably to indicate approaching menopause in older (aged 40-49), long-term users of depomedroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN). One-hundred and seventeen women using DMPA, 60 NET-EN users and 161 nonusers of contraception were recruited. At recruitment, serum FSH levels were measured and questions were asked regarding menopausal symptoms, menstrual cycle and date of last injection. Results of the recruitment blood test showed that 32% of the nonusers had FSH levels in the menopausal range >25.8 mIU/mL compared to 28% of the DMPA users and 9% of the NET-EN group. After adjusting for age, there was no significant difference between the 3 groups (p = 0.13). An increase of 1 year in age increased the FSH level by 3 mIU/mL (p < 0.001). All the hormonal contraceptive users were between 1 day and 12 weeks of their injection interval. Many had been using the injectable contraceptive method for over 10 years and almost all were amenorrheic at the time of recruitment. The data show that a raised FSH level can be detected during use of DMPA and NET-EN and could be used as a menopausal indicator without interrupting method use in this group of contraceptive users.

Structural integrity of the polyurethane female condom after multiple cycles of disinfection, washing, drying and relubrication.

The female condom provides an important alternative means of protection against HIV and other sexually transmitted infections for women, particularly in situations where partners are reluctant or refuse to use male condoms. The relatively high cost of the device, however, is a barrier to its use in resource-poor environments. This has led to some reuse of the product and two studies have demonstrated that female condoms can withstand a limited level of reuse without an excessive loss of structural integrity when washed with soap and water. A consultation on female condom reuse convened by the World Health Organization and the Joint United Nations Programme on AIDS in June 2000 recommended that all used female condoms should be disinfected immediately after use, before washing. The effect of such treatments on the female condom was not known. This study was undertaken to assess the effect of the disinfection, washing, drying and relubrication on the properties of the condom. Samples from three batches of female condoms were subjected to seven treatment cycles before being tested for structural integrity. In all cases the batches of condoms complied with the manufacturer's release specification for the product after treatment. Some minor changes in properties were seen but these were not considered important. There was evidence of a small increase in the number of condoms with holes following repeated disinfection and washing cycles, suggesting that excessive or rough handling can damage the condom. Condoms should therefore be handled carefully and inspected thoroughly for signs of damage after washing and drying before being stored with the intention of subsequently reusing the device.