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Supplemental Digital Content is Available in the Text., Background: The lack of acute and early HIV infection (AEHI) diagnosis and care contributes to high HIV incidence in resource-limited settings. We aimed to assess the yield of AEHI, predict and diagnose AEHI, and describe AEHI care outcomes in a public sector setting in Eswatini. Setting: This study was conducted in Nhlangano outpatient department from March 2019 to March 2020. Methods: Adults at risk of AEHI underwent diagnostic testing for AEHI with the quantitative Xpert HIV-1 viral load (VL) assay. AEHI was defined as the detection of HIV-1 VL on Xpert and either an HIV-seronegative or HIV-serodiscordant third-generation antibody-based rapid diagnostic test (RDT) result. First, the cross-sectional analysis obtained the yield of AEHI and established a predictor risk score for the prediction of AEHI using Lasso logistic regression. Second, diagnostic accuracy statistics described the ability of the fourth-generation antibody/p24 antigen–based Alere HIV-Combo RDT to diagnose AEHI (vs Xpert VL testing). Third, we described acute HIV infection care outcomes of AEHI-positive patients using survival analysis. Results: Of 795 HIV-seronegative/HIV-serodiscordant outpatients recruited, 30 (3.8%, 95% confidence interval: 2.6% to 5.3%) had AEHI. The predictor risk score contained several factors (HIV-serodiscordant RDT, women, feeling at risk of HIV, swollen glands, and fatigue) and had sensitivity and specificity of 83.3% and 65.8%, respectively, to predict AEHI. The HIV-Combo RDT had sensitivity and specificity of 86.2% and 99.9%, respectively, to diagnose AEHI. Of 30 AEHI-positive patients, the 1-month cumulative treatment initiation was 74% (95% confidence interval: 57% to 88%), and the 3-month viral suppression (

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015–2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Point-of-care urine-lipoarabinomannan (LAM) Alere Determine TB-LAM assay has shown utility diagnosing tuberculosis (TB) in HIV-positive, severely immunocompromised, TB-symptomatic patients. We assessed LAM results in severely immunocompromised patients, who had LAM systematically performed at new or follow-up HIV consultations. This was a prospective, observational study on consecutive ambulatory, > 15-year-old HIV-positive patients with CD4 < 100 cells/µL in Mozambique. Clinical assessments and LAM were performed for all and microscopy, Xpert, sputum culture, and chest X-ray for LAM-positive participants. Patients were followed up for 6 months. Of 360 patients, half were ART-naive. Lipoarabinomannan positivity was 11.9% (43/360), higher among symptomatic patients compared with asymptomatic: 18.5% (30/162), and 6.6% (13/198), respectively, P = 0.001. Tuberculosis was bacteriologically confirmed in 6/35 LAM-positive patients (2 of them asymptomatic). Lipoarabinomannan positivity was associated with higher risk of mortality (adjusted odds ratio [aOR]: 4.6, 95% CI: 1.3–15.6, P = 0.015). Systematic urine-LAM allows for rapid TB treatment initiation in severely immunocompromised HIV ambulatory patients and identifies patients at a higher risk of death.

Provision of drug-resistant tuberculosis (DR-TB) treatment is scarce in resource-limited settings. We assessed the feasibility of ambulatory DR-TB care for treatment expansion in rural Eswatini.Retrospective patient-level data were used to evaluate ambulatory DR-TB treatment provision in rural Shiselweni (Eswatini), from 2008 to 2016. DR-TB care was either clinic-based led by nurses or community-based at the patient's home with involvement of community treatment supporters for provision of treatment to patients with difficulties in accessing facilities. We describe programmatic outcomes and used multivariate flexible parametric survival models to assess time to adverse outcomes. Both care models were costed in supplementary analyses.Of 698 patients initiated on DR-TB treatment, 57% were women and 84% were HIV-positive. Treatment initiations increased from 27 in 2008 to 127 in 2011 and decreased thereafter to 51 in 2016. Proportionally, community-based care increased from 19% in 2009 to 77% in 2016. Treatment success was higher for community-based care (79%) than clinic-based care (68%, P = 0.002). After adjustment for covariate factors among adults (n = 552), the risk of adverse outcomes (death, loss to follow-up, treatment failure) in community-based care was reduced by 41% (adjusted hazard ratio 0.59, 95% CI: 0.39-0.91). Findings were supported by sensitivity analyses. The care provider's per-patient costs for community-based (USD13 345) and clinic-based (USD12 990) care were similar.Ambulatory treatment outcomes were good, and community-based care achieved better treatment outcomes than clinic-based care at comparable costs. Contextualised DR-TB care programmes are feasible and can support treatment expansion in rural settings.La fourniture de traitement de la tuberculose résistante aux médicaments (TB-R) est rare dans les pays à ressources limitées. Nous avons évalué la faisabilité des soins ambulatoires de la TB-R pour l'extension du traitement en zone rurale d'Eswatini. MÉTHODES: Des données rétrospectives au niveau du patient ont été utilisées pour évaluer la fourniture d'un traitement ambulatoire de la TB-R dans la zone rurale de Shiselweni (Eswatini), de 2008 à 2016. Les soins pour la TB-R étaient dispensés soit en clinique sous la direction d'infirmiers ou en milieu communautaire au domicile du patient avec l'implication des aidants au traitement pour la fourniture d'un traitement aux patients ayant des difficultés à accéder aux établissements. Nous décrivons ici les résultats programmatiques et avons utilisé des modèles de survie paramétriques flexibles multivariés pour évaluer le délai d'apparition de résultats défavorables. Les deux modèles de soins ont été chiffrés dans des analyses supplémentaires. RÉSULTATS: Sur 698 patients initiés sous traitement de la TB-R, 57% étaient des femmes et 84% étaient VIH positifs. Les initiations aux traitements sont passées de 27 en 2008 à 127 en 2011 et ont ensuite diminué à 51 en 2016. Proportionnellement, les soins communautaires ont augmenté de 19% en 2009 à 77% en 2016. Le taux de réussite du traitement était supérieur pour les soins communautaires (79%) que pour ceux dispensés en clinique (68%, P = 0,002). Après ajustement pour les facteurs de covariable chez les adultes (n = 552), le risque de résultats indésirables (décès, perte au suivi, échec du traitement) dans les soins communautaires a été réduit de 41% (rapport de risque ajusté de 0,59, IC95%: 0,39-0,91). Les résultats ont été étayés par des analyses de sensibilité. Les coûts par patient sur base du prestataire de soins pour les soins communautaires (13.345 USD) et en clinique (12.990 USD) étaient similaires.Les résultats des traitements ambulatoires ont été bons et les soins dispensés dans la communauté ont obtenu de meilleurs résultats que ceux dispensés en clinique à des coûts comparables. Des programmes de prise en charge contextualisés de la TB-R sont réalisables et peuvent soutenir l'expansion du traitement en milieu rural.

This paper assesses patient- and population-level trends in TB notifications during rapid expansion of antiretroviral therapy in Eswatini which has an extremely high incidence of both TB and HIV.Patient- and population-level predictors and rates of HIV-associated TB were examined in the Shiselweni region in Eswatini from 2009 to 2016. Annual population-level denominators obtained from projected census data and prevalence estimates obtained from population-based surveys were combined with individual-level TB treatment data. Patient- and population-level predictors of HIV-associated TB were assessed with multivariate logistic and multivariate negative binomial regression models.Of 11 328 TB cases, 71.4% were HIV co-infected and 51.8% were women. TB notifications decreased fivefold between 2009 and 2016, from 1341 to 269 cases per 100 000 person-years. The decline was sixfold in PLHIV vs. threefold in the HIV-negative population. Main patient-level predictors of HIV-associated TB were recurrent TB treatment (adjusted odds ratio [aOR] 1.40, 95% confidence interval [CI]: 1.19-1.65), negative (aOR 1.31, 1.15-1.49) and missing (aOR 1.30, 1.11-1.53) bacteriological status and diagnosis at secondary healthcare level (aOR 1.18, 1.06-1.33). Compared with 2009, the probability of TB decreased for all years from 2011 (aOR 0.69, 0.58-0.83) to 2016 (aOR 0.54, 0.43-0.69). The most pronounced population-level predictor of TB was HIV-positive status (adjusted incidence risk ratio 19.47, 14.89-25.46).This high HIV-TB prevalence setting experienced a rapid decline in TB notifications, most pronounced in PLHIV. Achievements in HIV-TB programming were likely contributing factors.Ce document évalue les tendances des notifications de la tuberculose (TB) à l’échelle des patients et de la population lors de l'expansion rapide du traitement antirétroviral à Eswatini, où l'incidence de la TB et du VIH est extrêmement élevée. MÉTHODES: Les prédicteurs et les taux de TB associée au VIH à l’échelle des patients et de la population ont été examinés dans la région de Shiselweni à Eswatini de 2009 à 2016. Les dénominateurs annuels à l’échelle de la population obtenus à partir des données de recensement projetées et des estimations de la prévalence obtenues à partir d'enquêtes de population ont été combinés avec des données de traitement de la TB à l’échelle individuel. Les prédicteurs de la TB associée au VIH à l’échelle du patient et de la population ont été évalués à l'aide de modèles de régression logistique multivariée et binomiale négative multivariée. RÉSULTATS: Sur 11.328 cas de TB, 71,4% étaient coinfectés par le VIH et 51,8% étaient des femmes. Les notifications de TB ont été réduites de 5,0 fois entre 2009 et 2016, passant de 1.341 à 269 cas par 100.000 personnes-années. Le déclin était de 6,0 fois chez les PVVIH contre 3,0 fois dans la population négative pour le VIH. Les principaux prédicteurs de la TB associée au VIH à l’échelle des patients étaient les traitements antituberculeux récurrents (rapport de cotes ajusté [aOR] 1,40; intervalle de confiance à 95% [IC]: 1,19 à 1,65), un statut bactériologique négatif (aOR: 1,31; 1,15 à 1,49) et manquant (aOR: 1,30; 1,11 à 1,53) et le diagnostic au niveau des soins de santé secondaires (AOR 1,18; 1,06 à 1,33). Par rapport à 2009, la probabilité de contracter la TB a diminué pour toutes les années, de 2011 (aOR: 0,69; 0,58 à 0,83) à 2016 (aOR: 0,5; 0,43 à 0,69). Le prédicteur le plus prononcé de la TB à l’échelle de la population était le statut VIH-positif (rapport de risque d'incidence ajusté: 19,47; 14,89 à 25,46).Ce contexte de prévalence élevée de la TB-VIH a connu un déclin rapide du nombre de notifications de TB, plus prononcé chez les PVVIH. Les réalisations dans la programmation VIH-TB étaient probablement des facteurs contributifs.

BackgroundKaposi’s sarcoma (KS) is a common HIV-associated malignancy frequently associated with poor outcomes. It is the most frequently diagnosed cancer in major cities of Mozambique. Antiretroviral therapy is the cornerstone of KS treatment, but many patients require cytotoxic chemotherapy. The traditional regimen in Mozambique includes conventional doxorubicin, bleomycin and vincristine, which is poorly tolerated. In 2016, pegylated liposomal doxorubicin was introduced at a specialized outpatient center in Maputo, Mozambique.MethodsWe performed a prospective, single-arm, open-label observational study to demonstrate the feasibility, safety, and outcomes of treatment with pegylated liposomal doxorubicin (PLD) in patients with AIDS-associated Kaposi sarcoma (KS) in a low-resource setting. Chemotherapy-naïve adults with AIDS-associated KS (T1 or T0 not responding to 6 months of antiretroviral therapy) were eligible if they were willing to follow up for 2 years. Patients with Karnofsky scores ResultsAt 24 months, 23 participants (20%) had died and 15 (13%) were lost to follow-up. Baseline CD4 p = 0.016), as was T1S1 disease compared to T1S0 disease (HR 2.7, 95%CI [1.1–6.4],p = 0.023). Ninety-two participants achieved complete or partial remission at any point (overall response rate 80%), including 15 (13%) who achieved complete remission. PLD was well-tolerated, and the most common AEs were neutropenia and anemia. Quality of life improved rapidly after beginning PLD.DiscussionPLD was safe, well-tolerated and effective as first-line treatment of KS in Mozambique. High mortality was likely due to advanced immunosuppression at presentation, underscoring the importance of earlier screening and referral for KS.

To assess long-term antiretroviral therapy (ART) outcomes during rapid HIV programme expansion in the public sector of Eswatini (formerly Swaziland).This is a retrospectively established cohort of HIV-positive adults (≥16 years) who started first-line ART in 25 health facilities in Shiselweni (Eswatini) between 01/2006 and 12/2014. Temporal trends in ART attrition, treatment expansion and ART coverage were described over 9 years. We used flexible parametric survival models to assess the relationship between time to ART attrition and covariates.Of 24 772 ART initiations, 6% (n = 1488) occurred in 2006, vs. 13% (n = 3192) in 2014. Between these years, median CD4 cell count at ART initiation increased (113-265 cells/mmProgrammatic outcomes improved during large expansion of the treatment cohort and increased ART coverage. Changes in ART programming may have contributed to better outcomes.Evaluer les résultats du traitement antirétroviral (ART) à long terme durant l'expansion rapide du programme de lutte contre le VIH dans le secteur public d'Eswatini (anciennement Swaziland). MÉTHODES: Il s'agit d'une cohorte établie de manière rétrospective d'adultes VIH positifs (≥ 16 ans) qui ont commencé un ART de première ligne dans 25 établissements de santé à Shiselweni (Eswatini) entre janvier 2006 et décembre 2014. Les tendances temporelles de l'attrition dans l’ART, de l'extension de la couverture ART ont été décrites sur 9 ans. Nous avons utilisé des modèles de survie paramétriques flexibles pour évaluer la relation entre le temps écoulé avant l'attrition dans l’ART et les covariables. RÉSULTATS: Sur 24.772 initiations à l’ART, 6% (n = 1.488) ont eu lieu en 2006 contre 13% (n = 3.192) en 2014. Entre ces années, le nombre médian de cellules CD4 au début du traitement ART a augmenté (113 à 265 cellules/mmLes résultats programmatiques se sont améliorés au cours de l'expansion importante de la cohorte de traitement et de l'augmentation de la couverture ART. Les changements apportés au programme ART peuvent avoir contribué à de meilleurs résultats.

INTRODUCTION: Identification of good prognostic marker for tuberculosis (TB) treatment response is a necessary step on the path towards a surrogate marker to reduce TB trial duration.METHODS: We performed a retrospective analysis on routinely collected data in 6 drug-resistant TB (DRTB) programs. Culture conversion, defined as two consecutive negative cultures, was assessed, and performance of culture conversion at Month 2 and Month 6 to predict treatment success were explored. To explore factors associated with positive predicted value (PPV) and the specificity of culture conversion, a multinomial logistic regression was fitted.RESULTS: This study included 634 patients: 68.5% were males; the median age was 35 years, 75.2% were previously treated for TB, 59.4% were resistant only to isoniazid and rifampicin and 18.1% resistant to fluoroquinolones. Culture conversion at Month 2 and 6 showed similar PPV while specificity was much higher for culture conversion at Month 2: 91.3% (95%CI 86.1–95.1). PPV of culture conversion at Month 2 did not vary strongly according to patients' characteristics, while specificity was slightly higher among patients with fluoroquinolone-resistant strains.CONCLUSION: Culture conversion at Month 2 is an acceptable prognostic marker for MDR-TB treatment. Considering the advantage of using an earlier marker, further evaluation as a surrogate marker is warranted to shorten TB trials.

Background Current 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 findings We 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. Conclusions LAM 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., Helena Huerga and colleagues assess a urine-based lipoarabinomannan assay for diagnosing tuberculosis in immunocompromised patients with HIV., Author summary Why was this study done? Tuberculosis (TB) is the leading cause of death in HIV-positive patients, but it remains difficult to diagnose. The availability of diagnostic tests is limited, and most require sputum samples, which are difficult to obtain from very sick patients. The lipoarabinomannan assay (LAM) is a urine-based point-of-care test that has shown utility in immunosuppressed HIV-positive patients. However, this test is not widely used. Current international guidelines recommend the use of the LAM test only in extremely immunocompromised HIV-positive, ambulatory patients. However, we hypothesized that the test could also be useful to diagnose TB in a broader group including less severely immunocompromised ambulatory patients. What did the researchers do and find? We conducted a prospective observational study in 6 health facilities in Malawi and Mozambique, enrolling HIV-positive, ambulatory patients with symptoms of TB. The clinicians conducted a clinical exam, requested diagnostic tests for TB (LAM in urine, microscopy, Xpert MTB/RIF assay [Xpert], culture in sputum, and chest radiography) at the first consultation, and followed the patients at subsequent visits over a 6-month period. Of the 456 enrolled patients, 205 (45%) had TB; of these, LAM was positive in 82.4% (169/205), microscopy in 33.7% (69/205), and Xpert in 40.0% (84/205). Using LAM in addition to the other available diagnostic tools increased the proportion of patients diagnosed with TB by 38.0% compared to a diagnostic algorithm including clinical exam, chest X-ray, and microscopy, and by 34.6% compared to an algorithm including clinical exam, chest X-ray, and Xpert. A similar increase was observed for less severely immunocompromised patients. What do these findings mean? The use of the urine-based LAM test can increase the proportion of immunocompromised HIV-positive patients diagnosed with TB, including patients who are less severely immunocompromised. LAM is useful in a broader population than what it is currently recommended for, and can be expanded for use in patients who are less severely immunocompromised.

BACKGROUND: The World Health Organization recommends adding bedaquiline or delamanid to multi drug-resistant tuberculosis (MDR-TB) regimens for which four effective drugs are not available, and delamanid for patients at high risk of poor outcome. OBJECTIVE: To identify patients at risk of unfavourable outcomes who may benefit from the new drugs. METHODS: Retrospective cohort study of treatment outcomes involving four to five effective drugs for 1524 months in programmes in Uzbekistan, Georgia, Armenia, Swaziland and Kenya between 2001 and 2011. RESULTS: Of 1433 patients, 48.5% had body mass index (BMI)

Background The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. Methods We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. Results Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. Conclusions As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.