Developing and planning country-specific integrated knowledge translation strategies: experiences from the GELA project in Malawi, Nigeria, and South Africa.

BACKGROUND: The Global Evidence, Local Adaptation (GELA) project aims to maximise the impact of research on poverty-related diseases by increasing researchers' and decision-makers' capacity to use global research to develop locally relevant guidelines for newborn and child health in Malawi, Nigeria and South Africa. To facilitate ongoing collaboration with stakeholders, we adopted an Integrated Knowledge Translation (IKT) approach within GELA. Given limited research on IKT in African settings, we documented our team's IKT capacity and skills, and process and experiences with developing and implementing IKT in these countries. METHODS: Six IKT champions and a coordinator formed the GELA IKT Working Group. We gathered data on our baseline IKT competencies and processes within GELA, and opportunities, challenges and lessons learned, from April 2022 to March 2023 (Year 1). Data was collected from five two-hour Working Group meetings (notes, presentation slides and video recordings); [2] process documents (flowcharts and templates); and [3] an open-ended questionnaire. Data was analysed using a thematic analysis approach. RESULTS: Three overarching themes were identified: [1] IKT approach applied within GELA [2], the capacity and motivations of IKT champions, and [3] the experiences with applying the GELA IKT approach in the three countries. IKT champions and country teams adopted an iterative approach to carry out a comprehensive mapping of stakeholders, determine stakeholders' level of interest in and influence on GELA using the Power-Interest Matrix, and identify realistic indicators for monitoring the country-specific strategies. IKT champions displayed varying capacities, strong motivation, and they engaged in skills development activities. Country teams leveraged existing relationships with their National Ministries of Health to drive responses and participation by other stakeholders, and adopted variable communication modes (e.g. email, phone calls, social media) for optimal engagement. Flexibility in managing competing interests and priorities ensured optimal participation by stakeholders, although the time and resources required by IKT champions were frequently underestimated. CONCLUSIONS: The intentional, systematic, and contextualized IKT approach carried out in the three African countries within GELA, provides important insights for enhancing the implementation, feasibility and effectiveness of other IKT initiatives in Africa and similar low- and middle-income country (LMIC) settings.

Cochrane Corner: The use of anticoagulants in patients hospitalised with COVID-19.

Background: In this Cochrane Corner, we highlight the main findings of a Cochrane Review by Flumignan et al. entitled 'Anticoagulants for people hospitalised with COVID-19' and discuss the implications of these findings for research and practice in South Africa. In particular, we underscore the need for additional, high-quality, randomised controlled trials comparing different intensities of anticoagulation in patients with COVID-19 illness. Individuals in the intensive care unit and those hospitalised with another illness who are incidentally found to be infected with SARS-CoV-2 should still only be treated with prophylactic-dose low-molecular-weight heparin. Contributions of the study: This Cochrane Corner summarises findings in a recent systematic review on the use of anticoagulation in people hospitalised with COVID-19, and provides insights on the implications of these findings for implementation by clinicians in South Africa. It highlights the need for clinicians to balance the benefits and harms of providing an anticoagulant, while considering the patients underlying risk for bleeding and thromboembolism.

Healthcare Delivery.

We report here on the process and findings of a research prioritisation exercise for universal health coverage (UHC) in South Africa, conducted during the course of 2019. As plans to roll out National Health Insurance (NHI) gather momentum and we transition into a pandemic recovery phase, we believe that it is now time to revisit these priorities, while recognising that experiences with the COVID-19 pandemic have revealed new system challenges and strengths and introduced new priorities. The UHC research priority-setting methodology followed a stepwise process of collation of evidence, expert brainstorming and the development of a survey completed by 68 members of the Public Health Association of South Africa. Themes related to leadership and governance were ranked most highly, and with other priorities generated, provide an initial road map of knowledge needs that could guide individual institutions and commissioning by funding bodies. We further reflect on the importance of researcher-decision-maker dialogue and strengthening the contribution of health policy and systems research to policy and practice, especially as new reforms are implemented.

Factors that influence parental and caregiver acceptance of routine childhood vaccination: Summary of a qualitative evidence synthesis.

We summarise a Cochrane review of qualitative evidence that explored parents' views and practices around routine childhood vaccination, and provide implications for research and practice that are relevant to the South African (SA) context. Many public health interventions to encourage vaccination are informed by an assumption that vaccine hesitancy is due to a lack of knowledge or irrational forms of thinking. The findings from this review suggest that childhood vaccination views and practices are complex social processes that are shaped by multiple factors and carry a variety of meanings. As such, we suggest that biomedical approaches must be supplemented by more nuanced and sociopolitically informed strategies for enhancing and sustaining childhood vaccination practices in SA.

Meta-analytic magic, ivermectin, and socially responsible reporting.

Some clinicians prescribe ivermectin for COVID-19 despite a lack of support from any credible South African professional body. They argue that when faced by clinical urgency, weak signals of efficacy should trigger action if harm is unlikely. Several recent reviews found an apparent mortality benefit by including studies at high risk of bias and with active rather than placebo controls. If these studies are discounted, the pooled mortality effect is no longer statistically significant, and evidence of benefit is very weak. Relying on this evidence could cause clinical harm if used to justify vaccine hesitancy. Clinicians remain responsible for ensuring that guidance they follow is both legitimate and reliable. In the ivermectin debate, evidence-based medicine (EBM) principles have largely been ignored under the guise thatin a pandemic the 'rules are different', probably to the detriment of vulnerable patients and certainly to the detriment of the profession's image. Medical schools and professional interest groups are responsible for transforming EBM from a taught but seldom-used tool into a process of lifelong learning, promoting a consistent call for evidence-based and unconflicted debate integral to clinical practice.

Rapid review of the effects of cloth and medical masks for preventing transmission of SARS-CoV-2 in community and household settings.

BACKGROUND: Evidence on mask use in the general population is needed to inform SARS-CoV-2 responses. OBJECTIVES: To assess the effectiveness of cloth and medical masks for preventing SARS-CoV-2 transmission in community settings. METHODS: Two rapid reviews were conducted searching three electronic databases (PubMed, Embase, Cochrane Library) and two clinical trials registries on 30 and 31 March 2020. RESULTS: We screened 821 records and assessed nine full-text articles for eligibility. One and seven RCTs were included for cloth and medical mask reviews, respectively. No SARS-CoV-2-specific RCTs and no cloth mask RCTs in community settings were identified. A single hospital-based RCT provided indirect evidence that, compared with medical masks, cloth masks probably increase clinical respiratory illnesses (relative risk (RR) 1.56; 95% confidence interval (CI) 0.98 - 2.49) and laboratory-confirmed respiratory virus infections (RR 1.54; 95% CI 0.88 - 2.70). Evidence for influenza-like illnesses (ILI) was uncertain (RR 13.00; 95% CI 1.69 - 100.03). Two RCTs provide low-certainty evidence that medical masks may make little to no difference to ILI infection risk versus no masks (RR 0.98; 95% CI 0.81 - 1.19) in the community setting. Five RCTs provide low-certainty evidence that medical masks may slightly reduce infection risk v. no masks (RR 0.81; 95% CI 0.55 - 1.20) in the household setting. CONCLUSIONS: Direct evidence for cloth and medical mask efficacy and effectiveness in the community is limited. Decision-making for mask use may consider other factors such as feasibility and SARS-CoV-2 transmission dynamics; however, well-designed comparative effectiveness studies are required.

Adolescent girls and young women: Policy-to-implementation gaps for addressing sexual and reproductive health needs in South Africa.

Sexual and reproductive health (SRH) services for adolescent girls and young women (AGYW) remain inadequate - both globally and in South Africa (SA). We systematically scoped the available policies and guidelines for SRH-related policy for AGYW in SA. We found many available policies and guidelines to address issues of family planning, HIV prevention and care and antenatal and maternal care. Despite the wealth of guidance, SA's high rates of pregnancy and HIV transmission continue unabated. Our policy review and analysis identified issues for researchers and policymakers to consider when developing and implementing programmes to improve SRH services. We suggest that considering national policies alongside evidence of what is effective, as well as contextual barriers to and enablers of strategies to address AGYW needs for SRH, are among the key steps to addressing the policy-to-implementation gap.

Essential medicine selection during the COVID-19 pandemic: Enabling access in uncharted territory.

The COVID-19 pandemic requires urgent decisions regarding treatment policy in the face of rapidly evolving evidence. In response, the South African Essential Medicines List Committee established a subcommittee to systematically review and appraise emerging evidence, within very short timelines, in order to inform the National Department of Health COVID-19 treatment guidelines. To date, the subcommittee has reviewed 14 potential treatments, and made recommendations based on local context, feasibility, resource requirements and equity. Here we describe the rapid review and evidence-to-decision process, using remdesivir and dexamethasone as examples. Our experience is that conducting rapid reviews is a practical and efficient way to address medicine policy questions under pandemic conditions.

Interventions for preventing unintended pregnancies among adolescents.

South Africa (SA) has an increasingly high rate of unintended pregnancies among adolescents, which are coupled with poor contraception knowledge. We highlight a systematic review that evaluated the effects of prevention interventions for unintended adolescent pregnancies, and provide implications for practice that are relevant to the SA context. The findings suggest the need for multifaceted interventions that are aligned with adolescent sexual and reproductive health best practices to address the unmet contraception knowledge gap, as well as unintended pregnancies among adolescents.

First social impact bond for the SAMRC: A novel financing strategy to address the health and social challenges facing adolescent girls and young women in South Africa.

A social impact bond (SIB) is an innovative financing mechanism to attract investors to social programmes traditionally funded by governments. In this article, in celebration of the 50th anniversary of the South African Medical Research Council (SAMRC), the authors describe the SAMRC's first foray into this new world of financing through a SIB to improve the health and quality of life of adolescent girls and young women (AGYW). The AGYW SIB is in its preparatory phase and is scheduled for implementation in 2020. The authors describe the mechanism, including financial flows and the process of customising the SIB to meet the needs of AGYW, focusing on HIV prevention and treatment and the prevention and management of unintended pregnancies in schoolgoing AGYW. The authors outline an approach to designing the package of interventions, the metrics associated with such a programme and the business model. It is hypothesised that the proposed approach will lead to an improvement in programmatic outcomes, monitoring and evaluation tools and cost-effectiveness, and will develop key learning data for the future use of SIBs in health service delivery.

South African clinical practice guidelines: A landscape analysis.

BACKGROUND: South Africa (SA) is in the process of implementing National Health Insurance (NHI), which will require co-ordination of health provision across sectors and levels of care. Clinical practice guidelines (CPGs) are tools for standardising and implementing care, and are intended to influence clinical decision-making with consequences for patient outcomes, health system costs and resource use. Under NHI, CPGs will be used to guide the provision of healthcare for South Africans. It is therefore important to explore the current landscape of CPG developers and development. OBJECTIVE: To identify and describe all CPGs available in the public domain produced by SA developers for the SA context. METHODS: We conducted a cross-sectional evaluation using a two-part search process: an iterative, electronic search of grey literature and relevant websites (161 websites searched), and a systematic search for peer-reviewed literature (PubMed) after publication year 2000. CPGs were identified, and data were extracted and categorised by two independent reviewers. Any discrepancies were referred to a third reviewer. Data extracted included a description of the developer, condition, and reporting of items associated with CPG quality. RESULTS: A search conducted in May 2017 identified 285 CPGs published after January 2000. Of those, 171 had been developed in the past 5 years. Developers included the national and provincial departments of health (DoH), professional societies and associations, ad hoc collaborations of clinicians, and the Council for Medical Schemes. Topics varied by developer; DoH CPGs focused on high-burden conditions (HIV/AIDS, tuberculosis and malaria), and other developers focused on non-communicable diseases. A conflict of interest statement was included in 23% of CPGs developed by societies or clinicians, compared with 4% of DoH CPGs. CONCLUSION: Accessing CPGs was challenging and required extensive searching. SA has many contributors to CPG development from the public and private sectors and across disciplines, but there is no formal co-ordination or prioritisation of topics for CPG development. Different versions of the CPGs were identified and key quality items were poorly reported, potentially affecting the usability and credibility of those available. There was substantial variation in CPG comprehensiveness and methodological approach. Establishing a national CPG co-ordinating unit responsible for developing standards for CPG development along with clinical quality standards, and supporting high-quality CPG development, is one essential step for moving forward with NHI.

Building capacity for development and implementation of clinical practice guidelines.

Robust, reliable and transparent methodologies are necessary to ensure that clinical practice guidelines (CPGs) meet international criteria. In South Africa (SA) and other low- and middle-income countries, upskilling and training of individuals in the processes of CPG development is needed. Since de novo CPG development is time-consuming and expensive, new emerging CPG-development approaches (adopting, contextualising, adapting and updating existing good-quality CPGs) are potentially more appropriate for our context. These emerging CPG-development methods are either not included or sparsely covered in existing training opportunities. The SA Guidelines Excellence (SAGE) team has responded innovatively to the need for CPG training in SA. We have revised an existing SA course and developed an online, open-access CPG-development toolkit. This Guideline Toolkit is a comprehensive guideline resource designed to assist individuals who are interested in knowing how to develop CPGs. Findings from the SAGE project can now be implemented with this innovative CPG training programme. This level of CPG capacity development has the potential to influence CPG knowledge, development, practices and uptake by clinicians, managers, academics and policy-makers around the country.

Antibiotic prescription patterns of South African general medical practitioners for treatment of acute bronchitis.

BACKGROUND: Antibiotic resistance is a significant public health problem. Prudent use of antibiotics is crucial in reducing this resistance. Acute bronchitis is a common reason for consultations with general medical practitioners, and antibiotics are often prescribed even though guidelines recommend not prescribing them for uncomplicated acute bronchitis. OBJECTIVE: To analyse the antibiotic prescription patterns of South African (SA) general medical practitioners in the treatment of acute bronchitis. METHODS: The 2013 claims for members of 11 health insurance schemes were analysed to assess antibiotic prescription patterns for patients diagnosed with acute bronchitis. The patterns were assessed by type of bronchitis, chronic health status of the patients, sex and age group. The types of antibiotic prescribed were also analysed. RESULTS: Of 166 821 events analysed, an antibiotic was prescribed in more than half (52.9%). There were significant differences by type of bronchitis and chronic health status. Patients with viral bronchitis were more likely to be prescribed an antibiotic than those with bacterial bronchitis (odds ratio (OR) 1.17, 95% confidence interval (CI) 1.08 - 1.26). Patients with a chronic illness were less likely to be prescribed an antibiotic than those without (OR 0.58, 95% CI 0.57 - 0.60). More than 70% of the antibiotics prescribed were cephalosporins, penicillins and other beta-lactams. CONCLUSIONS: Prescription rates of antibiotics for acute bronchitis by SA general medical practitioners are high. There is an urgent need to follow the guidelines for antibiotic use for acute bronchitis to reduce the likelihood of increasing resistance to available antibiotics.

South African Guidelines Excellence (SAGE): Adopt, adapt, or contextualise?

Clinical practice guideline (CPG) activities must be planned carefully for efficient use of available resources and evidence-based implementation. De novo development of CPGs may sometimes 'recreate the wheel' and delay implementation. Three innovative alternatives to de novo CPG development (adopt, contextualise or adapt) are outlined, which have greater potential than de novo development to best use the limited available resources, personnel and time in settings such as South Africa.

The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients.

BACKGROUND: Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions. METHODS: An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine. RESULTS: We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 µg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 µg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax. CONCLUSION: Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group. TRIAL REGISTRATION: Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients.

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC((0-8 h))] (P < 0.0001) and dihydroartemisinin AUC((60-68 h)) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T(max)). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.