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Abstract Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI

Background The burden of advanced HIV disease remains a significant concern in sub-Saharan Africa. In 2015, the World Health Organization released recommendations to treat all people living with HIV (PLHIV) regardless of CD4 (“treat all”) and in 2017 guidelines for managing advanced HIV disease. We assessed changes over time in the proportion of PLHIV with advanced HIV and their care cascade in two community settings in sub-Saharan Africa. Methods Cross-sectional population-based surveys were conducted in Ndhiwa (Kenya) in 2012 and 2018 and in Eshowe (South Africa) in 2013 and 2018. We recruited individuals aged 15-59 years. Consenting participants were interviewed and tested for HIV at home. All participants with HIV had CD4 count measured. Advanced HIV was defined as CD4

[This corrects the article DOI: 10.1371/journal.pone.0265488.].

Objectives Evidence on the acceptability of urine-based assays for tuberculosis (TB) diagnosis among patients remains limited. We sought to describe patients’ experiences and perceptions of urine sampling for TB testing at point of care.Setting Study sites in Kenya, Uganda, Mozambique and South Africa.Participants Adult ambulatory HIV patients enrolled in a TB diagnostic study were selected purposively.Intervention For this qualitative descriptive study, audiorecorded individual interviews conducted with consenting participants were translated, transcribed and analysed using content analysis. Ethical agreement was obtained from relevant ethical review committees.Results Fifty-eight participants were interviewed. Three domains were identified. Overall, participants described urine sampling as easy, rapid and painless, with the main challenge being lacking the urge. Urine was preferred to sputum sampling in terms of simplicity, comfort, stigma reduction, convenience and practicality. While perceptions regarding its trustworthiness for TB diagnosis differed, urine sampling was viewed as an additional mean to detect TB and beneficial for early diagnosis. Participants were willing to wait for several hours for same-day results to allay the emotional, physical and financial burden of having to return to collect results, and would rather not pay for the test. Facilitators of urine sampling included cleanliness and perceived privacy of sampling environments, comprehensive sampling instructions and test information, as well as supplies such as toilet paper and envelopes ensuring confort and privacy when producing and returning samples. Participants motivation for accepting urine-based TB testing stemmed from their perceived susceptibility to TB, the value they attributed to their health, especially when experiencing symptoms, and their positive interactions with the medical team.Conclusions This study suggests that urine sampling is well accepted as a TB diagnostic method and provides insights on how to promote patients’ uptake of urine-based testing and improve their sampling experiences. These results encourage the future broad use of urine-based assays at point of care.

Summary: Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette–Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69–4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97–8.75). The difference was large in countries with TB incidence rate

Background: Phenotypic drug-susceptibility testing (pDST), which relies on growth inhibition in the drug-containing media, remains a challenge for fastidious Mycobacterium tuberculosis complex (MTBc) isolates due to insufficient growth on the growth controls (GC). Middlebrook 7H11 (M7H11) medium contains casein hydrolysate, which may favor the growth of such strains. Method: In this study, we tested whether M7H11 reduces invalid results due to insufficient growth on the GCs and the turnaround time (TAT) of pDST for MTBc compared to Middlebrook 7H10 (M7H10) without affecting the accuracy of the pDST results and how it differs between rifampicin- and isoniazid-susceptible non multi-drug resistant (non-MDR), MDR and MDR with additional resistance to fluoroquinolones (Pre-XDR) MTBc isolates. We compared the proportions of invalid pDST results due to lack of growth on the GCs, TATs of valid parallel drug-susceptibility testings as an indicator of speed of MTBc growth, and colony-forming unit (CFU) count on the most diluted GC of the parallel pDSTs after equal incubation periods as an indicator of growth abundance on M7H11 and M7H10. We also analyzed the agreement between the pDST results of the same drug or drugs in the same drug class, tested in parallel on both media. Results: For MDR and pre-XDR isolates, relative to M7H10, M7H11 significantly reduced the occurrence of invalid pDST results due to insufficient growth on the GCs (odds ratio [OR] = ∞ [95% confidence interval (CI) 1.9–∞], P = 0.004 for MDR, OR = ∞ [95% CI 3.3–∞], P = 0.0001 for pre-XDR) and the TAT of pDSTs (OR = 17 [95% CI 2.6–710.4], P = 0.0001 for MDR, OR = 9.3 [95% CI 4.0–26.5], P < 0.0001 for pre-XDR). The growth abundance of MTBc on M7H11 was significantly higher compared to M7H10 (17 CFU on M7H10 vs. 28 on M7H11), irrespective of drug-resistance profiles. The agreement between the pDST results between the two media was high (Cohen's k > 0.98). Conclusion: Our study findings suggest that M7H11 is preferred over M7H10 for pDSTs of MTBc isolates.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Background: The novel urine-based FujiLAM test identifies tuberculosis in HIV-positive patients but may be challenging to use at point-of-care (POC). Objectives: We assessed the feasibility and acceptability of using the FujiLAM test at point of care in outpatient settings. Methods: We conducted a mixed methods study in four outpatient settings in Kenya, Mozambique, South Africa, and Uganda between November 2020 and September 2021. The test was performed at POC in existing clinic laboratories and consultation spaces. We performed direct observations in the four health facilities, individual questionnaires, proficiency testing evaluations, and individual interviews among healthcare workers performing the FujiLAM test (healthcare workers), and group discussions with programme managers. Results: Overall, 18/19 (95%) healthcare workers and 14/14 (100%) managers agreed to participate in the study. Most assessed healthcare workers, including lay health workers (10/11; 91%), met the minimum required theoretical knowledge and practical skill in performing the FujiLAM test. Most healthcare workers (17/18; 94%) found the FujiLAM test overall “Easy/Very easy” to perform. Some challenges were mentioned: many timed steps (5/18; 28%); ensuring correct incubation period (5/18; 28%); test result readability (4/18; 22%); and difficulties with cartridge buttons (3/18; 17%). Half of the healthcare workers regularly performing the test (4/7; 57%) found it “Easy” to integrate into routine activities. Most healthcare workers and managers believed that any healthcare worker could perform the test after adequate training. Conclusions: Implementing the FujiLAM test in outpatient POC settings is feasible and acceptable to healthcare workers and managers. This test can be performed in various clinic locations by any healthcare worker. The timed, multi-step test procedure is challenging and may affect the workload in resource-constrained health facilities.

Abstract Background Despite a dramatic reduction in HCV drug costs and simplified models of care, many countries lack important information on prevalence and risk factors to structure effective HCV services. Methods A cross-sectional, multi-stage cluster survey of HCV seroprevalence in adults 18 years and above was conducted, with an oversampling of those 45 years and above. One hundred forty-seven clusters of 25 households were randomly selected in two sets (set 1=24 clusters ≥18; set 2=123 clusters, ≥45). A multi-variable analysis assessed risk factors for sero-positivity among participants ≥45. The study occurred in rural Moung Ruessei Health Operational District, Battambang Province, Western Cambodia. Results A total of 5098 individuals and 3616 households participated in the survey. The overall seroprevalence was 2.6% (CI95% 2.3–3.0) for those ≥18 years, 5.1% (CI95% 4.6–5.7) for adults ≥ 45 years, and 0.6% (CI95% 0.3–0.9) for adults 18–44. Viraemic prevalence was 1.9% (CI95% 1.6–2.1), 3.6% (CI95% 3.2–4.0), and 0.5% (CI95% 0.2–0.8), respectively. Men had higher prevalence than women: ≥18 years male seroprevalence was 3.0 (CI95% 2.5–3.5) versus 2.3 (CI95% 1.9–2.7) for women. Knowledge of HCV was poor: 64.7% of all respondents and 57.0% of seropositive participants reported never having heard of HCV. Risk factor characteristics for the population ≥45 years included: advancing age (p

BackgroundConversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.MethodsWe used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.ResultsIn simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.ConclusionExtending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

IntroductionHigh coverage of antiretroviral therapy (ART) in people living with HIV (PLHIV) increases viral suppression at population level and may reduce incidence. Médecins sans Frontières, in collaboration with the South African Department of Health, has been working in Eshowe/Mbongolwane (KwaZulu Natal) since 2011 to increase access to quality HIV services. Five years after an initial survey, we conducted a second survey to measure progress in HIV diagnosis and viral suppression and to identify remaining gaps.MethodsA cross-sectional, population-based, stratified two-stage cluster survey was implemented in 2018, using the same design as in 2013. Consenting participants aged 15-59 years were interviewed and tested for HIV at home. Those HIV-positive were tested for HIV viral load (viral suppression defined as ResultsOverall, 3,278 individuals were included. The proportion of HIV-positive participants virally suppressed was 83.8% in 2018 compared to 57.1% in 2013 (pConclusionsViral suppression improved significantly from 2013 to 2018, in all age and gender groups of PLHIV. However, almost half of HIV-positive young men remained unsuppressed, while the majority of virally unsuppressed PLHIV were women and older adults. To continue lowering HIV transmission, specific strategies are needed to increase viral suppression in those groups.

Abstract Background At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens. Methods This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries. Discussion The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments. Trial registration This study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).

Abstract Background Empirical treatment of tuberculosis (TB) may be necessary in patients with negative or no Xpert MTB/RIF results. In a context with access to Xpert, we assessed mortality in the 6 months after the initial TB consultation among HIV-positive and HIV-negative patients who received empirical TB treatment or TB treatment based on bacteriological confirmation and we compared it with the mortality among those who did not receive TB treatment. Methods This prospective cohort study included consecutively adult patients with signs and symptoms of TB attending an outpatient TB clinic in Western Kenya. At the first consultation, patients received a clinical exam and chest X-ray. Sputum was collected for microscopy, Xpert and Mycobacterium tuberculosis complex (MTB) culture. Patients not started on TB treatment were reassessed after 5 days. All patients bacteriologically confirmed (positive Xpert or culture) received TB treatment. Empirical treatment was defined as a decision to start TB treatment without bacteriological confirmation. Patients were reassessed after 6 months. Results Of 606 patients included, 344/606 (56.8%) were women. Median age was 35 years [Interquartile Range (IQR):27–47] and 398/594 (67.0%) were HIV-positive. In total, 196/606 (32.3%) patients were Xpert- or culture-positive and 331/606 (54.6%) started TB treatment. Overall, 100/398 (25.1%) HIV-positive and 31/196 (15.8%) HIV-negative patients received empirical treatment. Mortality in the 6 months following the first consultation was 1.6 and 0.8/100 patient-months among HIV-positive and HIV-negative patients respectively. In the multivariate analyses, TB treatment - whether empirical or based on bacteriological confirmation- was not associated with increased mortality among HIV-positive patients (aHR:2.51, 95%CI:0.79–7.90 and aHR:1.25, 95%CI:0.37–4.21 respectively). However, HIV-negative patients who received empirical treatment had a higher risk of mortality (aHR:4.85, 95%CI:1.08–21.67) compared to those not started on treatment. HIV-negative patients treated for TB based on bacteriological confirmation did not have a different risk of mortality (aHR:0.77, 95%CI:0.08–7.41). Conclusions Our findings suggest that in a context with access to Xpert, clinicians should continue using empirical TB treatment in HIV-positive patients with signs and symptoms of TB and negative Xpert results. However, differential diagnoses other than TB should be actively sought before initiating empirical TB treatment, particularly in HIV-negative patients.

[This corrects the article DOI: 10.1371/journal.pone.0250933.].

BackgroundTuberculosis (TB) is a serious co-morbidity among children with severe acute malnutrition (SAM) and TB diagnosis remains particularly challenging in the very young. We explored whether, in a low HIV-prevalence setting, the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine may assist TB diagnosis in SAM children, a pediatric population currently not included in LAM-testing recommendations. To that end, we assessed LAM test-positivity among SAM children with and without signs or symptoms of TB.MethodsA cross-sectional assessment (February 2016-August 2017) included children Results102 (Group 1) and 100 children (Group 2) were included (median age 18 months, 59.4% male, 1.0% HIV-positive). In Group 1, 22 (21.6%) children were started on TB-treatment (probable TB) and none of the children in Group 2. LAM-positivity was 52.0% (53/102) and 37.0% (37/100) in Group 1 and 2, respectively. Low-intensity (Grade 1) LAM test-positivity was similarly high in both Groups (37.3% and 36.0%, respectively), while Grade 2 or 3-positives were mainly detected in Group 1 (Group 1: 14.7%, Group 2: 1.0%, p1 as positive, LAM-testing detected 22.7% (95%CI: 7.8, 45.4) among probable TB cases, while 99% (95%CI: 94.6, 99.9) of unlikely TB cases (Group 2) tested negative.ConclusionThese findings suggest the potential utility of LAM urine testing in HIV-negative children with SAM. Determine LAM-positivity with Grades >1 may identify HIV-negative SAM children that are eligible for rapid TB-treatment initiation, though low-intensity (Grade 1) LAM-positive results may not be helpful in this way. Further studies in this specific pediatric population are warranted, including evaluations of new generation LAM tests.

BACKGROUND:Tuberculosis (TB) is the leading cause of death among HIV-positive patients. We assessed the cost-effectiveness of including lateral-flow urine lipoarabinomannan (LF-LAM) in TB diagnostic algorithms for severely ill or immunosuppressed HIV-positive patients with symptoms of TB in Kenya. METHODS:From a decision-analysis tree, ten diagnostic algorithms were elaborated and compared. All algorithms included clinical exam. The costs of each algorithm were calculated using a 'micro-costing' method. The efficacy was estimated through a prospective study that included severely ill or immunosuppressed (CD4

Abstract Background The Joint United Nations Programme on HIV/AIDS (UNAIDS) has developed an ambitious strategy to end the AIDS epidemic. After eight years of antiretroviral therapy (ART) program we assessed progress towards the UNAIDS 90–90-90 targets in Mbongolwane and Eshowe, KwaZulu-Natal, South Africa. Methods We conducted a cross-sectional household-based community survey using a two-stage stratified cluster probability sampling strategy. Persons aged 15–59 years were eligible. We used face-to-face interviewer-administered questionnaires to collect information on history of HIV testing and care. Rapid HIV testing was performed on site and venous blood specimens collected from HIV-positive participants for antiretroviral drug presence test, CD4 count and viral load. At the time of the survey the CD4 threshold for ART initiation was 350 cells/μL. We calculated progression towards the 90–90-90 UNAIDS targets by estimating three proportions: HIV positive individuals who knew their status (first 90), those diagnosed who were on ART (second 90), and those on ART who were virally suppressed (third 90). Results We included 5649/6688 (84.5%) individuals. Median age was 26 years (IQR: 19–40), 62.3% were women. HIV prevalence was 25.2% (95% CI: 23.6–26.9): 30.9% (95% CI: 29.0–32.9) in women; 15.9% (95% CI: 14.0–18.0) in men. Overall progress towards the 90–90-90 targets was as follows: 76.4% (95% CI: 74.1–78.6) knew their status, 69.9% (95% CI: 67.0–72.7) of those who knew their status were on ART and 93.1% (95% CI: 91.0–94.8) of those on ART were virally suppressed. By sex, progress towards the 90–90-90 targets was: 79%–71%–93% among women; and 68%–68%–92% among men (p-values of women and men comparisons were

Abstract Background Accurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods. Methods Cross-sectional population-based survey in KwaZulu-Natal, South Africa. Individuals 15–59 years were eligible. Interviews included questions about ARV use. Rapid HIV testing was performed at the participants’ home. Blood specimens were collected for ARV detection, LAg-Avidity HIV incidence testing and viral load quantification in HIV-positive individuals. Multivariate logistic regression models were used to identify socio-demographic covariates associated with discordance between self-reported ART and ARV detection. Results Of the 5649 individuals surveyed, 1423 were HIV-positive. Median age was 34 years and 76.3% were women. ART coverage was estimated at 51.4% (95%CI:48.5–54.3), 53.1% (95%CI:50.2–55.9) and 56.1% (95%CI:53.5–58.8) using self-reported ART, ARV detection and both methods combined (classified as ART exposed if ARV detected and/or ART reported) respectively. ART coverage estimates using the 3 methods were fairly similar within sex and age categories except in individuals aged 15–19 years: 33.3% (95%CI:23.3–45.2), 33.8% (95%CI:23.9–45.4%) and 44.3% (95%CI:39.3–46.7) using self-reported ART, ARV detection and both methods combined. Viral suppression below 1000cp/mL in individuals on ART was estimated at 89.8% (95%CI:87.3–91.9), 93.1% (95%CI:91.0–94.8) and 88.7% (95%CI:86.2–90.7) using self-reported ART, ARV detection and both methods combined respectively. HIV incidence was estimated at 1.4 (95%CI:0.8–2.0) new cases/100 person-years when employing no measure of ARV use, 1.1/100PY (95%CI:0.6–1.7) using self-reported ART, and 1.2/100PY (95%CI:0.7–1.7) using ARV detection. In multivariate analyses, individuals aged 15–19 years had a higher risk of discordance on measures of ARV exposure (aOR:9.4; 95%CI:3.9–22.8), while migrants had a lower risk (aOR:0.3; 95%CI:0.1–0.6). Conclusions In KwaZulu-Natal, the method of identifying ARV use had little impact on estimates of ART coverage, viral suppression rate and HIV incidence. However, discordant results were more common in younger individuals. This may skew estimates of ART coverage and viral suppression, particularly in adolescent surveys.

Abstract Background Combined prevention interventions, including early antiretroviral therapy initiation, may substantially reduce HIV incidence in hyperendemic settings. Our aim was to assess the potential short-term impact of combined interventions on HIV spreading in the adult population of Mbongolwane and Eshowe (KwaZulu-Natal, South Africa) using sex- and age-specific scenarios, and age-targeted interventions. Methods A mathematical model was used with data on adults (15–59 years) from the Mbongolwane and Eshowe HIV Impact in Population Survey to compare the effects of various interventions on the HIV incidence rate. These interventions included increase in antiretroviral therapy (ART) coverage with extended eligibility criteria, increase in voluntary medical male circumcision (VMMC), and implementation of pre-exposure prophylaxis (PrEP) among women. Results With no additional interventions to the ones in place at the time of the survey (ART at CD4

BackgroundCurrent guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/μl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/μl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB.Methods and findingsWe conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/μl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/μl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/μl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results.ConclusionsLAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/μl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.

BackgroundThe prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings.Methods and findingsA cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/μl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance).ConclusionsThis risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.

Background: Determine TB-LAM is a urine-based point-of-care assay for diagnosis of tuberculosis (TB). Objective: To assess the feasibility of using LAM to diagnose TB in adult HIV-positive patients in resource-limited settings. Methods: We performed a multi-centric mixed-methods cross-sectional descriptive study in the Democratic Republic of Congo, Malawi, and Mozambique. We used the study and program monitoring tools to estimate user workload, turn-around time (TAT), and proportion of patients with LAM and sputum-based results. We conducted semi-structured interviews to assess the user acceptability of the LAM. Results: The duration of the LAM testing activity per patient was 27 min (IQR 26–29); staff continued with other duties whilst waiting for the result. More patients had a LAM versus a sputum-based result: 168/213 (78.9%) vs 77/213 (36.1%), p < 0.001 in DRC; 691/695 (99.4%) vs 429/695 (61.7%), p < 0.001 in Malawi; and 646/647 (99.8%) vs 262/647 (40.5%), p < 0.001 in Mozambique. The median TAT in minutes when LAM was performed in the consultation room was 75 (IQR 45–188) in DRC, 29 (IQR 27–39) in Malawi, and 36 (IQR 35–41) in Mozambique. In comparison, the overall median TAT for sputum-based tests (smear or GeneXpert) was 2 (IQR 1–3) days. The median time to the first anti-TB drug dose for LAM-positive patients was 155 (IQR 90–504) minutes in DRC and 90 (IQR 60–117) minutes in Mozambique. The overall inter-reader agreement for the interpretation of the LAM result as positive or negative was 98.9%, kappa 0.97 (95%CI 0.96–0.99). Overall, LAM users found the test easy to perform. Major concerns were use of the reading card and the prior requirement of CD4 results before LAM testing. Conclusion: It is feasible to implement the LAM test in low resource settings. The short TAT permitted same day initiation of TB treatment for LAM-positive patients.

Background: Despite substantial progress in antiretroviral therapy (ART) scale up, some people living with HIV (PLHIV) continue to present with advanced HIV disease, contributing to ongoing HIV-related morbidity and mortality. Objective: We aimed to quantify population-level estimates of advanced HIV from three high HIV prevalence settings in Sub-Saharan Africa. Methods: Three cross-sectional surveys were conducted in (Ndhiwa (Kenya): September–November 2012), (Chiradzulu (Malawi): February–May 2013) and (Eshowe (South Africa): July–October 2013). Eligible individuals 15–59 years old who consented were interviewed at home followed by rapid HIV test and CD4 count test if tested HIV-positive. Advanced HIV was defined as CD4 < 200 cells/µl. We used logistic regression to identify patient characteristics associated with advanced HIV. Results: Among 18,991 (39.2% male) individuals, 4113 (21.7%) tested HIV-positive; 385/3957 (9.7% (95% Confidence Interval [CI]: 8.8–10.7)) had advanced HIV, ranging from 7.8% (95%CI 6.4–9.5) Chiradzulu (Malawi) to 11.8% (95%CI 9.8–14.2) Ndhiwa (Kenya). The proportion of PLHIV with advanced disease was higher among men 15.3% (95% CI 13.2–17.5) than women 7.5% (95%CI 6.6–8.6) p < 0.001. Overall, 62.7% of all individuals with advanced HIV were aware of their HIV status and 40.3% were currently on ART. Overall, 65.6% of individuals not on ART had not previously been diagnosed with HIV, while only 29.6% of those on ART had been on ART for ≥6 months. Individuals with advanced HIV disease were more likely to be men (adjusted Odds Ratio [aOR]; 2.1 (95%CI 1.7–2.6), and more likely not to be on ART (aOR; 1.7 (95%CI 1.3–2.1). Conclusion: In our study, about 1 in 10 PLHIV had advanced HIV with nearly 40% of them unaware of their HIV status. However, a substantial proportion of patients with advanced HIV were established on ART. Our findings suggest the need for a dual focus on alternative testing strategies to identify PLHIV earlier as well as improving ART retention.

INTRODUCTION:There is a notable absence of consensus on how to generate estimates of population-level incidence. Incidence is a considerably more sensitive indicator of epidemiological trends than prevalence, but is harder to estimate. We used a novel hybrid method to estimate HIV incidence by age and sex in a rural district of KwaZulu-Natal, South Africa. METHODS:Our novel method uses an 'optimal weighting' of estimates based on an implementation of a particular 'synthetic cohort' approach (interpreting the age/time structure of prevalence, in conjunction with estimates of excess mortality) and biomarkers of 'recent infection' (combining Lag-Avidity, Bio-Rad Avidity and viral load results to define recent infection, and adapting the method for age-specific incidence estimation). Data were obtained from a population-based cross-sectional HIV survey conducted in Mbongolwane and Eshowe health service areas in 2013. RESULTS:Using the combined method, we find that age-specific HIV incidence in females rose rapidly during adolescence, from 1.33 cases/100 person-years (95% CI: 0.98,1.67) at age 15 to a peak of 5.01/100PY (4.14,5.87) at age 23. In males, incidence was lower, 0.34/100PY (0.00-0.74) at age 15, and rose later, peaking at 3.86/100PY (2.52-5.20) at age 30. Susceptible population-weighted average incidence in females aged 15-29 was estimated at 3.84/100PY (3.36-4.40), in males aged 15-29 at 1.28/100PY (0.68-1.50) and in all individuals aged 15-29 at 2.55/100PY (2.09-2.76). Using the conventional recency biomarker approach, we estimated HIV incidence among females aged 15-29 at 2.99/100PY (1.79-4.36), among males aged 15-29 at 0.87/100PY (0.22-1.60) and among all individuals aged 15-59 at 1.66/100PY (1.13-2.27). DISCUSSION:HIV incidence was very high in women aged 15-30, peaking in the early 20s. Men had lower incidence, which peaked at age 30. The estimates obtained from the hybrid method are more informative than those produced by conventional analysis of biomarker data, and represents a more optimal use of available data than either the age-continuous biomarker or synthetic cohort methods alone. The method is mainly useful at younger ages, where excess mortality is low and uncertainty in the synthetic cohort estimates is reasonably small. CONCLUSION:Application of this method to large-scale population-based HIV prevalence surveys is likely to result in improved incidence surveillance over methods currently in wide use. Reasonably accurate and precise age-specific estimates of incidence are important to target better prevention, diagnosis and care strategies.

BACKGROUND:Latest WHO guidelines recommend starting HIV-positive individuals on antiretroviral therapy treatment (ART) regardless of CD4 count. We assessed additional impact of adopting new WHO guidelines. METHODS:We used data of individuals aged 15-59 years from three HIV population surveys conducted in 2012 (Kenya) and 2013 (Malawi and South Africa). Individuals were interviewed at home followed by rapid HIV and CD4 testing if tested HIV-positive. HIV-positive individuals were classified as "eligible for ART" if (i) had ever been initiated on ART or (ii) were not yet on ART but met the criteria for starting ART based on country's guidelines at the time of the survey (Kenya-CD4< = 350 cells/μl and WHO Stage 3 or 4 disease, Malawi as for Kenya plus lifelong ART for all pregnant and breastfeeding women, South Africa as for Kenya plus ART for pregnant and breastfeeding women until cessation of breastfeeding). FINDINGS:Of 18,991 individuals who tested, 4,113 (21.7%) were HIV-positive. Using country's ART eligibility guidelines at the time of the survey, the proportion of HIV-infected individuals eligible for ART was 60.0% (95% CI: 57.2-62.7) (Kenya), 73.4% (70.8-75.8) (South Africa) and 80.1% (77.3-82.6) (Malawi). Applying WHO 2013 guidelines (eligibility at CD4< = 500 and Option B+ for pregnant and breastfeeding women), the proportions eligible were 82.0% (79.8-84.1) (Kenya), 83.7% (81.5-85.6) (South Africa) and 87.6% (85.0-89.8) (Malawi). Adopting "test and treat" would mean a further 18.0% HIV-positive individuals (Kenya), 16.3% (South Africa) and 12.4% (Malawi) would become eligible. In all countries, about 20% of adolescents (aged 15-19 years), became eligible for ART moving from WHO 2013 to "test and treat" while no differences by sex were observed. CONCLUSION:Countries that have already implemented 2013 WHO recommendations, the burden of implementing "test and treat" would be small. Youth friendly programmes to help adolescents access and adhere to treatment will be needed.

Determine-TB LAM assay is a urine point-of-care test useful for TB diagnosis in HIV-positive patients. We assessed the incremental diagnostic yield of adding LAM to algorithms based on clinical signs, sputum smear-microscopy, chest X-ray and Xpert MTB/RIF in HIV-positive patients with symptoms of pulmonary TB (PTB).Prospective observational cohort of ambulatory (either severely ill or CD4

Despite high reported coverage for routine and supplementary immunization, in 2010 in Malawi, a large measles outbreak occurred that comprised 134,000 cases and 304 deaths. Although the highest attack rates were for young children (2.3%, 7.6%, and 4.5% for children 15 years of age were highly affected (1.0% and 0.4% for persons 15–19 and >19 years, respectively; 28% of all cases). A survey in 8 districts showed routine coverage of 95.0% for children 12–23 months; 57.9% for children 9–11 months; and 60.7% for children covered during the last supplementary immunization activities in 2008. Vaccine effectiveness was 83.9% for 1 dose and 90.5% for 2 doses. A continuous accumulation of susceptible persons during the past decade probably accounts for this outbreak. Countries en route to measles elimination, such as Malawi, should improve outbreak preparedness. Timeliness and the population chosen are crucial elements for reactive campaigns.

BACKGROUND: The 2007 WHO algorithm for diagnosis of smear-negative pulmonary tuberculosis (PTB) including Mycobacterium tuberculosis (MTB) culture was evaluated in a HIV prevalent area of Kenya. METHODS: PTB smear-negative adult suspects were included in a prospective diagnostic study (2009-2011). In addition, program data (2008-2009) were retrospectively analysed. At the first consultation, clinical examination, chest X-ray, and sputum culture (Thin-Layer-Agar and Lowenstein-Jensen) were performed. Patients not started on TB treatment were clinically re-assessed after antibiotic course. The algorithm performance was calculated using culture as reference standard. RESULTS: 380 patients were included prospectively and 406 analyzed retrospectively. Culture was positive for MTB in 17.5% (61/348) and 21.8% (72/330) of cases. Sensitivity of the clinical-radiological algorithm was 55.0% and 31.9% in the prospective study and the program data analysis, respectively. Specificity, positive and negative predictive values were 72.9%, 29.7% and 88.6% in the prospective study and 79.8%, 30.7% and 80.8% in the program data analysis. Performing culture increased the number of confirmed TB patients started on treatment by 43.3% in the prospective study and by 44.4% in the program data analysis. Median time to treatment of confirmed TB patients was 6 days in the prospective study and 27 days in the retrospective study. Inter-reader agreement for X-ray interpretation between the study clinician and a radiologist was low (Kappa coefficient = 0.11, 95%CI: 0.09-0.12). In a multivariate logistic analysis, past TB history, number of symptoms and signs at the clinical exam were independently associated with risk of overtreatment. CONCLUSION: The clinical-radiological algorithm is suboptimal to diagnose smear-negative PTB. Culture increases significantly the proportion of confirmed TB cases started on treatment. Better access to rapid MTB culture and development of new diagnostic tests is necessary.

BACKGROUND: Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Médecins sans Frontières introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools. METHODS: We conducted a cross-sectional survey amongst a series of new TB patients receiving 6 months of standard TB chemotherapy with FDC under SAT. Adherence was assessed at home with urine testing for Isoniazid (INH), pill count, interviewer-administered questionnaire and visual analogue scale (VAS). RESULTS: In November 2008 and in June 2009, 212 of 279 eligible patients were assessed for adherence. Overall, 95.2% [95%CI: 91.3-97.7] of the patients reported not having missed a tablet in the last 4 days. On the VAS, complete adherence was estimated at 92.5% [95%CI: 88.0-95.6]. INH urine test was positive for 97.6% [95%CI: 94.6-99.2] of the patients. Pill count could be assessed among only 70% of the interviewed patients. Among them, it was complete for 82.3% [95%CI: 75.1-88.1]. Among the 212 surveyed patients, 193 (91.0%) were successfully treated (cured or treatment completed). The data suggest a fair agreement between the questionnaire and the INH urine test (k = 0.43) and between the questionnaire and the VAS (k = 0.40). Agreement was poor between the other adherence tools. CONCLUSION: These results suggest that SAT, together with the FDC, allows achieving appropriate adherence to antituberculosis treatment in a high TB and HIV burden area. The use of a combination of a VAS and a questionnaire can be an adequate approach to monitor adherence to TB treatment in routine program conditions.