Resistance-informed versus empirical management of viraemia in children and adolescents with HIV in Lesotho and Tanzania (GIVE MOVE trial): a multisite, open-label randomised controlled trial.

BACKGROUND: Children and adolescents with HIV taking antiretroviral therapy (ART) have high rates of viraemia. We assessed if genotypic resistance testing (GRT) to inform onward treatment improved treatment outcomes in Lesotho and Tanzania, two countries with little access to GRT. METHODS: The Genotype-Informed Versus Empirical Management of Viremia (GIVE MOVE) open-label, parallel-group randomised controlled trial enrolled children and adolescents with HIV between the ages of 6 months and 19 years, taking ART, and with a viral load at least 400 copies per mL. Participants were recruited from ten clinical centres and hospitals in Lesotho and Tanzania. Participants were electronically randomly allocated 1:1 to receive either GRT with expert recommendation (GRT group) or repeat viral-load testing and empirical onward treatment (usual care group). Participants and study staff were not masked, but the endpoint committee and laboratory staff conducting viral-load testing were. Participants in both groups received at least three sessions of enhanced adherence counselling, and in the GRT group, blood for GRT assessed via Sanger sequencing was drawn at enrolment. The composite primary endpoint was death, hospitalisation, a new WHO HIV clinical stage 4 event, or not having documented viral suppression of less than 50 copies per mL at 36 weeks in the modified intention-to-treat population, which excluded participants who were retrospectively found to be ineligible after randomisation. Serious adverse events were analysed in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT04233242) and the trial status is completed. FINDINGS: Between March 3, 2020, and July 5, 2022, 286 participants were enrolled and 284 were included in the modified intention-to-treat analysis (144 in the GRT group and 140 in the usual care group). Of these participants, 158 (56%) were female and 126 (44%) were male. Five (3%) in the GRT group and four (3%) in the usual care group did not complete follow-up but were included in the primary analysis. The median age across both groups was 14 years (IQR 9-16). The composite primary endpoint occurred in 67 (47%) participants in the GRT group and 73 (52%) in the usual care group (adjusted odds ratio 0·79 [95% CI 0·49 to 1·27]; adjusted risk difference -0·06 [95% CI -0·17 to 0·06]; p=0·34); all participants reaching the composite primary endpoint had no documented viral suppression at 36 weeks. No deaths were recorded, and only one clinical stage 4 event requiring hospitalisation occurred (in the usual care group); this was the only serious adverse event recorded in the study. INTERPRETATION: GRT-informed management did not significantly improve treatment outcomes for children and adolescents with viraemia while taking ART. FUNDING: Fondation Botnar, Swiss National Science Foundation, and Gottfried and Julia Bangerter-Rhyner Foundation. TRANSLATIONS: For the Sesotho and Swahili translations of the abstract see Supplementary Materials section.

Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design A scoping review.

OBJECTIVE: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies. STUDY DESIGN AND SETTING: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with post-randomization consent for the intervention group and no specific post-randomization consent for the usual care control group. Information from identified TwiCs were extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to non-uptake of interventions and informed consent procedure. RESULTS: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46;17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46;100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for non-uptake of the intervention, anticipating a median non-uptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for non-uptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%). CONCLUSIONS: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial non-uptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs.

Antibody and T-cell response to bivalent booster SARS-CoV-2 vaccines in people with compromised immune function (COVERALL-3).

BACKGROUND: Bivalent mRNA vaccines, designed to combat emerging SARS-CoV-2 variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months post vaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/ml (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a five-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with HIV or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare.

Community-based management of arterial hypertension and cardiovascular risk factors by lay village health workers for people with controlled and uncontrolled blood pressure in rural Lesotho: joint protocol for two cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT Twic 1 and ComBaCaL aHT TwiC 2).

BACKGROUND: Arterial hypertension (aHT) is a major cause for premature morbidity and mortality. Control rates remain poor, especially in low- and middle-income countries. Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems may help to overcome the current aHT care cascade gaps. However, evidence on the effectiveness of comprehensive VHW-led aHT care models, in which VHWs provide antihypertensive drug treatment and manage cardiovascular risk factors is scarce. METHODS: Using the trials within the cohort (TwiCs) design, we are assessing the effectiveness of VHW-led aHT and cardiovascular risk management in two 1:1 cluster-randomized trials nested within the Community-Based chronic disease Care Lesotho (ComBaCaL) cohort study (NCT05596773). The ComBaCaL cohort study is maintained by trained VHWs and includes the consenting inhabitants of 103 randomly selected villages in rural Lesotho. After community-based aHT screening, adult, non-pregnant ComBaCaL cohort participants with uncontrolled aHT (blood pressure (BP) ≥ 140/90 mmHg) are enrolled in the aHT TwiC 1 and those with controlled aHT (BP < 140/90 mmHg) in the aHT TwiC 2. In intervention villages, VHWs offer lifestyle counseling, basic guideline-directed antihypertensive, lipid-lowering, and antiplatelet treatment supported by a tablet-based decision support application to eligible participants. In control villages, participants are referred to a health facility for therapeutic management. The primary endpoint for both TwiCs is the proportion of participants with controlled BP levels (< 140/90 mmHg) 12 months after enrolment. We hypothesize that the intervention is superior regarding BP control rates in participants with uncontrolled BP (aHT TwiC 1) and non-inferior in participants with controlled BP at baseline (aHT TwiC 2). DISCUSSION: The TwiCs were launched on September 08, 2023. On May 20, 2024, 697 and 750 participants were enrolled in TwiC 1 and TwiC 2. To our knowledge, these TwiCs are the first trials to assess task-shifting of aHT care to VHWs at the community level, including the prescription of basic antihypertensive, lipid-lowering, and antiplatelet medication in Africa. The ComBaCaL cohort and nested TwiCs are operating within the routine VHW program and countries with similar community health worker programs may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05684055. Registered on January 04, 2023.

Characteristics, Progression, and Output of Randomized Platform Trials: A Systematic Review.

Importance: Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice. Objective: To determine the characteristics, progression, and output of randomized platform trials. Evidence Review: In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm. Findings: The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%]). Conclusions and Relevance: This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.

Evaluation of COVID-19 antigen rapid diagnostic tests for self-testing in Lesotho and Zambia.

INTRODUCTION: The use of antigen rapid tests (Ag-RDTs) for self-testing is an important element of the COVID-19 control strategy and has been widely supported. However, scale-up of self-testing for COVID-19 in sub-Saharan Africa is still insufficient and there is limited evidence on the acceptability of self-testing and agreement between Ag-RDT self-testing and Ag-RDT testing by professional users. A joint collaboration (Botnar Research Centre for Child Health-European & Developing countries Clinical Trials Partnership)was established between Lesotho and Zambia to address these gaps in relation to Ag-RDT self-testing and contribute to increasing its use in the region. METHODS: A cross-sectional study was conducted with qualitative and quantitative data analysis. Firstly, 14 in-depth cognitive interviews (5 in Zambia and 9 in Lesotho) were performed to assess the participants' understanding of the instructions for use (IFU) for self-testing. In a second step, evaluation of test agreement between Ag-RDT self-testing and Ag-RDT testing by professional user using SD Biosensor STANDARD Q COVID-19 Ag-RDT was performed. In Zambia, usability and acceptability of self-testing were also assessed. RESULTS: Cognitive interviews in Lesotho and Zambia showed overall good understanding of IFU. In Zambia, acceptability of self-testing was high, though some participants had difficulties in conducting certain steps in the IFU correctly. Agreement between Ag-RDT self-test and Ag-RDT by professional users in Lesotho (428 participants) and Zambia (1136 participants) was high, 97.3% (403/414, 95% CI: 95.3-98.7) and 99.8% (1116/1118, 95% CI: 99.4-100) respectively. CONCLUSION: Findings from this study support the use of Ag-RDT self-testing within COVID-19 control strategies in sub-Saharan Africa, contributing to increase the testing capacity and access in hard-to reach settings.

Community-based models of care for adolescent and adult depression, suicidal behavior, anxiety, trauma, and substance use in Africa: a scoping review.

Background: Community-based care (CBC), where care is delivered outside of the traditional health facility setting, has been proposed to narrow the mental health (MH) and substance use (SU) treatment gap in Africa. Objective: This scoping review aims to comprehensively summarize CBC models addressing adolescent and adult MH (depression, anxiety, trauma, suicidal behavior) and (non-tobacco) SU problems in Africa. Methods: We searched PsycINFO, Embase, Scopus, CINAHL, and Medline Ovid. Studies and protocols were included if they reported on CBC intervention's effects on MH or SU symptoms/ diagnoses, acceptability, feasibility, or patient engagement in care, regardless of whether the intervention itself was designed specifically for MH or SU. Results: Among 11,477 screened publications, 217 were eligible. Of the unique intervention studies (n = 206), CBC models were classified into the following approaches (non-mutually exclusive): psychotherapeutic (n = 144), social (n = 81), lifestyle/physical health (n = 55), economic (n = 26), and psychopharmacological (n = 2). While quantitative results suggest possible efficacy of CBC models, description of CBC location was often poor. Fewer interventions addressed suicidal behavior (n = 12), the needs of adolescents (n = 49), or used traditional healers or religious figures as providers (n = 3). Conclusion: Many CBC models have been tested on MH and SU in Africa and should be critically appraised and meta-analyzed in subsequent reviews, where possible.

Same-day versus rapid ART initiation in HIV-positive individuals presenting with symptoms of tuberculosis: Protocol for an open-label randomized non-inferiority trial in Lesotho and Malawi.

BACKGROUND: In absence of contraindications, same-day initiation (SDI) of antiretroviral therapy (ART) is recommended for people testing HIV-positive who are ready to start treatment. Until 2021, World Health Organization (WHO) guidelines considered the presence of TB symptoms (presumptive TB) a contraindication to SDI due to the risk of TB-immune reconstitution inflammatory syndrome (TB-IRIS). To reduce TB-IRIS risk, ART initiation was recommended to be postponed until results of TB investigations were available, and TB treatment initiated if active TB was confirmed. In 2021, the WHO guidelines changed to recommending SDI even in the presence of TB symptoms without awaiting results of TB investigations based on the assumption that TB investigations often unnecessarily delay ART initiation, increasing the risk for pre-ART attrition from care, and noting that the clinical relevance of TB-IRIS outside the central nervous system remains unclear. However, this guideline change was not based on conclusive evidence, and it remains unclear whether SDI of ART or TB test results should be prioritized in people with HIV (PWH) and presumptive TB. DESIGN AND METHODS: SaDAPT is an open-label, pragmatic, parallel, 1:1 individually randomized, non-inferiority trial comparing two strategies for the timing of ART initiation in PWH with presumptive TB ("ART first" versus "TB results first"). PWH in Lesotho and Malawi, aged 12 years and older (re)initiating ART who have at least one TB symptom (cough, fever, night sweats or weight loss) and no signs of intracranial infection are eligible. After a baseline assessment, participants in the "ART first" arm will be offered SDI of ART, while those in the "TB results first" arm will be offered ART only after active TB has been confirmed or refuted. We hypothesize that the "ART first" approach is safe and non-inferior to the "TB results first" approach with regard to HIV viral suppression (<400 copies/ml) six months after enrolment. Secondary outcomes include retention in care and adverse events consistent with TB-IRIS. EXPECTED OUTCOMES: SaDAPT will provide evidence on the safety and effects of SDI of ART in PWH with presumptive TB in a pragmatic clinical trial setting. TRIAL REGISTRATION: The trial has been registered on clinicaltrials.gov (NCT05452616; July 11 2022).

Implementing focused echocardiography and AI-supported analysis in a population-based survey in Lesotho: implications for community-based cardiovascular disease care models.

In settings where access to expert echocardiography is limited, focused echocardiography, combined with artificial intelligence (AI)-supported analysis, may improve diagnosis and monitoring of left ventricular hypertrophy (LVH). Sixteen nurses/nurse-assistants without prior experience in echocardiography underwent a 2-day hands-on intensive training to learn how to assess parasternal long axis views (PLAX) using an inexpensive hand-held ultrasound device in Lesotho, Southern Africa. Loops were stored on a cloud-drive, analyzed using deep learning algorithms at the University Hospital Basel, and afterwards confirmed by a board-certified cardiologist. The nurses/nurse-assistants obtained 756 echocardiograms. Of the 754 uploaded image files, 628 (83.3%) were evaluable by deep learning algorithms. Of those, results of 514/628 (81.9%) were confirmed by a cardiologist. Of the 126 not evaluable by the AI algorithm, 46 (36.5%) were manually evaluable. Overall, 660 (87.5%) uploaded files were evaluable and confirmed. Following short-term training of nursing cadres, a high proportion of obtained PLAX was evaluable using AI-supported analysis. This could be a basis for AI- and telemedical support in hard-to-reach areas with minimal resources.

Bridging the gap: identifying factors impacting mRNA severe acute respiratory syndrome coronavirus 2 vaccine booster response in people with HIV-1.

OBJECTIVES: This study aimed to investigate the association of demographic and clinical characteristics, including HIV-specific parameters with the antibody response to a third dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in people with HIV-1 (PWH). DESIGN: Post hoc analysis of data collected during the observational extension of the COrona VaccinE tRiAL pLatform trial (COVERALL-2) nested into the Swiss HIV Cohort Study (SHCS). METHODS: Serological measurements were conducted on a total of 439 PWH who had received a third dose of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Antibody reactivity was assessed using the multifactorial ABCORA immunoassay that defines SARS-CoV-2 seroconversion and predicts neutralization activity. The association between log transformed antibody reactivity and various baseline factors, including vaccine type, demographics, immune and viral status, smoking status, comorbidities, infection history, and co-medication with chemotherapy and immunosuppressive drugs, was investigated using a multivariable linear regression model. RESULTS: Antibody response to third SARS-CoV-2 vaccination was significantly lower among PWH with CD4 + cell count less than 350 cells/µl [ratio of means 0.79; 95% confidence interval (CI) 0.65-0.95]. Having a detectable HIV-1 viral load at least 50 copies/ml and being on concurrent chemotherapy was associated with an overall lower humoral immune response (ratio of means 0.75; 95% CI 0.57-1.00 and 0.34; 95% CI 0.22-0.52, respectively). CONCLUSION: The study highlights the importance of optimal antiretroviral treatment for PWH, emphasizing the need for timely intervention to enhance the vaccine immunogenicity in this population. Moreover, it underscores the significance of sequential mRNA vaccination and provides important evidence for informing vaccine guidelines.

Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: A scoping review.

INTRODUCTION: The prevalence of type 2 diabetes mellitus (T2DM) and associated morbidity and mortality are increasing in sub-Saharan Africa (SSA). To facilitate access to quality care and improve treatment outcomes, there is a need for innovative community care models and optimized use of non-physician healthcare workers bringing diagnosis and care closer to patients' homes. AIM: We aimed to describe with a scoping review different models of community-based care for non-pregnant adults with T2DM in SSA, and to synthesize the outcomes in terms of engagement in care, blood sugar control, acceptability, and end-organ damage. We further aimed to critically appraise the different models of care and compare community-based to facility-based care if data were available. METHODS: We searched Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus, supplemented with backward and forward citation searches. We included cohort studies, randomized trials and case-control studies that reported on non-pregnant individuals diagnosed with T2DM in SSA, who received a substantial part of care in the community. Only studies which reported at least one of our outcomes of interest were included. A narrative analysis was done, and comparisons made between community-based and facility-based models, where within-study comparison was reported. RESULTS: We retrieved 5,335 unique studies, four of which met our inclusion criteria. Most studies were excluded because interventions were facility-based; community care interventions described in the studies were only add-on features of a primarily facility-based care; and studies did not report outcomes of interest. The included studies reported on a total of 383 individuals with T2DM. Three different community care models were identified. 1) A community-initiated model where diagnosis, treatment and monitoring occurred primarily in the community. This model reported a higher linkage and engagement in care at 9 months compared to the corresponding facility model, but only slight reductions of average blood glucose levels at six months compared to baseline. 2) A facility-originated community model where after treatment initiation, a substantial part of follow-up was offered at community level. Two studies reported such a model of care, both had as core component home-delivery of medication. Acceptability of this approach was high. But neither study found improved T2DM control when compared to facility care 3) An eHealth model with high acceptability scores for both patients and care providers, and an absolute 1.76% reduction in average HbA1c levels at two months compared to baseline. There were no reported outcomes on end-organ damage. All four studies were rated as being at high risk for bias. CONCLUSION: Evidence on models of care for persons with T2DM in SSA where a substantial part of care is shifted to the community is scant. Whereas available literature indicates high acceptability of community-based care, we found no conclusive data on their effectiveness in controlling blood sugar and preventing complications. Evidence from larger scale studies, ideally randomized trials with clinically relevant endpoints is needed before roll-out of community-based T2DM care can be recommended in SSA.

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

Background: After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. Methods: In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. Results: Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). Conclusions: People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov).

Facilitators and barriers to COVID-19 testing in community and clinical settings: Lessons learned from Lesotho and Zambia.

The sudden emergence of the coronavirus disease 2019 (COVID-19) had a devastating impact on health systems and population health globally. To combat the spread of COVID-19, countries enacted guidelines and safety measures, including testing, contact tracing, and quarantine. It was unclear the extent to which uptake of COVID-19 testing and other health initiatives would be accepted in countries with a history of dealing with widespread communicable disease transmission such as HIV or Tuberculosis. The objective of this study was to understand and compare the facilitators and barriers to COVID-19 testing at hospital sites in two rural communities in Lesotho and community spaces (referred to as hubs) in one urban community in Zambia during active phases of COVID-19 pandemic. Individual interviews and focus group discussions (FGDs) were held during March-October 2021 to explore facilitators and barriers to COVID-19 testing. FGDs with 105 community members and health care workers, and 16 individual interviews with key informants and four mystery shoppers were conducted across the two countries. In Zambia, four mystery shopper observations, and eight hub observations were also conducted. Individual country codebooks were developed and combined; thematic analyses were then conducted using the combined codebook. Findings were compared across the two countries, and most were consistent across the two countries. Two primary themes emerged that related to both barriers and facilitators: (1) structural conditions; (2) social implications and attitudes. The structural conditions that operated as barriers in both countries included public health isolation measures and misinformation. In Lesotho, the cost of tests was an additional barrier. The only structural facilitators were in Zambia where the community hubs were found to be accessible and convenient. The social implication barriers related to fear of isolation, stigma, and mental health implications because of quarantine, perceived pain of the test, and compromised privacy. Social facilitators that led to people testing included experiencing COVID-19 firsthand and knowing people who had died because of COVID-19. Across both countries, primary barriers and facilitators to COVID-19 related to structural conditions and social implications and attitudes. Public health measures can be at odds with social and economic realities; pandemic response should balance public health control and the socio-economic needs. Data from Zambia revealed that community-based settings have the potential to increase uptake of testing services. Community-based campaigns to normalize and reduce stigma for COVID-19 testing services are needed.

Community-based type 2 diabetes care by lay village health workers in rural Lesotho: protocol for a cluster-randomized trial within the ComBaCaL cohort study (ComBaCaL T2D TwiC).

BACKGROUND: Type 2 diabetes (T2D) poses a growing public health burden, especially in low- and middle-income countries (LMICs). Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems (CDSS) are promising approaches to tackle the current T2D care gap in LMICs. However, evidence on the effectiveness of lay worker-led T2D care models, in which VHWs initiate and monitor drug treatment in addition to community-based screening and referral services, is lacking. METHODS: We are conducting a cluster-randomized trial nested within the Community-Based Chronic Disease Care Lesotho (ComBaCaL) cohort study (NCT05596773) using the trial within cohort (TwiC) design to assess the effectiveness of a VHW-led, CDSS-assisted T2D care model in rural Lesotho. Participants are non-pregnant members of the ComBaCaL cohort study with T2D. The ComBaCaL cohort study is conducted in approximately 100 villages in two rural districts in Lesotho and is managed by trained and supervised VHWs. In intervention villages, VHWs offer a community-based T2D care package including lifestyle counselling, first-line oral antidiabetic, lipid-lowering, and antiplatelet treatment guided by a tablet-based CDSS to participants who are clinically eligible, as well as treatment support to participants who prefer or clinically require facility-based T2D care. In control clusters, all participants will be referred to a health facility for T2D management. The primary endpoint is the mean glycosylated haemoglobin (HbA1c) 12 months after enrolment. Secondary endpoints include the 10-year risk for cardiovascular events estimated using the World Health Organization risk prediction tool. DISCUSSION: The trial was launched on May 13, 2023, and has enrolled 226 participants at the date of submission (October 6, 2023). To our knowledge, the trial is the first to assess task-shifting of T2D care to VHWs at the community level, including the prescription of first-line antidiabetic, lipid-lowering, and antiplatelet medication in sub-Saharan Africa, and will thus provide the missing evidence on the effectiveness of such a T2D care model in this setting. The study is operating within the established Lesotho VHW programme. Similar community health worker programmes which exist across sub-Saharan Africa may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05743387. Registered on February 24 2023.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

High Rates of Undiagnosed Target Organ Damage Among Adults with Elevated Blood Pressure or Diabetes Mellitus in a Community-Based Survey in Lesotho.

INTRODUCTION: Prevalence of elevated blood pressure (BP) and diabetes mellitus (DM) is increasing in sub-Saharan Africa. Data on target organ damage such as retinopathy, left ventricular hypertrophy (LVH), renal impairment and peripheral neuropathy (PN) among persons with elevated BP and/or DM in sub-Saharan Africa remain scarce. AIM: To determine at community-level the prevalence of retinopathy, LVH, renal impairment, and PN among adults with elevated BP and/or DM, and assess the association of elevated BP and/or DM with target organ damage in Lesotho. METHODS: During a household-based survey, a sub-sample of adults with elevated BP (≥ 140/90 mmHg) and/or DM (glycosylated hemoglobin ≥ 6.5%), as well as comparators (BP < 140/90 mmHg, HbA1c < 6.5%) were screened for retinopathy, LVH, renal impairment, and PN. We used multivariable logistic regression for inferential analysis. RESULTS: Out of 6108 participants screened during the survey, 420 with elevated BP only, 80 with DM only, 61 with elevated BP and DM, and 360 comparators were assessed for target organ damage. Among those with elevated BP, and among those with DM with or without elevated BP, prevalence of retinopathy was 34.6% (89/257) and 14.4% (15/104); renal impairment was 45.0% (156/347) and 42.4% (56/132), respectively. Among those with elevated BP, 2.3% (7/300) and 65.7% (224/341) had LVH and left ventricular concentric remodeling, respectively. PN, only assessed among those with DM, was present in 32.6% (42/129). Elevated BP was associated with increased odds of retinopathy (aOR, 19.13; 95% CI, 8.52-42.94; P < 0.001) and renal impairment (aOR, 1.80; 95% CI, 1.27-2.55; P = 0.001). Presence of both elevated BP and DM was associated with an increased odds of retinopathy (aOR, 16.30; 95%CI, 5.69-46.68; P < 0.001), renal impairment (aOR, 2.55; 95% CI, 1.35-4.81; P = 0.004), and PN (aOR, 2.13; 95% CI, 1.04-4.38; P = 0.040). CONCLUSION: We found a high prevalence of undiagnosed target organ damage among adults with elevated BP and/or DM during community-based screening. These findings emphasize the importance of regular prevention and screening activities in this setting.

Head-to-head comparison of the WHO STEPwise approach with immediate unattended and delayed unattended automated blood pressure measurements during household-based screening: a diagnostic accuracy study in Lesotho.

Background: WHO introduced the STEPwise approach to surveillance (STEPS) to monitor trends in non-communicable diseases. For arterial hypertension, the STEPS protocol takes the average of the last two out of three standard blood pressure measurements (SBPM). This study assesses the diagnostic accuracy of SBPM, same-day and next-day unattended automated measurement (uABP), with 24 h ambulatory measurement (24 h-ABPM) as reference. Methods: This diagnostic accuracy study was done within a population-based household survey on cardiovascular risk factors in two districts in Northern Lesotho. Adults (aged ≥ 18 years) with elevated SBPM (defined as ≥140/90 mmHg), and 2:1 age- and sex-matched participants with normal SBPM during the survey were recruited. Following SBPM, first uABP readings were obtained on survey day. Afterwards, participants received a 24 h-ABPM device. Second uABP readings were taken 24 h later, after retrieval of the 24 h-ABPM. The main outcome was overall diagnostic accuracy of all screening measurements (SBPM, first uABP, and second uABP), determined using area under the receiver operating characteristic curve (AUROC), with 24 h-ABPM as a reference. Findings: Between November 2, 2021 and August 31, 2022, 275 participants (mean age 58 years (SD: 16 years), 163 (59%) female) were enrolled, 183 of whom had elevated and 92 had normal SBPM. Mean difference between systolic daytime 24 h-ABPM and screening measurements was highest for SBPM (mean difference: -13 mmHg; 95% CI: -14 to -11). Mean difference between diastolic daytime 24 h-ABPM and diastolic SBPM was -2 mmHg (95% CI: -4 to -1), whereas no difference was found for mean diastolic first uABP (mean difference: -1 mmHg; 95% CI: -2.0 to 0.3); and mean diastolic second uABP (mean difference: 1.0 mmHg; 95% CI: -0.4 to 2.3). White coat hypertension was highest with SBPM (55 [20%]), followed by first uABP (27 [9.8%]), and second uABP (18 [6.5%]). Using systolic daytime 24 h-ABPM as a reference, the uABPs had higher AUROC (first uABP: 87% [95% CI: 83-91]; second uABP: 88% [95% CI: 84-92]); SBPM: (79% [95% CI: 74-85]). This difference was significant between first uABP and SBPM (P = 0.0024), and between second uABP and SBPM (P = 0.0017). Interpretation: uABP had better diagnostic performance than SBPM. Integration of uABP into STEPS protocol should be considered. Funding: Swiss Agency for Development and Cooperation under the ComBaCaL project, and the World Diabetes Foundation.

Impact of a multi-disease integrated screening and diagnostic model for COVID-19, TB, and HIV in Lesotho.

The surge of the COVID-19 pandemic challenged health services globally, and in Lesotho, the HIV and tuberculosis (TB) services were similarly affected. Integrated, multi-disease diagnostic services were proposed solutions to mitigate these disruptions. We describe and evaluate the effect of an integrated, hospital-based COVID-19, TB and HIV screening and diagnostic model in two rural districts in Lesotho, during the period between December 2020 and August 2022. Adults, hospital staff, and children above 5 years attending two hospitals were pre-screened for COVID-19 and TB symptoms. After a positive pre-screening, participants were offered to enroll in a service model that included clinical evaluation, chest radiography, SARS-CoV-2, TB, and HIV testing. Participants diagnosed with COVID-19, TB, or HIV were contacted after 28 days to evaluate their health status and linkage to HIV and/or TB care services. Of the 179160 participants pre-screened, 6623(3.7%) pre-screened positive, and 4371(66%) were enrolled in this service model. Of the total 458 diagnoses, only 17 happened in children. One positive rapid antigen test for SARS-CoV-2 was found per 11 participants enrolled, one Xpert-positive TB case was diagnosed per 85 people enrolled, and 1 new HIV diagnosis was done per 182 people enrolled. Of the 321(82.9%) participants contacted after 28 days of diagnosis, 304(94.7%) reported to be healthy. Of the individuals that were newly diagnosed with HIV or TB, 18/24(75.0%) and 46/51(90.1%) started treatment within 28 days of the diagnosis. This screening and diagnostic model successfully maintained same-day, integrated COVID-19, TB, and HIV testing services, despite frequent disruptions caused by the surge of COVID-19 waves, healthcare seeking patterns, and the volatile context (social measures, travel restrictions, population lockdowns). There were positive effects in avoiding diagnostic delays and ensuring linkage to services, however, diagnostic yields for adults and children were low. To inform future preparedness plans, research will need to identify essential health interventions and how to optimize them along each phase of the emergency response.