Diagnostic Yield of Urine Xpert MTB/RIF Ultra in Adults With Suspected Extrapulmonary Tuberculosis.

We assessed the diagnostic yield of urine GeneXpert MTB/RIF Ultra and factors associated with a positive test among adult patients suspected to have extrapulmonary tuberculosis. Urine Ultra was positive in 14% of participants with definite or probable tuberculosis. Hospitalization, disseminated tuberculosis, and human immunodeficiency virus infection were associated with a positive result.

Simultaneous alleviation of verification and reference standard biases in a community-based tuberculosis screening study using Bayesian latent class analysis.

BACKGROUND: Estimation of prevalence and diagnostic test accuracy in tuberculosis (TB) prevalence surveys suffer from reference standard and verification biases. The former is attributed to the imperfect reference test used to bacteriologically confirm TB disease. The latter occurs when only the participants screening positive for any TB-compatible symptom or chest X-ray abnormality are selected for bacteriological testing (verification). Bayesian latent class analysis (LCA) alleviates the reference standard bias but suffers verification bias in TB prevalence surveys. This work aims to identify best-practice approaches to simultaneously alleviate the reference standard and verification biases in the estimates of pulmonary TB prevalence and diagnostic test performance in TB prevalence surveys. METHODS: We performed a secondary analysis of 9869 participants aged ≥15 years from a community-based multimorbidity screening study in a rural district of KwaZulu-Natal, South Africa (Vukuzazi study). Participants were eligible for bacteriological testing using Xpert Ultra and culture if they reported any cardinal TB symptom or had an abnormal chest X-ray finding. We conducted Bayesian LCA in five ways to handle the unverified individuals: (i) complete-case analysis, (ii) analysis assuming the unverified individuals would be negative if bacteriologically tested, (iii) analysis of multiply-imputed datasets with imputation of the missing bacteriological test results for the unverified individuals using multivariate imputation via chained equations (MICE), and simultaneous imputation of the missing bacteriological test results in the analysis model assuming the missing bacteriological test results were (iv) missing at random (MAR), and (v) missing not at random (MNAR). We compared the results of (i)-(iii) to the analysis based on a composite reference standard (CRS) of Xpert Ultra and culture. Through simulation with an overall true prevalence of 2.0%, we evaluated the ability of the models to alleviate both biases simultaneously. RESULTS: Based on simulation, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the assumption that the missing data are MAR and MNAR alleviate the reference standard and verification biases. CRS-based analysis and Bayesian LCA assuming the unverified are negative for TB alleviate the biases only when the true overall prevalence is <3.0%. Complete-case analysis produced biased estimates. In the Vukuzazi study, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the MAR and MNAR assumptions produced overall PTB prevalence of 0.9% (95% Credible Interval (CrI): 0.6-1.9) and 0.7% (95% CrI: 0.5-1.1) respectively alongside realistic estimates of overall diagnostic test sensitivity and specificity with substantially overlapping 95% CrI. The CRS-based analysis and Bayesian LCA assuming the unverified were negative for TB produced 0.7% (95% CrI: 0.5-0.9) and 0.7% (95% CrI: 0.5-1.2) overall PTB prevalence respectively with realistic estimates of overall diagnostic test sensitivity and specificity. Unlike CRS-based analysis, Bayesian LCA of multiply-imputed data using MICE mitigates both biases. CONCLUSION: The findings demonstrate the efficacy of these advanced techniques in alleviating the reference standard and verification biases, enhancing the robustness of community-based screening programs. Imputing missing values as negative for bacteriological tests is plausible under realistic assumptions.

Computer-aided detection thresholds for digital chest radiography interpretation in tuberculosis diagnostic algorithms.

Objectives: Use of computer-aided detection (CAD) software is recommended to improve tuberculosis screening and triage, but threshold determination is challenging if reference testing has not been performed in all individuals. We aimed to determine such thresholds through secondary analysis of the 2019 Lesotho national tuberculosis prevalence survey. Methods: Symptom screening and chest radiographs were performed in participants aged ≥15 years; those symptomatic or with abnormal chest radiographs provided samples for Xpert MTB/RIF and culture testing. Chest radiographs were processed using CAD4TB version 7. We used six methodological approaches to deal with participants who did not have bacteriological test results to estimate pulmonary tuberculosis prevalence and assess diagnostic accuracy. Results: Among 17 070 participants, 5214 (31%) had their tuberculosis status determined; 142 had tuberculosis. Prevalence estimates varied between methodological approaches (0.83-2.72%). Using multiple imputation to estimate tuberculosis status for those eligible but not tested, and assuming those not eligible for testing were negative, a CAD4TBv7 threshold of 13 had a sensitivity of 89.7% (95% CI 84.6-94.8) and a specificity of 74.2% (73.6-74.9), close to World Health Organization (WHO) target product profile criteria. Assuming all those not tested were negative produced similar results. Conclusions: This is the first study to evaluate CAD4TB in a community screening context employing a range of approaches to account for unknown tuberculosis status. The assumption that those not tested are negative - regardless of testing eligibility status - was robust. As threshold determination must be context specific, our analytically straightforward approach should be adopted to leverage prevalence surveys for CAD threshold determination in other settings with a comparable proportion of eligible but not tested participants.

Statistical methods applied for the assessment of the HIV cascade and continuum of care: a systematic scoping review.

OBJECTIVES: This scoping review aims to identify and synthesise existing statistical methods used to assess the progress of HIV treatment programmes in terms of the HIV cascade and continuum of care among people living with HIV (PLHIV). DESIGN: Systematic scoping review. DATA SOURCES: Published articles were retrieved from PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Complete and Excerpta Medica dataBASE (EMBASE) databases between April and July 2022. We also strategically search using the Google Scholar search engine and reference lists of published articles. ELIGIBILITY CRITERIA: This scoping review included original English articles that estimated and described the HIV cascade and continuum of care progress in PLHIV. The review considered quantitative articles that evaluated either HIV care cascade progress in terms of the Joint United Nations Programme on HIV and AIDS targets or the dynamics of engagement in HIV care. DATA EXTRACTION AND SYNTHESIS: The first author and the librarian developed database search queries and screened the retrieved titles and abstracts. Two independent reviewers and the first author extracted data using a standardised data extraction tool. The data analysis was descriptive and the findings are presented in tables and visuals. RESULTS: This review included 300 articles. Cross-sectional study design methods were the most commonly used to assess the HIV care cascade (n=279, 93%). In cross-sectional and longitudinal studies, the majority used proportions to describe individuals at each cascade stage (276/279 (99%) and 20/21 (95%), respectively). In longitudinal studies, the time spent in cascade stages, transition probabilities and cumulative incidence functions was estimated. The logistic regression model was common in both cross-sectional (101/279, 36%) and longitudinal studies (7/21, 33%). Of the 21 articles that used a longitudinal design, six articles used multistate models, which included non-parametric, parametric, continuous-time, time-homogeneous and discrete-time multistate Markov models. CONCLUSIONS: Most literature on the HIV cascade and continuum of care arises from cross-sectional studies. The use of longitudinal study design methods in the HIV cascade is growing because such methods can provide additional information about transition dynamics along the cascade. Therefore, a methodological guide for applying different types of longitudinal design methods to the HIV continuum of care assessments is warranted.

Predictors of spontaneous remission and recovery among women with untreated perinatal depression in India and Pakistan.

Background: Mothers with perinatal depression can show different symptom trajectories and may spontaneously remit from depression, however, the latter is poorly understood. This is the first study which sought to investigate predictors of spontaneous remission and longer-term recovery among untreated women with perinatal depression. Methods: We analysed data from two randomised controlled trials in women with perinatal depression in India and Pakistan. Analyses were restricted to women in the control groups who did not receive active treatment. Generalised estimating equations and logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for within-person correlation. Results: In multivariable analyses, remission was associated with a husband who is not working (adjusted OR, aOR = 2.04, 95% CI 1.02-4.11), lower Patient Health Questionnaire-9 score at baseline (aOR = 0.43, 95% CI 0.20-0.90 for score of ≥20 vs. 10-14) and better social support at baseline (aOR = 2.37, 95% CI 1.32-4.27 for high vs. low social support). Conclusions: Women with low baseline severity may remit from perinatal depression with adequate social support from family and friends. These factors are important contributors to the management of perinatal depression and the prevention of clinical worsening, and should be considered when designing low-threshold psychological interventions.

Improving anaemia diagnosis using peripheral blood smear with remote interpretation in adults living with HIV with moderate to severe anaemia: A prospective study nested within the Kilombero and Ulanga antiretroviral cohort.

INTRODUCTION: In low-resource settings, anaemia is a very common condition. Identification of anaemia aetiologies remains challenging due to the lack of diagnostic tools and expertise. We aimed to improve anaemia diagnostics using peripheral blood smear (PBS) with remote interpretation in people living with HIV (PLHIV) with moderate to severe anaemia. METHODS: We conducted a prospective study nested within the Kilombero and Ulanga Antiretroviral Cohort, including non-pregnant PLHIV aged ≥18 years presenting with moderate (haemoglobin 7.0-9.9 g/dl) or severe (<7.0 g/dl) anaemia at any visit from January 2019 to December 2020. For each participant, ten PBS images, full blood count and clinical details were shared with a haematologist for remote interpretation (enhanced care). Identification of anaemia etiologies and potential impact on treatment was compared between enhanced and standard care. RESULTS: Among 400 PLHIV with moderate to severe anaemia, 349 (87%) were female, median age was 40 years (interquartile range (IQR) 35-46)), 65 (17%) had a body mass index <18.5 kg/m2, 215 (54%) had HIV WHO stage III/IV, 79 (20%) had a CD4 cell count <200 cells/µl and 317 (89%) had HIV viral load <100 copies/ml. Severe anaemia was diagnosed in 84 (21%). Suspected multiple aetiologies were documented more frequently by enhanced care compared to standard care 267 (67%) vs 20 (5%); p<0.001. Suspected iron deficiency was the most frequent aetiology (n = 337; 84%), followed by chronic disease (n = 199; 50%), folate/vitamin B12 deficiency (n = 78; 20%) and haemoglobinopathy (n = 83; 21%). In 272 participants (68%), enhanced care revealed additional clinically relevant findings with impact on the treatment recommendation. CONCLUSION: Remote interpretation of PBS combined with clinical information and blood cell count results can provide insights to the suspected aetiological diagnosis of moderate and severe anaemia in rural low-resource settings and impact specific treatment.

Body mass index trends and its impact of under and overweight on outcome among PLHIV on antiretroviral treatment in rural Tanzania: A prospective cohort study.

INTRODUCTION: Increased body weight is an important risk factor for cardiovascular disease and is increasingly reported as a health problem in people living with HIV (PLHIV). There is limited data from rural sub-Saharan Africa, where malnutrition usually presents with both over- and undernutrition. We aimed to determine the prevalence and risk factors of underweight and overweight/obesity in PLHIV enrolled in a cohort in rural Tanzania before the introduction of integrase inhibitors. METHODS: This nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort included adults aged ≥19 years initiated on antiretroviral therapy between 01/2013 and 12/2018 with follow-up through 06/2019. Body Mass Index (BMI) was classified as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), or overweight/obese (≥25.0 kg/m2). Stratified piecewise linear mixed models were used to assess the association between baseline characteristics and follow-up BMI. Cox proportional hazard models were used to assess the association between time-updated BMI and death/loss to follow-up (LTFU). RESULTS: Among 2,129 patients, 22,027 BMI measurements (median 9 measurements: interquartile range 5-15) were analysed. At baseline, 398 (19%) patients were underweight and 356 (17%) were overweight/obese. The majority of patients were female (n = 1249; 59%), and aged 35-44 years (779; 37%). During the first 9 months, for every three additional months on antiretroviral therapy, BMI increased by 2% (95% confidence interval 1-2%, p<0.0001) among patients underweight at baseline and by 0.7% (0.5-0.6%, p<0.0001) among participants with normal BMI. Over a median of 20 months of follow-up, 107 (5%) patients died and 592 (28%) were LTFU. Being underweight was associated with >2 times the hazard of death/LTFU compared to participants with normal BMI. CONCLUSION: We found a double burden of malnutrition, with underweight being an independent predictor of mortality. Monitoring and measures to address both states of malnutrition among PLHIV should be integrated into routine HIV care.

Transitioning to Dolutegravir in a Programmatic Setting: Virological Outcomes and Associated Factors Among Treatment-Naive Patients With HIV-1 in the Kilombero and Ulanga Antiretroviral Cohort in Rural Tanzania.

Background: Virological outcome data after programmatic transition from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based to dolutegravir (DTG)-based antiretroviral therapy (ART) regimens in sub-Saharan Africa (SSA) outside of clinical trials are scarce. We compared viral suppression and associated factors in treatment-naïve people living with HIV (PLHIV) starting DTG- based versus NNRTI-based ART. Methods: We compared virological suppression at 12 months, after treatment initiation in the two cohorts of participants aged ≥15 years, initiating DTG- and NNRTI-based ART. Drug resistance was assessed among participants with viremia ≥50 copies/mL on DTG. Results: Viral suppression was achieved for 165/195 (85%) and 154/211 (73%) participants in the DTG- and NNRTI- cohorts, respectively (P = 0.003). DTG-based ART was associated with >2 times the odds of viral suppression versus NNRTI-based ART (adjusted odds ratio, 2.10 [95% confidence interval {CI}, 1.12-3.94]; adjusted risk ratio, 1.11 [95% CI, 1.00-1.24]). HIV-1 genotypic resistance testing (GRT) before ART initiation was done in 14 of 30 viremic participants on DTG, among whom nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and protease inhibitors resistance was detected in 0 (0%), 2 (14%) and 1 (7%), respectively. No resistance was found in the 2 of 30 participants with available GRT at the time of viremia ≥50 copies/mL. Conclusions: Virological suppression at 1 year was higher in participants initiating DTG- versus NNRTI-based ART. In those with viremia ≥50 copies/mL on DTG-based ART, there was no pretreatment or acquired resistance to the DTG co-administered NRTIs, although the number of samples tested was small.

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.

Ultrasononography in Managing Extrapulmonary Tuberculosis: A Randomized, Controlled, Parallel, Superiority, Open-Label Trial.

BACKGROUND: Patients with suspected extrapulmonary tuberculosis are often treated empirically. We hypothesized that extended focused assessment with sonography for human immunodeficiency virus (HIV) and tuberculosis (eFASH), in combination with other tests, would increase the proportion of correctly managed patients with suspected extrapulmonary tuberculosis. METHODS: This trial in adults with suspected extrapulmonary tuberculosis was performed in a rural and an urban hospital in Tanzania. Participants were randomized 1:1 to intervention or routine care, stratified by site and HIV status. All participants underwent clinical evaluation, chest radiography, and testing with sputum Xpert MTB/RIF and urine Xpert MTB/RIF Ultra assays. The intervention was a management algorithm based on results of eFASH plus microbiology, adenosine deaminase (ADA), and chest radiography. The primary outcome was the proportion of correctly managed patients. The presence of positive microbiological or ADA results defined definite tuberculosis. An independent end-point review committee determined diagnoses of probable or no tuberculosis. We evaluated outcomes using logistic regression models, adjusted for randomization stratification factors. RESULTS: From September 2018 to October 2020, a total of 1036 patients were screened and 701 were randomized (350 to the intervention and 351 to the control group). Of participants in the intervention group, 251 (72%) had a positive eFASH outcome. In 258 (74%) of the intervention and 227 (65%) of the control participants antituberculosis was initiated treatment at baseline. More intervention participants had definite tuberculosis (n = 124 [35%]), compared with controls (n = 85 [24%]). There was no difference between groups for the primary outcome (intervention group, 266 of 286 [93%]; control group, 245 of 266 [92%]; odds ratio, 1.14 [95% confidence interval: .60-2.16]; P = .68). There were no procedure-associated adverse events. CONCLUSIONS: eFASH did not change the proportion of correctly managed patients but increased the proportion of those with definite tuberculosis. CLINICAL TRIALS REGISTRATION: Pan African Registry: PACTR201712002829221.

Stigma-directed services (Stig2Health) to improve 'linkage to care' for people living with HIV in rural Tanzania: study protocol for a nested pre-post implementation study within the Kilombero and Ulanga Antiretroviral Cohort.

Background: HIV-related stigma is a major barrier to the timely linkage and retention of patients in HIV care in sub-Saharan Africa, where most people living with HIV/AIDS reside. In this implementation study we aim to evaluate the effect of stigma-directed services on linkage to care and other health outcomes in newly diagnosed HIV-positive patients. Methods: In a nested project of the Kilombero and Ulanga Antiretroviral Cohort in rural Tanzania, we conduct a prospective observational pre-post study to assess the impact of a bundle of stigma-directed services for newly diagnosed HIV positive patients. Stigma-directed services, delivered by a lay person living with HIV, are i) post-test counseling, ii) post-test video-assisted teaching, iii) group support therapy and group health education, and iv) mobile health. Patients receiving stigma services (enrolled from 1 st February 2020 to 31 st August 2021) are compared to a historical control receiving the standard of care (enrolled from 1 st July 2017 to 1 st February 2019). The primary outcome is 'linkage to care'. Secondary endpoints are retention in care, viral suppression, death and clinical failure at 6-12 months (up to 31 st August 2022). Self-reported stigma and depression are assessed using the Berger Stigma scale and the PHQ-9 questionnaire, respectively. The sample size calculation was based on cohort data from 2018. Assuming a pre-intervention cohort of 511 newly diagnosed adults of whom 346 (68%) were in care and on antiretroviral treatment (ART) at 2 months, a 10% increase in linkage (from 70 to 80%), a two-sided type I error rate of 5%, and 90% power, 321 adults are required for the post-implementation group. Discussion: We expect that integration of stigma-directed services leads to an increase of proportions of patients in care and on ART. The findings will provide guidance on how to integrate stigma-directed services into routine care in rural sub-Saharan Africa.

The Chronic Diseases Clinic of Ifakara (CDCI)-Establishing a Model Clinic for Chronic Care Delivery in Rural Sub-Saharan Africa.

The rollout of antiretroviral drugs in sub-Saharan Africa to address the huge health impact of the HIV pandemic has been one of the largest projects undertaken in medical history and is an unprecedented medical success story. However, the path has been and still is characterized by many far reaching implementational challenges. Here, we report on the building and maintaining of a role model clinic in Ifakara, rural Southwestern Tanzania, within a collaborative project to support HIV services within the national program, training for staff and integrated research to better understand local needs and improve patients' outcomes.

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.

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.

Prevalence, incidence and predictors of renal impairment in persons with HIV receiving protease-inhibitors in rural Tanzania.

OBJECTIVE: Ritonavir-boosted protease inhibitors (bPI) in people living with HIV (PLWH) have been associated with renal impairment. Limited data are available from rural sub-Saharan Africa. METHODS: Using data from the Kilombero and Ulanga Antiretroviral Cohort Study (KIULARCO) in rural Tanzania from 2005-01/2020, we assessed the prevalence of renal impairment (estimated glomerular filtration rate <60 mL/min/1.73m2) at the time of switch from first-line antiretroviral treatment (ART) to bPI-regimen and the incidence of renal impairment on bPI. We assessed risk factors for renal impairment using logistic and Cox regression models. RESULTS: Renal impairment was present in 52/687 PLWH (7.6%) at the switch to bPI. Among 556 participants with normal kidney function at switch, 41 (7.4%) developed renal impairment after a median time of 3.5 (IQR 1.6-5.1) years (incidence 22/1,000 person-years (95%CI 16.1-29.8)). Factors associated with renal impairment at switch were older age (adjusted odds ratio (aOR) 1.55 per 10 years; 95%CI 1.15-2.11), body mass index (BMI) <18.5 kg/m2 (aOR 2.80 versus ≥18kg/m2; 95%CI 1.28-6.14) and arterial hypertension (aOR 2.33; 95%CI 1.03-5.28). The risk of renal impairment was lower with increased duration of ART use (aOR 0.78 per one-year increase; 95%CI 0.67-0.91). The renal impairment incidence under bPI was associated with older age (adjusted hazard ratio 2.01 per 10 years; 95%CI 1.46-2.78). CONCLUSIONS: In PLWH in rural sub-Saharan Africa, prevalence and incidence of renal impairment among those who were switched from first-line to bPI-regimens were high. We found associations between renal impairment and older age, arterial hypertension, low BMI and time on ART.

Estimating intervention effectiveness in trials of malaria interventions with contamination.

BACKGROUND: In cluster randomized trials (CRTs) or stepped wedge cluster randomized trials (SWCRTs) of malaria interventions, mosquito movement leads to contamination between trial arms unless buffer zones separate the clusters. Contamination can be accounted for in the analysis, yielding an estimate of the contamination range, the distance over which contamination measurably biases the effectiveness. METHODS: A previously described analysis for CRTs is extended to SWCRTs and estimates of effectiveness are provided as a function of intervention coverage. The methods are applied to two SWCRTs of malaria interventions, the SolarMal trial on the impact of mass trapping of mosquitoes with odor-baited traps and the AvecNet trial on the effect of adding pyriproxyfen to long-lasting insecticidal nets. RESULTS: For the SolarMal trial, the contamination range was estimated to be 146 m ([Formula: see text] credible interval [Formula: see text] km), together with a [Formula: see text] ([Formula: see text] credible interval [Formula: see text]) reduction of Plasmodium infection, compared to the [Formula: see text] reduction estimated without accounting for contamination. The estimated effectiveness had an approximately linear relationship with coverage. For the AvecNet trial, estimated contamination effects were minimal, with insufficient data from the cluster boundary regions to estimate the effectiveness as a function of coverage. CONCLUSIONS: The contamination range in these trials of malaria interventions is much less than the distances Anopheles mosquitoes can fly. An appropriate analysis makes buffer zones unnecessary, enabling the design of more cost-efficient trials. Estimation of the contamination range requires information from the cluster boundary regions and trials should be designed to collect this.

Analysis of contamination in cluster randomized trials of malaria interventions.

BACKGROUND: In cluster randomized trials (CRTs) of interventions against malaria, mosquito movement between households ultimately leads to contamination between intervention and control arms, unless they are separated by wide buffer zones. METHODS: This paper proposes a method for adjusting estimates of intervention effectiveness for contamination and for estimating a contamination range between intervention arms, the distance over which contamination measurably biases the estimate of effectiveness. A sigmoid function is fitted to malaria prevalence or incidence data as a function of the distance of households to the intervention boundary, stratified by intervention status and including a random effect for the clustering. The method is evaluated in a simulation study, corresponding to a range of rural settings with varying intervention effectiveness and contamination range, and applied to a CRT of insecticide treated nets in Ghana. RESULTS: The simulations indicate that the method leads to approximately unbiased estimates of effectiveness. Precision decreases with increasing mosquito movement, but the contamination range is much smaller than the maximum distance traveled by mosquitoes. For the method to provide precise and approximately unbiased estimates, at least 50% of the households should be at distances greater than the estimated contamination range from the discordant intervention arm. CONCLUSIONS: A sigmoid approach provides an appropriate analysis for a CRT in the presence of contamination. Outcome data from boundary zones should not be discarded but used to provide estimates of the contamination range. This gives an alternative to "fried egg" designs, which use large clusters (increasing costs) and exclude buffer zones to avoid bias.

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.

The HIV care cascade in sub-Saharan Africa: systematic review of published criteria and definitions.

INTRODUCTION: The HIV care cascade examines the attrition of people living with HIV from diagnosis to the use of antiretroviral therapy (ART) and suppression of viral replication. We reviewed the literature from sub-Saharan Africa to assess the definitions used for the different steps in the HIV care cascade. METHODS: We searched PubMed, Embase and CINAHL for articles published from January 2004 to December 2020. Longitudinal and cross-sectional studies were included if they reported on at least one step of the UNAIDS 90-90-90 cascade or two steps of an extended 7-step cascade. A step was clearly defined if authors reported definitions for numerator and denominator, including the description of the eligible population and methods of assessment or measurement. The review protocol has been published and registered in Prospero. RESULTS AND DISCUSSION: Overall, 3364 articles were screened, and 82 studies from 19 countries met the inclusion criteria. Most studies were from Southern (38 studies, 34 from South Africa) and East Africa (29 studies). Fifty-eight studies (71.6%) were longitudinal, with a median follow-up of three years. The medium number of steps covered out of 7 steps was 3 (interquartile range [IQR] 2 to 4); the median year of publication was 2015 (IQR 2013 to 2019). The number of different definitions for the numerators ranged from four definitions (for step "People living with HIV") to 21 (step "Viral suppression"). For the denominators, it ranged from three definitions ("Diagnosed and aware of HIV status") to 14 ("Viral suppression"). Only 12 studies assessed all three of the 90-90-90 steps. Most studies used longitudinal data, but denominator-denominator or denominator-numerator linkages over several steps were rare. Also, cascade data are lacking for many countries. Our review covers the academic literature but did not consider other data, such as government reports on the HIV care cascade. Also, it did not examine disengagement and reengagement in care. CONCLUSIONS: The proportions of patients retained at each step of the HIV care cascade cannot be compared between studies, countries and time periods, nor meta-analysed, due to the many different definitions used for numerators and denominators. There is a need for standardization of methods and definitions.

"Linkage to care" among people living with HIV - definition in the era of "universal test and treat" in a sub-Sahara African setting.

BACKGROUND: Prompt linkage to human immunodeficiency virus (HIV) care after diagnosis is of utmost importance for individual health and reduction of HIV transmission. Different definitions for "linkage to care" have challenged comparisons as a public health marker. Its meaning in the era of "universal test and treat" has transformed in all settings, but is most relevant in sub-Sahara Africa, where the burden of new HIV infection is still highest. METHODS: For this narrative review on "linkage to care" definitions with a focus on sub-Saharan Africa, we searched PubMed/Medline between September and December 2020, restricted to the period 2000­2020 using Boolean operators: "HIV" AND ("linkage to care" OR "engagement in care") and screened for institutional definitions of "linkage to care". Additionally, as one example of a rural sub-Saharan African setting, we analysed linkage steps within the Chronic Diseases Clinic Ifakara (CDCI) and its associated Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in rural Tanzania between 1 January 2017 and 31 March 2019. RESULTS: We analysed 81 articles that included "linkage to care" within different study settings and HIV organisations. Major differences in defining "linkage to care" exist, according to setting and location, patient populations and the timing of steps within the linkage process. We identified 16 different numerators and 10 denominators used to define linkage with time periods ranging from "same day as diagnosis" up to 12 months after diagnosis among 34 original articles from sub-Saharan Africa. At the CDCI, 1149/1671 (69%) newly diagnosed individuals were enrolled into care after diagnosis. Three months after enrolment into care, 94%, 86%, 85% and 71% of enrolled patients had a laboratory evaluation, a clinical evaluation, were initiated on treatment and had a first clinical follow-up visit after initiation of treatment, respectively. DUSCUSSION: To address the inconsistency in defining "linkage to care" and in order to guarantee the comparability of "linkage to care" in the sub-Saharan Africa region, we support the definition from the European region with some adaptions. We suggest a priority list of care indicators if more than one care indicator is available for successful "linkage to care" in the era of "universal test and treat" for sub-Sahara Africa.