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The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines.We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021.One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p 0.001).In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.

Summary Evaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the potential reasons for the increasing popularity of cluster trials in low-income and middle-income countries. We also draw on key areas of global health research for an assessment of common trial planning practices, and we address their methodological shortcomings and pitfalls. Lastly, we discuss alternative approaches for population-level intervention trials that could be useful for research undertaken in low-income and middle-income countries for situations in which the use of cluster randomisation might not be appropriate.

Supplemental Digital Content is Available in the Text., Introduction: The World Health Organization recommends differentiated service delivery (DSD) to support resource-limited health systems in providing patient-centered HIV care. DSD offers alternative care models to clinic-based care for people living with HIV who are stable on antiretroviral therapy (ART). Despite good patient-related outcomes, there is limited evidence of their sustainability. Our review evaluated the reporting of sustainability indicators of DSD interventions conducted in sub-Saharan Africa (SSA). Methods: We searched PubMed and EMBASE for studies conducted between 2000 and 2019 assessing DSD interventions targeting HIV-positive individuals who are established in ART in sub-Saharan Africa. We evaluated them through a comprehensive sustainability framework of constructs categorized into 6 domains (intervention design, process, external environment, resources, organizational setting, and people involvement). We scored each construct 1, 2, or 3 for no, partial, or sufficient level of evidence, respectively. Interventions with a calculated sustainability score (overall and domain-specific) of >90% or domain-specific median score >2.7 were considered likely to be sustainable. Results: Overall scores ranged from 69% to 98%. Top scoring intervention types included adherence clubs (98%) and community ART groups (95%) which comprised more than half of interventions. The highest scoring domains were design (2.9) and organizational setting (2.8). The domains of resources (2.4) and people involvement (2.3) scored lowest revealing potential areas for improvement to support DSD sustainability. Conclusions: With the right investment in stakeholder involvement and domestic funding, DSD models generally show potential for sustainability. Our results could guide informed decisions on which DSD intervention is likely to be sustainable per setting and highlight areas that could motivate further research.

Objective: To assess the time from HIV diagnosis to ART initiation and the effect of rapid ART initiation (i.e. within 7 days of HIV diagnosis) on attrition and virologic and immunologic responses among MSM in Burkina Faso, Côte d’Ivoire, Mali, and Togo. Design: Prospective cohort study between 2015 and 2019. Methods: MSM aged 18 years or older newly diagnosed with HIV infection were eligible to participate. ART was proposed to participants upon HIV diagnosis, irrespective of clinical stage and CD4+ cell count, and was initiated as soon as possible, with no specific time frame. Determinants of rapid ART initiation and its effect on treatment outcomes were assessed using multivariate analyses. Results: Of 350 MSM, 335 (95.7%) initiated ART after a median time of 5 days. Of the latter, 216 (64.5%) had rapid ART initiation. The 335 participants were followed up for a median time of 24.1 months. One hundred and eleven (33.1%) were not retained in care. Rapid ART initiation was less likely in participants with a CD4+ cell count at least 200 cells/μl [adjusted odds ratio (aOR) 0.37, 95% confidence interval (CI) 0.15–0.88]. It improved viral load suppression (aOR 6.96, 95% CI 1.98–24.46) but had no effect on attrition (aOR 0.87, 95% CI 0.57–1.33) or CD4+ cell count increase (adjusted coefficient 28.23, 95% CI −17.00 to 73.45). Conclusion: These results in MSM in West Africa support the WHO recommendation for rapid ART initiation. Clinics need to develop context-specific strategies for rapid ART initiation and for retaining MSM in HIV care. ClinicalTrials.gov, number NCT02626286.

Tuberculosis (TB) remains a leading cause of morbidity and mortality among people living with HIV. HIV-associated TB disproportionally affects African countries, particularly vulnerable groups at risk for both TB and HIV. Currently available TB diagnostics perform poorly in people living with HIV; however, new diagnostics such as Xpert Ultra and lateral flow urine lipoarabinomannan assays can greatly facilitate diagnosis of TB in people living with HIV. TB preventive treatment has been underutilized despite its proven benefits independent of antiretroviral therapy (ART). Shorter regimens using rifapentine can support increased availability and scale-up. Mortality is high in people with HIV-associated TB, and timely initiation of ART is critical. Programs should provide decentralized and integrated TB and HIV care in settings with high burden of both diseases to improve access to services that diagnose TB and HIV as early as possible. The new prevention and diagnosis tools recently recommended by WHO offer an immense opportunity to advance our fight against HIV-associated TB. They should be made widely available and scaled up rapidly supported by adequate funding with robust monitoring of the uptake to advance global TB elimination.

Background We conducted a systematic review and network meta-analysis to identify which human immunodeficiency virus (HIV) self-testing (HIVST) distribution strategies are most effective. Methods We abstracted data from randomized controlled trials and observational studies published between 4 June 2006 and 4 June 2019. Results We included 33 studies, yielding 6 HIVST distribution strategies. All distribution strategies increased testing uptake compared to standard testing: in sub-Saharan Africa, partner HIVST distribution ranked highest (78% probability); in North America, Asia, and the Pacific regions, web-based distribution ranked highest (93% probability), and facility based distribution ranked second in all settings. Across HIVST distribution strategies HIV positivity and linkage was similar to standard testing. Conclusions A range of HIVST distribution strategies are effective in increasing HIV testing. HIVST distribution by sexual partners, web-based distribution, as well as health facility distribution strategies should be considered for implementation to expand the reach of HIV testing services., We conducted a systematic review and network meta-analysis to assess effectiveness of human immunodeficiency virus self-test (HIVST) distribution strategies. HIVST distribution by sexual partners in sub-Saharan Africa and web-based in North America, Asia and the Pacific region resulted in the highest uptake.

This paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. We discuss challenges with current trial planning and designs that are often used in clinical trial research undertaken in low-income and middle-income countries, as an overview of the global health trials landscape. Finally, we discuss the importance of collaborative work in global health research towards generating sustainable and culturally appropriate research environments.

Task sharing has been one of the most important enabling policies supporting the global expansion of access to HIV testing and treatment. The WHO public health approach, which relies on delivery of antiretroviral therapy (ART) by nurses, has enabled a trebling of the number of people receiving ART during the past decade. WHO recognises that HIV pre-exposure prophylaxis (PrEP) can also be provided by nurses; however, many countries still do not have policies in place that support nurse provision of PrEP. In sub-Saharan Africa, most countries allow nurses to prescribe ART, but only a few countries have policies in place that allow nurses to prescribe PrEP. Nurse-led PrEP delivery is particularly low in the Asia-Pacific region, which has some of the world's fastest growing epidemics. Even in many high-income countries, PrEP scale-up has been limited because policies often require medical doctors or specialists to prescribe. Service providers in many countries are coming to realise that scaling up access to PrEP cannot be achieved by medical doctors alone, and nurse-led PrEP delivery can help to lay the groundwork for supporting uptake of other HIV prevention approaches that will become available in the future. Countries with policies that authorise nurses to prescribe ART could be early adopters and help to pave the way for wider adoption of nurse-led PrEP delivery.

Background\ud Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource‐limited settings.\ud \ud Objectives\ud To determine the accuracy of simple measures of ART adherence (including patient self‐report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non‐suppressed viral load in people living with HIV and receiving ART treatment.\ud \ud Search methods\ud The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African‐Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases.\ud \ud Selection criteria\ud We included studies of all designs that evaluated a simple measure of adherence (index test) such as self‐report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity.\ud \ud Data collection and analysis\ud We screened studies, extracted data, and assessed risk of bias using QUADAS‐2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta‐analysis or comparison of adherence measures. We explored heterogeneity using pre‐defined subgroup analysis.\ud \ud Main results\ud We included 51 studies involving children and adults with HIV, mostly living in low‐ and middle‐income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self‐report.\ud \ud ‐ Self‐report questionnaires (25 studies, 9211 participants; very low‐certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%.\ud \ud ‐ Self‐report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low‐certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%.\ud \ud ‐ Tablet counts (12 studies, 3466 participants; very low‐certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%.\ud \ud ‐ Electronic monitoring devices (3 studies, 186 participants; very low‐certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%.\ud \ud ‐ Pharmacy records or secondary databases (6 studies, 2254 participants; very low‐certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%.\ud \ud ‐ Composite measures (9 studies, 1513 participants; very low‐certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%.\ud \ud Across all included studies, the ability of adherence measures to detect viral non‐suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision.\ud \ud The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results.\ud \ud Authors' conclusions\ud We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non‐suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

WHO has established a Global Clinical Platform for the clinical characterisation of COVID-19 among hospitalised individuals. We assessed whether people living with HIV hospitalised with COVID-19 had increased odds of severe presentation and of in-hospital mortality compared with individuals who were HIV-negative and associated risk factors.Between Jan 1, 2020, and July 1, 2021, anonymised individual-level data from 338 566 patients in 38 countries were reported to WHO. Using the Platform pooled dataset, we performed descriptive statistics and regression analyses to compare outcomes in the two populations and identify risk factors.Of 197 479 patients reporting HIV status, 16 955 (8·6%) were people living with HIV. 16 283 (96.0%) of the 16 955 people living with HIV were from Africa; 10 603 (62·9%) were female and 6271 (37·1%) were male; the mean age was 45·5 years (SD 13·7); 6339 (38·3%) were admitted to hospital with severe illness; and 3913 (24·3%) died in hospital. Of the 10 166 people living with HIV with known antiretroviral therapy (ART) status, 9302 (91·5%) were on ART. Compared with individuals without HIV, people living with HIV had 15% increased odds of severe presentation with COVID-19 (aOR 1·15, 95% CI 1·10-1·20) and were 38% more likely to die in hospital (aHR 1·38, 1·34-1·41). Among people living with HIV, male sex, age 45-75 years, and having chronic cardiac disease or hypertension increased the odds of severe COVID-19; male sex, age older than 18 years, having diabetes, hypertension, malignancy, tuberculosis, or chronic kidney disease increased the risk of in-hospital mortality. The use of ART or viral load suppression were associated with a reduced risk of poor outcomes; however, HIV infection remained a risk factor for severity and mortality regardless of ART and viral load suppression status.In this sample of hospitalised people contributing data to the WHO Global Clinical Platform for COVID-19, HIV was an independent risk factor for both severe COVID-19 at admission and in-hospital mortality. These findings have informed WHO immunisation policy that prioritises vaccination for people living with HIV. As the results mostly reflect the data contribution from Africa, this analysis will be updated as more data from other regions become available.None.For the French translation of the abstract see Supplementary Materials section.

Objective To propose a taxonomy and framework that identifies and presents actionable statements in guidelines. Study design and setting We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework. Results The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process. Conclusion The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users.

Nathan Ford and co-authors discuss the systematic identification of research gaps in improving HIV service delivery.

Introduction Adolescents and young people comprise a growing proportion of new HIV infections globally, yet current approaches do not effectively engage this group, and adolescent HIV‐related outcomes are the poorest among all age groups. Providing psychosocial interventions incorporating psychological, social, and/or behavioural approaches offer a potential pathway to improve engagement in care and health and behavioural outcomes among adolescents and young people living with HIV (AYPLHIV). Methods A systematic search of all peer‐reviewed papers published between January 2000 and July 2020 was conducted through four electronic databases (Cochrane Library, PsycINFO, PubMed and Scopus). We included randomized controlled trials evaluating psychosocial interventions aimed at improving engagement in care and health and behavioural outcomes of AYPLHIV aged 10 to 24 years. Results and discussion Thirty relevant studies were identified. Studies took place in the United States (n = 18, 60%), sub‐Saharan Africa (Nigeria, South Africa, Uganda, Zambia, Zimbabwe) and Southeast Asia (Thailand). Outcomes of interest included adherence to antiretroviral therapy (ART), ART knowledge, viral load data, sexual risk behaviours, sexual risk knowledge, retention in care and linkage to care. Overall, psychosocial interventions for AYPLHIV showed important, small‐to‐moderate effects on adherence to ART (SMD = 0.3907, 95% CI: 0.1059 to 0.6754, 21 studies, n = 2647) and viral load (SMD = −0.2607, 95% CI −04518 to −0.0696, 12 studies, n = 1566). The psychosocial interventions reviewed did not demonstrate significant impacts on retention in care (n = 8), sexual risk behaviours and knowledge (n = 13), viral suppression (n = 4), undetectable viral load (n = 5) or linkage to care (n = 1) among AYPLHIV. No studies measured transition to adult services. Effective interventions employed various approaches, including digital and lay health worker delivery, which hold promise for scaling interventions in the context of COVID‐19. Conclusions This review highlights the potential of psychosocial interventions in improving health outcomes in AYPLHIV. However, more research needs to be conducted on interventions that can effectively reduce sexual risk behaviours of AYPLHIV, as well as those that can strengthen engagement in care. Further investment is needed to ensure that these interventions are cost‐effective, sustainable and resilient in the face of resource constraints and global challenges such as the COVID‐19 pandemic.

The identification and appropriate management of people with advanced HIV disease is a key component in the HIV response. People with HIV who are hospitalised are at a higher risk of death, a risk that might persist after discharge. The aims of this study were to estimate the frequency of negative post-discharge outcomes, and to determine risk factors for such outcomes in people with HIV.Using a broad search strategy combining terms for hospital discharge and HIV infection, we searched MEDLINE via PubMed and Embase from Jan 1, 2003 to Nov 30, 2021 to identify studies reporting outcomes among people with HIV following discharge from hospital. We estimated pooled proportions of readmissions and deaths after hospital discharge using random-effects models. We also did subgroup analyses by setting, region, duration of follow-up, and advanced HIV status at admission, and sensitivity analyses to assess heterogeneity.We obtained data from 29 cohorts, which reported outcomes of people living with HIV after hospital discharge in 92 781 patients. The pooled proportion of patients readmitted to hospital after discharge was 18·8% (95% CI 15·3-22·3) and 14·1% (10·8-17·3) died post-discharge. In sensitivity analyses, no differences were identified in the proportion of patients who were readmitted or died when comparing studies published before 2016 with those published after 2016. Post-discharge mortality was higher in studies from Africa (23·1% [16·5-29·7]) compared with the USA (7·5% [4·4-10·6]). For studies that reported both post-discharge mortality and readmission, the pooled proportion of patients who had this composite adverse outcome was 31·7% (23·9-39·5). Heterogeneity was moderate, and largely explained by patient status and linkage to care. Reported risk factors for readmission included low CD4 cell count at admission, longer length of stay, discharge against medical advice, and not linking to care following discharge; inpatient treatment with antiretroviral therapy (ART) during hospitalisation was protective of post-discharge mortality.More than a quarter of patients with HIV had an adverse outcome after hospital discharge with no evidence of improvement in the past 15 years. This systematic review highlights the importance of ensuring post-discharge referral and appropriate management, including ART, to reduce mortality and readmission to hospital among this group of high-risk patients.BillMelinda Gates Foundation.For the French and Spanish translations of the abstract see Supplementary Materials section.

Improvements in geospatial health data and tailored human immunodeficiency virus (HIV) testing, prevention and treatment have led to greater microtargeting of the HIV response, based on location, risk, clinical status and disease burden. These approaches show promise for achieving control of the HIV epidemic. At the same time, United Nations Member States have committed to achieving broader health and development goals by 2030, including universal health coverage (UHC). HIV epidemic control will facilitate UHC by averting the need to commit ever-increasing resources to HIV services. Yet an overly targeted HIV response could also distort health systems, impede integration and potentially threaten broader health goals. We discuss current approaches to achieving both UHC and HIV epidemic control, noting potential areas of friction between disease-specific microtargeting and integrated health systems, and highlighting opportunities for convergence that could enhance both initiatives. Examples of these programmatic elements that could be better aligned include: improved information systems with unique identifiers to track and monitor individuals across health services and the life course; strengthened subnational data use; more accountable supply chains that supply a broad range of services; and strengthened community-based services and workforces. We argue that the response both to HIV and to broader health threats should use these areas of convergence to increase health systems efficiency and mitigate the harm of any potential decrease in health funding. Further investments in implementation and monitoring of these programme elements will be needed to make progress towards both UHC and HIV epidemic control.Les améliorations des données sanitaires géospatiales et la personnalisation du dépistage, de la prévention et du traitement du virus de l'immunodéficience humaine (VIH) ont permis de développer le micro-ciblage de la réponse au VIH, en fonction du lieu, du risque, de la situation clinique et de la charge de morbidité. Ces approches sont prometteuses pour lutter contre l'épidémie de VIH. Dans le même temps, les États membres des Nations Unies se sont engagés à atteindre des objectifs plus larges de santé et de développement d'ici 2030, notamment la couverture sanitaire universelle. Cette dernière sera facilitée par la lutte contre l'épidémie de VIH, qui réduira la nécessité de consacrer toujours plus de ressources aux services liés au VIH. Cependant, une réponse au VIH trop ciblée pourrait également distordre les systèmes de santé, empêcher leur intégration et potentiellement nuire aux objectifs de santé plus vastes. Nous abordons ici les approches actuelles en matière de couverture sanitaire universelle et de lutte contre l'épidémie de VIH, en notant les points de friction potentiels entre un micro-ciblage spécifique à certaines maladies et des systèmes de santé intégrés, ainsi que les opportunités de convergence qui pourraient être bénéfiques aux deux initiatives. Parmi les éléments de programmes qui pourraient être mieux coordonnés, nous pouvons citer: l'amélioration des systèmes d'information avec des identifiants uniques permettant de suivre les personnes dans leur parcours de soins et tout au long de leur vie; la plus grande utilisation des données infranationales; la responsabilisation des chaînes d'approvisionnement qui fournissent un grand nombre de services; et le renforcement des services et des intervenants communautaires. Nous soutenons que la réponse au VIH et à d'autres menaces sanitaires devrait exploiter ces domaines de convergence pour accroître l'efficacité des systèmes de santé et atténuer le préjudice d'une éventuelle baisse des fonds alloués à la santé. Il sera nécessaire d'investir davantage dans la mise en œuvre et le suivi de ces éléments de programmes pour avancer, aussi bien vers la couverture sanitaire universelle que dans la lutte contre l'épidémie de VIH.Las mejoras en los datos geoespaciales de salud y las pruebas, la prevención y el tratamiento adaptados al virus de la inmunodeficiencia humana (VIH) han conducido a una mayor focalización de la respuesta al VIH, basada en la ubicación, el riesgo, el estado clínico y la carga de la enfermedad. Estos enfoques son prometedores para lograr el control de la epidemia del VIH. Al mismo tiempo, los Estados Miembros de las Naciones Unidas se han comprometido a alcanzar objetivos de salud y desarrollo de mayor alcance para 2030, incluida la cobertura universal de salud (universal health coverage, UHC). El control de la epidemia del VIH facilitará la UHC porque evitará la necesidad de comprometer recursos cada vez mayores para los servicios del VIH. Sin embargo, una respuesta al VIH demasiado específica también podría distorsionar los sistemas de salud, impedir la integración y amenazar potencialmente los objetivos de salud de mayor alcance. Se discuten los enfoques actuales para lograr tanto la atención primaria de salud como el control de la epidemia del VIH, se señalan las posibles áreas de fricción entre la focalización específica de la enfermedad y los sistemas integrados de salud, y se destacan las oportunidades de convergencia que podrían mejorar ambas iniciativas. Entre los ejemplos de estos elementos programáticos que podrían alinearse mejor se incluyen: sistemas de información mejorados con identificadores únicos para hacer un seguimiento y monitoreo de las personas a través de los servicios de salud y el curso de la vida; el fortalecimiento del uso de datos a nivel subnacional; cadenas de suministro más responsables que proveen una amplia gama de servicios; y el fortalecimiento de los servicios en la comunidad y las fuerzas de trabajo. Se argumenta que la respuesta tanto al VIH como a las amenazas para la salud en general debe utilizar estas áreas de convergencia para aumentar la eficiencia de los sistemas de salud y mitigar el daño de cualquier posible disminución en la financiación de la salud. Se necesitarán más inversiones en la ejecución y el monitoreo de estos elementos del programa para avanzar tanto en el control de la epidemia de VIH como en la UHC.أدت التحسينات في بيانات الصحة الجغرافية المكانية، واختبار فيروس نقص المناعة البشرية (HIV)، والوقاية منه وعلاجه، إلى زيادة الاستهداف الدقيق للاستجابة لفيروس نقص المناعة البشرية، بناءً على الموقع والمخاطر والحالة السريرية وعبء المرض.تمثل هذه الأساليب وعداً بتحقيق السيطرة على وباء فيروس نقص المناعة البشرية.وفي نفس الوقت، التزمت الدول الأعضاء في الأمم المتحدة بتحقيق أهدافاً أوسع للصحة وللتنمية بحلول عام 2030، بما يشمل التغطية الصحية الشاملة (UHC).سوف تؤدي مكافحة وباء فيروس نقص المناعة البشرية (HIV) إلى تسهيل التغطية الصحية الشاملة عن طريق تجنب الحاجة إلى تخصيص موارد متزايدة دائماً لخدمات فيروس نقص المناعة البشرية.إلا أن الاستجابة المفرطة المستهدفة لفيروس نقص المناعة البشرية قد تؤدي أيضاً لتشويه الأنظمة الصحية، وتعويق التكامل، ومن المحتمل أن تهدد الأهداف الصحية الأوسع نطاقاً.نحن نناقش الأساليب الحالية لتحقيق كل من التغطية الصحية الشاملة، ومكافحة وباء فيروس نقص المناعة البشرية، مع ملاحظة مجالات التداخل المحتملة بين الاستهداف الدقيق للأمراض المحددة، والنظم الصحية المتكاملة، وتسليط الضوء على فرص التقارب التي يمكن أن تعزز كلتا المبادرتين.من أمثلة هذه العناصر البرمجية التي يمكن تنسيقها بشكل أفضل:أنظمة معلومات محسّنة ذات معرّفات فريدة لتتبع ومراقبة الأفراد عبر الخدمات الصحية ومسار الحياة؛ وتعزيز استخدام البيانات دون الوطنية؛ وسلاسل إمداد أكثر مساءلة توفر مجموعة واسعة من الخدمات؛ وخدمات مجتمعية وقوى عاملة مدعمة.نحن نزعم أن الاستجابة لكل من فيروس نقص المناعة البشرية، والتهديدات الصحية الأوسع نطاقاً، ينبغي أن تعتمد على هذه المجالات للتقارب من أجل زيادة كفاءة النظم الصحية، وتخفيف ضرر أي انخفاض محتمل في التمويل الصحي.ستكون هناك حاجة إلى مزيد من الاستثمارات في تنفيذ ومراقبة عناصر هذه البرنامج، لإحراز تقدم نحو كل من التغطية الصحية الشاملة ومكافحة فيروس نقص المناعة البشرية.基于地点、风险、临床特征和疾病负担的地理空间健康数据的改进以及专门的艾滋病 (HIV) 检测、预防和治疗，使得应对艾滋病病毒的工作有了更为微观的目标。这些方法显示对艾滋病疫情的控制有望实现。同时，联合国各成员国已承诺到 2030 年实现更广泛的健康和发展目标，其中包括全民健康覆盖 (UHC)。对艾滋病疫情有所控制将避免对艾滋病服务需求投入资源的不断增加，从而推进全民健康覆盖。然而，过度针对性的艾滋病应对措施也会干扰医疗系统，阻碍一体化并可能危及更广泛健康目标的实现。我们讨论了当前实现全民健康覆盖和艾滋病疫情控制的方法，指明了针对特定疾病的微观目标与整合的医疗系统间可能会有冲突的领域，并着重强调了促进这两项举措融合的机会。更好地协调这些有关计划要素的示例有：改进的信息系统，具有可在医疗服务和整个生命历程中跟踪并监控个人的唯一标识符；强化对地方数据的使用；用于提供广泛服务的更负责任的供应链；并加强基于社区的服务和员工培养。我们认为，对艾滋病和更广泛的健康威胁的应对措施都应使用此类融合领域，以提高医疗系统的效率并减轻医疗资金可能减少的危害。为了在全民健康覆盖和艾滋病疫情控制方面取得进展，需要在此类计划要素的执行和监测方面进一步投资。.Совершенствование сбора геопространственных данных о состоянии здоровья населения и индивидуализация процессов тестирования, лечения и профилактики ВИЧ привели к повышению микроадресации мероприятий по борьбе с ВИЧ с учетом местоположения, риска, клинического состояния и бремени заболевания. Эти подходы позволяют надеяться на обеспечение эффективного контроля над эпидемией ВИЧ. В то же время государства-члены ООН взяли на себя обязательства по расширению целей в области здравоохранения и развития к 2030 году, включая обеспечение всеобщего охвата услугами здравоохранения (UHC). Контроль над эпидемией ВИЧ будет содействовать обеспечению UHC, поскольку отпадет необходимость направлять постоянно растущее количество ресурсов на борьбу с ВИЧ. Однако слишком целенаправленный характер мероприятий по борьбе с ВИЧ может перекосить системы здравоохранения, замедлить процессы интеграции и несет в себе потенциальную угрозу достижению более широких целей в сфере здравоохранения. Авторы обсуждают существующие подходы к обеспечению UHC и контроля над эпидемией ВИЧ, отмечая потенциальные области конфликта между микроадресацией для конкретных заболеваний и объединенными системами здравоохранения, а также выявляя возможности для конвергенции, которые бы содействовали реализации обеих инициатив. Необходимо обеспечить согласованность следующих элементов программы: усовершенствованных информационных систем с уникальными идентификаторами для отслеживания и мониторинга отдельных лиц и оказываемых им медицинских услуг на протяжении всей жизни; более активного использования данных на субнациональном уровне; обеспечения жесткого учета и контроля в цепочках поставок для широкого спектра услуг, а также укрепления системы услуг, оказываемых по месту проживания, и развития соответствующих трудовых ресурсов. Авторы отмечают, что меры по борьбе с ВИЧ и другими угрозами в области здравоохранения должны опираться на эти области конвергенции с целью повышения эффективности систем здравоохранения и уменьшения вреда в результате потенциального сокращения финансирования. Необходимы дальнейшие инвестиции в реализацию и мониторинг этих программных элементов, чтобы добиться прогресса в обеспечении UHC и контроля над эпидемией ВИЧ.

Supplemental Digital Content is Available in the Text., Background: There have been a range of quality improvement (QI) and quality assurance initiatives in low- and middle-income countries to improve antiretroviral therapy (ART) treatment outcomes for people living with HIV. To date, these initiatives have not been systematically assessed and little is known about how effective, cost-effective, or sustainable these strategies are in improving clinical outcomes. Methods: We conducted a systematic review adhering to PRISMA guidelines (PROSPERO ID: CRD42017071848), searching PubMed, MEDLINE, Embase, Web of Science, and the Cochrane database of controlled trials for articles reporting on the effectiveness of QI and quality assurance initiatives in HIV programs in low- and middle-income countries in relation to ART uptake, retention in care, adherence, viral load suppression, mortality, and other outcomes including cost-effectiveness and long-term sustainability. Results: One thousand eight hundred sixty articles were found, of which 29 were included. QI approaches were categorized as follows: (1) health system approaches using QI methods; (2) QI learning networks including collaboratives; (3) standard-based methods that use QI tools to improve performance gaps; and (4) campaigns using QI methods. The greatest improvements were seen in ART uptake [median increase of 14.0%; interquartile range (IQR) −9.0 to 29.3], adherence [median increase of 22.0% (IQR −7.0 to 25.0)], and viral load suppression [median increase 26.0% (IQR −8.0 to 26.0)]. Conclusions: QI interventions can be effective in improving clinical outcomes; however, there was significant variability, making it challenging to identify which aspects of interventions lead to clinical improvements. Standardizing reporting and assessment of QI initiatives is needed, supported by national quality policies and directorates, and robust research.

Purpose of review To summarize global efforts to accelerate access to simpler, safer and more affordable antiretroviral drugs and how this has shaped HIV treatment policy over the last decade, and outline future priorities. Several expert consultations aimed at aligning opportunities for optimization of antiretroviral drugs have been convened by WHO in partnership with academic institutions, international agencies, innovators and manufacturers. The increased access to lifelong treatment for people living with HIV also brings about new challenges in the long-term use of antiretrovirals (ARVs). Recent findings The article describes the evolution of global research agenda on ARV optimization ascribing the characteristics of a target product profile, the importance of sequencing of first-line and second-line regimens, the role of programmatic data when looking at policy transition for new ARVs, inclusion of more subpopulations living with HIV, as well as the challenges in identifying what improvements can be made in an era where drugs are already safe, tolerable and efficacious. Summary Within a framework of evolving treatment harmonization and simplification, future therapeutic options in development must take into consideration safety and efficacy across a range of patient populations as well the mode of administration in the context of lifelong therapy.

Optimising community health worker (CHW) programmes requires evidence-based policies on their education,\ud deployment, and management. This guideline aims to inform efforts by planners, policy makers, and managers to\ud improve CHW programmes as part of an integrated approach to strengthen primary health care and health systems.\ud The development of this guideline followed the standard WHO approach to developing global guidelines. We\ud conducted one overview of reviews, 15 systematic reviews (each one on a specific policy question), and a survey of\ud stakeholders’ views on the acceptability and feasibility of the interventions under consideration. We assessed the\ud quality of systematic reviews using the AMSTAR tool, and the certainty of the evidence using the GRADE methodology.\ud The overview of reviews identified 122 eligible articles and the systematic reviews identified 137 eligible primary\ud studies. The stakeholder perception survey obtained inputs from 96 respondents. Recommendations were developed\ud in the areas of CHW selection, preservice education, certification, supervision, remuneration and career advancement,\ud planning, community embeddedness, and health system support. These are the first evidence-based global guidelines\ud for health policy and system support to optimise community health worker programmes. Key considerations for\ud implementation include the need to define the role of CHWs in relation to other health workers and plan for the\ud health workforce as a whole rather than by specific occupational groups; appropriately integrate CHW programmes\ud into the general health system and existing community systems; and ensure internal coherence and consistency\ud across different policies and programmes affecting CHWs.

Background Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy. Methods We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model. Results Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups. Conclusions HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.

Peter Ehrenkranz and co-authors present a cyclical cascade of care for people with HIV infection, aiming to facilitate assessment of outcomes.

In global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive trial designs, as well as the master protocol framework that can help to harmonise clinical trial research efforts in global health research. We provide a general framework for more efficient trial research, and we discuss the importance of considering different study designs in the planning stage with statistical simulations. We conclude this second Series paper by discussing the methodological and operational complexity of adaptive trial designs and master protocols and the current funding challenges that could limit uptake of these approaches in global health research.

This systematic review aimed to compare body weight gain associated outcomes over time between dolutegravir (DTG)-based antiretroviral (ART) regimens to other ART regimens, to compare tenofovir alafenamide (TAF)-based regimens, and to evaluate the associated prognostic factors.Systematic searches of MEDLINE, Embase, and CENTRAL for RCTs and observational studies comparing ART regimens were conducted on 13 September 2021. Outcomes of interest included: change in body weight, body mass index (BMI), waist circumference; and risk of hyperglycaemia and diabetes. Network meta-analyses were conducted at 12, 24, 48, 96 and 144 weeks using two networks differentiated by 3rd agents and backbone agents.The review identified 113 publications reporting on 73 studies. DTG-based regimens led to statistically higher weight gains than efavirenz-based regimens at all time points (mean difference: 1·99 kg at 96 weeks; 95% credible interval: 0·85-3·09) and was higher over time than low-dose efavirenz-, elvitegravir-, and rilpivirine-based regimens. They were comparable to raltegravir-, bictegravir- and atazanavir-based regimens. For backbones, TAF led to higher weight gain relative to tenofovir disoproxil fumarate (TDF), abacavir, and zidovudine. Prognostic factor analysis showed both low CD4 cell count and high HIV RNA viral load at baseline were consistently associated with higher weight gain, while sex was an effect modifier to African origins.DTG-based regimens lead to larger average weight gains than some other ART regimens and TAF leads to larger average weight gains than all other backbone antiretrovirals. Further research is needed to better understand long-term outcomes and their relationship to other metabolic outcomes.The WHO Global HIV, Hepatitis and Sexually Transmitted Infections Programmes.

BACKGROUND As countries move towards the UNAIDS's 95-95-95 targets and with strong evidence that undetectable equals untransmittable, it is increasingly important to assess whether those with HIV who are receiving antiretroviral therapy (ART) achieve viral suppression. We estimated the proportions of children and adolescents and adults with viral suppression at 1, 2, and 3 years after initiating ART. METHODS In this retrospective cohort study, seven regional cohorts from the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium contributed data from individuals initiating ART between Jan 1, 2010, and Dec 31, 2019, at 148 sites in 31 countries with annual viral load monitoring. Only people with HIV who started ART after the time a site started routine viral load monitoring were included. Data up to March 31, 2020, were analysed. We estimated the proportions of children and adolescents (aged

Summary Background Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. Methods We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. Findings Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49–0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43–1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. Interpretation Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. Funding National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Item does not contain fulltext BACKGROUND: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. SETTING: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland. METHODS: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. RESULTS: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. CONCLUSION: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of, Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn

Background To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. Findings We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92). Interpretation The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. Funding WHO.

Objectives World Health Organization (WHO) guidelines for health programmes and healthcare delivery are the foundation of its technical leadership in public health and essential to decision-making globally. A key function of guideline development is to identify areas in which further evidence is needed because filling these gaps will lead to future improvements in population health. The objective of this study was to examine the knowledge gaps and research questions for addressing those gaps generated through the WHO guideline development process, with the goal of informing future strategies for improving and strengthening the guideline development process. Study design We did a systematic, retrospective analysis of research questions identified in the published guidelines. Methods We analyzed guidelines published between January 1, 2008, and December 31, 2018, by the Communicable Diseases Cluster in five disease areas: tuberculosis (TB), HIV, malaria, TB-HIV, and neglected tropical diseases (NTDs). Research questions were extracted independently by two researchers. We analyzed the distribution of research questions by disease and by topic category and did a qualitative assessment of optimum practice for research question generation during the guideline development process. Results A total of 48 guidelines were included: 26 on HIV, 1 on malaria, 11 on TB, 5 on TB/HIV, and 5 on NTDs. Overall, 36 (75%) guidelines encompassed a total of 360 explicit research questions; the remainder did not contain specific research questions. The number of research questions that focused on TB was 49, TB/HIV was 38, HIV was 250, and NTDs was 23. The number of research questions that focused on diagnosis was 43 (11.9%) of 360, prevention was 62 (17.2%), treatment was 103 (28.6%), good practice was 12 (3.3%), service delivery was 86 (23.8%), and other areas was 54 (15%). Research questions were often not formulated in a specific or actionable way and were hard to identify in the guideline. Examples of good practice identified by the review team involved the generation of specific and narrowly defined research questions, with accompanying recommendations for appropriate study design. Conclusions The WHO must strengthen its approach to identifying and presenting research questions during the guideline development process. Ensuring access to research questions is a key next step in adding value to the guideline development process., Highlights • We examined the knowledge gaps generated through the World Health Organization (WHO) guideline development process to inform future strategies. • We focused on five disease areas: tuberculosis (TB), HIV, malaria, TB-HIV, and neglected tropical diseases. • Research questions were often not formulated in a specific or actionable way and were hard to be identified. • The WHO must strengthen its approach in identifying research questions during the guideline development process.

Purpose of review To review recent progress in public health efforts to address HIV, and the extent to which key approaches can be applied to three key epidemics that commonly co-occur with HIV: TB, viral hepatitis, and STIs. Recent findings The public health approach to tackling HIV in low-income and middle-income settings relied on standardized treatment regimens and monitoring approaches, task sharing and community involvement, and decentralized and integrated service delivery. These approaches can all be applied to three key epidemics that commonly co-occur with HIV: TB, viral hepatitis, and STIs. Summary HIV, viral hepatitis, and STIs share common routes of infection, and HIV weakens the immune system, increasing the risk of TB. A public health approach can be applied to address these syndemics.

Summary Background In 2016, of the estimated 257 million people living with chronic hepatitis B virus (HBV) infection worldwide, only a small proportion was diagnosed and treated. The insufficiency of information on the proportion of people infected with HBV who are eligible for treatment limits the interpretation of global treatment coverage. We aimed to estimate the proportion of people with chronic HBV infection who were eligible for antiviral treatment worldwide, based on the WHO 2015 guidelines. Methods In this systematic review and meta-analysis, we searched Medline, EMBASE, and the Cochrane databases from Jan 1, 2007, to Jan 31, 2018, for studies describing HBsAg-positive people in the population or health-care facilities. We extracted information from published studies using a standardised form to estimate the frequency of cirrhosis, abnormal alanine aminotransferase (ALT), HBV DNA exceeding 2000 IU/mL or 20 000 IU/mL, presence of HBeAg, and eligibility for treatment as per WHO and other guidelines as reported in the studies. We pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020132345. Findings Of the 13 497 studies, 162 were eligible and included in our analysis. These studies included 145 789 participants. The pooled estimate of the proportion of cirrhosis was 9% (95% CI 8–10), ranging from 6% (4–8) in community settings to 10% (9–11) in clinic settings. Examining the proportion of participants who had characteristics used to determine eligibility in the WHO guidelines, 1750 (10·1%) of 17 394 had HBV DNA exceeding 20 000 IU/mL, and 20 425 (30·8%) of 66 235 had ALT above the upper limit of normal. 32 studies reported eligibility for treatment according to WHO or any other guidelines, with a pooled estimate of eligibility at 19% (95% CI 18–20), ranging from 12% (6–18) for studies in community settings to 25% (19–30) in clinic settings. Interpretation Many studies described people with HBV infection, but few reported information in a way that allowed assessment of eligibility for treatment. Although about one in ten of the 257 million people with HBV infection (26 million) might be in urgent need of treatment because of cirrhosis, a larger proportion (12–25%) is eligible for treatment in accordance with different guidelines. Future studies describing people with HBV infection should report on treatment eligibility, according to broadly agreed definitions. Funding WHO and US Centers for Disease Control and Prevention.

Baseline CD4 testing rates declined from 73% to 21% between 2013 and 2018 with adoption of "Treat All" in Uganda. Advanced human immunodeficiency virus (HIV) disease (CD4 count 200 cells/µL) remained common (24% of those tested in 2018, 83% of whom had World Health Organization stage I/II disease). Despite frequent presentation with advanced HIV disease, CD4 testing has declined dramatically.

Background: HIV implemention research evolves rapidly and is often complex and poorly characterized, making synthesis of data on HIV implementation strategies inherently difficult. This is further compromised by prolonged data abstraction processes, restrictions on study design and delays in publication of review findings, at times resulting in outdated and irrelevant systematic reviews. The LIVE project aims to overcome some of these challenges by conducting rapid living systematic reviews and meta-analyses.Methods: The LIVE team will generate a series of systematic reviews exploring implementation strategies targeted at improving HIV cascade outcomes. We will search Embase and Medline databases for studies conducted after 2004, using predefined search terms to identify studies conducted in any age group or setting, and using implementation strategies - targeting policy makers, society, health organizations, health workers, and patients and their families - to prevent HIV, increase HIV testing, increase ART linkage and retention, and improve viral suppression rates and survival. Randomized controlled trials and observational studies will be identified through optimized searches conducted six-monthly and features of the implementation strategies and methodological quality will be assessed using recognized tools. Review teams will publish living systematic review protocols on PROSPERO. Review results will be presented on a publically facing dashboard, with review updates conducted on a six monthly basis, and publication in peer reviewed journals supporting living review processes.Discussion: Living reviews based on both pragmatic and explanatory HIV implementation research and supported by an ongoing data abstraction process will generate rapid reviews in the HIV field which are current, relevant and maximally useful to patients, health workers and policy makers.

Introduction Several antiretroviral drugs are being considered for the treatment of COVID‐19, the disease caused by a newly identified coronavirus, (SARS‐CoV‐2). We systematically reviewed the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials. Methods Three databases were screened from inception to 30 March 2020 for studies reporting clinical outcomes of patients with SARS, MERS or COVID‐19 treated with antiretrovirals. Results From an initial screen of 433 titles, two randomized trials and 24 observational studies provided clinical outcome data on the use of antiretroviral drugs; most studies reported outcomes using LPV/r as treatment. Of the 21 observational studies reporting treatment outcomes, there were three studies among patients with SARS, six studies among patients with MERS and 12 studies among patients with COVID‐19. In one randomized trial 99 patients with severe COVID‐19 illness were randomized to receive LPV/r (400/100 mg twice a day) and 100 patients to standard of care for 14 days: LPV/r was not associated with a statistically significant difference in time to clinical improvement, although LPV/r given within 12 days of symptoms was associated with shorter time to clinical improvement; 28 day mortality was numerically lower in the LPV/r group (14/99) compared to the control group (25/100), but this difference was not statistically significant. The second trial found no benefit. The certainty of the evidence for the randomized trials was low. In the observational studies 3 out of 361 patients who received LPV/r died; the certainty of evidence was very low. Three studies reported a possible protective effect of LPV/r as post‐exposure prophylaxis. Again, the certainty of the evidence was very low due to uncertainty due to limited sample size. Conclusions On the basis of the available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID‐19.

IntroductionWHO recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa.MethodsWe analysed data from 14 HIV treatment programs with over 300 clinics in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in years 2005-2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count 3) or failing to suppress viral replication (>1000 HIV-RNA copies/ml) after ART initiation. We used mixed effect logistic regression to assess time trends adjusted for age and sex.ResultsAmong 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017. The percentage starting with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018. VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested but fewer than 2% were tested in the other four countries. The probability of having a CD4 cell count at ART start declined by 14% each year (odds ratio [OR] 0.86; 95% CI 0.86-0.86); the probability of advanced HIV disease declined by 20% per year (OR 0.80; 95% CI 0.80-0.81). The increase in VL testing after ART start was only modest (OR 1.06; 95% CI 1.05-1.06) and there was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99-1.01).ConclusionsCD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub-Saharan Africa.

BACKGROUND: The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens.METHODS: We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted.FINDINGS: Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain.INTERPRETATION: In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators.FUNDING: Bill & Melinda Gates Foundation.

Introduction The World Health Organization (WHO) recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa. Methods We analysed data from 14 HIV treatment programmes in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in 2005 to 2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count 1000 HIV‐RNA copies/mL) after ART initiation. We used mixed effect logistic regression to assess time trends adjusted for age and sex. Results Among 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017; the probability declined by 14% each year (odds ratio (OR) 0.86; 95% CI 0.86 to 0.86). Frequency of CD4 testing also declined. The percentage starting ART with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018; each year the probability declined by 20% (OR 0.80; 95% CI 0.80 to 0.81). VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested, but fewer than 2% were tested in the other four countries. The probability of VL testing after ART start increased only modestly each year (OR 1.06; 95% CI 1.05 to 1.06). The percentage with unsuppressed VL was 8.6%. There was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99 to 1.01). Conclusions CD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub‐Saharan Africa.

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services.

Background: HIV self-testing (HIVST) has the potential to reach underserved populations in need of HIV testing services. Given the range of possible distribution strategies available to those implementing HIV self-testing, we undertook a systematic review and network meta-analysis (NMA) to evaluate the comparative effects of self-test distribution strategies on HIV testing uptake. Methods: We searched electronic databases, clinical trial registries and conference abstracts for randomized controlled trials (RCTs) that compared HIVST distribution strategies with each other or with traditional HIV testing by health care workers (HCWs) at health facilities or in the community, between 4 June 2006 and 4 June 2019, and applied PRISMA guided systematic review techniques and GRADE methodology for network meta-analyses. We grouped HIVST distribution strategies into six categories based on who distributed the self-test and where and how the test was distributed. We used Bayesian Hierarchical random logit models to generate network estimates and rank comparative effects of each strategy on HIV testing uptake. To account for heterogeneity and avoid intransitivity we divided networks by regions and conducted sensitivity analyses and meta-regression. We plan updating the review every six months or at the time of publication of important new studies. PROSPERO registration number: CRD42018088078. Findings: Searches yielded 14,333 records, resulting in 24 RCTs for inclusion. There was substantial heterogeneity of setting, target population and HIVST distribution strategies. For HIV testing uptake in the sub-Saharan Africa network, partner HIVST distribution (predominantly distribution to male partners) ranked highest (1st, 78% probability) compared to five other HIV testing strategies: traditional facility-based HIV testing (RR: 2.39, 95% CrI 1.65-3.45), facility-based HIVST distribution (RR:1.42; 95%CI: 0.87-2.31), health worker community HIVST distribution (RR:1.68; 95%CI: 0.90-3.14), health worker community traditional HIV testing (1.74; 95%CI: 0.60-5.08) and peer community HIVST distribution (RR:1.82; 95%CI:1.00-3.27). Facility based HIVST distribution ranked 2nd (46% probability) and traditional facility-based testing ranked lowest - 6th (64% probability). In the North American-Asia and Pacific region network where the focus was primarily on men who have sex with men (MSM), web-based and mail HIVST distribution ranked highest (ranked 1st with 93% probability) compared to two testing strategies: traditional facility-based self-testing (RR 1.53, 95% CrI 1.1-2.41), and facility-based HIVST distribution (RR: 1.15; 95%CI: 0.57 -2.00). All HIVST strategies ranked higher than traditional HIV testing services at health facilities in terms of HIV testing uptake. This analysis was limited by few studies contributing to network estimates, substantial qualitative heterogeneity of testing strategies and the use of self-reported outcomes which resulted in findings being downgraded to low or very low certainty evidence in the GRADE system. Interpretation: HIVST increases testing for underserved groups (specifically men). Distribution by sexual partners in sub-Saharan Africa and through mail among MSM populations in North AmericanAsia and Pacific region, combined with direct HIVST distribution by HCWs at health facilities, could be considered for implementation in these settings. Taken together, these analyses demonstrate the application of network meta-analysis techniques to explore HIVST implementation approaches in RCTs. A living approach will incorporate research findings as they emerge and enable the public health community to reach firm conclusions about HVST distribution strategies rapidly. Funding: NIH: K24 AI134413; Bill and Melinda Gates Foundation: OPP1215984 Declaration of Interests: Authors have no competing interests.

Partnerships between researchers and policymakers can improve uptake and integration of scientific evidence. This article describes the research-policy partnership between the International epidemiology Databases to Evaluate AIDS (IeDEA) ( www.iedea.org) and the World Health Organization (WHO), which was established in 2014. IeDEA is an international research consortium, which analyses data on almost 2 million people living with HIV under care in routine settings in 46 countries in Asia-Pacific, the Caribbean, Central and South America, North America and sub-Saharan Africa. Five multiregional analyses were identified to inform the WHO on progress towards the second and third 90s of the 90-90-90 targets in adults and children: (i) trends in CD4 cell counts at the start of antiretroviral therapy (ART); (ii) delays from enrolment in HIV care to ART initiation; (iii) the impact of ART guideline changes; (iv) retention in care, mortality and loss to follow-up; and (v) viral suppression within the first 3 years after initiating ART. Results from these analyses were contributed to the 2015 and 2016 WHO global HIV progress reports, will contribute to the 2018 report, and were published in academic journals. The partnership has been mutually beneficial: discussion of WHO policy agendas led to more policy-framed, relevant and timely IeDEA research, and the collaboration provided the WHO with timely access to the latest data from IeDEA, as it was shared prior to peer-review publication.

Purpose of review Guidelines developed by the WHO aim to provide recommendations to support best practice in health delivery, with a focus on low-income and middle-income countries. As part of the guideline development process, critical knowledge gaps are identified and one of the core functions of WHO guidelines is to set forth priorities for future research. A review of research priorities identified through the WHO guideline development has recently been promoted as one approach to building an overarching priority research agenda in a given area. This paper outlines priorities for HIV-associated TB research identified in WHO HIV and TB guidelines published since 2015. Recent findings Nine guidelines were reviewed and 29 priority research questions were identified. Research priorities were identified for prevention of HIV-associated TB (11 questions), screening of latent and active TB in people living with HIV (six questions), treatment of drug sensitive (four questions), and drug-resistant (two questions) TB, and treatment of HIV in people coinfected with TB (three questions). Summary Multiple approaches to defining priority research questions for health research exist. Research priorities that arise from the WHO guideline development process are limited to those areas for which guidelines are developed. One strength of this approach is that it takes as a starting point a desire to make actionable recommendations for policy makers. WHO is working to further refine the formulation of research questions within the guideline development process.

In 2015, the World Health Organization (WHO) recommended that all people living with HIV (PLWH) should start antiretroviral therapy (ART) irrespective of clinical or immune status. This recommendation followed almost 20 years of research into the clinical and population-level benefits and risks of starting ART early compared with deferring treatment. This article summarises the ways in which observational data support the work of WHO, including the support provided by the International epidemiology Databases to Evaluate AIDS (IeDEA), taking the example of ‘treat all’.