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Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic . Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches , while maintaining proven prevention measures using a vaccines-plus approach that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

Background: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.Methods: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.Findings: Between March 22, 2020, and Jan 29, 2021, 14304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.Interpretation: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Objective To assess whether exposure to high temperatures in pregnancy is associated with increased risk for preterm birth, low birth weight, and stillbirth. Design Systematic review and random effects meta-analysis. Data sources Medline and Web of Science searched up to September 2018, updated in August 2019. Eligibility criteria for selecting studies Clinical studies on associations between high environmental temperatures, and preterm birth, birth weight, and stillbirths. Results 14 880 records and 175 full text articles were screened. 70 studies were included, set in 27 countries, seven of which were countries with low or middle income. In 40 of 47 studies, preterm births were more common at higher than lower temperatures. Exposures were classified as heatwaves, 1°C increments, and temperature threshold cutoff points. In random effects meta-analysis, odds of a preterm birth rose 1.05-fold (95% confidence interval 1.03 to 1.07) per 1°C increase in temperature and 1.16-fold (1.10 to 1.23) during heatwaves. Higher temperature was associated with reduced birth weight in 18 of 28 studies, with considerable statistical heterogeneity. Eight studies on stillbirths all showed associations between temperature and stillbirth, with stillbirths increasing 1.05-fold (1.01 to 1.08) per 1°C rise in temperature. Associations between temperature and outcomes were largest among women in lower socioeconomic groups and at age extremes. The multiple temperature metrics and lag analyses limited comparison between studies and settings. Conclusions Although summary effect sizes are relatively small, heat exposures are common and the outcomes are important determinants of population health. Linkages between socioeconomic status and study outcomes suggest that risks might be largest in low and middle income countries. Temperature rises with global warming could have major implications for child health. Systematic review registration PROSPERO CRD 42019140136 and CRD 42018118113.

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Poor HIV care retention impedes optimal treatment outcomes in persons living with HIV. Women trying to become pregnant may be motivated by periconception horizontal and vertical transmission concerns and thus more likely to attend HIV care visits than women not trying to conceive. We estimated the effect of fertility intentions on HIV care attendance over 12 months among non-pregnant, HIV-positive women aged 18–35 years who were on or initiating antiretroviral therapy in Johannesburg, South Africa. The percentage of women attending an HIV care visit decreased from 93.4% in the first quarter to 82.8% in the fourth quarter. Fertility intentions were not strongly associated with care attendance in this cohort of reproductive-aged women; however, attendance declined over time irrespective of childbearing plans. These findings suggest a need for reinforced efforts to support care engagement and risk reduction, including safer conception practices for women wishing to conceive.

Access to quality-assured medical products improves health and save lives. However, one third of the world’s population lacks timely access to quality-assured medicines while estimates indicate that at least 10% of medicine in low- and middle-income countries (LMICs) are substandard or falsified (SF), costing approximately US$ 31 billion annually. National regulatory authorities are the key government institutions that promote access to quality-assured medicines and combat SF medical products but despite progress, regulatory capacity in LMICs is still insufficient. Continued and increased investment in regulatory system strengthening (RSS) is needed. We have therefore reviewed existing global normative documents and resources and engaged with our networks of global partners and stakeholders to identify three critical challenges being faced by NRAs in LMICs that are limiting access to medical products and impeding detection of and response to SF medicines. The challenges are; implementing value-added regulatory practices that best utilize available resources, a lack of timely access to new, quality medical products, and limited evidence-based data to support post-marketing regulatory actions. To address these challenges, we have identified seven focused strategies; advancing and leveraging convergence and reliance initiatives, institutionalizing sustainability, utilizing risk-based approaches for resource allocation, strengthening registration efficiency and timeliness, strengthening inspection capacity and effectiveness, developing and implementing risk-based post-marketing quality surveillance systems, and strengthening regulatory management of manufacturing variations. These proposed solutions are underpinned by 13 focused recommendations, which we believe, if financed, technically supported and implemented, will lead to stronger health system and as a consequence, positive health outcomes.

Environmental DNA (eDNA) analysis is a rapid, cost-effective, non-invasive biodiversity monitoring tool which utilises DNA left behind in the environment by organisms for species detection. The method is used as a species-specific survey tool for rare or invasive species across a broad range of ecosystems. Recently, eDNA and ‘metabarcoding’ have been combined to describe whole communities rather than focusing on single target species. However, whether metabarcoding is as sensitive as targeted approaches for rare species detection remains to be evaluated. The great crested newt Triturus cristatus is a flagship pond species of international conservation concern and the first UK species to be routinely monitored using eDNA. We evaluate whether eDNA metabarcoding has comparable sensitivity to targeted real-time quantitative PCR (qPCR) for T. cristatus detection. Extracted eDNA samples (N = 532) were screened for T. cristatus by qPCR and analysed for all vertebrate species using High-Throughput Sequencing technology. With qPCR and a detection threshold of 1/12 positive qPCR replicates, newts were detected in 50% of ponds. Detection decreased to 32% when the threshold was increased to 4/12 positive qPCR replicates. With metabarcoding, newts were detected in 34% of ponds without a detection threshold, and in 28% of ponds when a threshold (0.028%) was applied. Therefore, qPCR provided greater detection than metabarcoding but metabarcoding detection with no threshold was equivalent to qPCR with a stringent detection threshold. The proportion of T. cristatus sequences in each sample was positively associated with the number of positive qPCR replicates (qPCR score) suggesting eDNA metabarcoding may be indicative of eDNA concentration. eDNA metabarcoding holds enormous potential for holistic biodiversity assessment and routine freshwater monitoring. We advocate this community approach to freshwater monitoring to guide management and conservation, whereby entire communities can be initially surveyed to best inform use of funding and time for species-specific surveys.

OBJECTIVES: The objective of this research was to design relevant, tailored oral pre-exposure prophylaxis (PrEP) and early antiretroviral (ART) interventions for female sex workers (FSWs) in South Africa. This paper examines the methods, process and outcomes of employing an inductive approach to formative research exploring intervention feasibility and acceptability. SETTING: Research was conducted in several sex work-related settings including five sites in and around clinics and stakeholder offices. PARTICIPANTS: Participants in this research included stakeholders, experts in the field and FSWs. This included at least 25 separate engagements, 14 local organisations and 8 focus group discussions (FGDs) with 69 participants, in addition to ad hoc meetings. RESULTS: The first set of outcomes consisted of five selected methods: (1) stakeholder consultations; (2) site assessments and selection; (3) field observations and mapping; (4) development of supportive structures to encourage retention and intervention adherence; (5) FGDs conducted with FSWs to explore specifics of acceptability. In terms of feasibility, two sites were selected in central Johannesburg and Pretoria out of five considered. The urban site contexts varied, necessitating adjustments to intervention implementation. There was overall support for PrEP and early ART from stakeholders and FSWs. Concerns included potential issues with adherence to PrEP (and early ART), possible reduction in condom use, resistance to antiretrovirals and burden on scarce resources. These concerns indicated where special attention should be focused on education, messaging and programming as well as development of supportive structures. CONCLUSIONS: The inductive approach allowed for a wide range of perspectives, defining population needs and accessibility. This research illustrated how similar sex work environments can vary and how implementation of interventions may not be uniform across contexts. Lessons learnt in details could assist in future project designs and implementation of new interventions where feasibility, social and cultural factors affecting acceptability must be considered.

An innovative service for the palliative and end-of-life care of people with dementia was introduced at a UK hospice. This evaluation involved analysis of audit data, semi-structured interviews with project staff (n=3) and surveys of family carers (n=15) and professionals (n=20). The service has increased access to palliative, end-of-life care and other services. Improvements were reported in the knowledge, confidence and care skills of family carers and professionals. Carers felt better supported and it was perceived that the service enabled more patients to be cared for at home or in their usual place of care.

Background: In vitro, animal, biological and observational clinical studies suggest that some hormonal methods, particularly depot medroxyprogesterone acetate – DMPA, may increase women’s risk of HIV acquisition. DMPA is the most common contraceptive used in many countries worst affected by the HIV epidemic. To provide robust evidence for contraceptive decision-making among women, clinicians and planners, we are conducting the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study in four countries with high HIV incidence and DMPA use: Kenya, South Africa, Swaziland, and Zambia (Clinical Trials.gov identifier NCT02550067). Study design: We randomized HIV negative, sexually active women 16-35 years old requesting effective contraception and agreeing to participate to either DMPA, the copper T 380A intrauterine device or levonorgestrel implant. Participants attend a contraception support visit after 1 month and quarterly visits thereafter for 12 to 18 months. Participants receive a standard HIV prevention package and contraceptive side-effect management at each visit. The primary outcome is HIV seroconversion. Secondary outcomes include pregnancy, serious adverse events and method discontinuation. The sample size of 7800 women provides 80% power to detect a 50% difference in HIV risk between any of the three method pairs, assuming 250 incident infections per comparison. Ethical considerations: Several WHO consultations have concluded that current evidence on HIV risk associated with DMPA is inconclusive and that a randomized trial is needed to guide policy, counselling and choice. Previous studies suggest that women without a specific contraceptive preference are willing to accept randomization to different contraceptive methods. Stringent performance standards are monitored by an independent data and safety monitoring board approximately every 6 months. The study has been conducted with extensive stakeholder engagement. Conclusions: The ECHO study is designed to provide robust evidence on the relative risks (HIV acquisition) and benefits (pregnancy prevention) between three effective contraceptive methods.

BACKGROUND: Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. METHODS AND FINDINGS: The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. CONCLUSIONS: PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa.

Objective. To describe the epidemiology of incomplete abortion (spontaneous miscarriage and illegally induced) in South Africa.Design. Multicentre, prospective, descriptive study.Setting. Fifty-six public hospitals in nine provinces (a stratified, random sample of all hospitals treating gynaecological emergencies).Patients. All women of gestation under 22 weeks who presented with incomplete abortion during the 2-week study period.Main outcome measures. Incidence of, morbidity associated with and mortality from incomplete abortion.Main results. An estimated 44 686 (95% Cl 35 633 - 53 709) women per year were admitted to South Africa's public hospitals with incomplete abortion. An estimated 425 (95% Cl 78 - 735) women die in public hospitais from complications of abortion. Fifteen per cent (95% Cl 13 18) of patients have severe morbidity while a further 19% (95% Cl 16 - 22) have moderate morbidity, as assessed by categories designed for the study which largely reflect infection. There were marked inter-provincial differences and inter-age group differences in trimester of presentation and proportion of patients with appreciable morbidity.Conclusions. Incomplete abortions and, in particular, unsafe abortions are an important cause of mortality and morbidity in South Africa. The methods used in this study underestimate the true incidence for reasons that are discussed. A high priority should be given to the prevention of unsafe abortion.

Immune activation, characterized by polyclonal B-cell activation, accelerated T-cell turnover, dendritic cell depletion, and elevated proinflammatory cytokine levels, is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection [1]. Immune stimulation by HIV-1 contributes to the depletion of CD4+ T cells, rather than to the purging of virus, and has been associated with accelerated progression of HIV-1 disease [2–5]. The dysregulation of cytokines, important markers of immune activation, has been shown to contribute to viral replication and disease progression [6, 7]. While the relationship between HIV-1 pathogenesis and persistent immune activation has been well described [1, 2], the role of systemic inflammatory response and immune activation in HIV-1 transmission is less understood. Increased immune activation in persons infected with HIV-1 could result in increased viral replication that could facilitate HIV-1 infectiousness and onward transmission [8, 9], but no data have directly explored this hypothesis. Furthermore, for HIV-1–uninfected persons, immune activation and an elevated inflammatory response before infection has also been hypothesized to potentially heighten susceptibility and facilitate HIV-1 acquisition; however, few studies have directly compared systemic immune activation between those who acquire HIV-1 and those who are exposed but remain uninfected with HIV-1. Naranbhai et al found significant association between markers of systemic immune activation, including cytokine concentrations, and HIV-1 acquisition among women [10], but few other data are available on the role of systemic immune function in HIV-1 acquisition or transmission. Insight into the roles of innate and adaptive immune functions and HIV-1 susceptibility and infectiousness is an important factor in the development of effective prophylactic and therapeutic HIV-1 vaccines, as well as strategies for HIV-1 prevention, such as preexposure prophylaxis and microbicides. Findings from the Step HIV-1 vaccine trial showed that, in a prime-boost HIV-1 vaccine strategy based on an adenovirus type 5 (Ad5) vector, there was a trend toward increased HIV-1 acquisition among Ad5-seropositive individuals. This finding indicated that the amnestic immune response elicited was harmful [11], suggesting a challenge for vaccine development and a critical need to better understand how immune activation affects HIV-1 transmission. In African populations, where both HIV-1 infection and other infectious diseases are frequently prevalent, chronic immune activation may be heightened by the presence of other infections, both systemic and mucosal, that could contribute to increased susceptibility and infectiousness [12]. The aim of the present study was to assess whether differences in markers of immune activation, as measured by a data from a panel of cytokines, were associated with an increased risk of HIV-1 transmission among heterosexual HIV-1–serodiscordant couples. Assessment of these factors in cases of virologically linked HIV-1 transmission in a prospective cohort of HIV-1–serodiscordant couples permitted simultaneous evaluation of the relationship between systemic immune activation and both the heightened susceptibility of HIV-1–uninfected partners and the infectiousness of HIV-1–infected partners.

STUDY QUESTION: Do injectable and oral contraceptives increase the risk of human immunodeficiency virus (HIV) acquisition in women? SUMMARY ANSWER: After adjusting for confounders, evidence of a significantly increased risk of HIV remained for women using injectable depo-medroxyprogesterone (DMPA) (hazard ratio = 1.49, 95% confidence interval (1.06-2.08)) but not for injectable norethisterone-enanthate (Net-En) or oral contraceptive pills (OC). WHAT IS KNOWN ALREADY: An association between the use of some types of hormonal contraception (HC) methods and an increased risk of HIV, possibly through changes in the genital tract environment and alterations in the immune response, has been previously observed, although not consistently. A recent systematic review of these studies has highlighted the need for more definitive evidence. STUDY DESIGN, SIZE, DURATION: A secondary data analysis of the MDP301 phase 3 microbicide trial was conducted to estimate the effects of use of different methods of HC on the risk of HIV acquisition in women. HIV-negative women (n = 8663) with a median age of 28 years were included in the analysis; 382 HIV seroconverted by 52 weeks follow-up; 10% of women-years were lost to follow-up before 52 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Contraceptive use was reported at each 4-weekly visit. Cox proportional hazards (PH) models were used to estimate the effects of baseline and current use of injectable DMPA, injectable Net-En and OC compared with no HC, on the risk of HIV, adjusting for baseline and time-updated covariates. Causal effects for 52 weeks of HC use compared with no HC were estimated in a weighted Cox model, censoring women at deviation from baseline HC use (or non-use) or pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, 2499 (29%) women were on DMPA, 1180 (14%) on Net-En, and 1410 (16%) on OC; 3574 (40%) not on HC, started HC in follow-up. Adjusted hazard ratios (HR) for baseline HC use, compared with no HC, were 1.38 (95% confidence interval (CI) 1.07-1.78) for DMPA; 1.18 (0.86-1.62) for Net-En and 0.97 (0.68-1.38) for OC. The estimated causal effects of DMPA and Net-En over 52 weeks were: HR = 1.49 (95% CI 1.06-2.08) and HR = 1.31 (95% CI 0.62-1.61), respectively. LIMITATIONS, REASONS FOR CAUTION: A main limitation of the study was that it was a secondary analysis of data from a study that was not designed to investigate this question. Despite our best efforts, we cannot exclude residual confounding to explain the effect of DMPA. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study should be reviewed by the World Health Organization to determine whether current recommendations on the use of DMPA in settings with high HIV prevalence require modification. STUDY FUNDING/COMPETING INTERESTS: MDP is a partnership of African and European academic/government institutions with commercial organizations, which is funded by the UK Government (DFID and MRC), with support from IPM and EDCTP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: None.

Additional file 2: Table S1. Table of the raw data analysed using Genstat v18, VSNi, Rothampstead, UK.

Association between perspectives on acceptability collected at 12Â months and attendance at all four study visits. (DOCX 29 kb)

Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa

Introduction : Oral pre-exposure prophylaxis (PrEP) is a promising new prevention approach for those most at risk of HIV infection. However, there are concerns that behavioural disinhibition, specifically reductions in condom use, might limit PrEP’s protective effect. This study uses the case of female sex workers (FSWs) in Johannesburg, South Africa, to assess whether decreased levels of condom use following the introduction of PrEP may limit HIV risk reduction. Methods: We developed a static model of HIV risk and compared HIV-risk estimates before and after the introduction of PrEP to determine the maximum tolerated reductions in condom use with regular partners and clients for HIV risk not to change. The model incorporated the effects of increased STI exposure owing to decreased condom use. Noting that condom use with regular partners is generally low, we also estimated the change in condom use tolerated with clients only, to still achieve 50 and 90% risk reduction on PrEP. The model was parameterized using data from Hillbrow, Johannesburg. Sensitivity analyses were performed to ascertain the robustness of our results. Results: Reductions in condom use could be tolerated by FSWs with lower baseline condom use (65%). For scenarios where 75% PrEP effectiveness is attained, 50% HIV-risk reduction on PrEP would be possible even with 100% reduction in condom use from consistent condom use as high as 70% with clients. Increased exposure to STIs through reductions in condom use had limited effect on the reductions in condom use tolerated for HIV risk not to increase on PrEP. Conclusions: PrEP is likely to be of benefit in reducing HIV risk, even if reductions in condom use do occur. Efforts to promote consistent condom use will be critical for FSWs with high initial levels of condom use, but with challenges in adhering to PrEP.

Additional file 1. Additional information on the methodology employed in the study.

Additional file 3: Figure S1. Real-time PCR scores and statistical analysis for two ponds over a 12-month period.

South Africa has been engaged in pharmacovigilance (PV) activities to assess the impact of adverse drug reactions on public safety and health for 40 years. Activities have evolved from passive regulatory reporting to encompass active surveillance systems. The HIV and AIDS and TB epidemics stimulated pharmacoepidemiological research into the risks associated with medicines used in the standardised regimens of mass treatment programmes. Specific safety concerns, supported by robust local cohort data, have prompted major changes to national and international treatment policies. This chapter describes the expanding body of local knowledge and the historical and emergent surveillance systems that address the burden of drug-related harms, noting the challenges to health system responsiveness. The South African context presents a unique opportunity to characterise the scale and nature of such harms in mass HIV and AIDS and TB treatment programmes. The use of complex regimens at scale poses new PV challenges. There is an urgent need to develop cohesive, sustainable systems to support evidence-based decisions on appropriate regimen choices, while minimising medicine-associated risks. The increasing use of computerised clinical, laboratory and dispensing records, with unique patient identifiers facilitating data linkage, will increase PV surveillance capacity. A coherent national PV framework is an essential part of medicines policy, encompassing regulatory, programmatic and individual needs. Key pillars of this framework include: (i) consolidation and expansion of active and passive PV surveillance, optimising existing programmes; (ii) prioritising post-marketing monitoring within the new health products regulatory authority; and (iii) instilling a culture of active risk management in clinical practice through the creation of effective channels of communication and feedback into policy and practice.

Factors associated with participant retention; a generalised estimating equations analysis. (DOCX 28 kb)

BACKGROUND: Progress in achieving maternal health goals and the rates of reductions in deaths from individual conditions have varied over time and across countries. Assessing whether research priorities in maternal health align with the main causes of mortality, and those factors responsible for inequitable health outcomes, such as health system performance, may help direct future research. The study thus investigated whether the research done in low- and middle-income countries (LMICs) matched the principal causes of maternal deaths in these settings. METHODS: Systematic mapping was done of maternal health interventional research in LMICs from 2000 to 2012. Articles were included on health systems strengthening, health promotion; and on five tracer conditions (haemorrhage, hypertension, malaria, HIV and other sexually transmitted infections (STIs)). Following review of 35,078 titles and abstracts in duplicate, data were extracted from 2292 full-text publications. RESULTS: Over time, the number of publications rose several-fold, especially in 2004-2007, and the range of methods used broadened considerably. More than half the studies were done in sub-Saharan Africa (55.4 %), mostly addressing HIV and malaria. This region had low numbers of publications per hypertension and haemorrhage deaths, though South Asia had even fewer. The proportion of studies set in East Asia Pacific dropped steadily over the period, and in Latin America from 2008 to 2012. By 2008-2012, 39.1 % of articles included health systems components and 30.2 % health promotion. Only 5.4 % of studies assessed maternal STI interventions, diminishing with time. More than a third of haemorrhage research included health systems or health promotion components, double that of HIV research. CONCLUSION: Several mismatches were noted between research publications, and the burden and causes of maternal deaths. This is especially true for South Asia; haemorrhage and hypertension in sub-Saharan Africa; and for STIs worldwide. The large rise in research outputs and range of methods employed indicates a major expansion in the number of researchers and their skills. This bodes well for maternal health if variations in research priorities across settings and topics are corrected.

Background Robust population size estimates of female sex workers and other key populations in South Africa face multiple methodological limitations, including inconsistencies in surveillance and programmatic indicators. This has, consequently, challenged the appropriate allocation of resources and benchmark-setting necessary to an effective HIV response. A 2013-2014 integrated biological and behavioral surveillance (IBBS) survey from South Africa showed alarmingly high HIV prevalence among female sex workers in South Africa's three largest cities of Johannesburg (71.8%), Cape Town (39.7%), and eThekwini (53.5%). The survey also included several multiplier-based population size estimation methods. Objective The objective of our study was to present the selected population size estimation methods used in an IBBS survey and the subsequent participatory process used to estimate the number of female sex workers in three South African cities. Methods In 2013-2014, we used respondent-driven sampling to recruit independent samples of female sex workers for IBBS surveys in Johannesburg, Cape Town, and eThekwini. We embedded multiple multiplier-based population size estimation methods into the survey, from which investigators calculated weighted estimates and ranges of population size estimates for each city's female sex worker population. Following data analysis, investigators consulted civil society stakeholders to present survey results and size estimates and facilitated stakeholder vetting of individual estimates to arrive at consensus point estimates with upper and lower plausibility bounds. Results In total, 764, 650, and 766 female sex workers participated in the survey in Johannesburg, Cape Town, and eThekwini, respectively. For size estimation, investigators calculated preliminary point estimates as the median of the multiple estimation methods embedded in the IBBS survey and presented these to a civil society-convened stakeholder group. Stakeholders vetted all estimates in light of other data points, including programmatic experience, ensuring inclusion only of plausible point estimates in median calculation. After vetting, stakeholders adopted three consensus point estimates with plausible ranges: Johannesburg 7697 (5000-10,895); Cape Town 6500 (4579-9000); eThekwini 9323 (4000-10,000). Conclusions Using several population size estimates methods embedded in an IBBS survey and a participatory stakeholder consensus process, the South Africa Health Monitoring Survey produced female sex worker size estimates representing approximately 0.48%, 0.49%, and 0.77% of the adult female population in Johannesburg, Cape Town, and eThekwini, respectively. In data-sparse environments, stakeholder engagement and consensus is critical to vetting of multiple empirically based size estimates procedures to ensure adoption and utilization of data-informed size estimates for coordinated national and subnational benchmarking. It also has the potential to increase coherence in national and key population-specific HIV responses and to decrease the likelihood of duplicative and wasteful resource allocation. We recommend building cooperative and productive academic-civil society partnerships around estimates and other strategic information dissemination and sharing to facilitate the incorporation of additional data as it becomes available, as these additional data points may minimize the impact of the known and unknown biases inherent in any single, investigator-calculated method.

BackgroundThe efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis.MethodsWe examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts.ResultsTransmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060).ConclusionsCondoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.

Results on inequalities in access to maternal health services across different populations groups in South Africa. (DOCX 35Â kb)

Results on inequalities in maternal health outcomes across different populations groups in South Africa. (DOCX 26Â kb)

Results on inequalities in maternal health outcomes across different populations groups in South Africa. (DOCX 26Â kb)

BACKGROUND Immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected persons beginning antiretroviral therapy (ART) has been incompletely characterized for herpes simplex virus type 2 (HSV-2). METHODS We evaluated genital ulcer disease (GUD) and HSV-2-associated GUD at quarterly visits or when spontaneously reported at monthly visits in 3381 HIV/HSV-2-coinfected individuals in a placebo-controlled trial of suppressive acyclovir therapy to prevent HIV transmission, 349 of whom initiated ART during the study. Incidence was calculated for months before and after ART initiation, and incidence rate ratios (IRRs) were calculated. RESULTS GUD incidence increased from 15.0 episodes per 100 person-years before ART to 26.9 episodes per 100 person-years in the first full quarter after ART initiation (IRR, 1.83;P= .03), and the incidence of HSV-2-associated GUD increased from 8.1 to 19.0 episodes per 100 person-years (IRR, 2.20;P= .02). Subsequently, the incidence of GUD was similar to that before ART, although the numbers were small. Persons receiving suppressive acyclovir had fewer GUD episodes, but the IRR after beginning ART was similar in the acyclovir and placebo groups. CONCLUSIONS Initiation of ART in HIV/HSV-2-coinfected persons is associated with a transient increase in GUD and HSV-2 GUD. Acyclovir reduces the incidence of GUD but does not prevent an increase in GUD incidence during the first quarter following initiation of ART.

ObjectiveThe objective of this study is to assess whether antiretroviral therapy (ART) may diminish the effectiveness of hormonal contraceptive methods.MethodsUsing data from 5153 HIV-infected women followed prospectively for 1-3 years in three HIV prevention studies in Africa, we compared incident pregnancy rates by contraceptive method (implant, injectable, oral or none) and ART use. Multivariable Cox regression models were used to determine adjusted hazard ratios (aHRs) and test interactions between each method and ART use.ResultsDuring follow-up, 9% of women ever used implants, 40% used injectables and 14% used oral contraceptives; 31% of women ever used ART, mostly nevirapine (75% of ART users) or efavirenz-based (15%). Among women not using contraception, pregnancy rates were 13.2 and 22.5 per 100 women-years for those on and not on ART, respectively. Implants greatly reduced the incidence of pregnancy among both women on ART [aHR 0.06, 95% confidence interval (95% CI) 0.01-0.45] and not on ART (aHR 0.05, 95% CI 0.02-0.11). Injectables (aHR 0.18 on ART and aHR 0.20 not on ART) and oral contraceptives (aHR 0.37 on ART and aHR 0.36 not on ART) also reduced pregnancy risk, though by lesser degrees. ART use did not significantly diminish contraceptive effectiveness, although all methods showed nonstatistically significant reduced effectiveness when concurrently using efavirenz.ConclusionHormonal contraceptive methods are highly effective in reducing pregnancy risk in HIV-infected women, including those concurrently using ART. Studies of potential interactions between ART and contraceptives should evaluate real-world effectiveness of contraceptive methods; in this study, implants were the most effective method to prevent pregnancy, even during ART use.

1. Knowledge of species distribution is critical to ecological management and conservation biology. Effective management requires the detection of populations, which can sometimes be at low densities and is usually based on visual detection and counting. 2. Recently, there has been considerable interest in the detection of short species-specific environmental DNA (eDNA) fragments to allow aquatic species monitoring within different environments due to the potential of greater sensitivity over traditional survey methods which can be time-consuming and costly. 3. Environmental DNA analysis is increasingly being used in the detection of rare or invasive species and has also been applied to eDNA persistence studies and estimations of species biomass and distribution. When combined with next-generation sequencing methods, it has been demonstrated that entire faunas can be identified. 4. Different environments require different sampling methodologies, but there remain areas where laboratory methodologies could be standardized to allow results to be compared across studies. 5. Synthesis and applications. We review recently published studies that use eDNA to moni- tor aquatic populations, discuss the methodologies used and the application of eDNA analysis as a survey tool in ecology. We include innovative ideas for how eDNA can be used for conservation and management citing test cases, for instance, the potential for on-site analyses, including the application of eDNA analysis to carbon nanotube platforms or laser transmission spectroscopy to facilitate rapid on-site detections. The use of eDNA monitoring is already being adopted in the UK for ecological surveys.

Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C-infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.

BACKGROUND: Short-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated. METHODS: We randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation. RESULTS: A total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events. CONCLUSIONS: A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).

To compare the sexual behaviors of young people in South Africa (SA) and the United States (US) with the aim of better understanding the potential role of sexual behavior in HIV transmission in two countries with strikingly different HIV epidemics.

Understanding sexual behavior following diagnosis of acute HIV infection (AHI) is key to developing prevention programs targeting individuals diagnosed with AHI. We conducted separate qualitative and quantitative interviews with individuals newly diagnosed (n = 19) with AHI at 1-, 4- and 12-weeks post-diagnosis and one qualitative interview with individuals who had previously been diagnosed with AHI (n = 18) in Lilongwe, Malawi and Johannesburg, South Africa between October 2007 and June 2008. The majority of participants reported engaging in sexual activity following diagnosis with AHI with a significant minority reporting unprotected sex during this time. Most participants perceived to have changed their behavior following diagnosis. However, participants reported barriers to condom use and abstinence, in particular, long term relationships and the need for disclosure of sero-status. Understanding of increased infectiousness during AHI was limited. Participants reported a desire for a behavioral intervention at the time of AHI diagnosis, however, there were differences by country in the types of interventions participants found acceptable. Studies are underway to determine the feasibility, acceptability and potential effectiveness of interventions designed for individuals with AHI.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Search strategy. (DOCX 25 kb)

Search strategy. (DOCX 25 kb)

INTRODUCTION: Female sex workers (FSWs) are at high-risk for HIV acquisition in South Africa, where the advent of new HIV prevention and treatment interventions represent the potential to significantly impact the epidemic. This paper focuses on aspects of PrEP acceptability as a new intervention within the context of a larger service delivery programme including the simultaneous rollout of early ART. This paper explores PrEP acceptability among the FGD participants as future potential users. METHODS: FGDs were conducted in two clinic-based sites in Johannesburg and Pretoria. They aimed to explore community-level, multi-dimensional acceptability of PrEP within the context of imminent implementation alongside early ART in the TAPS Demonstration Project. Sex worker peer educators recruited participants from varying sex work locales. Facilitation was in English with adaptation by facilitators into local languages as needed. Transcripts were translated and transcribed into English. Thematic analysis was used to analyse the data. RESULTS: Four FGDs were conducted in each site for a total of eight FDGs and 69 participants. Demographics were largely similar across the sites. Overall, there was strong acceptability of PrEP among participants and positive anticipation for the imminent delivery of PrEP in the local sex worker clinics. Themes arising from the discussions exploring aspects of PrEP acceptability included: awareness and understanding of PrEP; PrEP motivations including choice, control, and vulnerability, managing PrEP risks and worries; and, de-stigmatizing and empowering PrEP delivery. Participant discussions and recommendations highlighted the importance of developing clear education and messaging to accurately convey the concept of PrEP, and intervention integration into supportive and tailored services. CONCLUSIONS: Through the course of these FGDs, PrEP became a positive and highly anticipated prevention option among the FSWs participants who endorsed implementation in their communities. Effective integration of PrEP into existing services will include comprehensive health programming where ART is also available, appropriate messaging, and support.

Mapping search strategy and protocol. (PDF 1497 kb)

Research topics and quality in countries and regions. (DOCX 38 kb)

Mapping search strategy and protocol. (PDF 1497 kb)

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Search strategy for review. (DOCX 25 kb)

Search strategy for review. (DOCX 25 kb)

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)