COVID-19 screening in low resource settings using artificial intelligence for chest radiographs and point-of-care blood tests.

Artificial intelligence (AI) systems for detection of COVID-19 using chest X-Ray (CXR) imaging and point-of-care blood tests were applied to data from four low resource African settings. The performance of these systems to detect COVID-19 using various input data was analysed and compared with antigen-based rapid diagnostic tests. Participants were tested using the gold standard of RT-PCR test (nasopharyngeal swab) to determine whether they were infected with SARS-CoV-2. A total of 3737 (260 RT-PCR positive) participants were included. In our cohort, AI for CXR images was a poor predictor of COVID-19 (AUC = 0.60), since the majority of positive cases had mild symptoms and no visible pneumonia in the lungs. AI systems using differential white blood cell counts (WBC), or a combination of WBC and C-Reactive Protein (CRP) both achieved an AUC of 0.74 with a suggested optimal cut-off point at 83% sensitivity and 63% specificity. The antigen-RDT tests in this trial obtained 65% sensitivity at 98% specificity. This study is the first to validate AI tools for COVID-19 detection in an African setting. It demonstrates that screening for COVID-19 using AI with point-of-care blood tests is feasible and can operate at a higher sensitivity level than antigen testing.

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.

Head-to-head comparison of nasal and nasopharyngeal sampling using SARS-CoV-2 rapid antigen testing in Lesotho.

OBJECTIVES: To assess the real-world diagnostic performance of nasal and nasopharyngeal swabs for SD Biosensor STANDARD Q COVID-19 Antigen Rapid Diagnostic Test (Ag-RDT). METHODS: Individuals ≥5 years with COVID-19 compatible symptoms or history of exposure to SARS-CoV-2 presenting at hospitals in Lesotho received two nasopharyngeal and one nasal swab. Ag-RDT from nasal and nasopharyngeal swabs were performed as point-of-care on site, the second nasopharyngeal swab used for polymerase chain reaction (PCR) as the reference standard. RESULTS: Out of 2198 participants enrolled, 2131 had a valid PCR result (61% female, median age 41 years, 8% children), 84.5% were symptomatic. Overall PCR positivity rate was 5.8%. The sensitivity for nasopharyngeal, nasal, and combined nasal and nasopharyngeal Ag-RDT result was 70.2% (95%CI: 61.3-78.0), 67.3% (57.3-76.3) and 74.4% (65.5-82.0), respectively. The respective specificity was 97.9% (97.1-98.4), 97.9% (97.2-98.5) and 97.5% (96.7-98.2). For both sampling modalities, sensitivity was higher in participants with symptom duration ≤ 3days versus ≤ 7days. Agreement between nasal and nasopharyngeal Ag-RDT was 99.4%. CONCLUSIONS: The STANDARD Q Ag-RDT showed high specificity. Sensitivity was, however, below the WHO recommended minimum requirement of ≥ 80%. The high agreement between nasal and nasopharyngeal sampling suggests that for Ag-RDT nasal sampling is a good alternative to nasopharyngeal sampling.

Effectiveness of a peer educator-coordinated preference-based differentiated service delivery model on viral suppression among young people living with HIV in Lesotho: The PEBRA cluster-randomized trial.

BACKGROUND: Southern and Eastern Africa is home to more than 2.1 million young people aged 15 to 24 years living with HIV. As compared with other age groups, this population group has poorer outcomes along the HIV care cascade. Young people living with HIV and the research team co-created the PEBRA (Peer Educator-Based Refill of ART) care model. In PEBRA, a peer educator (PE) delivered services as per regularly assessed patient preferences for medication pick-up, short message service (SMS) notifications, and psychosocial support. The cluster-randomized trial compared PEBRA model versus standard clinic care (no PE and ART refill done by nurses) in 3 districts in Lesotho. METHODS AND FINDINGS: Individuals taking antiretroviral therapy (ART) aged 15 to 24 years at 20 clinics (clusters) were eligible. In the 10 clinics randomized to the intervention arm, participants were offered the PEBRA model, coordinated by a trained PE and supported by an eHealth application (PEBRApp). In the 10 control clusters, participants received standard nurse-coordinated care without any service coordination by a PE. The primary endpoint was 12-month viral suppression below 20 copies/mL. Analyses were intention-to-treat and adjusted for sex. From November 6, 2019 to February 4, 2020, we enrolled 307 individuals (150 intervention, 157 control; 218 [71%] female, median age 19 years [interquartile range, IQR, 17 to 22]). At 12 months, 99 of 150 (66%) participants in the intervention versus 95 of 157 (61%) participants in the control arm had viral suppression (adjusted odds ratio (OR) 1.27; 95% confidence interval [CI] [0.79 to 2.03]; p = 0.327); 4 of 150 (2.7%) versus 1 of 157 (0.6%) had died (adjusted OR 4.12; 95% CI [0.45 to 37.62]; p = 0.210); and 12 of 150 (8%) versus 23 of 157 (14.7%) had transferred out (adjusted OR 0.53; 95% CI [0.25 to 1.13]; p = 0.099). There were no significant differences between arms in other secondary outcomes. Twenty participants (11 in intervention and 9 in control) were lost to follow-up over the entire study period. The main limitation was that the data collectors in the control clusters were also young peers; however, they used a restricted version of the PEBRApp to collect data and thus were not able to provide the PEBRA model. The trial was prospectively registered on ClinicalTrials.gov (NCT03969030). CONCLUSIONS: Preference-based peer-coordinated care for young people living with HIV, compared to nurse-based care only, did not lead to conclusive evidence for an effect on viral suppression. TRIAL REGISTRATION: clinicaltrials.gov, NCT03969030, https://clinicaltrials.gov/ct2/show/NCT03969030.

Dolutegravir in real life: Self-reported mental and physical health outcomes after transitioning from efavirenz- to dolutegravir-based antiretroviral therapy in a prospective cohort study in Lesotho.

INTRODUCTION: HIV programmes across many countries in Africa have recently transitioned people living with HIV from efavirenz (EFV)- to dolutegravir (DTG)-containing antiretroviral therapy (ART). As both drugs are associated with neuropsychiatric adverse effects, this study assessed the mental health and HIV/ART-associated symptoms of people living with HIV before and after transition to DTG. METHODS: The prospective DO-REAL cohort enrolled people starting DTG-based ART in Lesotho from February to December 2020. For this analysis within DO-REAL, we included adults changing from tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/EFV to TDF/3TC/DTG within first-line therapy. At transition and 16 weeks thereafter, participants completed the Patient Health Questionnaire-9 (PHQ-9; depression screening), the 12-item Short-Form Health Survey (SF-12; mental and physical health), and a modified HIV Symptom Index (mHSI; HIV/ART-related symptoms). We also assessed weight change. We used McNemar tests with Bonferroni corrections to assess binary outcomes. CLINICALTRIALS: gov: NCT04238767. RESULTS: Among 1228 participants, 1131 completed follow-up. Of these, 60.0% were female, the median age was 46 years (interquartile range [IQR] 38-55), and the median time taking ART was 5.7 years (IQR 3.5-8.9). No change was observed for weight or overall PHQ-9 or SF-12 outcomes. However, three mHSI items decreased at follow-up: 'feeling sad/down/depressed' (bothered 6.0% vs. 3.3% of participants at least 'a little' before vs. after transition; adjusted p = 0.048); 'feeling nervous/anxious' (7.4% vs. 3.4%; adjusted p = 0.0009); and 'nightmares, strange/vivid dreams' (6.3% vs. 3.5%; adjusted p = 0.027). Individual PHQ-9 or SF-12 items also improved. Being symptom free across all measures increased from 5.1% to 11.4% (p < 0.0001). CONCLUSIONS: We observed no negative impacts and potential moderate improvements with DTG, providing further support for the rollout of DTG.

Diagnosis of SARS-CoV-2 infection from breath - a proof-of-concept study.

Bioaerosol capture and analysis is emerging as a non-invasive diagnostic method for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this proof-of-concept study conducted in Lesotho, we evaluated the novel and simple AL2 bioaerosol detection device in comparison to conventional nasopharyngeal sampling methods. We demonstrated for the first time that SARS-CoV-2 can be detected using the AL2 bioaerosol capture device. However, studies with a larger sample size are needed to further evaluate this bioaerosol capture device for the detection of SARS-CoV-2.

High Unreported Mortality in Children and Youth (<25 Years) Living With HIV Who Were Lost to Care From Antiretroviral Therapy Programs in Southern Africa: Results From a Multicountry Tracing Study.

BACKGROUND: Antiretroviral therapy program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS: We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS: Among 680 children and youth aged <25 years on antiretroviral therapy who were lost and traced in Southern Africa between October 2017 and November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared with infants aged <2 years [adjusted hazard ratio: 0.40 (95% confidence interval: 0.31 to 0.51)]. CONCLUSIONS: Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.

Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa.

INTRODUCTION: Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. METHODS: Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. RESULTS: In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). CONCLUSIONS: At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.

Determining the acceptability of point-of-care urine tenofovir testing and its performance in predicting HIV RNA suppression.

BACKGROUND: The detection of tenofovir (TFV) metabolites by point-of-care (POC) urine lateral flow immunoassays (LFIA) indicates adherence to tenofovir-containing HIV pre-exposure prophylaxis. However, the association between urine TFV metabolites as detected by LFIA and HIV viral load suppression in people receiving TFV-based antiretroviral therapy (ART) is unknown as is patient and clinician acceptability of POC urine LFIA testing in clinical practice in low- and middle-income country settings. METHODS: We enrolled 409 people living with HIV from two HIV clinics in Lesotho and investigated the performance of POC urine LFIA TFV testing in predicting viral suppression. We interviewed 12 study participants and conducted a focus-group discussion with 5 clinicians to gather opinions on POC urine TFV testing. RESULTS: Using a viral load threshold of 1000 copies/mL, 398 (98%) participants were virologically suppressed, and 8 were viremic. Tenofovir was detected in the urine of 405 (99%) participants. The sensitivity of the POC urine LFIA test in detecting TFV in participants with viral suppression was 99.3% (95% CI: 97.8-99.8); the specificity was 12.5% (95% CI: 0.3-52.6). The positive and negative predictive values were 98.3% and 25%, respectively. Point-of-care urine TFV testing was viewed favorably by both participants and clinicians. However, clinicians stated that the 2-3-days detection window of the assay studied limits adherence categorization. CONCLUSIONS: In our study cohort, urine POC TFV testing demonstrated high sensitivity in predicting viral suppression, but low specificity and negative predictive value. Urine POC TFV testing was highly acceptable to participants and clinicians; however, clinicians expressed concern about its clinical utility because of its limitations. While further research is needed to assess performance in less adherent populations, this test may support adherence counseling in some clinical settings.

Feasibility of implementing the advanced HIV disease care package as part of community-based HIV/TB activities: a mixed-methods study protocol.

INTRODUCTION: Although the advanced HIV disease (AHD) care package reduces morbidity and mortality in people with AHD (defined in people living with HIV as WHO stage 3 or 4, CD4 count <200 cells/µL or age <5 years), it is barely implemented in many countries. A novel point-of-care CD4 test rapidly identifies AHD. We evaluate the feasibility of implementing the AHD care package as part of community-based HIV/tuberculosis services. METHODS AND ANALYSIS: This two-phased study is guided by the Medical Research Council framework for evaluation of complex interventions. Stage 1 is a stakeholder consultation to define tools and indicators to assess feasibility of the AHD care package. Stage 2 is the implementation of the AHD care package during a facility-based tuberculosis diagnostic accuracy study in high-burden HIV/tuberculosis settings. Consenting adults with tuberculosis symptoms in two sites in Lesotho and South Africa are eligible for inclusion. HIV-positive participants are included in the feasibility study and are offered a CD4 test, a tuberculosis-lipoarabinomannan assay and those with CD4 count of ≤200 cells/µL a cryptococcal antigen lateral flow assay. Participants are referred for clinical management following national guidelines. The evaluation includes group discussions, participant observation (qualitative strand) and a semistructured questionnaire to assess acceptability among implementers. The quantitative strand also evaluates process compliance (process rating and process cascade) and early outcomes (vital and treatment status after twelve weeks). Thematic content analysis, descriptive statistics and data triangulation will be performed. ETHICS AND DISSEMINATION: The National Health Research and Ethics Committee, Lesotho, the Human Sciences Research Council Research Ethics Committee and Provincial Department of Health, South Africa and the Ethikkommission Nordwest- und Zentralschweiz, Switzerland, approved the protocol. Dissemination will happen locally and internationally at scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04666311.

Viral suppression after transition from nonnucleoside reverse transcriptase inhibitor- to dolutegravir-based antiretroviral therapy: A prospective cohort study in Lesotho (DO-REAL study).

OBJECTIVES: Since 2018, the World Health Organization has recommended dolutegravir (DTG)-containing antiretroviral therapy (ART) for most people living with HIV. Country programmes across Africa have subsequently transitioned from other, mostly nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART to DTG-based ART. This study aims to assess the virological impact of programmatic transitioning to DTG-based ART in Lesotho. METHODS: The prospective Dolutegravir in Real-Life in Lesotho (DO-REAL) cohort enrols people living with HIV initiating or transitioning to DTG-based ART in Lesotho. Here, we present data from participants who transitioned from NNRTI- to DTG-based ART between February and December 2020. Blood samples collected at transition and at 16 weeks' follow-up (window 8-32 weeks) were used for viral load (VL) and resistance testing. RESULTS: Among 1347 participants, follow-up data was available for 1225. The majority (60%) were female, median age at transition was 47 years [interquartile range (IQR): 38-56], and median (IQR) time since ART initiation was 5.9 (3.5-9.0) years. Among those with complete VL data, the rate of viral suppression to < 100 copies/mL was 1093/1116 (98%) before, 1073/1116 (96%) at, and 1098/1116 (98%) after transition. Even among those with a VL ≥ 100 copies/mL at transition, 42/44 (95%) achieved suppression to < 100 copies/mL at follow-up. Seven participants had a VL ≥ 1000 copies/mL at follow-up and did not harbour any integrase mutations associated with resistance to DTG. CONCLUSIONS: The high levels of viral suppression observed are encouraging regarding virological outcomes upon programmatic transitioning from NNRTI- to DTG-based ART.

Tracing People Living With Human Immunodeficiency Virus Who Are Lost to Follow-up at Antiretroviral Therapy Programs in Southern Africa: A Sampling-Based Cohort Study in 6 Countries.

BACKGROUND: Attrition threatens the success of antiretroviral therapy (ART). In this cohort study, we examined outcomes of people living with human immunodeficiency virus (PLHIV) who were lost to follow-up (LTFU) during 2014-2017 at ART programs in Southern Africa. METHODS: We confirmed LTFU (missed appointment for ≥60 or ≥90 days, according to local guidelines) by checking medical records and used a standardized protocol to trace a weighted random sample of PLHIV who were LTFU in 8 ART programs in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, 2017-2019. We ascertained vital status and identified predictors of mortality using logistic regression, adjusted for sex, age, time on ART, time since LTFU, travel time, and urban or rural setting. RESULTS: Among 3256 PLHIV, 385 (12%) were wrongly categorized as LTFU and 577 (17%) had missing contact details. We traced 2294 PLHIV (71%) by phone calls, home visits, or both: 768 (34% of 2294) were alive and in care, including 385 (17%) silent transfers to another clinic; 528 (23%) were alive without care or unknown care; 252 (11%) had died. Overall, the status of 1323 (41% of 3256) PLHIV remained unknown. Mortality was higher in men than women, higher in children than in young people or adults, and higher in PLHIV who had been on ART <1 year or LTFU ≥1 year and those living farther from the clinic or in rural areas. Results were heterogeneous across sites. CONCLUSIONS: Our study highlights the urgent need for better medical record systems at HIV clinics and rapid tracing of PLHIV who are LTFU.

The Suboptimal Pediatric HIV Viral Load Cascade: Multidistrict Cohort Study Among Children Taking Antiretroviral Therapy in Lesotho, Southern Africa.

BACKGROUND: Children living with HIV and taking antiretroviral therapy (ART) are a priority group for routine viral load (VL) monitoring. As per Lesotho guidelines, a VL ≥1000 copies/mL ("unsuppressed") should trigger adherence counseling and a follow-up VL; 2 consecutive unsuppressed VLs ("virologic failure") qualify for switching to second-line ART, with some exceptions. Here, we describe the pediatric VL cascade in Lesotho. METHODS: In a prospective open cohort study comprising routine VL results from 22 clinics in Lesotho, we assessed outcomes along the VL cascade for children who had at least 1 VL test from January 2016 through June 2020. Data were censored on February 10, 2021. RESULTS: In total, 1215 children received 5443 VL tests. The median age was 10 years (interquartile range 7-13) and 627/1215 (52%) were female; 362/1215 (30%) had at least 1 unsuppressed VL. A follow-up VL was available for 325/362 (90%), although only for 159/362 (44%) within 6 months of the first unsuppressed VL. Of those with a follow-up VL, 172/329 (53%) had virologic failure and 123/329 (37%) qualified for switching to second-line ART. Of these, 55/123 (45%) were ever switched, although only 9/123 (7%) were switched within 12 weeks of the follow-up VL. Delays were more pronounced in rural facilities. Overall, 100/362 (28%) children with an unsuppressed VL received a timely follow-up VL and, if required, a timely regimen switch. CONCLUSIONS: Despite access to VL monitoring, clinical management was suboptimal. HIV programs should prioritize timely clinical action to maximize the benefits of VL monitoring.

Offering ART refill through community health workers versus clinic-based follow-up after home-based same-day ART initiation in rural Lesotho: The VIBRA cluster-randomized clinical trial.

BACKGROUND: Community-based antiretroviral therapy (ART) dispensing by lay workers is an important differentiated service delivery model in sub-Sahara Africa. However, patients new in care are generally excluded from such models. Home-based same-day ART initiation is becoming widespread practice, but linkage to the clinic is challenging. The pragmatic VIBRA (Village-Based Refill of ART) trial compared ART refill by existing lay village health workers (VHWs) versus clinic-based refill after home-based same-day ART initiation. METHODS AND FINDINGS: The VIBRA trial is a cluster-randomized open-label clinical superiority trial conducted in 249 rural villages in the catchment areas of 20 health facilities in 2 districts (Butha-Buthe and Mokhotlong) in Lesotho. In villages (clusters) randomized to the intervention arm, individuals found to be HIV-positive during a door-to-door HIV testing campaign were offered same-day ART initiation with the option of refill by VHWs. The trained VHWs dispensed drugs and scheduled clinic visits for viral load measurement at 6 and 12 months. In villages randomized to the control arm, participants were offered same-day ART initiation with clinic-based ART refill. The primary outcome was 12-month viral suppression. Secondary endpoints included linkage and 12-month engagement in care. Analyses were intention-to-treat. The trial was registered on ClinicalTrials.gov (NCT03630549). From 16 August 2018 until 28 May 2019, 118 individuals from 108 households in 57 clusters in the intervention arm, and 139 individuals from 130 households in 60 clusters in the control arm, were enrolled (150 [58%] female; median age 36 years [interquartile range 30-48]; 200 [78%] newly diagnosed). In the intervention arm, 48/118 (41%) opted for VHW refill. At 12 months, 46/118 (39%) participants in the intervention arm and 64/139 (46%) in the control arm achieved viral suppression (adjusted risk difference -0.07 [95% CI -0.20 to 0.06]; p = 0.256). Arms were similar in linkage (adjusted risk difference 0.03 [-0.10 to 0.16]; p = 0.630), but engagement in care was non-significantly lower in the intervention arm (adjusted risk difference -0.12 [-0.23 to 0.003]; p = 0.058). Seven and 0 deaths occurred in the intervention and control arm, respectively. Of the intervention participants who did not opt for drug refill from the VHW at enrollment, 41/70 (59%) mentioned trust or conflict issues as the primary reason. Study limitations include a rather small sample size, 9% missing viral load measurements in the primary endpoint window, the low uptake of the VHW refill option in the intervention arm, and substantial migration among the study population. CONCLUSIONS: The offer of village-based ART refill after same-day initiation led to similar outcomes as clinic-based refill. The intervention did not amplify the effect of home-based same-day ART initiation alone. The findings raise concerns about acceptance and safety of ART delivered by lay health workers after initiation in the community. TRIAL REGISTRATION: Registered with Clinicaltrials.gov (NCT03630549).

Extensive drug resistance during low-level HIV viraemia while taking NNRTI-based ART supports lowering the viral load threshold for regimen switch in resource-limited settings: a pre-planned analysis from the SESOTHO trial.

OBJECTIVES: WHO guidelines on ART define the HIV-1 viral load (VL) threshold for treatment failure at 1000 copies/mL. The Switch Either near Suppression Or THOusand (SESOTHO) trial, conducted in Lesotho from 2017 to 2020, found that patients with persistent viraemia below this threshold (100-999 copies/mL) benefit from switching to second-line ART. This pre-planned nested study assesses the prevalence of resistance-associated mutations (RAMs) in SESOTHO trial participants. METHODS: The SESOTHO trial [registered at ClinicalTrials.gov (NCT03088241)] enrolled 80 persons taking NNRTI-based first-line ART with low-level HIV-1 viraemia (100-999 copies/mL) and randomized them (1:1) to switch to a PI-based second-line regimen (switch) or continue on first-line therapy (control). We sequenced relevant regions of the viral pol gene using plasma samples obtained at enrolment and 36 weeks. RAMs were classified with the Stanford HIV Drug Resistance Database. RESULTS: Sequencing data were obtained for 37/80 (46%) participants at baseline and 26/48 (54%) participants without viral suppression to <50 copies/mL at 36 weeks (21 control participants and 5 switch participants). At baseline, 31/37 (84%) participants harboured high-level resistance to at least two drugs of their current regimen. At 36 weeks, 17/21 (81%) control participants harboured resistance to at least two drugs of their current regimen, while no PI-associated resistance was detected in the 5 switch participants with ongoing viraemia. CONCLUSIONS: Among persons with low-level viraemia while taking NNRTI-based first-line ART enrolled in the SESOTHO trial, the majority harboured HIV-1 with RAMs that necessitate ART modification. These findings support lowering the VL threshold triggering a switch to second-line ART in future WHO guidelines.

The coArtHA trial-identifying the most effective treatment strategies to control arterial hypertension in sub-Saharan Africa: study protocol for a randomized controlled trial.

BACKGROUND: Arterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa. METHODS: In this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged < 65 years and ≥ 65 years, respectively. Clinical manifestations of end-organ damage and cost-effectiveness at 6 months are secondary endpoints. DISCUSSION: This trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region. TRIAL REGISTRATION: Clinicaltrials.gov NCT04129840 . Registered on 17 October 2019 ( https://www.clinicaltrials.gov/ ).

Genotype-Informed Versus Empiric Management Of VirEmia (GIVE MOVE): study protocol of an open-label randomised clinical trial in children and adolescents living with HIV in Lesotho and Tanzania.

BACKGROUND: Globally, the majority of people living with HIV have no or only limited access to HIV drug resistance testing to guide the selection of antiretroviral drugs. This is of particular concern for children and adolescents, who experience high rates of treatment failure. The GIVE MOVE trial assesses the clinical impact and cost-effectiveness of routinely providing genotypic resistance testing (GRT) to children and adolescents living with HIV who have an unsuppressed viral load (VL) while taking antiretroviral therapy (ART). METHODS: GIVE MOVE is an open-label randomised clinical trial enrolling children and adolescents (≥6 months to <19 years) living with HIV with a VL ≥400 copies/mL (c/mL) while taking first-line ART. Recruitment takes place at sites in Lesotho and Tanzania. Participants are randomised in a 1:1 allocation to a control arm receiving the standard of care (3 sessions of enhanced adherence counselling, a follow-up VL test, continuation of the same regimen upon viral resuppression or empiric selection of a new regimen upon sustained elevated viremia) and an intervention arm (GRT to inform onward treatment). The composite primary endpoint is the occurrence of any one or more of the following events during the 36 weeks of follow-up period: i) death due to any cause; ii) HIV- or ART-related hospital admission of ≥24 h duration; iii) new clinical World Health Organisation stage 4 event (excluding lymph node tuberculosis, stunting, oral or genital herpes simplex infection and oesophageal candidiasis); and iv) no documented VL <50 c/mL at 36 weeks follow-up. Secondary and exploratory endpoints assess additional health-related outcomes, and a nested study will assess the cost-effectiveness of the intervention. Enrolment of a total of 276 participants is planned, with an interim analysis scheduled after the first 138 participants have completed follow-up. DISCUSSION: This randomised clinical trial will assess if the availability of resistance testing improves clinical outcomes in children and adolescents with elevated viremia while taking ART. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov ( NCT04233242 ; registered 18.01.2020). More information: www.givemove.org .

Home-based oral self-testing for absent and declining individuals during a door-to-door HIV testing campaign in rural Lesotho (HOSENG): a cluster-randomised trial.

BACKGROUND: In sub-Saharan Africa, home-based HIV testing is validated and accepted, but coverage is low because household members are often absent during home-based testing campaigns. We aimed to measure the effect of a secondary distribution of oral-fluid HIV self-tests on coverage during home-based testing in rural Lesotho. METHODS: The Home-Based Self-Testing (HOSENG) trial was a cluster-randomised, non-blinded superiority trial in rural villages in the catchment area of 20 health facilities of two districts in Lesotho (Butha-Buthe and Mokhotlong). Eligible villages had a consenting village chief and at least one registered village health worker; eligible households had a consenting representative aged 18 years or older. The HOSENG trial provided a recruitment platform for the interlinked Village-Based Refill of Antiretroviral Therapy (VIBRA) trial. Villages were randomly assigned 1:1:1:1 with block sizes of four to one of four groups: VIBRA control and HOSENG control; VIBRA control and HOSENG intervention; VIBRA intervention and HOSENG control; and VIBRA intervention and HOSENG intervention. Randomisation was stratified by district, village size, and access to the nearest health facility. An independent statistician was responsible for the computer-generated randomisation list. In the intervention group, oral-fluid HIV self-tests were left for absent or declining household members (aged ≥12 years) during a home visit from the HIV testing campaign team. One present household member was trained on self-test use. Distributed self-tests were followed up by village health workers. In control village clusters, absent or declining household members were referred to the clinic for HIV testing. The primary outcome was HIV testing coverage among all household members aged 12 years or older within 120 days, defined as a confirmed HIV test result or known status, reported in testing registers at the health facilities or on the follow-up forms of the village health worker. Adjusted random-effects logistic regression with individuals as the unit of analysis was used. This trial is registered with ClinicalTrials.gov, NCT03598686. FINDINGS: Between July 26, 2018, and Dec 12, 2018, 3091 consenting households with 7816 household members aged 12 years or older were enrolled and randomly assigned (intervention: 57 village clusters, 1620 households, 4174 household members; control: 49 village clusters, 1471 households, 3642 household members). In the control group, 38 (3%) of 1455 initially absent or declining household members tested at a clinic within 120 days. In the intervention group, 841 (53%) of 1601 initially absent or declining household members had a confirmed status within 120 days; 12 (1%) of 841 tested at the clinic and 829 (99%) used their self-test kit. This resulted in a testing coverage of 2201 (60%) of 3642 in the control group versus 3386 (81%) of 4174 in the intervention group (odds ratio 3·00 [95% CI 2·52-3·59]; p<0·0001). INTERPRETATION: Secondary distribution of oral-fluid HIV self-tests during home-based testing increases testing coverage substantially and thus presents a promising add-on during testing campaigns. FUNDING: Swiss National Science Foundation.

Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomized controlled trial in Lesotho.

BACKGROUND: Current World Health Organization (WHO) antiretroviral therapy (ART) guidelines define virologic failure as two consecutive viral load (VL) measurements ≥1,000 copies/mL, triggering empiric switch to next-line ART. This trial assessed if patients with sustained low-level HIV-1 viremia on first-line ART benefit from a switch to second-line treatment. METHODS AND FINDINGS: This multicenter, parallel-group, open-label, superiority, randomized controlled trial enrolled patients on first-line ART containing non-nucleoside reverse transcriptase inhibitors (NNRTI) with two consecutive VLs ≥100 copies/mL, with the second VL between 100-999 copies/mL, from eight clinics in Lesotho. Consenting participants were randomly assigned (1:1), stratified by facility, demographic group, and baseline VL, to either switch to second-line ART (switch group) or continued first-line ART (control group; WHO guidelines). The primary endpoint was viral suppression (<50 copies/mL) at 36 weeks. Analyses were by intention to treat, using logistic regression models, adjusted for demographic group and baseline VL. Between August 1, 2017, and August 7, 2019, 137 individuals were screened, of whom 80 were eligible and randomly assigned to switch (n = 40) or control group (n = 40). The majority of participants were female (54 [68%]) with a median age of 42 y (interquartile range [IQR] 35-51), taking tenofovir disoproxil fumarate/lamivudine/efavirenz (49 [61%]) and on ART for a median of 5.9 y (IQR 3.3-8.6). At 36 weeks, 22/40 (55%) participants in the switch versus 10/40 (25%) in the control group achieved viral suppression (adjusted difference 29%, 95% CI 8%-50%, p = 0.009). The switch group had significantly higher probability of viral suppression across different VL thresholds (<20, <100, <200, <400, and <600 copies/mL) but not for <1,000 copies/mL. Thirty-four (85%) participants in switch group and 21 (53%) in control group experienced at least one adverse event (AE) (p = 0.002). No hospitalization or death or other serious adverse events were observed. Study limitations include a follow-up period too short to observe differences in clinical outcomes, missing values in CD4 cell counts due to national stockout of reagents during the study, and limited generalizability of findings to other than NNRTI-based first-line ART regimens. CONCLUSIONS: In this study, switching to second-line ART among patients with sustained low-level HIV-1 viremia resulted in a higher proportion of participants with viral suppression. These results endorse lowering the threshold for virologic failure in future WHO guidelines. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov, NCT03088241.

"If it is left, it becomes easy for me to get tested": Use of oral self-tests and community health workers to maximize the potential of home-based HIV testing among adolescents in Lesotho.

INTRODUCTION: Home-based HIV testing fails to reach high coverage among adolescents and young adults (AYA), mainly because they are often absent during the day of home-based testing. ADORE (ADolescent ORal tEsting) is a mixed-method nested study among AYA in rural Lesotho, measuring the effect of home-based secondary distribution of oral HIV self-tests (HIVST) on coverage, as well as exploring how AYA perceive this HIV self-testing model. METHODS: ADORE study was nested in a cluster-randomized trial. In intervention village-clusters, oral HIVST were left for household members who were absent or declined testing during a testing campaign. One present household member was trained on HIVST use. Distributed HIVST were followed up by village health workers (VHW). In control clusters no self-tests were distributed. The quantitative outcome was testing coverage among AYA (age 12 to 24) within 120 days, defined as a confirmed HIV test result or known status, using adjusted random-effects logistic regression on the intention-to-treat population. Qualitatively, we conducted in-depth interviews among both AYA who used and did not use the distributed HIVST. RESULTS: From July 2018 to December 2018, 49 and 57 villages with 1471 and 1620 consenting households and 1236 and 1445 AYA in the control and intervention arm, respectively, were enrolled. On the day of the home-visit, a testing coverage of 37% (461/1236) and 41% (596/1445) in the control and the intervention arm, respectively, were achieved. During the 120 days follow-up period, an additional 23 and 490 AYA in control and intervention clusters, respectively, knew their status. This resulted in a testing coverage of 484/1236 (39%) in the control versus 1086/1445 (75%) in the intervention arm (aOR 8.80 [95% CI 5.81 to 13.32]; p < 0.001). 21 interviews were performed. Personal assistance after the secondary distribution emerged as a key theme and VHWs were generally seen as a trusted cadre. CONCLUSIONS: Secondary distribution of HIVST for AYA absent or refusing to test during home-based testing in Lesotho resulted in an absolute 36% increase in coverage. Distribution should, however, go along with clear instructions on the use of the HIVST and a possibility to easily access more personal support.