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Abstract Background World Health Organization recommended community-based ART (CBART) approaches to improve access to antiretroviral treatment (ART) and treatment outcomes among key populations living with (KPLHIV). Key populations (KP) are female sex workers, men who have sex with men, persons who inject drugs, and transgender people. How CBART for KP (KP-CBART) worked and why, for whom and in what circumstances it worked within KP communities or at community sites, are yet to be described. The aim of this study is to describe the different KP-CBART approaches or models in Nigeria, identifying the context conditions and mechanisms that are likely to produce the desired outcomes. Method Building on our previous study eliciting an initial programme theory for KP-CBART, we used a multiple case design and cross-case analysis to evaluate 3 KP-CBART approaches, namely: One Stop Shop clinic; community drop-in centre; and outreach venue. Between 2021 and 2023, we conducted a retrospective cohort study, 99 indepth interviews and 5 focused group discussions with various actors. Using realist evaluation, we synthesised context-mechanism-outcome configurations (CMOCs) and developed programme theory for each of the cases and an overall theory. Result The analysis showed the central importance of decentralizing ART service delivery to a safe place within the community for KPLHIV. The provision of ART in a KP friendly environment triggered a feeling of safety and trust in the healthcare workers among KPLHIV, resulting in KP-CBART acceptance and improved ART uptake, medication adherence and retention on ART. KP community engagement in ART delivery, peer support through support group meetings, and linkages with KP-led organizations improved self-efficacy, fostered solidarity and a sense of belonging among KP. These resources encouraged and motivated clients to engage with the KP-CBART model. However, fear of disclosure of HIV and KP status, and lack of trust between KP groups, demotivated and discouraged KPLHIV from initiating ART and continuing their treatment in KP-CBART. Conclusion To optimise access to ART and treatment outcomes for KPLHIV, policy makers and health practitioners should ensure the provision of a safe place for ART service delivery that can be trusted by the clients and the KP communities.

Abstract Introduction Evidence on the real-world effects of “Treat All” on attrition has not been systematically reviewed. We aimed to review existing literature to compare attrition 12 months after antiretroviral therapy (ART) initiation, before and after “Treat All” was implemented in Sub-Saharan Africa and describe predictors of attrition. Methods We searched Embase, Google Scholar, PubMed, and Web of Science in July 2020 and created alerts up to the end of June 2023. We also searched for preprints and conference abstracts. Two co-authors screened and selected the articles. Risk of bias was assessed using the modified Newcastle–Ottawa Scale. We extracted and tabulated data on study characteristics, attrition 12 months after ART initiation, and predictors of attrition. We calculated a pooled risk ratio for attrition using random-effects meta-analysis. Results Eight articles and one conference abstract (nine studies) out of 8179 screened records were included in the meta-analysis. The random-effects adjusted pooled risk ratio (RR) comparing attrition before and after “Treat All” 12 months after ART initiation was not significant [RR = 1.07 (95% Confidence interval (CI): 0.91–1.24)], with 92% heterogeneity (I2). Being a pregnant or breastfeeding woman, starting ART with advanced HIV, and starting ART within the same week were reported as risk factors for attrition both before and after “Treat All”. Conclusions We found no significant difference in attrition before and after “Treat All” one year after ART initiation. While “Treat All” is being implemented widely, differentiated approaches to enhance retention should be prioritised for those subgroups at risk of attrition. PROSPERO number CRD42020191582 .

Abstract Background Chest X-ray offers high sensitivity and acceptable specificity as a tuberculosis screening tool, but in areas with a high burden of tuberculosis, there is often a lack of radiological expertise to interpret chest X-ray. Computer-aided detection systems based on artificial intelligence are therefore increasingly used to screen for tuberculosis-related abnormalities on digital chest radiographies. The CAD4TB software has previously been shown to demonstrate high sensitivity for chest X-ray tuberculosis-related abnormalities, but it is not yet calibrated for the detection of non-tuberculosis abnormalities. When screening for tuberculosis, users of computer-aided detection need to be aware that other chest pathologies are likely to be as prevalent as, or more prevalent than, active tuberculosis. However, non­-tuberculosis chest X-ray abnormalities detected during chest X-ray screening for tuberculosis remain poorly characterized in the sub-Saharan African setting, with only minimal literature. Case presentation In this case series, we report on four cases with non-tuberculosis abnormalities detected on CXR in TB TRIAGE + ACCURACY (ClinicalTrials.gov Identifier: NCT04666311), a study in adult presumptive tuberculosis cases at health facilities in Lesotho and South Africa to determine the diagnostic accuracy of two potential tuberculosis triage tests: computer-aided detection (CAD4TB v7, Delft, the Netherlands) and C-reactive protein (Alere Afinion, USA). The four Black African participants presented with the following chest X-ray abnormalities: a 59-year-old woman with pulmonary arteriovenous malformation, a 28-year-old man with pneumothorax, a 20-year-old man with massive bronchiectasis, and a 47-year-old woman with aspergilloma. Conclusions Solely using chest X-ray computer-aided detection systems based on artificial intelligence as a tuberculosis screening strategy in sub-Saharan Africa comes with benefits, but also risks. Due to the limitation of CAD4TB for non-tuberculosis-abnormality identification, the computer-aided detection software may miss significant chest X-ray abnormalities that require treatment, as exemplified in our four cases. Increased data collection, characterization of non-tuberculosis anomalies and research on the implications of these diseases for individuals and health systems in sub-Saharan Africa is needed to help improve existing artificial intelligence software programs and their use in countries with high tuberculosis burden.

Objectives: High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). Design/methods: TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. Results: Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% [95% confidence interval: 1.0,14.3]). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. Conclusion: We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.

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.

[This corrects the article DOI: 10.1371/journal.pone.0271910.].

Introduction In sub-Saharan African (SSA) countries endemic for tuberculosis (TB), previous TB is a significant risk factor for non-tuberculous mycobacterial pulmonary disease (NTM-PD). The deployment of GeneXpert MTB/RIF in pulmonary TB diagnostic work-up regularly identifies symptomatic patients with a positive smear microscopy but negative GeneXpert, indicative of NTM presence. This scoping review outlines recent evidence for NTM-PD diagnosis and management in SSA.Objective The review’s objective was to outline the risk factors, available diagnostics, management options and outcomes of NTM-PD in high-burden TB settings in SSA using the population-concept-context framework.Design and data sources We searched existing literature from PubMed, Web of Science, African Journals Online, Google Scholar and grey literature. Studies published between January 2005 and December 2022 were retained. Data were extracted into Rayyan software and Mendeley and summarised using Excel.Results We identified 785 potential articles, of which 105 were included in the full-text review, with 7 papers retained. Included articles used international criteria for diagnosing NTM-PD. Multiple papers were excluded due to non-application of the criteria, suggesting challenging application in the SSA setting. Identified risk factors include previous TB, smoking and mining. Most commonly, chest radiography and not CT was used for the radiological diagnosis of PD, which may miss early changes related to NTM-PD. Molecular methods for NTM species identification were employed in research settings, usually at referral centres, but were unavailable for routine care. Most studies did not report a standardised approach to treatment and they were not offered treatment for the specific disease, marking a lack of guidance in treatment decision-making. When treatment was provided, the outcome was often not reported due to the lack of implementation of standardised outcome definitions.Conclusions These outlined challenges present a unique opportunity for researchers to undertake further studies in NTM-PD and proffer solutions more applicable to SSA.

Abstract Background The community-based antiretroviral therapy delivery (CBART) model was implemented in Benue State in Nigeria to increase access of key populations living with HIV (KPLHIV) to antiretroviral treatment. Key populations (KP) are female sex workers, men who have sex with men, persons who inject drugs, and transgender people. Evidence shows that the CBART model for KP (KP-CBART) can improve HIV outcomes along the cascade of HIV care and treatment in sub-Saharan Africa. However, how KP-CBART works, for whom, why, and under what circumstances it generates specific outcomes are not yet clear. Therefore, the aim of this study is to identify the initial programme theory (IPT) of the KP-CBART in Benue State using a realist approach. Method The study design is exploratory and qualitative, exploring the implementation of KP-CBART. We reviewed the intervention logic framework & guidelines for the KP-CBART in Nigeria, conducted a desk review of KP-CBART in Sub-Saharan Africa (SSA) and interviewed programme managers in the Benue HIV programme between November 2021 and April 2022. Findings were synthesized using the Context-Mechanism-Outcome (CMO) heuristic tool to explain the relationship between the different types of CBART models, contextual factors, actors, mechanisms and outcomes. Using a generative causality logic (retroduction and abduction), we developed, following a realist approach, CMO configurations (CMOc), summarized as an empirically testable IPT. Result We developed 7 CMOc and an IPT of the KP-CBART. Where KPLHIV receive ART in a safe place while living in a setting of punitive laws, harassment, stigma and discrimination, KP will adhere to treatment and be retained in care because they feel safe and trust the healthcare providers. Where KPLHIV are involved in the design, planning and implementation of HIV services; medication adherence and retention in care will improve because KP clients perceive HIV services to be KP-friendly and participate in KP-CBART. Conclusion Implementation of CBART model where KPLHIV feel safe, trust healthcare providers, and participate in HIV service delivery can improve medication adherence and retention in care. This programme hypothesis will be tested and refined in the next phase of the realist evaluation of KP-CBART.

Objectives: To describe treatment outcomes for rifampicin-resistant tuberculosis (Rr-TB) started on standard regimen and the frequency of acquired drug resistance in patients treated using the standard treatment regimen (STR) in Cameroon between 2015-2019. Methods: This is a retrospective cohort study. Rr-TB patients were initiated on the STR, including a fluoroquinolone (FQ), a second-line injectable drug (SLI), and companion drugs. In case of resistance to fluoroquinolones (FQr) at baseline, FQ, SLI and ethionamide were replaced by bedaquiline, delamanid, and linezolid in a modified treatment regimen (mTR), FQr-mTR. In case of resistance to SLI (SLIr) at baseline, SLI was replaced by linezolid (LZD), SLIr-mTR. Logistic regression and competing risk regression were used to estimate predictors of early (first eight weeks) mortality and overall mortality, respectively. Results: Of 709 patients started on a standard regimen, treatment success occurred in 84.7% (587/693), 72.7% (8/11) and 100% (10/10) of patients treated with STR, FQr-mTR and SLIr-mTR as final regimens, respectively. Three (0.6%) patients acquired FQr during treatment. Early mortality occurred in 4.1% (29/709) and was associated with being HIV positive, male sex and being underweight. Overall mortality was associated with missing drug-susceptibility testing results at baseline, being HIV positive, age>40 and male sex. Conclusion: Programmatic management of Rr-TB, with additional second-line drug resistance treated with mTR, resulted in excellent treatment outcomes.

Abstract Background Since the scale-up of routine viral load (VL) testing started in 2016, there is limited evidence on VL suppression rates under programmatic settings and groups at risk of non-suppression. We conducted a study to estimate VL non-suppression (> 1000 copies/ml) and its risk factors using "routine" and "repeat after enhanced adherence counselling (EAC)" VL results. Methods We conducted an analytic cross-sectional study using secondary VL testing data collected between 2014 and 2018 from a centrally located laboratory. We analysed data from routine tests and repeat tests after an individual received EAC. Our outcome was viral load non-suppression. Bivariable and multivariable logistic regression was performed to identify factors associated with having VL non-suppression for routine and repeat VL. Results We analysed 103,609 VL test results (101,725 routine and 1884 repeat test results) collected from the country’s ten provinces. Of the 101,725 routine and 1884 repeat VL tests, 13.8% and 52.9% were non-suppressed, respectively. Only one in seven (1:7) of the non-suppressed routine VL tests had a repeat test after EAC. For routine VL tests; males (vs females, adjusted odds ratio (aOR) = 1.19, [95% CI 1.14–1.24]) and adolescents (10–19 years) (vs adults (25–49 years), aOR = 3.11, [95% CI 2.9–3.31]) were more at risk of VL non-suppression. The patients who received care at the secondary level (vs primary, aOR = 1.21, [95% CI 1.17–1.26]) and tertiary level (vs primary, aOR = 1.63, [95% CI 1.44–1.85]) had a higher risk of VL non-suppression compared to the primary level. Those that started ART in 2014–2015 (vs

During TB-case finding, we assessed the feasibility of implementing the advanced HIV disease (AHD) care package, including VISITECT CD4 Advanced Disease (VISITECT), a semiquantitative test to identify a CD4≤200cells/μl. Adult participants with tuberculosis symptoms, recruited near-facility in Lesotho and South-Africa between 2021-2022, were offered HIV testing (capillary blood), Xpert MTB/RIF and Ultra, and MGIT culture (sputum). People living with HIV (PLHIV) were offered VISITECT (venous blood) and Alere tuberculosis-lipoarabinomannan (AlereLAM, urine) testing. AHD was defined as a CD4≤200cells/μl on VISITECT or a positive tuberculosis test. A CD4≤200cells/μl on VISITECT triggered Immy cryptococcal antigen (Immy CrAg, plasma) testing. Participants were referred with test results. To evaluate feasibility, we assessed i) acceptability and ii) intervention delivery of point-of-care diagnostics among study staff using questionnaires and group discussions, iii) process compliance, and iv) early effectiveness (12-week survival and treatment status) in PLHIV. Predictors for 12-week survival were assessed with logistic regression. Thematic content analysis and triangulation were performed. Among PLHIV (N = 676, 48.6% of 1392 participants), 7.8% were newly diagnosed, 81.8% on ART, and 10.4% knew their HIV status but were not on ART. Among 676 PLHIV, 41.7% had AHD, 29.9% a CD4≤200cells/μl and 20.6% a tuberculosis diagnosis. Among 200 PLHIV tested with Immy CrAg, 4.0% were positive. The procedures were acceptable for study staff, despite intervention delivery challenges related to supply and the long procedural duration (median: 73 minutes). At 12 weeks, among 276 PLHIV with AHD and 328 without, 3.3% and 0.9% had died, 84.8% and 92.1% were alive and 12.0% and 7.0% had an unknown status, respectively. Neither AHD nor tuberculosis status were associated with survival. Implementing AHD care package diagnostics was feasible during tuberculosis-case finding. AHD was prevalent, and not associated with survival, which is likely explained by the low specificity of VISITECT. Challenges with CD4 testing and preventive treatment uptake require addressing.

IntroductionHIV viral load (VL) testing in resource-limited settings is often centralised, limiting access. In Myanmar, we assessed outcomes according to VL access and the VL cascade (case management after a first high VL result) before and after near point-of-care (POC) VL was introduced.MethodsRoutine programme data from people living with HIV (PLHIV) on antiretroviral therapy (ART) were used. We assessed the odds of getting a VL test done by year. Attrition and mortality two years after ART initiation were compared between three groups of PLHIV with different access to VL testing using Kaplan-Meier analysis. We compared VL cascades in those with a first VL result before and after near POC VL testing became available. With logistic regression, predictors of confirmed virological failure after a first high VL in the POC era were explored.ResultsAmong 4291 PLHIV who started ART between July 2009 and June 2018, 794 (18.5%) became eligible for VL testing when it was not available, 2388 (55.7%) when centralised laboratory-based VL testing was available, and 1109 (25.8%) when near POC VL testing was available. Between 2010 and 2019, the odds of getting a VL test among those eligible increased with each year (OR: 5.21 [95% CI: 4.95-5.48]). Attrition and mortality were not different in the three groups. When comparing PLHIV with a first VL result before and after implementation of the near POC VL testing, in the latter, more had a first VL test (92% versus 15%, pConclusionNear POC VL testing enabled rapid increase of VL coverage and a well-managed VL cascade in Myanmar.

Diagnostic accuracy studies in pulmonary tuberculosis (PTB) are complicated by the lack of a perfect reference standard. This limitation can be handled using latent class analysis (LCA), assuming independence between diagnostic test results conditional on the true unobserved PTB status. Test results could remain dependent, however, e.g. with diagnostic tests based on a similar biological basis. If ignored, this gives misleading inferences. Our secondary analysis of data collected during the first year (May 2018 –May 2019) of a community-based multi-morbidity screening program conducted in the rural uMkhanyakude district of KwaZulu Natal, South Africa, used Bayesian LCA. Residents of the catchment area, aged ≥15 years and eligible for microbiological testing, were analyzed. Probit regression methods for dependent binary data sequentially regressed each binary test outcome on other observed test results, measured covariates and the true unobserved PTB status. Unknown model parameters were assigned Gaussian priors to evaluate overall PTB prevalence and diagnostic accuracy of 6 tests used to screen for PTB: any TB symptom, radiologist conclusion, Computer Aided Detection for TB version 5 (CAD4TBv5≥53), CAD4TBv6≥53, Xpert Ultra (excluding trace) and culture. Before the application of our proposed model, we evaluated its performance using a previously published childhood pulmonary TB (CPTB) dataset. Standard LCA assuming conditional independence yielded an unrealistic prevalence estimate of 18.6% which was not resolved by accounting for conditional dependence among the true PTB cases only. Allowing, also, for conditional dependence among the true non-PTB cases produced a 1.1% plausible prevalence. After incorporating age, sex, and HIV status in the analysis, we obtained 0.9% (95% CrI: 0.6, 1.3) overall prevalence. Males had higher PTB prevalence compared to females (1.2% vs. 0.8%). Similarly, HIV+ had a higher PTB prevalence compared to HIV- (1.3% vs. 0.8%). The overall sensitivity for Xpert Ultra (excluding trace) and culture were 62.2% (95% CrI: 48.7, 74.4) and 75.9% (95% CrI: 61.9, 89.2), respectively. Any chest X-ray abnormality, CAD4TBv5≥53 and CAD4TBv6≥53 had similar overall sensitivity. Up to 73.3% (95% CrI: 61.4, 83.4) of all true PTB cases did not report TB symptoms. Our flexible modelling approach yields plausible, easy-to-interpret estimates of sensitivity, specificity and PTB prevalence under more realistic assumptions. Failure to fully account for diagnostic test dependence can yield misleading inferences.

Background: In application studies of latent class analysis (LCA) evaluating imperfect diagnostic tests, residual dependence among the diagnostic tests still remain even after conditioning on the true disease status due to measured variables known to affect prevalence and/or alter diagnostic test accuracy. Presence of severe comorbidities such as HIV in pulmonary tuberculosis (PTB) diagnosis alter the prevalence of PTB and affect the diagnostic performance of the available imperfect tests in use. This violates two key assumptions of LCA: (1) that the diagnostic tests are independent conditional on the true disease status (2) that the sensitivity and specificity remain constant across subpopulations. This leads to incorrect inferences. Methods: Through simulation we examined implications of likely model violations on estimation of prevalence, sensitivity and specificity among passive case-finding presumptive PTB patients with or without HIV. Jointly conditioning on PTB and HIV, we generated independent results for five diagnostic tests and analyzed using Bayesian LCA with Probit regression, separately for sets of five and three diagnostic tests using four working models allowing: (1) constant PTB prevalence and diagnostic accuracy (2) varying PTB prevalence but constant diagnostic accuracy (3) constant PTB prevalence but varying diagnostic accuracy (4) varying PTB prevalence and diagnostic accuracy across HIV subpopulations. Vague Gaussian priors with mean 1 and unknown variance were assigned to the model parameters with unknown variance assigned Inverse Gamma prior. Results: Models accounting for heterogeneity in diagnostic accuracy produced consistent estimates while the model ignoring it produces biased estimates. The model ignoring heterogeneity in PTB prevalence only is less problematic. With five diagnostic tests, the model assuming homogenous population is robust to violation of the assumptions. Conclusion: Well-chosen covariate-specific adaptations of the model can avoid bias implied by recognized heterogeneity in PTB patient populations generating otherwise dependent test results in LCA.

Introduction Key populations (KP) living with HIV are underserved and often face social and health system barriers to HIV care. To optimise access to quality HIV services among KP, the WHO recommended community-based approaches to HIV service delivery for KP. However, to inform the successful rollout and scale-up of community-based antiretroviral therapy service delivery models for KP (KP-CBART), there is a need to study the programme implementation. This study aims to evaluate the outcomes of KP-CBART in Benue State Nigeria using a realist impact evaluation approach. Our evaluation question is: what are the mechanisms and context conditions that drive successful community-based implementation and how do these lead to better retention in care, treatment adherence and viral suppression among which categories of KP?Methods and analysis This study will be conducted in three phases, relying on a mixed-method design and following the realist evaluation cycle. The first phase is the development of the initial programme theory grounded in a scoping review, programme and policy document review and in-depth interviews with key stakeholders. In phase 2, findings from case studies of KP-CBART programme implementation in one Nigerian state are used to test the initial programme theory and to refine it. The quantitative part is a retrospective cohort study. All HIV-positive KP clients enrolled into the KP-CBART between 2016 and 2020 will be included in the study. While maximum variation and data saturation will inform sample size for the qualitative part, an estimated 90 purposively selected study participants will be interviewed. In phase 3, findings will be synthesised into a middle-range theory through cross-case analysis. The heuristic intervention, context, agents, mechanisms and outcomes (ICAMO) tool will be used to refine the initial programme theory.Ethics and dissemination The study protocol was approved by the Institutional Review Boards of APIN Public Health Initiatives (IRB022-FR), Institute of Tropical Medicine Antwerp (1503/21), and the Benue State Ministry of Health and Human Services (MOH/STA/204/VOL1/154). Written informed consent will be obtained from all study participants. Study results will be disseminated through stakeholders meeting, peer-reviewed journals and conferences.

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in patients with HIV-associated tuberculosis (TB) starting antiretroviral treatment (ART) in sub-Saharan Africa. The PredART-trial recently showed that prophylactic prednisone reduces the incidence of paradoxical TB-IRIS by 30% in a population at high risk. This paper reports the impact of the intervention on health-related quality of life (HRQoL), a secondary endpoint of the trial, measured by an amended version of the PROQOL-HIV instrument—the instrument’s validity and reliability is also assessed.MethodsA total of 240 adult participants (antiretroviral treatment (ART)-naïve, TB-HIV co-infected with CD4 count ≤100 cells/μL) were recruited and randomized (1:1) to (1) a prednisone arm or (2) a placebo arm. In this sub-study of the PredART-trial we evaluated (1) the performance of an HIV-specific HR-QoL instrument amended for TB-IRIS, i.e., the PROQOL-HIV/TB in patients with HIV-associated TB starting ART (reliability, internal and external construct validity and invariance across time) and (2) the impact of prednisone on self-reported HR-QoL in this population through mixed models.ResultsThe PROQOL-HIV/TB scale displayed acceptable internal reliability and good internal and external validity. This instrument, including the factor structure with the eight sub-dimensions, can thus be applied for measuring HR-QoL among HIV-TB patients at high risk for TB-IRIS. Prophylactic prednisone was statistically significantly associated only with the ‘Physical Health and Symptoms’-subscale: a four-week course of prednisone resulted in an earlier improvement in the physical dimension of HR-QoL compared to placebo.ConclusionWe demonstrated that the PROQOL-HIV/TB scale adequately measures different aspects of self-reported HR-QoL in HIV-TB patients. Although more research is needed to understand how other domains related to HR-QoL can be improved, targeting patients at high risk for developing TB-IRIS with a four-week course of prednisone has a beneficial effect on the physical aspects of patient-reported quality of life.

Abstract Background Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. Methods We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months’ standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox’s regression was performed to identify risk factors for virological failure. Results We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0–39.1) and a median observation time of 5.4 years (IQR 3.7–7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20–1.89; p

Abstract Objective We conducted a descriptive cross-sectional study using survey and programme data to assess district-level performance along the HIV care cascade (HIV testing target achievement, linkage to ART and ART coverage) in order to formulate district-specific recommendations, taking into consideration prevalence and yield of testing. Results Data from 60 districts were analysed. Forty-eight districts (80.0%) surpassed 90% of their 2018 HIV testing targets. Linkage to ART was less than 90% in 40 districts (83.3%). Thirty districts (50.0%) had ART coverage above 90%. Of the 30 districts with suboptimal (

Abstract Introduction We aim to report on results and challenges of different methods used for hepatitis C (HCV) genotyping in a Cambodian HCV/HIV coinfection project. Methods Samples of 106 patients were available. HCV genotyping was initially (63 samples) done by the LightPower Taqman real-time PCR method (Viet A Corp.) and quality controlled using the Versant 2.0 line probe assay (Siemens Healthcare). Next, following interim quality control results, all 106 samples were (re)genotyped with Versant 2.0, complemented with 5′UTR/core sequencing for uninterpretable/incomplete Versant results. Results Using Versant, 103 (97.2%) of the 106 HCV-coinfected patients had an interpretable genotype result: 1b (50.5%), 6 non-a/non-b (30.1%), 1a (6.8%), 6a or b (4.9%), 2 (3.9%), 1 (2.9%) and 3 (1.0%). For 16 samples that were interpreted as genotype 1 or 1b per Versant's current instructions, it could not be excluded that it concerned a genotype 6 infection as the core region line patterns on the Versant test strip were unavailable, inconclusive or atypical. Upon sequencing, seven of these were genotyped as 1b and nine as genotype 6. Combining Versant and sequencing results, a definitive genotype was assigned in 104 patients: 1b (44.2%), 6 non-a/non-b (39.4%), 1a (6.7%), 6a or b (4.8%), 2 (3.8%) and 3 (1.0%). Genotyping by LightPower and Versant was discordant for 23 (of 63) samples. The LightPower assay misclassified all genotype 6 non-a/non-b samples as genotype 1, which indicates that this assay is only using 5′UTR information. Conclusions HCV genotype 1b and genotype 6 non-a/non-b were most common. With Versant 2.0 (using 5′UTR and core information), genotype classification (1 or 6) remained inconclusive in 15% of samples. The locally available method (LightPower assay) failed to identify genotype 6 non-a/non-b, which highlights that methods using 5′UTR information only should not be used in Cambodia. Regional/national guidelines should be explicit about this. Trial Registration This study was performed as part of a larger cross-sectional study on the burden of hepatitis C coinfection in HIV patients in Cambodia (Clinical.trials.gov: HCV-Epi NCT02361541).

Abstract Background Hepatitis C virus (HCV) infection is a major global health problem. WHO guidelines recommend screening all people living with HIV for hepatitis C. Considering the limited resources for health in low and middle income countries, targeted HCV screening is potentially a more feasible screening strategy for many HIV cohorts. Hence there is an interest in developing clinician-friendly tools for selecting subgroups of HIV patients for whom HCV testing should be prioritized. Several statistical methods have been developed to predict a binary outcome. Multiple studies have compared the performance of different predictive models, but results were inconsistent. Methods A cross-sectional HCV diagnostic study was conducted in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh, Cambodia. We compared the performance of logistic regression, Spiegelhalter-Knill-Jones and CART to predict Hepatitis C co-infection in this cohort. We estimated the number of HCV co-infections that would be missed. To correct for over-optimism, the leave-one-out bootstrap estimator was used for estimating this quantity. Results Logistic regression misses the fewest HCV co-infections (8%), but would still refer 98% of HIV patients for HCV testing. Spiegelhalter-Knill-Jones (SKJ) and CART respectively miss 12% and 29% of HCV co-infections but would only refer about 30% for HCV testing. Conclusions In our dataset, logistic regression has the highest log-likelihood and smallest proportions of HCV co-infections missed but Spiegelhalter-Knill-Jones has the highest area under the ROC curve. The likelihood ratios estimated by Spiegelhalter-Knill-Jones might be easier to interpret for clinicians than odds ratios estimated by logistic regression or the decision tree from CART. CART is the most flexible method, and no model has to be specified regarding presence of interactions and form of the relationship between outcome and predictor variables.

BackgroundThe control of Ebola virus disease (EVD) outbreaks relies on rapid diagnosis and prompt action, a daunting task in limited-resource contexts. This study develops prediction scores that can help healthcare workers improve their decision-making at the triage-point of EVD suspect-cases during EVD outbreaks.MethodsWe computed accuracy measurements of EVD predictors to assess their diagnosing ability compared with the reference standard GeneXpert® results, during the eastern DRC EVD outbreak. We developed predictive scores using the Spiegelhalter-Knill-Jones approach and constructed a clinical prediction score (CPS) and an extended clinical prediction score (ECPS). We plotted the receiver operating characteristic curves (ROCs), estimated the area under the ROC (AUROC) to assess the performance of scores, and computed net benefits (NB) to assess the clinical utility (decision-making ability) of the scores at a given cut-off. We performed decision curve analysis (DCA) to compare, at a range of threshold probabilities, prediction scores' decision-making ability and to quantify the number of unnecessary isolation.ResultsThe analysis was done on data from 10432 subjects, including 651 EVD cases. The EVD prevalence was 6.2% in the whole dataset, 14.8% in the subgroup of suspects who fitted the WHO Ebola case definition, and 3.2% for the set of suspects who did not fit this case definition. The WHO clinical definition yielded 61.6% sensitivity and 76.4% specificity. Fatigue, difficulty in swallowing, red eyes, gingival bleeding, hematemesis, confusion, hemoptysis, and a history of contact with an EVD case were predictors of EVD. The AUROC for ECPS was 0.88 (95%CI: 0.86-0.89), significantly greater than this for CPS, 0.71 (95%CI: 0.69-0.73) (p < 0.0001). At -1 point of score, the CPS yielded a sensitivity of 85.4% and specificity of 42.3%, and the ECPS yielded sensitivity of 78.8% and specificity of 81.4%. The diagnostic performance of the scores varied in the three disease contexts (the whole, fitting or not fitting the WHO case definition data sets). At 10% of threshold probability, e.g. in disease-adverse context, ECPS gave an NB of 0.033 and a net reduction of unnecessary isolation of 67.1%. Using ECPS as a joint approach to isolate EVD suspects reduces the number of unnecessary isolations by 65.7%.ConclusionThe scores developed in our study showed a good performance as EVD case predictors since their use improved the net benefit, i.e., their clinical utility. These rapid and low-cost tools can help in decision-making to isolate EVD-suspicious cases at the triage point during an outbreak. However, these tools still require external validation and cost-effectiveness evaluation before being used on a large scale.

IntroductionDespite HIV viral load (VL) monitoring being serial, most studies use a cross-sectional design to evaluate the virological status of a cohort. The objective of our study was to use a simplified approach to calculate viraemic-time: the proportion of follow-up time with unsuppressed VL above the limit of detection. We estimated risk factors for higher viraemic-time and whether viraemic-time predicted mortality in a second-line antiretroviral treatment (ART) cohort in Myanmar.MethodsWe conducted a retrospective cohort analysis of people living with HIV (PLHIV) who received second-line ART for a period >6 months and who had at least two HIV VL test results between 01 January 2014 and 30 April 2018. Fractional logistic regression assessed risk factors for having higher viraemic-time and Cox proportional hazards regression assessed the association between viraemic-time and mortality. Kaplan-Meier curves were plotted to illustrate survival probability for different viraemic-time categories.ResultsAmong 1,352 participants, 815 (60.3%) never experienced viraemia, and 172 (12.7%), 214 (15.8%), and 80 (5.9%) participants were viraemic ConclusionsKey populations were at risk for having a higher viraemic-time on second-line ART. Viraemic-time predicts clinical outcomes. Differentiated services should target subgroups at risk for a higher viraemic-time to control both HIV transmission and mortality.

Abstract Background To achieve the ambitious 90–90-90 UNAIDS targets, access to routine viral load (VL) is critical. To measure VL, Rwanda has relied on a national reference laboratory for years. In 2014, a VL testing platform was implemented in a rural District in the Northern Province. Here we analyze the uptake of VL testing, identification of risks for detectable VL (≥1000 copies/ml), and the management of patients with a detectable VL. Methods A retrospective cohort study of patients who started ART between July 2012 and June 2015 and followed until end December 2016. Using descriptive statistics, we describe the VL cascade, from VL uptake to the start of second-line ART in patients diagnosed with virological failure. We estimate predictors of having a detectable VL using logistic regression. Results The uptake of VL testing increased progressively between 2013 and 2016, raising from 25.6% (39/152) in 2013 up to 93.2% (510/547) in 2016.In 2016, 88.5% (n = 451) of patients tested, had a suppressed VL. Predictors of having a detectable VL included being male (aOR 2.1; 95%CI 1.12–4.02; p = 0.02), being a sex worker (aOR 6.4; 95%CI 1.1–36.0; p = 0.04), having a WHO clinical stage IV when starting ART (aOR 8.8; 95%CI 1.8–43.0; p

WHO recommends hepatitis C (HCV) screening for all people living with HIV (PLHIV). Yet, HCV coinfection was shown to be rare in some Sub-Saharan HIV cohorts, and targeted testing was suggested more efficient for such settings. We studied HCV prevalence among Ghanaian PLHIV, and assessed the external validity of a score to guide targeted testing. This score was initially derived from a Cambodian HIV cohort, and uses as predictors: age, household member/partner with liver disease, diabetes, generalized pruritus, AST, platelets, and AST-to-platelet ratio index. We enrolled 4,023 PLHIV, most from Greater Accra and Central regions, 28.4% were male, median age was 47 years, and high-risk behavior was reported to be rare. HCV seroprevalence was 0.57%, and HCV-RNA was detectable in 0.5%. Sequencing revealed genotype 1(b) and 2(q/r) infections. The discriminatory performance of the score was suboptimal in the Ghanaian setting. The area under the curve was 0.69 (95% CI 0.59-0.79). HCV coinfection prevalence was very low in this Ghanaian PLHIV cohort with reported low-risk of onward transmission. To avoid the cost of screening all PLHIV in similar cohorts in resource-constrained settings, further research to develop better tools/scores to guide targeted HCV testing is needed.

BackgroundKey populations (KP) are disproportionately infected with HIV and experience barriers to HIV care. KP include men who have sex with men (MSM), female sex workers (FSW), persons who inject drugs (PWID) and transgender people (TG). We implemented three different approaches to the delivery of community-based antiretroviral therapy for KP (KP-CBART) in Benue State Nigeria, including One Stop Shop clinics (OSS), community drop-in-centres (DIC), and outreach venues. OSS are community-based health facilities serving KP only. DIC are small facilities led by lay healthcare providers and supported by an outreach team. Outreach venues are places in the community served by the outreach team. We studied long-term attrition of KP and virological non-suppression.MethodThis is a retrospective cohort study of KP living with HIV (KPLHIV) starting ART between 2016 and 2019 in 3 0SS, 2 DIC and 8 outreach venues. Attrition included lost to follow-up (LTFU) and death. A viral load >1000 copies/mL showed viral non-suppression. Survival analysis was used to assess retention on ART. Cox regression and Firth logistic regression were used to assess risk factors for attrition and virological non-suppression respectively.ResultOf 3495 KPLHIV initiated on ART in KP-CBART, 51.8% (n = 1812) were enrolled in OSS, 28.1% (n = 982) in DIC, and 20.1% (n = 701) through outreach venues. The majority of participants were FSW-54.2% (n = 1896), while 29.8% (n = 1040), 15.8% (n = 551) and 0.2% (n = 8) were MSM, PWID, and TG respectively. The overall retention in the programme was 63.5%, 55.4%, 51.2%, and 46.7% at 1 year, 2 years, 3 years, and 4 years on ART. Of 1650 with attrition, 2.5% (n = 41) died and others were LTFU. Once adjusted for other factors (age, sex, place of residence, year of ART enrollment, WHO clinical stage, type of KP group, and KP-CBART approach), KP-CBART approach did not predict attrition. MSM were at a higher risk of attrition (vs FSW; adjusted hazard ratio (aHR) 1.27; 95%CI: 1.14-1.42). Of 3495 patients, 48.4% (n = 1691) had a viral load test. Of those, 97.8% (n = 1654) were virally suppressed.ConclusionAlthough long-term retention in care is low, the virological suppression was optimal for KP on ART and retained in community-based ART care. However, viral load testing coverage was sub-optimal. Future research should explore the perspectives of clients on reasons for LTFU and how to adapt approach to CBART to meet individual client needs.

BACKGROUND:The last evaluation to assess outcomes for patients receiving antiretroviral therapy (ART) through the Zimbabwe public sector was conducted in 2011, covering the 2007-2010 cohorts. The reported retention at 6, 12, 24 and 36 months were 90.7%, 78.1%, 68.8% and 64.4%, respectively. We report findings of a follow-up evaluation for the 2012-2015 cohorts to assess the implementation and impact of recommendations from this prior evaluation. METHODS:A nationwide retrospective study was conducted in 2016. Multi-stage proportional sampling was used to select health facilities and study participants records. The data extracted from patient manual records included demographic, baseline clinical characteristics and patient outcomes (active on treatment, died, transferred out, stopped ART and lost to follow-up (LTFU)) at 6, 12, 24 and 36 months. The data were analysed using Stata/IC 14.2. Retention was estimated using survival analysis. The predictors associated with attrition were determined using a multivariate Cox regression model. RESULTS:A total of 3,810 participants were recruited in the study. The median age in years was 35 (IQR: 28-42). Overall, retention increased to 92.4% (p-value = 0.060), 86.5% (p-value

BACKGROUND:Meta-analyses on impact of isoniazid-resistant tuberculosis informed the World Health Organization recommendation of a levofloxacin-strengthened rifampicin-based regimen. We estimated the effect of initial rifampicin resistance (Rr) and/or isoniazid resistance (Hr) on treatment failure or relapse. We also determined the frequency of missed initial and acquired Rr to estimate the impact of true Hr. METHODS:Retrospective analysis of 7291 treatment episodes with known initial isoniazid and rifampicin status obtained from individual patient databases maintained by the Damien Foundation Bangladesh over 20 years. Drug susceptibility test results were confirmed by the programme's designated supra-national tuberculosis laboratory. To detect missed Rr among isolates routinely classified as Hr, rpoB gene sequencing was done randomly and on a sample selected for suspected missed Rr. RESULTS:Initial Hr caused a large recurrence excess after the 8-month regimen for new cases (rifampicin for two months), but had little impact on rifampicin-throughout regimens: (6 months, new cases; 3.8%; OR 0.8, 95%CI:0.3,2.8; 8 months, retreatment cases: 7.3%, OR 1.8; 95%CI:1.3,2.6). Rr was missed in 7.6% of randomly selected "Hr" strains. Acquired Rr was frequent among recurrences on rifampicin-throughout regimens, particularly after the retreatment regimen (31.9%). It was higher in mono-Hr (29.3%; aOR 3.5, 95%CI:1.5,8.5) and poly-Hr (53.3%; aOR 10.2, 95%CI 4.4,23.7) than in susceptible tuberculosis, but virtually absent after the 8-month new case regimen. Comparing Bangladesh (low Rr prevalence) with a high Rr prevalence setting,true Hr corrected for missed Rr caused only 2-3 treatment failures per 1000 TB cases (of whom 27% were retreatments) in both. CONCLUSIONS:Our analysis reveals a non-negligible extent of misclassifying as isoniazid resistance of what is actually missed multidrug-resistant tuberculosis. Recommending for such cases a "strengthened" regimen containing a fluoroquinolone provokes a direct route to extensive resistance while offering little benefit against the minor role of true Hr tuberculosis in rifampicin-throughout first-line regimen.

SETTING:Since August 2016, after the Ebola outbreak, the Guinean National Tuberculosis Programme and Damien Foundation implemented the shorter treatment regimen (STR) for multidrug-resistant tuberculosis (MDR-TB) in the three MDR-TB sites of Conakry. Previously, the longer regimen was used to treat MDR-TB. OBJECTIVES:In a post-Ebola context, with a weakened health system, we describe the MDR-TB treatment uptake, patients characteristics, treatment outcomes and estimate the effect of using the longer versus STR on having a programmatically adverse outcome. DESIGN:This is a retrospective cohort study in RR-TB patients treated with either the longer regimen or STR. RESULTS:In Conakry, in 2016 and 2017, 131 and 219 patients were diagnosed with rifampicin-resistant tuberculosis (RR-TB); and 108 and 163 started treatment, respectively. Of 271 patients who started treatment, 75 were treated with the longer regimen and 196 with the STR. Patients characteristics were similar regardless of the regimen except that the median age was higher among those treated with a longer regimen (30 years (IQR:24-38) versus 26 years (IQR:21-39) for the STR. Patients treated with a STR were more likely to obtain a programmatically favorable outcome (74.0% vs 58.7%, p = 0.01) as lost to follow up was higher among those treated with a longer regimen (20.0% vs 8.2%, p = 0.006). Patients on a longer regimen were more than 2 times more likely (aOR: 2.5; 95%CI:1.3,4.7) to have a programmatically adverse outcome as well as being 45 years or older (aOR: 2.8; 95%CI:1.3,6.2), HIV positive (aOR:3.3; 95%CI:1.6,6.6) and attendance at a clinic without NGO support (aOR:3.0; 95%:1.6,5.7). CONCLUSION:In Guinea, patients treated with the STR were more likely to have a successful outcome than those treated with the longer MDR-TB treatment regimen. Lost to follow-up was higher in patients on the longer regimen. However, STR treatment outcomes were less good than those reported in the region.

BackgroundSince the scale-up of the HIV "Treat All" recommendation, evidence on its real-world effect on predictors of attrition (either death or lost to follow-up) is lacking. We conducted a retrospective study using Zimbabwe ART program data to assess the association between "Treat All" and, patient-mix, programmatic characteristics, retention and predictors of attrition.MethodsWe used patient-level data from the electronic patient monitoring system (ePMS) from the nine districts, which piloted the "Treat All" recommendation. We compared patient-mix, programme characteristics, retention and predictors of attrition (lost to follow-up, death or stopping ART) in two cohorts; before (April/May 2016) and after (January/February 2017) "Treat All". Retention was estimated using survival analysis. Predictors of attrition were determined using a multivariable Cox regression model. Interactions were used to assess the change in predictors of attrition before and after "Treat All".ResultsWe analysed 3787 patients, 1738 (45.9%) and 2049 (54.1%) started ART before and after "Treat All", respectively. The proportion of men was higher after "Treat All" (39.4.% vs 36.2%, p = 0.044). Same-day ART initiation was more frequent after "Treat All" (43.2% vs 16.4%; pConclusionAttrition was higher after "Treat All"; being male, WHO Stage 4, and pregnancy predicted attrition in both before and after Treat All. However, pregnancy became a less strong risk factor for attrition after "Treat All" implementation.

IntroductionAfghanistan is affected by one of the world's longest protracted armed conflicts, frequent natural disasters, disease outbreaks and large population movements and it suffers from a high burden of tuberculosis (TB), including rifampicin-resistant TB (RR-TB). The study shows Médecins Sans Frontières' experiences with care for patients with RR-TB in Kandahar Province. We describe the uptake of RR-TB treatment, how World Health Organisation criteria for the choice between the short and an individualized regimen were implemented, and treatment outcomes.MethodsThis is a retrospective cohort analysis of routinely collected data from RR-TB patients enrolled in care from 2016 until 2019. Descriptive analysis was performed to present characteristics of patients and treatment outcomes. Multivariable Cox analysis was performed to identify risk factors for having an unfavourable treatment outcome.ResultsOut of 146 enrolled RR-TB patients, 112 (76.7%) started treatment: 41 (36.6%) and 71 (63.4%) with the short and individualized treatment regimen, respectively. Of 82 with results for fluoroquinolone susceptibility, 39 (47.6%) had fluoroquinolone-resistant TB. Seven patients with initially fluoroquinolone-resistant TB and three pregnant women started the short regimen and 18 patients eligible for the short regimen started the injectable-free individualized regimen. Overall, six-month smear and culture conversion were 98.7% and 97.1%, respectively; treatment success was 70.1%. Known initial fluoroquinolone resistance (aHR 3.77, 95%CI:1.53-9.27) but not choice of regimen predicted having an unfavourable outcome.ConclusionEven though criteria for the choice of treatment regimen were not applied strictly, we have achieved acceptable outcomes in this cohort. To expand RR-TB care, treatment regimens should fit provision at primary health care level and take patient preferences into account.

Abstract Background A recently published Ugandan study on tuberculosis (TB) diagnosis in HIV-positive patients with presumptive smear-negative TB, which showed that out of 90 patients who started TB treatment, 20% (18/90) had a positive Xpert MTB/RIF (Xpert) test, 24% (22/90) had a negative Xpert test, and 56% (50/90) were started without Xpert testing. Although Xpert testing was available, clinicians did not use it systematically. Here we aim to show more objectively the process of clinical decision-making. First, we estimated that pre-test probability of TB, or the prevalence of TB in smear-negative HIV infected patients with signs of presumptive TB in Uganda, was 17%. Second, we argue that the treatment threshold, the probability of disease at which the utility of treating and not treating is the same, and above which treatment should be started, should be determined. In Uganda, the treatment threshold was not yet formally established. In Rwanda, the calculated treatment threshold was 12%. Hence, one could argue that the threshold was reached without even considering additional tests. Still, Xpert testing can be useful when the probability of disease is above the treatment threshold, but only when a negative Xpert result can lower the probability of disease enough to cross the treatment threshold. This occurs when the pre-test probability is lower than the test-treat threshold, the probability of disease at which the utility of testing and the utility of treating without testing is the same. We estimated that the test-treatment threshold was 28%. Finally, to show the effect of the presence or absence of arguments on the probability of TB, we use confirming and excluding power, and a log10 odds scale to combine arguments. Conclusion If the pre-test probability is above the test-treat threshold, empirical treatment is justified, because even a negative Xpert will not lower the post-test probability below the treatment threshold. However, Xpert testing for the diagnosis of TB should be performed in patients for whom the probability of TB was lower than the test-treat threshold. Especially in resource constrained settings clinicians should be encouraged to take clinical decisions and use scarce resources rationally.

Background: Ethiopia is one of the countries which has scaled up antiretroviral treatment (ART) over the past decade. This study reviews the performance of the ART program in Ethiopia during the past decade, and identifies successes and weaknesses toward ending AIDS in the country. Methods: A review and synthesis of data was conducted using multiple data sources: reports from all health facilities in Ethiopia to the Federal Ministry of Health, HIV/AIDS estimates and projections, and retrospective cohort and cross-sectional studies conducted between 2005/6 and 2014/15. Findings: The ART program has been successful over several critical areas: (1) ART coverage improved from 4% to 54%; (2) the median CD4 count/mm3 at the time of ART initiation increased from 125 in 2005/6 to 231 in 2012/13; (3) retention in care after 12 months on ART has increased from 82% to 92%. In spite of these successes, important challenges also remain: (1) ART coverage is not equitable: among regions (5.6%-93%), between children (25%) and adults (60%), and between female (54%) and male patients (69%); (2) retention in care is variable among regions (83%-94%); and, (3) the shift to second-line ART is slow and low (0·58%). Interpretation: The findings suggest that the ART program should sustain the successes and reflect on the shortcomings toward the goal of ending AIDS. It is important to capitalize on and calibrate the interventions and approaches utilized to scale up ART in the past. Analysis of the treatment cascade, in order to pinpoint the gaps and identify appropriate solutions, is commendable in this regard.

By using data from a 2015 clinical trial on Ebola convalescent-phase plasma in Guinea, we assessed the prevalence of electrolyte and metabolic abnormalities at admission and their predictive value to stratify patients into risk groups. Patients underwent testing with a point-of-care device. We used logistic regression to construct a prognostic model and summarized the predictive value with the area under the receiver operating curve. Abnormalities were common among patients, particularly hypokalemia, hypocalcemia, hyponatremia, raised creatinine, high anion gap, and anemia. Besides age and PCR cycle threshold value, renal dysfunction, low calcium levels, and low hemoglobin levels were independently associated with increased risk for death. A prognostic model using all 5 factors was highly discriminatory (area under the receiver operating curve 0.95; 95% CI 0.90–0.99) and enabled the definition of risk criteria to guide targeted care. Most patients had a very low (80%) risk for death.

Background: Most studies evaluate active case findings (ACF) for bacteriologically confirmed TB. Adapted diagnostic approaches are needed to identify cases with lower bacillary loads. Objectives: To assess the likelihood of diagnosing all forms of TB, including clinically diagnosed pulmonary and extra-pulmonary TB, using different ACF algorithms in Cambodia. Methods: Clients were stratified into ‘high-risk’ (presumptive TB plus TB contact, or history of TB, or presumptive HIV infection; n = 12,337) and ‘moderate-risk’ groups (presumptive TB; n = 28,804). Sputum samples were examined by sputum smear microscopy (SSM) or Xpert MTB/RIF (Xpert). Initially, chest X-ray using a mobile radiography unit was a follow-up test after a negative sputum examination [algorithms A (Xpert/X-ray) and B (SSM/X-ray)]. Subsequently, all clients received an X-ray [algorithms C (X-ray+Xpert) and D (Xray+SSM/Xpert)]. X-rays were interpreted on the spot. Results: Between 25 August 2014 and 31 March 2016, 2217 (5.4%) cases with all forms of TB cases were diagnosed among 41,141 adults. The majority of TB cases (1488; 67.1%) were diagnosed using X-ray. When X-rays were taken and interpreted the same day the sputum was collected, same-day diagnosis more than doubled. Overall, the number needed to test (NNT) to diagnose one case was 18.6 (95%CI:17.9–19.2). In the high-risk group the NNT was lower [algorithm D: NNT = 17.3(15.9–18.9)] compared with the ‘moderate-risk group’ [algorithm D: NNT = 20.8(19.6–22.2)]. In the high-risk group the NNT was lower when using Xpert as an initial test [algorithm A: NNT = 12.2(10.8–13.9) or algorithm C: NNT = 11.2(9.6–13.0)] compared with Xpert as a follow-up test [algorithm D: NNT = 17.3(15.9–18.9)]. Conclusion: To diagnose all TB forms, X-ray should be part of the diagnostic algorithm. The combination of X-ray and Xpert testing for high-risk clients was the most effective ACF approach in this setting.

Visceral pentastomiasis is usually found incidentally during surgery. We describe a case of visceral pentastomiasis discovered during inguinoscrotal hernia surgery for a man from Benin, Africa. Because surgical removal of nymphs is needed for symptomatic patients only, this patient’s asymptomatic pentastomiasis was not treated and he recovered from surgery uneventfully.

Impaired lung function is common in people with a history of tuberculosis. Host-directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We discuss the immunological processes that cause lung damage, focusing on studies performed in humans, and using chest radiograph abnormalities as a marker for pulmonary damage. We highlight the roles of matrix metalloproteinases, neutrophils, eicosanoids and cytokines, like tumor necrosis factor-α and interleukin 1β, as well as the role of HIV co-infection. Finally, we focus on various existing drugs that affect one or more of the immunological mediators of lung damage and could therefore play a role as host-directed therapy.

The epidemiology of hepatitis C in Cambodia is not well-known. We evaluated the prevalence of hepatitis C virus (HCV) and risk factors in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh to strengthen the evidence for suitable HCV testing strategies among people living with HIV (PLWH) in Cambodia. All consenting adult PLWH without a history of HCV treatment were tested for HCV between November 2014 and May 2016 according to the CDC algorithm (HCV antibody II electro-chemiluminescence immunoassay, followed by COBAS® AmpliPrep/COBAS® TaqMan® HCV PCR and INNO-LIA® HCV Score immunoblot end-testing). Genotyping was performed using the line probe assay Versant HCV genotype 2.0®. The study enrolled a total of 3045 patients (43% males, median age: 42.5 years, 55 years (11.2%). Genotype 1b (45%) and 6 (41%) were predominant. Coinfected patients had a higher aspartate-to-platelet ratio index, lower platelets, a lower HBsAg positivity rate and more frequent diabetes. Based on logistic regression, blood transfusion antecedents (adjusted odds ratio 2.9; 95% CI 1.7-4.9), unsafe medical injections (2.0; 1.3-3.2), and partner (3.4; 1.5-7.6) or household member (2.4; 1.3-3.2) with liver disease were independently associated with HCV in women. However, having a tattoo/scarification (1.9; 1.1-3.4) and household member (3.1; 1.3-7.3) with liver disease were associated with HCV in men. Thus, our study found intermediate endemicity of active hepatitis C in a large Cambodian HIV cohort and provides initial arguments for targeted HCV screening (>50 years, partner/household member with liver disease, diabetes, increased aspartate-to-platelet ratio index) as efficient way forward.

Although HIV disease stage at ART initiation critically determines ART outcomes, few reports have longitudinally monitored this within Asia. Using prospectively collected data from a large ART program at Sihanouk Hospital Center of Hope in Cambodia, we report on the change in patient characteristics and outcomes over a ten-year period.We conducted a retrospective analysis including all adults (≥ 18 years old) starting ART from March 2003-March 2013 in a non-governmental hospital in Phnom Penh, Cambodia. The cumulative incidence of death, lost to follow-up (LTFU), attrition (death or LTFU) and first line treatment failure were calculated using Kaplan-Meier methods. Independent risk factors for these outcomes were determined using Cox regression modeling.Over the ten-year period, 3581 patients initiated ART with a median follow-up time of 4.8 years (IQR 2.8-7.2). The median age was 35 years (IQR 30-41), 54% were female. The median CD4 count at ART initiation increased from 22 cells/μL (IQR 4-129) in 2003 to 218 (IQR 57-302) in 2013. Over the 10 year period, a total of 282 (7.9%) individuals died and 433 (12.1%) were defined LTFU. Program attrition (died or LTFU) was 11.1% (95% CI: 10.1%- 12.4%) at one year, 16.3% (95% CI: 15.1%-17.6%) at three years, 19.8% (95% CI: 18.5%-21.2%) at five years and 23.3% (95% CI: 21.6-25.1) at ten years. Male sex and low baseline body mass index (BMI) were associated with increased attrition. Factors independently associated with mortality included a low baseline CD4 count, older age, male sex, low baseline BMI and hepatitis B co-infection. Individuals aged above 40 years old had an increased risk of mortality but were less likely to LTFU. There were a total of 137 individuals with first line ART failure starting second line treatment. The probability of first line failure was estimated at 2.8% (95% CI: 2.3%-3.4%) at 3 years, 4.6% (95% CI: 3.9%-5.5%) at 5 years and 7.8% (95% CI 4.8%-12.5%) at ten years of ART. The probability was particularly high in the first few program years. A lower risk was observed among individuals starting ART during the 2006-2008 period. Factors independently associated with an increased risk of treatment failure included ART-experience, NVP-based ART and a baseline CD4 count below 200 cells/μL.Overall program outcomes were fair, and generally compare well to other reports from the region. Despite gradually earlier initiation of ART over the ten year period, ART is still initiated at too low CD4 count levels, warranting increased efforts for early HIV diagnosis and enrolment/retention into HIV care. Tailored strategies for poor prognostic groups (older age, male, low BMI) should be designed and evaluated.

In Ethiopia, case fatality rates among subgroups of visceral leishmaniasis (VL) patients are high. A clinical prognostic score for death in VL patients could contribute to optimal management and reduction of these case fatality rates. We aimed to identify predictors of death from VL, and to develop and externally validate a clinical prognostic score for death in VL patients, in a high HIV co-infection burden area in Ethiopia.We conducted a retrospective cohort study in north west Ethiopia. Predictors with an adjusted likelihood ratio ≥1.5 or ≤0.67 were retained to calculate the predictor score. The derivation cohort consisted of 1686 VL patients treated at an upgraded health center and the external validation cohort consisted of 404 VL patients treated in hospital. There were 99 deaths in the derivation cohort and 53 deaths in the external validation cohort. The predictors of death were: age >40 years (score +1); HIV seropositive (score +1); HIV seronegative (score -1); hemoglobin ≤6.5 g/dl (score +1); bleeding (score +1); jaundice (score +1); edema (score +1); ascites (score +2) and tuberculosis (score +1). The total predictor score per patient ranged from -1 to +5. A score of -1, indicated a low risk of death (1.0%), a score of 0 an intermediate risk of death (3.8%) and a score of +1 to +5, a high risk of death (10.4-85.7%). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval: 0.79-0.87) in derivation, and 0.78 (95% confidence interval: 0.72-0.83) in external validation.The overall performance of the score was good. The score can enable the early detection of VL cases at high risk of death, which can inform operational, clinical management guidelines, and VL program management. Implementation of focused strategies could contribute to optimal management and reduction of the case fatality rates.

OBJECTIVE: To determine if implementation of 2010 World Health Organization (WHO) guidelines on antiretroviral therapy (ART) initiation reduced delay from tuberculosis diagnosis to initiation of ART in a Cambodian urban hospital. METHODS: A retrospective cohort study was conducted in a nongovernmental hospital in Phnom Penh that followed new WHO guidelines in patients with human immunodeficiency virus (HIV) and tuberculosis. All ART-naïve, HIV-positive patients initiated on antituberculosis treatment over the 18 months before and after guideline implementation were included. A competing risk regression model was used. FINDINGS: After implementation of the 2010 WHO guidelines, 190 HIV-positive patients with tuberculosis were identified: 53% males; median age, 38 years; median baseline CD4+ T-lymphocyte (CD4+ cell) count, 43 cells/µL. Before implementation, 262 patients were identified; 56% males; median age, 36 years; median baseline CD4+ cell count, 59 cells/µL. With baseline CD4+ cell counts < 50 cells/µL, median delay to ART declined from 5.8 weeks (interquartile range, IQR: 3.7-9.0) before to 3.0 weeks (IQR: 2.1-4.4) after implementation (P < 0.001); with baseline CD4+ cell counts > 50 cells/µL, delay dropped from 7.0 (IQR: 5.3-11.3) to 3.6 (IQR: 2.9-5.3) weeks (P < 0.001). The probability of ART initiation within 4 and 8 weeks after tuberculosis diagnosis rose from 23% and 65%, respectively, before implementation, to 62% and 90% after implementation. A non-significant increase in 6-month retention and antiretroviral substitution was seen after implementation. CONCLUSION: Implementation of 2010 WHO recommendations in a routine clinical setting shortens delay to ART. Larger studies with longer follow-up are needed to assess impact on patient outcomes.

OBJECTIVE: To appraise the process of development and clinical content of national human immunodeficiency virus (HIV) clinical practice guidelines of countries in the eastern Mediterranean and to formulate recommendations for future guideline development and adaptation. METHODS: Twenty-three countries in the World Health Organization (WHO) Eastern Mediterranean and United Nations Children's Fund Middle East and North Africa regions were invited to submit national HIV clinical practice guidelines for review. The guideline development methodology was assessed using an adaptation of the Appraisal of Guidelines Research and Evaluation (AGREE) instrument and guideline content, using a checklist to evaluate concordance with WHO 2006 generic guidelines. FINDINGS: Twelve countries submitted 20 guidelines developed between 2004 and 2009. Median scores were poor (i.e.

BACKGROUND:Diagnostic guidelines for Visceral Leishmaniasis (VL) in the East African region are complex. Patients meeting the VL clinical case definition should be tested by rK39 rapid diagnostic test (RDT) followed by the Direct Agglutination Test (DAT) or tissue aspiration if RDT-negative. Otherwise, RDT-positive patients should be started on VL treatment. We evaluated how this guideline is adhered to by assessing the routine clinical practice in a university hospital in North-West Ethiopia. METHODS:Retrospective record analysis was done for all patients who had an rK39-RDT done at University of Gondar (UoG) Hospital between June 2012 and June 2013. We described the diagnostic work-up performed and the proportion initiated on VL treatment by test result. RESULTS/FINDINGS:From a total of 928 patients tested, 308 (33.2%) were rK39 RDT-positive. Spleen or bone marrow aspiration was done for 237 (77.2%) RDT-positive patients. Of these, 165 were confirmed parasitologically, yielding a positive predictive value of 69.6%. Only 126 (20.3%) of the 620 patients with a negative rK39 test underwent further testing by tissue aspiration, of which 22 (17.5%) were also parasitology positive. HIV test results were available for 570 (61.4%) patients and 36 (6.3%) were HIV-infected. Of the 187 parasitologically confirmed patients, 182 (97.3%) were started on VL treatment. CONCLUSIONS/DISCUSSION:A negative rK39 test was often not followed by further testing and a positive rK39 test result was followed by tissue aspiration in three out of four cases. Further research is required to understand why the diagnostic work-up did not comply with the guidelines, including evaluating adherence to the VL clinical case definition and quality of rK39-RDT testing.

Early HIV diagnosis and enrolment in care is needed to achieve early antiretroviral treatment (ART) initiation. Studies on HIV disease stage at enrolment in care from Asian countries are limited. We evaluated trends in and factors associated with late HIV disease presentation over a ten-year period in the largest ART center in Cambodia.We conducted a retrospective analysis of program data including all ARV-naïve adults (> 18 years old) enrolling into HIV care from March 2003-December 2013 in a non-governmental hospital in Phnom Penh, Cambodia. We calculated the proportion presenting with advanced stage HIV disease (WHO clinical stage IV or CD4 cell count

BACKGROUND:Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients. METHODS:A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4 mg/kg pentamidine-isethionate diluted in normal-saline were started for 12 months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point. RESULTS:Seventy-four patients were included. The probability of relapse-free survival at 6 months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50 cells/μl, 5/7 (71.4%) than those with counts above 200 cells/μl, 2/12 (16.7%), (p = 0.005). CONCLUSION:Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.

In the wake of the HIV epidemic, visceral leishmaniasis (VL), a disseminated protozoan infection caused by the Leishmania donovani complex, has been re-emerging, particularly in North Ethiopia where up to 40% of patients with VL are co-infected with HIV. Management of VL in HIV co-infection is complicated by increased drug toxicity, and high treatment failure and relapse rates with all currently available drugs, despite initiation of antiretroviral treatment. Tackling L. donovani infection before disease onset would thus be a logical approach. A screen-and-treat approach targeting latent or the early stage of infection has successfully been implemented in other HIV-associated opportunistic infections. While conceptually attractive in the context of VL-HIV, the basic understanding and evidence underpinning such an approach is currently lacking. Prospective cohort studies will have to be conducted to quantify the risk of VL in different risk groups and across CD4 cell count levels. This will allow developing clinical prognostic tools, integrating clinical, HIV and Leishmania infection markers. Interventional studies will be needed to evaluate prophylactic or pre-emptive treatment strategies for those at risk, ideally relying on an oral (combination) regimen. Issues like tolerability, emergence of resistance and drug interactions will require due attention. The need for maintenance therapy will have to be assessed. Based on the risk-benefit data, VL risk cut-offs will have to be identified to target treatment to those most likely to benefit. Such a strategy should be complemented with early initiation of antiretroviral treatment and other strategies to prevent HIV and Leishmania infection.

Visceral Leishmaniasis (VL) is an important protozoan opportunistic disease in HIV patients in endemic areas. East Africa is second to the Indian subcontinent in the global VL caseload and first in VL-HIV coinfection rate. Because of the alteration in the disease course, the diagnostic challenges, and the poor treatment responses, VL with HIV coinfection has become a very serious challenge in East Africa today. Field experience with the use of liposomal amphotericin B in combination with miltefosine, followed by secondary prophylaxis and antiretroviral drugs, looks promising. However, this needs to be confirmed through clinical trials. Better diagnostic and follow-up methods for relapse and prediction of relapse should also be looked for. Basic research to understand the immunological interaction of the two infections may ultimately help to improve the management of the coinfection.