Evaluation of C-Reactive Protein and Computer-Aided Analysis of Chest X-rays as Tuberculosis Triage Tests at Health Facilities in Lesotho and South Africa.

BACKGROUND: To improve tuberculosis case-finding, rapid, non-sputum triage tests need to be developed according to the World Health Organization target product profile (TPP) (>90% sensitivity, >70% specificity). We prospectively evaluated and compared artificial intelligence-based, computer-aided detection software, CAD4TBv7, and C-reactive protein assay (CRP) as triage tests at health facilities in Lesotho and South Africa. METHODS: Adults (≥18 years) presenting with ≥1 of the 4 cardinal tuberculosis symptoms were consecutively recruited between February 2021 and April 2022. After informed consent, each participant underwent a digital chest X-ray for CAD4TBv7 and a CRP test. Participants provided 1 sputum sample for Xpert MTB/RIF Ultra and Xpert MTB/RIF and 1 for liquid culture. Additionally, an expert radiologist read the chest X-rays via teleradiology. For primary analysis, a composite microbiological reference standard (ie, positive culture or Xpert Ultra) was used. RESULTS: We enrolled 1392 participants, 48% were people with HIV and 24% had previously tuberculosis. The receiver operating characteristic curve for CAD4TBv7 and CRP showed an area under the curve of .87 (95% CI: .84-.91) and .80 (95% CI: .76-.84), respectively. At thresholds corresponding to 90% sensitivity, specificity was 68.2% (95% CI: 65.4-71.0%) and 38.2% (95% CI: 35.3-41.1%) for CAD4TBv7 and CRP, respectively. CAD4TBv7 detected tuberculosis as well as an expert radiologist. CAD4TBv7 almost met the TPP criteria for tuberculosis triage. CONCLUSIONS: CAD4TBv7 is accurate as a triage test for patients with tuberculosis symptoms from areas with a high tuberculosis and HIV burden. The role of CRP in tuberculosis triage requires further research. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier: NCT04666311.

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.

Decentralization of viral load testing to improve HIV care and treatment cascade in rural Tanzania: observational study from the Kilombero and Ulanga Antiretroviral Cohort.

INTRODUCTION: Monitoring HIV viral load (HVL) in people living with HIV (PLHIV) on antiretroviral therapy (ART) is recommended by the World Health Organization. Implementation of HVL testing programs have been affected by logistic and organizational challenges. Here we describe the HVL monitoring cascade in a rural setting in Tanzania and compare turnaround times (TAT) between an on-site and a referral laboratory. METHODS: In a nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) we included PLHIV aged ≥ 15 years, on ART for ≥ 6 months after implementation of routine HVL monitoring in 2017. We assessed proportions of PLHIV with a blood sample taken for HVL, whose results came back, and who were virally suppressed (HVL < 1000 copies/mL) or unsuppressed (HVL ≥ 1000 copies/mL). We described the proportion of PLHIV with unsuppressed HVL and adequate measures taken as per national guidelines and outcomes among those with low-level viremia (LLV; 100-999 copies/mL). We compare TAT between on-site and referral laboratories by Wilcoxon rank sum tests. RESULTS: From 2017 to 2020, among 4,454 PLHIV, 4,238 (95%) had a blood sample taken and 4,177 (99%) of those had a result. Of those, 3,683 (88%) were virally suppressed. In the 494 (12%) unsuppressed PLHIV, 425 (86%) had a follow-up HVL (102 (24%) within 4 months and 158 (37%) had virologic failure. Of these, 103 (65%) were already on second-line ART and 32/55 (58%) switched from first- to second-line ART after a median of 7.7 months (IQR 4.7-12.7). In the 371 (9%) PLHIV with LLV, 327 (88%) had a follow-up HVL. Of these, 267 (82%) resuppressed to < 100 copies/ml, 41 (13%) had persistent LLV and 19 (6%) had unsuppressed HVL. The median TAT for return of HVL results was 21 days (IQR 13-39) at the on-site versus 59 days (IQR 27-99) at the referral laboratory (p < 0.001) with PLHIV receiving the HVL results after a median of 91 days (IQR 36-94; similar for both laboratories). CONCLUSION: Robust HVL monitoring is achievable in remote resource-limited settings. More focus is needed on care models for PLHIV with high viral loads to timely address results from routine HVL monitoring.

Failure to return pillbox is a predictor of being lost to follow-up among people living with HIV on antiretroviral therapy in rural Tanzania.

OBJECTIVES: Pill count is used to assess drug adherence in people living with HIV (PLHIV). Carrying a pillbox is associated with fear of concealment and stigma and might indicate poor adherence and predict someone who will be lost to follow-up (LTFU). We therefore assessed the association between pillbox return and being LTFU in rural Tanzania. METHODS: This is a nested study of the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). We included PLHIV aged ≥ 18 years enrolled in KIULARCO between January 2013 and March 2019 with follow-up through January 2020, who were on antiretroviral treatment (ART) for ≥ 6 months. Baseline was defined as the latest ART initiation or KIULARCO enrolment. We determined the association between time-dependent failed pillbox return updated at every visit and LTFU using Kaplan-Meier estimation and Cox models. RESULTS: Among 2552 PLHIV included in the study, 1735 (68.0%) were female, 959 (40.3%) had a WHO stage III/IV and 1487 (66.4%) had a CD4 cell count < 350 cells/µL. The median age was 38.4 years [interquartile range (IQR): 31.7-46.2]. During a median follow-up of 33.1 months (IQR: 17.5-52.4), 909 (35.6%) participants were LTFU, 43 (1.7%) died and 194 (7.6%) had transferred to another clinic. The probability of being LTFU was higher among PLHIV with failed pillbox return than among those who returned their pillbox [30.0%, 95% confidence interval (CI): 26.8-33.2% vs. 19.4%, 95% CI: 17.4-21.6%, respectively, at 24 months (hazard ratio = 1.67, 95% CI: 1.46-1.90; p < 0.001)]. CONCLUSIONS: Failed pillbox return was associated with a higher risk of being LTFU and could be used as a simple tool to identify PLHIV for appropriate interventions to reduce their chance of being LTFU.

Causes of death and associated factors over a decade of follow-up in a cohort of people living with HIV in rural Tanzania.

BACKGROUND: Nearly half of HIV-related deaths occur in East and Southern Africa, yet data on causes of death (COD) are scarce. We determined COD and associated factors among people living with HIV (PLHIV) in rural Tanzania. METHODS: PLHIV attending the Chronic Diseases Clinic of Ifakara, Morogoro are invited to enrol in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). Among adults (≥ 15 years) enrolled in 2005-2018, with follow-up through April 2019, we classified COD in comprehensive classes and as HIV- or non-HIV-related. In the subset of participants enrolled in 2013-2018 (when data were more complete), we assessed cause-specific mortality using cumulative incidences, and associated factors using proportional hazards models. RESULTS: Among 9871 adults (65% female, 26% CD4 count < 100 cells/mm3), 926 (9%) died, among whom COD were available for 474 (51%), with missing COD mainly in earlier years. The most common COD were tuberculosis (N = 127, 27%), non-AIDS-related infections (N = 72, 15%), and other AIDS-related infections (N = 59, 12%). Cardiovascular and renal deaths emerged as important COD in later calendar years, with 27% of deaths in 2018 attributable to cardiovascular causes. Most deaths (51%) occurred within the first six months following enrolment. Among 3956 participants enrolled in 2013-2018 (N = 203 deaths, 200 with COD ascertained), tuberculosis persisted as the most common COD (25%), but substantial proportions of deaths from six months after enrolment onwards were attributable to renal (14%), non-AIDS-related infections (13%), other AIDS-related infections (10%) and cardiovascular (10%) causes. Factors associated with higher HIV-related mortality were sex, younger age, living in Ifakara town, HIV status disclosure, hospitalisation, not being underweight, lower CD4 count, advanced WHO stage, and gaps in care. Factors associated with higher non-HIV-related mortality included not having an HIV-positive partner, lower CD4 count, advanced WHO stage, and gaps in care. CONCLUSION: Incidence of HIV-related mortality was higher than that of non-HIV-related mortality, even in more recent years, likely due to late presentation. Tuberculosis was the leading specific COD identified, particularly soon after enrolment, while in later calendar years cardiovascular and renal causes emerged as important, emphasising the need for improved screening and management.

Incidence, Treatment and Outcome of Patients with Retroperitoneal Soft-Tissue Sarcoma in Switzerland 2005-2015: A Population-Based Analysis.

BACKGROUND: Reports on the epidemiology and mortality of retroperitoneal soft tissue sarcoma (RSTS) in Switzerland are scarce. This study investigates the incidence and outcomes of surgically treated RSTS inpatients in Switzerland depending on the hospital type and size. METHODS: Data from the Swiss Federal Statistical Office were used to conduct a retrospective analysis of all RSTS inpatients and hospitalizations in Switzerland between 2005 and 2015. RSTS was identified by the code C48.x of the International Classification of Diseases (ICD-10). Sarcoma centers were identified by the annual total number of sarcoma patients (> 50 patients/year). The analysis of yearly incidence, age distribution as well as in-hospital complication and mortality was performed for non- and surgical-treated patients. A centralization of treating sarcoma patients was analyzed by the trend of hospitalizations in sarcoma centers and high-volume hospitals. RESULTS: During 2005-2015, 2.801 hospitalizations (1651 patients) were admitted to Swiss hospitals with the primary diagnosis of a RSTS. The yearly number of RSTS patients and the incidence (1.91/100.000) stayed constant within these 11 years. There were five sarcoma centers. We saw a clear trend of RSTS patients being treated (especially surgically) in centers over the 11 years. The complication rate of surgical-treated patients was higher in sarcoma centers (55% vs. 40%), though the overall mortality rate was lower (3.2% vs. 9.1%). CONCLUSION: Centralization of RSTS treatment to certified sarcoma centers leads to a lower overall mortality rate and thus is highly recommended.

The Role of Human Immunodeficiency Virus (HIV) Asymptomatic Status When Starting Antiretroviral Therapy on Adherence and Treatment Outcomes and Implications for Test and Treat: The Swiss HIV Cohort Study.

BACKGROUND: Since the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes. METHODS: PLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure. RESULTS: Of 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1-4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93-1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76-1.00]) and less likely to develop resistance (14% vs 27%, P < .001) than symptomatic PLHIV. CONCLUSIONS: Despite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

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).

Recognition and management of clinically significant drug-drug interactions between antiretrovirals and co-medications in a cohort of people living with HIV in rural Tanzania: a prospective questionnaire-based study.

BACKGROUND: The extent to which drug-drug interactions (DDIs) between antiretrovirals (ARVs) and co-medications are recognized and managed has not been thoroughly evaluated in limited-resource settings. OBJECTIVES: This prospective questionnaire-based study aimed to determine the prevalence and risk factors for unrecognized/incorrectly managed DDIs in people living with HIV followed-up at the Chronic Diseases Clinic of Ifakara (CDCI) and enrolled in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). METHODS: We prospectively included ARV-treated adults receiving ≥1 co-medication coming for a follow-up visit at the CDCI between March and July 2017. Using a structured questionnaire, physicians were requested to identify potentially clinically significant DDIs in the prescribed treatment, to provide recommendations for their management and to indicate any hurdles to implement the recommendations. Prescriptions were subsequently screened for DDIs using the Liverpool DDIs database. Identified clinically significant DDIs and their recommended management according to the DDIs database were compared with the information provided in the questionnaires. RESULTS: Among 334 participants, the median age was 47 years (IQR = 40-56 years), 69% were female and 82% had ≥1 non-communicable disease (NCD). Overall, 129 participants had ≥1 clinically relevant DDI, which was not recognized and/or incorrectly managed in 56 participants (43%). Of those, 6 (11%) were due to limited monitoring options or medication affordability issues. In the multivariable logistic regression, the presence of ≥1 NCD was associated with an increased risk for unrecognized/incorrect DDI management (OR = 15.8; 95% CI = 1.8-139.6). CONCLUSIONS: Recognition/appropriate management of DDIs is suboptimal, highlighting the need for educational programmes, pharmacovigilance activities and increased access to medications and monitoring options. This should become a focus of HIV programmes given the increasing burden of NCDs in sub-Saharan Africa.