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HIV recency assays are used to distinguish recently acquired infection from long-term infection among individuals newly diagnosed with HIV. Since 2015, the World Health Organisation recommends the use of an algorithm to assess recency of infections which is based on an HIV recency assay and viral load (VL) quantification. We determined the proportion of recent HIV infections among participants of the VIBRA (Village-Based Refill of Antiretroviral therapy) cluster-randomized trial in Lesotho and assessed risk factors for these recent infections. The VIBRA trial recruited individuals living with HIV and not taking antiretroviral therapy during a door-to-door HIV testing campaign in two rural districts (Butha-Buthe and Mokhotlong). Samples were collected from participants newly diagnosed and tested for HIV recency using the Asanté HIV-1 Rapid Recency Assay and VL using the Roche Cobas System. Clinical and socio-demographic data were extracted from the trial database. Univariate analysis was conducted to determine factors associated with recent compared to long-term infection. Participants were recruited from August 2018 to May 2019 and 184 patient-samples included in this study. The majority were female (108 [59%]) with a median age of 36 years (interquartile range 30-50 years). We found 13 (7.0%) recent infections, while 171 (93.0%) were classified as long-term HIV infections. No conclusive evidence for risk factors of recent infection was found. During door-to-door testing among a general population sample in rural Lesotho, 7% of those who were newly diagnosed had acquired HIV in the preceding 6 months. More efforts and research are needed to curb ongoing transmissions in these rural communities.

BackgroundHIV recency assays are used to distinguish recently acquired infection from long-term infection among individuals newly diagnosed with HIV. Since 2015, the World Health Organisation recommends the use of an algorithm to assess recency of infections which is based on an HIV recency assay and viral load (VL) quantification. We determined the proportion of recent HIV infections among participants of the VIBRA (Village-Based Refill of Antiretroviral therapy) cluster-randomized trial in Lesotho and assessed risk factors for these recent infections.MethodsThe VIBRA trial recruited individuals living with HIV and not taking antiretroviral therapy during a door-to-door HIV testing campaign in two rural districts (Butha-Buthe and Mokhotlong). Samples were collected from participants newly diagnosed and tested for HIV recency using the Asanté HIV-1 Rapid Recency Assay and VL using the Roche Cobas System. Clinical and socio-demographic data were extracted from the trial database. Univariate analysis was conducted to determine factors associated with recent compared to long-term infection.ResultsParticipants were recruited from August 2018 to May 2019 and 184 patient-samples included in this study. The majority were female (108 [59%]) with a median age of 36 years (interquartile range 30-50 years). We found 13 (7.0%) recent infections, while 171 (93.0%) were classified as long-term HIV infections. No conclusive evidence for risk factors of recent infection was found.ConclusionsDuring door-to-door testing among a general population sample in rural Lesotho, 7% of those who were newly diagnosed had acquired HIV in the preceding 6 months. More efforts and research are needed to curb ongoing transmissions in these rural communities.

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. 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. 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. Registered with Clinicaltrials.gov (NCT03630549).

We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

For HIV-positive individuals on antiretroviral therapy (ART), the World Health Organization (WHO) recommends routine viral load (VL) monitoring. We report on the cascade of care in individuals with unsuppressed VL after introduction of routine VL monitoring in a district in Lesotho. In Butha-Buthe district 12 clinics (11 rural, 1 hospital) send samples for VL testing to the district laboratory. We included data from patients aged ≥15 years from Dec 1, 2015 to November 1, 2018. As per WHO guidelines VL <1000 copies/mL are considered suppressed, those ≥1000copies/mL unsuppressed. Patients with unsuppressed VL receive adherence counseling and follow-up VL within 8-12 weeks. Two consecutively unsuppressed VLs should trigger switch to second-line ART. For analysis of the VL monitoring cascade we defined care to be \"according to guidelines\" if patients with unsuppressed VL received a follow-up VL within <180 days and follow-up VL was either re-suppressed, or again unsuppressed and the individual was switched to second-line within 90 days. For 9,949 individuals 24,948 VL tests were available. The majority were female (73%), median age 41 years (interquartile range 33-52), and 58% seen at rural clinics. Overall, 25% (260/1028) of individuals were managed according to guidelines: 40% (410/1028) had a follow-up VL within 180 days of their initial unsuppressed VL and 25% (260/1028) of those either re-suppressed or switched to second-line within 90 days. Female patients were more likely to have a follow-up VL done, (p = 0.015). In rural clinics rates of two consecutively unsuppressed VLs were higher than in the hospital (64% vs. 44%, p<0.001), and rural clinics were less likely to switch these patients to second-line (35% vs. 66%, p<0001). Our data show that in a real-life setting availability of routine VL monitoring may not be exploited to its potential. A lack of timely follow-up after a first unsuppressed VL and reluctance to switch patients with confirmed virological failure, reduce the benefit of VL monitoring, i.e. in the rural clinics. Future studies will have to assess models of care which ensure that VL results are met with an action and make use of scalable innovative approaches.

In 2019, 600'000 people in Africa died of heart failure and heart diseases will increase on the continent. It is crucial to understand the regional etiologies and risk factors for heart failure and underlying heart diseases. However, echocardiography data from rural Africa are scarce and from Lesotho non-existent. This study aims to examine the occurrence, characteristics and etiology of heart failure and heart diseases using echocardiography data from a referral hospital in rural Lesotho. We conducted a retrospective cohort study at Seboche Mission Hospital, the only referral hospital in Butha-Buthe district (Lesotho) with an echocardiography department. We included data from all individuals referred to the department between January 2020 and May 2021. From non-hospitalized patients echocardiographic diagnosis, sex and age were available, from hospitalized patients additional sociodemographic and clinical data could be extracted. In the study period, a total of 352 echocardiograms were conducted; 213 had abnormal findings (among them 3 children). The majority of adult participants (130/210; 64%) were female and most frequent heart diseases were hypertensive (62/210, 30%), valvular (39/210, 19%) and chronic pulmonary (37/210, 18%). Heart failure represented 11% of hospitalizations in the same period. Among the 126 hospitalized heart failure patients, the most common etiology was chronic pulmonary heart disease (32/126; 25%). Former mine workers and people with a history of tuberculosis were more likely to have a chronic pulmonary heart disease. The leading cause of heart disease in this setting is hypertension. However, in contrast to other African epidemiological studies, chronic pulmonary heart disease is unexpectedly common. There is an urgent need to improve awareness and knowledge about lung diseases, make diagnostic and therapeutic options available and increase prevention.

The interleukin-6 (IL-6) inhibitors tocilizumab and sarilumab have been repurposed for COVID-19 treatment. However, discrepancies exist across global and national COVID-19 guidelines, with limited data on the comparative effectiveness between these therapeutics especially during the delta/omicron periods. With the approval of NHS England and Public Health Scotland, we compared their effectiveness among adults hospitalised with COVID-19 using electronic health records data through the OpenSAFELY-TPP (England) and EAVE II (Scotland) platforms. Following the target trial emulation framework, 10,487 patients treated between July 2021 and February 2022, when both drugs were frequently prescribed, were included. In England, 1150 (20.1%) of 5710 participants receiving tocilizumab died by day 28 compared with 820 (20.4%) of 4025 participants receiving sarilumab (adjusted hazard ratio [aHR] 1.07, 95% CI 0.96-1.19). In Scotland, 114 (29.4%) of 388 participants receiving tocilizumab died by day 28 compared with 97 (27.0%) of 359 participants receiving sarilumab (aHR 0.92, 95% CI 0.68-1.23). There was no evidence of a difference in time to hospital discharge between the groups, and no credible effect modification by variant of concern, vaccination status, age, sex, ethnicity, body mass index, or comorbidities. Our findings provide supportive evidence for both drugs as alternative therapeutic options in COVID-19 in-patient management. Using electronic health record databases in England and Scotland, this study compared tocilizumab and sarilumab in over 10,000 hospitalised COVID-19 patients and found no meaningful difference in survival, supporting both as acceptable treatments.

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. 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). 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. clinicaltrials.gov, NCT03969030, https://clinicaltrials.gov/ct2/show/NCT03969030.

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. 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. 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. The trial is registered at ClinicalTrials.gov, NCT03088241.

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.