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COVID-19 vaccine became available in Tanzania during the first wave of the Omicron variant. During that time community seroprevalence of SARS-CoV-2 was already at 50%-80%. To date, it remains largely unknown whether ongoing vaccination with the primary series vaccines has any meaningful immune-boosting effects against newer Omicron subvariants. Therefore, we tested cross-neutralizing capacity of antibodies elicited by infection, vaccination, or both against SARS-CoV-2 Omicron subvariants BA.1, and the newer subvariants BQ.1.1 and XBB.1.5. that were unexperienced by this population. Participants who were either SARS-CoV-2 infected-only (n = 28), infected vaccinated (n = 22), or vaccinated-only (n = 73) were recruited from Dar-es-Salaam, Tanzania, between April and December 2022. Plasma 50% neutralization titers (NT 50 ) against SARS-CoV-2 wild-type strain and Omicron subvariants were quantified by a lentiviral-based pseudo-virus assay. Percentage of participants with neutralizing activity against WT and BA.1 was high (>85%) but was reduced against BQ.1.1 (64%-77%) and XBB.1.5 (35%-68%) subvariants. The low median cross-neutralization titer was slightly higher in the infected vaccinated group compared to vaccine-only group against BQ.1.1 (NT 50 148 vs. 85, p = 0.032) and XBB.1.5 (NT 50 85 vs. 37 p = 0.022) subvariants. In contrast, vaccine-boost among the infected vaccinated did not result to increased cross-neutralization compared to infected-only participants (BQ.1.1 [NT 50 of 148 vs. 100, p = 0.501] and XBB.1.5 [NT 50 86 vs. 45, p = 0.474]). We report severely attenuated neutralization titers against BQ.1.1 and XBB.1.5 subvariants among vaccinated participants, which marginally improved in the infected vaccinated participants. Our findings call for further studies to evaluate effectiveness of the primary series vaccines in preventing severe infection and mortality against the newer variants., (© 2024 Wiley Periodicals LLC.)

Objective: To describe rates of retention in care and control of hypertension, diabetes and HIV among participants receiving integrated care services for a period of up to 24 months in East Africa., Methods: Between 5 October 2018 and 23 June 2019 participants enrolled into a prospective cohort study evaluating the feasibility of integrated care delivery for HIV, diabetes and hypertension from a single point of care in Tanzania and Uganda (MOCCA study). Integrated care clinics were established in 10 primary healthcare facilities and care was provided routinely according to national guidelines. Initial follow-up was 12 months. Outcomes were rates of retention in care, proportions of participants with controlled hypertension (blood pressure <140/90 mmHg), diabetes (fasting blood glucose <7.0 mmol/L) and HIV (plasma viral load <1000 copies/ml). The study coincided with the COVID-19 pandemic response. Afterwards, all participants were approached for extended follow-up by a further 12 months in the same clinics. We evaluated outcomes of the cohort at the end of long-term follow-up., Results: The MOCCA study enrolled 2273 participants of whom 1911 (84.5%) were retained in care after a median follow-up of 8 months (Interquartile range: 6.8-10.7). Among these, 1283/1911 (67.1%) enrolled for a further year of follow-up, 458 (24.0%) were unreachable, 71 (3.7%) reverted to vertical clinics (clinics providing services dedicated to study conditions), 31 (1.6%) died and 68 (3.6%) refused participation. Among participants who enrolled for longer follow-up, mean age was 51.4 ± 11.7 years, 930 (72.5%) were female and 509 (39.7%) had multiple chronic conditions. Overall, 1236 (96.3%) [95% confidence interval 95.2%-97.3%] participants were retained in care, representing 1236/2273 (54.3%) [52.3%-56.4%] of participants ever enrolled in the study. Controlled hypertension, diabetes and HIV at the end of follow-up was, 331/618 (53.6%) [49.5%-57.5%], 112/354 (31.6%) [26.8%-36.8%] and 332/343 (96.7%) [94.3%-98.4%] respectively., Conclusion: Integrated care can achieve high rates of retention in care long term, but control of blood pressure and blood sugar remains low., (© 2024 The Authors Tropical Medicine & International Health published by John Wiley & Sons Ltd.)

Background: HIV services in Tanzania are facility-based but facilities are often overcrowded. Differentiated care models (DCM) have been introduced into the National Guidelines. We piloted a Community Health Worker (CHW)-led HIV treatment club model (CHW-DCM) in an urban region, and assessed its effectiveness in comparison to the standard of care (SoC, facility-based model), in terms of stability in care, loss to follow-up (LTFU) and treatment adherence., Methods: In two clinics in the Shinyanga region, clients established on ART (defined as stable clients by national guidelines as on first-line ART >6 months, undetectable viral load, no opportunistic infections or pregnancy, and good adherence) were offered CHW-DCM. This prospective cohort study included all stable clients who enrolled in CHW-DCM between July 2018 and March 2020 (CHW-DCM) and compared them to stable clients who remained in SoC during that period. Multivariable Cox regression models were used to analyse factors associated with continued stability in care and the risk of LTFU during 18 months of follow-up; treatment adherence was assessed by pill count and compared using Chi-square tests., Results: Of 2472 stable clients, 24.5% received CHW-DCM and 75.5% SoC. CHW-DCM clients were slightly older (mean 42.8 vs. 37.9 years) and more likely to be female (36.2% vs. 32.2%). Treatment adherence was better among CHW-DCM than SoC: 96.6% versus 91.9% and 98.5% versus 92.2%, respectively (both p = 0.001). SoC clients were more likely to not remain stable over time than CHW-DCM (adjusted Hazard ratio [AHR] = 2.68; 95% CI: 1.86-3.90). There was no difference in LTFU (adjusted hazard ratio [AHR] = 1.54; 95%CI: 0.82-2.93)., Conclusion: Clients attending CHW-DCM demonstrated better stability in care and treatment adherence than SoC, and the risk of LTFU was not increased. These findings demonstrate the potential of CHW in delivering community-based HIV services in the local Tanzanian context. These results could be used to extend this CHW-DCM model to similar settings., (© 2024 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Hypertension and diabetes are chronic conditions that cause major morbidity and mortality worldwide. Whether health insurance financing is associated with improved retention in chronic care in Tanzania, is unknown. Our study establishes the effect of health insurance on retention and the determinants for retention in care among patients attending diabetes and hypertension clinics. We used a Cohort design to study participants enrolled in a cluster-randomized trial of integrated management of HIV, diabetes, and hypertension compared with standard vertical care in the INTE-AFRICA trial. Fifteen health facilities in Dar es Salam and Pwani regions were enrolled, with 1716 participants. Our sample size had 95% power to detect a 50% to 60% retention difference between the insured and uninsured groups (95% CI). We compared proportions using χ2 tests and obtained prevalence and rate ratios by Generalised Linear Models. We studied 1716 participants for 1612.3 Person-years (PY). At the study's end, 1351 persons were alive and retained in care. Among the insured participants (26.0%), females accounted for 65.9%. Middle-aged adults contributed 58.8% of insured participants. We observed high retention rates (retention incidence rate IR: 83.80/100 PY; 95% CI (79.40-88.40)). There was no difference in retention among insured and uninsured patients (adjusted rate ratio aRR: 1.00; 95% CI, 0.94-1.06). Being middle-aged or senior-aged adults compared to young adults, having diabetes alone or hypertension alone compared to both conditions, having the comorbidity of diabetes or hypertension with HIV compared to a single condition, and attending health centres and hospitals compared to dispensaries were significantly associated with retention in care. This study showed no effect of health insurance on retention in diabetic and hypertension care clinics. However, age, medical diagnosis, morbidity, and type of health facility attended were associated with retention in care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Manisha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions., Competing Interests: TSo declares a receipt of funding from the Global Fund for conducting the TB prevalence survey in Mongolia. All other authors declare no competing interests., (Copyright: © 2024 Hamada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) demonstrate good diagnostic accuracy in distinguishing lung cancer patients from healthy individuals, primarily in HIV-negative populations. We determined the sensitivity (Se), specificity (Sp), and area under the curve (AUC) of the NLR and PLR in discriminating between people living with HIV (PLWH) with and without lung cancer., Methods: This is a comparative analysis of secondary data. Cases were PLWH with lung cancer from a retrospective cohort treated at the Uganda Cancer Institute. Controls were unmatched PLWH without lung cancer who were randomly selected from three HIV clinics in Uganda. Se, Sp, and AUC analysis and determination of optimal cutoffs were performed using receiver operating characteristic (ROC) curves., Results: Of 115 PLWH (18 cases and 97 controls), 83 (72.2%) were female, 110 (95.7) were on ART, and the median (IQR) age was 46 (38-51) years. The median (IQR) NLR was higher among cases than controls (3.53 (3.14-7.71) vs. 0.92 (0.67-1.09), p   < 0.001). Similarly, the PLR was higher among cases than controls (237.5 (177.8-361.6) vs. 123.6 (100.6-155.4), p =0.001). At a cutoff of 2.44, the respective Se, Sp, and AUC of the NLR were 87.5% (95% CI: 61.7%-98.4%), 100% (95% CI: 96.2%-100%), and 0.94 (95% CI: 0.85-1.00, p   < 0.001). Similarly, the respective Se, Sp, and AUC for the PLR were 75% (95% CI: 47.6%-92.7%), 87.2% (95% CI: 78.8%-93.2%), and 0.81 (95% CI: 0.70-0.93, p   < 0.001) at a cutoff of 196.3., Conclusion: The NLR and PLR discriminated PLWH with and without lung cancer and could be useful in PLWH with respiratory symptoms in whom lung cancer can easily be misdiagnosed as other lung pathology., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Joseph Baruch Baluku et al.)

Background: Tanzania is 1 of 20 countries where the majority of unvaccinated and undervaccinated children reside. Prior research identified substantial rural-urban disparities in the coverage and timeliness of childhood vaccinations in Tanzania, with children in rural settings being more likely to receive delayed or no vaccinations. Further research is necessary to identify effective and scalable interventions that can bridge rural-urban gaps in childhood vaccination while accounting for multifaceted barriers to vaccination., Objective: This protocol describes a type 1 effectiveness-implementation hybrid study to evaluate Chanjo Kwa Wakati (timely vaccination in Kiswahili), a community-based digital health intervention to improve vaccination timeliness. The intervention combines human resources (community health workers), low-cost digital strategies (electronic communication, digital case management, and task automation), a vaccination knowledge intervention, and insights from behavioral economics (reminders and incentives) to promote timely childhood vaccinations., Methods: The study will be conducted in 2 predominantly rural regions in Tanzania with large numbers of unvaccinated or undervaccinated children: Shinyanga and Mwanza. Forty rural health facilities and their catchment areas (clusters) will be randomized to an early or delayed onset study arm. From each cluster, 3 cohorts of mother-child dyads (1 retrospective cohort and 2 prospective cohorts) will be enrolled in the study. The timeliness and coverage of all vaccinations recommended during the first year of life will be observed for 1200 children (n=600, 50% intervention group children and n=600, 50% nonintervention group children). The primary effectiveness outcome will be the timeliness of the third dose of the pentavalent vaccine (Penta3). Quantitative surveys, vaccination records, study logs, fidelity checklists, and qualitative interviews with mothers and key informants will inform the 5 constructs of the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework. The results will be used to develop an implementation blueprint to guide future adaptations and scale-up of Chanjo Kwa Wakati., Results: The study was funded in August 2022. Data collection is expected to last from February 2024 to July 2027., Conclusions: This study will address the lack of rigorous evidence on the effectiveness of community-based digital health interventions for promoting vaccination coverage and timeliness among children from sub-Saharan Africa and identify potential implementation strategies to facilitate the deployment of vaccination promotion interventions in low- and middle-income countries., Trial Registration: ClinicalTrials.gov NCT06024317; https://www.clinicaltrials.gov/study/NCT06024317., International Registered Report Identifier (irrid): PRR1-10.2196/52523., (©Lavanya Vasudevan, Jan Ostermann, Nathan Thielman, Joy Noel Baumgartner, David Solomon, Anna Mosses, Amy Hobbie, Nicole L Hair, Chen Liang, Marco van Zwetselaar, Sayoki Mfinanga, Esther Ngadaya. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 12.01.2024.)

Background: The rising prevalence of non-communicable diseases (NCDs) alongside the continuing high burden of HIV poses a serious challenge to middle- and low-income countries' healthcare systems. Pilot studies of integrated models of service delivery for HIV, hypertension and diabetes have demonstrated that they are feasible and acceptable among patients and care providers. This study assessed multi-stakeholders' perspectives of the delivery and receipt of integrated care in Tanzania., Methods: A qualitative process evaluation was conducted in Dar es Salaam region of Tanzania where the integrated service delivery model was implemented from July to November 2021. In-depth interviews were held with seven key informants at the national, regional and district levels, eight healthcare providers, two researchers working at the integrated clinic and forty patients benefiting from integrated services at a large hospital. Three focus group discussions were held with community leaders and residents of the hospital's catchment area, and clinic level observations were conducted. Thematic analysis was conducted followed by the use of Bronfenbrenner's ecological model to identify factors pertinent to sustaining and scaling up of the integrated model., Results: Participants of the study at all levels were aware of the increased prevalence of NCDs specifically for hypertension and diabetes and were concerned about the trend of increasing co-morbid conditions among people living with HIV (PLHIV). The integrated service delivery model was positively perceived by stakeholders because of its multiple benefits for both patients and the healthcare system. These include stigma and discrimination reduction, improved quality of care, efficient use of limited resources, cost and time saving, reduced duplication of services and fostering of early detection for undiagnosed conditions. The organisation of the clinic was critical in increased satisfaction. Several challenges were observed, which included costs for NCD services relative to free care for HIV and inconsistent availability of NCD medications., Conclusion: Stakeholders reported numerous benefits of the integrated service delivery model that are fundamental in improving the health of many Tanzanians living with NCDs and HIV. These benefits highlight the need for policy and decision-makers to sustain and expand the integrated service delivery model as a solution to many challenges facing the health system especially at the primary care level., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania., Methods: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688., Findings: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; p non-inferiority <0·0001 unadjusted) and -0·36% (-1·99 to 1·28; p non-inferiority <0·0001 adjusted)., Interpretation: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV., Funding: European Union Horizon 2020 and Global Alliance for Chronic Diseases., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA., Methods: Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat., Results: In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs., Conclusions/interpretation: Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV., Trial Registration: The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257., Funding: This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research., (© 2023. The Author(s).)

Background: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection., Methods: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379., Findings: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01)., Interpretation: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals., Funding: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis., Translations: For the French and Portuguese translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AL, DSL, and JB all received support for this project from European and Developing Countries Clinical Trials Partnership (EDCTP), paid to their institutions. AL has received grants from EDCTP, the National Institute for Health and Care Research, and the National Institutes of Health, and consultancy fees from Unitaid to advise on the Unitaid-CHAI Advanced HIV Disease programme, all paid to St George's University of London; AL is also the Chair and Lead of the End AIDS Action Group, which encompasses the work of the Cryptococcal Meningitis Action gorup, an unfunded role. RR received a grant from The National Institute of Allergy and Infectious Diseases, paid to their institution. OL receives consulting fees and payments or honoraria of less than US$1000 per year from Gilead Sciences; and is part of the advisory board for Mundipharma. THa received an investigator award from Gilead Sciences and has received payments or honoraria from Gilead Sciences and Pfizer for speaking fees. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities., Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I 2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679)., Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I 2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs., Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB., Funding: None., Competing Interests: TSo declares a receipt of funding from the Global Fund for conducting the TB prevalence survey in Mongolia. All other authors declare no competing interests., (© 2023 The Authors.)

Background: HIV prevalence in Tanzania is still high at 4.7% among adults. Regular HIV testing is consistently advocated in the country to increase the level of awareness of HIV status, thus contributing to national HIV prevention. We report findings from three years of implementation of an HIV Test and Treat project utilizing provider-initiated and client-initiated testing and counselling (PITC and CITC). This study compared the effectiveness of PITC versus CITC in HIV case detection by the different departments of health facilities., Method: This retrospective cross-sectional study used health facility-based HIV testing data collected from adults aged 18 years and above between June 2017 - July 2019 in the Shinyanga region, Tanzania. Chi-square and logistic regression analysis were used to assess determinants of yield (HIV positivity)., Results: A total of 24,802 HIV tests were performed of which 15,814 (63.8%) were by PITC and 8,987 (36.2%) by CITC. Overall HIV positivity was 5.7%, higher among CITC at 6.6% than PITC at 5.2%. TB and IPD departments had the highest HIV positivity 11.8% and 7.8% respectively. Factors associated with a positive test were testing at a department in the facility compared to CITC, first-time test, and being or having been married compared to being single., Conclusion: Success in identifying HIV + patients was highest among people visiting the clinic for HIV testing (CITC) and first-time testers. With PITC, HIV + patient detection differed between departments, suggesting divergent risk profiles of respective clients and/or divergent HIV alertness of staff. This underscores the importance of increased targeting for PITC to identify HIV + patients., (© 2023. The Author(s).)

Objective: To compare cytogenetic abnormalities among people living with HIV (PLWH) with and without previous exposure to Mycobacterium tuberculosis (Mtb) (both latent tuberculosis infection [LTBI] and active tuberculosis [TB])., Methods: Adult PLWH (≥18 years) were randomly selected at three HIV clinics in Uganda. Previous active TB was confirmed in the clinics' TB records. LTBI was defined as a positive QuantiFERON-TB Gold Plus assay. Participants' buccal mucosal exfoliated cells were examined (per 2000 cells) using the buccal micronucleus assay for chromosomal aberrations (micronuclei and/or nuclear buds), cytokinetic defects (binucleated cells), proliferative potential (normal differentiated cells and basal cell frequency) and/or cell death (condensed chromatin, karyorrhexis, pyknotic and karyolytic cells)., Results: Among 97 PLWH, 42 (43.3%) had exposure to Mtb;16 had previous successfully treated active TB and 26 had LTBI. PLWH with exposure to Mtb had a higher median number of normal differentiated cells (1806.5 [1757.0 - 1842.0] vs. 1784.0 [1732.0 - 1843.0], p = 0.031) and fewer karyorrhectic cells (12.0 [9.0 - 29.0] vs. 18.0 [11.0 - 30.0], p = 0.048) than those without. PLWH with LTBI had fewer karyorrhectic cells than those without (11.5 [8.0 - 29.0] vs. 18.0 [11 - 30], p = 0.006)., Conclusion: We hypothesized that previous exposure to Mtb is associated with cytogenetic damage among PLWH. We found that exposure to Mtb is associated with more normal differentiated cells and less frequent karyorrhexis (a feature of apoptosis). It is unclear whether this increases the propensity for tumorigenesis., Competing Interests: Declaration of Competing Interest The authors declare no relevant conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Tuberculosis (TB) remains a major cause of morbidity and mortality, especially in sub-Saharan Africa. We qualitatively evaluated the implementation of an Evidence-Based Multiple Focus Integrated Intensified TB Screening package (EXIT-TB) in the East African region, aimed at increasing TB case detection and number of patients receiving care., Objective: We present the accounts of participants from Tanzania, Kenya, Uganda, and Ethiopia regarding the implementation of EXIT-TB, and suggestions for scaling up., Methods: A qualitative descriptive design was used to gather insights from purposefully selected healthcare workers, community health workers, and other stakeholders. A total of 27, 13, 14, and 19 in-depth interviews were conducted in Tanzania, Kenya, Uganda, and Ethiopia respectively. Data were transcribed and translated simultaneously and then thematically analysed., Results: The EXIT-TB project was described to contribute to increased TB case detection, improved detection of Multidrug-resistant TB patients, reduced delays and waiting time for diagnosis, raised the index of TB suspicion, and improved decision-making among HCWs. The attributes of TB case detection were: (i) free X-ray screening services; (ii) integrating TB case-finding activities in other clinics such as Reproductive and Child Health clinics (RCH), and diabetic clinics; (iii), engagement of CHWs, policymakers, and ministry level program managers; (iv) enhanced community awareness and linkage of clients; (v) cooperation between HCWs and CHWs, (vi) improved screening infrastructure, (vii) the adoption of the new simplified screening criteria and (viii) training of implementers. The supply-side challenges encountered ranged from disorganized care, limited space, the COVID-19 pandemic, inadequate human resources, inadequate knowledge and expertise, stock out of supplies, delayed maintenance of equipment, to absence of X-ray and GeneXpert machines in some facilities. The demand side challenges ranged from delayed care seeking, inadequate awareness, negative beliefs, fears towards screening, to financial challenges. Suggestions for scaling up ranged from improving service delivery, access to diagnostic equipment and supplies, and infrastructure, to addressing client fears and stigma., Conclusion: The EXIT-TB package appears to have contributed towards increasing TB case detection and reducing delays in TB treatment in the study settings. Addressing the challenges identified is needed to maximize the impact of the EXIT-TB intervention., (© 2023. The Author(s).)

Background: Globally, approximately 19.7 million children remain under-vaccinated; many more receive delayed vaccinations. Sustained progress towards global vaccination targets requires overcoming, or compensating for, incrementally greater barriers to vaccinating hard-to-reach and hard-to-vaccinate children. We prospectively assessed pregnant women's valuations of routine childhood vaccinations and preferences for alternative incentives to inform interventions aiming to increase vaccination coverage and timeliness in southern Tanzania., Methods: Between August and December 2017, 406 women in their last trimester of pregnancy were enrolled from health facilities and communities in the Mtwara region of Tanzania and asked contingent valuation questions about their willingness to vaccinate their child if they were (a) given an incentive, or (b) facing a cost for each vaccination. Interval censored regressions assessed correlates of women's willingness to pay (WTP) for timely vaccinations. Participants were asked to rank monetary and non-monetary incentive options for the timely vaccination of their children., Findings: All women expected to get their children vaccinated according to the recommended schedule, even without incentives. Nearly all women (393; 96.8 %) were willing to pay for vaccinations. The average WTP was Tanzania Shilling (Tsh) 3,066 (95 % confidence interval Tsh 2,523-3,610; 1 USD ∼ Tsh 2,200) for each vaccination. Women's valuations of timely vaccinations varied significantly with vaccine-related knowledge and attitudes, economic status, and rural vs urban residence. Women tended to prefer non-monetary over monetary incentives for the timely vaccination of their children., Interpretation: Women placed a high value on timely childhood vaccinations, suggesting that unexpected system-level barriers rather than individual-level demand factors are likely to be the primary drivers of missed vaccinations. Systematic variation in the value of vaccinations across women reflects variation in perceived benefits and opportunity costs. In this setting, nonmonetary incentives and other interventions to increase demand and compensate for system-level barriers hold significant potential for improving vaccination coverage and timeliness., Clinicaltrialsgov Protocol: NCT03252288., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Over the past decade, there have been increasing reports of non-tuberculous mycobacteria (NTM) species being implicated in tuberculosis (TB) treatment failure or misdiagnosed as TB. Inadequate awareness of NTM pulmonary disease among healthcare workers (HCWs) may contribute to a low index of suspicion for patients presenting to their hospitals. In this study, we assessed the awareness of NTM pulmonary disease (NTM-PD) among front desk HCWs in Northern Tanzania. A cross-sectional descriptive survey was carried out among front desk HCWs in four administrative regions of Northern Tanzania. A standardized questionnaire was administered to consented participants from four clusters; clinicians, laboratory scientists, nurses, and pharmacists serving TB patients from Regional and District Health Facilities. Each participant was asked a set of questions, scored and the total score for each participant was determined. An awareness score was used to measure the level of awareness. The average score for all participants was estimated including the 95% confidence interval (CI). The overall awareness score was 24.1%, 95% CI 22.0-26.2%. History of training, experience in TB care, level of health facilities, age group, and setting were found to be statistically associated with the level of awareness of study participants. More than two-thirds (67%) of participants believe that pulmonary NTM and TB are clinically similar and 60% are not aware that AFB Microscopy cannot distinguish between the two. Only 13% of participants could mention at least one risk factor for NTM pulmonary disease. The level of awareness of NTM pulmonary disease was poor among HCWs in the surveyed TB clinics. National TB Programs are advised to include a topic on NTM in various on-job TB training packages for HCWs., Competing Interests: The authors have declared that no competing interest exists., (Copyright: © 2023 Maya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The standard face-to-face training for the integrated management of childhood illness (IMCI) continues to be plagued by concerns of low coverage of trainees, the prolonged absence of trainees from the health facility to attend training and the high cost of training. Consequently, the distance learning IMCI training model is increasingly being promoted to address some of these challenges in resource-limited settings. This paper examines participants' accounts of the paper-based IMCI distance learning training programme in three district councils in Mbeya region, Tanzania., Methods: A cross-sectional qualitative descriptive design was employed as part of an endline evaluation study of the management of possible serious bacterial infection in Busokelo, Kyela and Mbarali district councils of Mbeya Region in Tanzania. Key informant interviews were conducted with purposefully selected policymakers, partners, programme managers and healthcare workers, including beneficiaries and training facilitators., Results: About 60 key informant interviews were conducted, of which 53% of participants were healthcare workers, including nurses, clinicians and pharmacists, and 22% were healthcare administrators, including district medical officers, reproductive and child health coordinators and programme officers. The findings indicate that the distance learning IMCI training model (DIMCI) was designed to address concerns about the standard IMCI model by enhancing efficiency, increasing outputs and reducing training costs. DIMCI included a mix of brief face-to-face orientation sessions, several weeks of self-directed learning, group discussions and brief face-to-face review sessions with facilitators. The DIMCI course covered topics related to management of sick newborns, referral decisions and reporting with nurses and clinicians as the main beneficiaries of the training. The problems with DIMCI included technological challenges related to limited access to proper learning technology (e.g., computers) and unfriendly learning materials. Personal challenges included work-study-family demands, and design and coordination challenges, including low financial incentives, which contributed to participants defaulting, and limited mentorship and follow-up due to limited funding and transport., Conclusion: DIMCI was implemented successfully in rural Tanzania. It facilitated the training of many healthcare workers at low cost and resulted in improved knowledge, competence and confidence among healthcare workers in managing sick newborns. However, technological, personal, and design and coordination challenges continue to face learners in rural areas; these will need to be addressed to maximize the success of DIMCI., (© 2023. The Author(s).)

Background: Voluntary Medical Male Circumcision (VMMC) is a surgical procedure done by a qualified medical personnel using anesthesia. In Tanzania, there is a gap between adult men who are not circumcised and adolescents. This calls for a review of the current situation of VMMC services in the community at large in order to inform policymakers and stakeholders involved in the fight against HIV and other sexually transmitted diseases. The present study explored the factors influencing utilisation of VMMC services among adult males in Lindi Region, Tanzania., Materials and Methods: A cross-sectional study was conducted among adults male (15-49 years). Data were collected by using a structured modified measure evaluation quantitative Version 2 questionnaire using a Tablet/Android device with an Open Data Kit (ODK) application (Google Inc. California, USA)., Results: The socio-demographic set up of the study participants was mainly composed of males less than 30yrs, single, unemployed, with primary education as the highest level of study and of a Muslim faith. Majority of the respondents (92%) recommended circumcision to a male family member who is not yet circumcised. The study showed that improved sexual performance (81%), penile hygiene (97%) and circumcision as a modern civilization (96%) to be the key factors that motivated respondents' utilisation of VMMC services. However, only 20.6% of the respondents could barely say that VMMC is a surgical procedure done by qualified medical personnel under anaesthesia. The major reasons for recommending the utilisation of VMMC services to their family members were the VMMC usefulness in preventing STIs (48.9%), cultural practices and norms (31.5%), improved penile hygiene (17.4%) and religious reasons (2.2%)., Conclusion: VMMC is positively favoured by the local coastal communities of the Lindi region of Tanzania Mainland. Our findings may be inferred to reflect on the other neighbouring regions with similar sociocultural set ups such as Mtwara, Pwani, Rural Dar es Salaam and Tanga and the isles of Unguja and Pemba. Programs addressing VMMC may be well instituted in these local communities with high degree of favourability and success., (© The East African Health Research Commission 2023.)

Extrapulmonary tuberculosis (EPTB) in People Living with HIV (PLWHIV) is a diagnostic challenge. Our immunochemistry based MPT64 antigen detection test has shown improved sensitivity compared to current laboratory tests in the resource limited diagnostic setting. The aim of this study was to validate the implementability and diagnostic performance of the test in PLWHIV and HIV negative adults in a HIV endemic Tanzanian setting. Adult (>18 y) presumptive EPTB patients were prospectively enrolled at Mbeya Zonal Referral Hospital and followed to the end of treatment or until an alternative diagnosis was reached. Suspected sites of infection were sampled and were subject to routine diagnostics, GeneXpert MTB/RIF assay and the MPT64 test. The performance of the diagnostics tests was assessed using a composite reference standard that included clinical suspicion, mycobacterial culture, response to anti-tuberculosis (TB) therapy, cytological and radiological findings. Patients (N = 168) were categorized as 21 confirmed TB, 23 probable TB and 44 possible TB cases, 69 patients were categorized as non-TB cases and 11 were uncategorized. In the TB group, the three most common infections were adenitis (41%), peritonitis (19%) and pleuritis (14%). The TB and non-TB groups did not differ in HIV seropositivity (46% vs 42%) Among HIV negative and PLWHIV, the MPT64 test had a sensitivity of (91% vs 78%), specificity (75% vs 86%), positive predictive value (80% vs 88%), negative predictive value (89% vs 74%), and accuracy (84% vs 81%), respectively. Performance was not significantly reduced in PLWHIV, and sensitivity was higher than in the currently used tests, including the GeneXpert MTB/RIF assay. The MPT64 test improved the diagnosis of EPTB, irrespective of HIV status. The test performed better than currently used diagnostic test. The test was implementable in a tertiary level hospital with basic pathology services in a HIV endemic Tanzanian setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Grønningen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Investments into 'Blue Skies' fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB., Methods: We review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental 'blue skies research' are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection., Findings: The COVID-19 pandemic has shown that making available adequate funding for priority investments into 'Blue skies research' to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research., Conclusions: Blue Skies research is required to pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead Blue Skies research., Competing Interests: Declaration of Competing Interest All authors have an interest in TB. All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The unprecedented and ongoing COVID-19 pandemic has exposed weaknesses in African countries' health systems. The impact of shifted focus on COVID-19 for the past 2 years on routine health services, especially those for the epidemics of Tuberculosis, HIV/AIDS and Malaria, have been dramatic in both quantity and quality., Methods: In this article, we reflect on the COVID-19 related disruptions on the Tuberculosis, HIV/AIDS and Malaria routine health services across Africa., Results: The COVID-19 pandemic resulted in disruptions of routine health services and diversion of already limited available resources in sub-Saharan Africa. As a result, disease programs like TB, malaria and HIV have recorded gaps in prevention and treatment with the prospects of reversing gains made towards meeting global targets. The extent of the disruption is yet to be fully quantified at country level as most data available is from modelling estimates before and during the pandemic., Conclusions: Accurate country-level data is required to convince donors and governments to invest more into revamping these health services and help prepare for managing future pandemics without disruption of routine services. Increasing government expenditure on health is a critical part of Africa's economic policy. Strengthening health systems at various levels to overcome the negative impacts of COVID-19, and preparing for future epidemics will require strong visionary political leadership. Innovations in service delivery and technological adaptations are required as countries aim to limit disruptions to routine services., Competing Interests: Conflict of Interest All authors have no conflicts of interest to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Although HIV continues to have a high prevalence among adults in sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCD) such as diabetes and hypertension is increasing rapidly. There is an urgent need to expand the capacity of healthcare systems in SSA to provide NCD services and scale up existing chronic care management pathways. A scoping review mapped extant policy and evidence based literature on the feasibility of integrating NCD care with HIV in the region., Methods: A scoping review methodology was utilised to conduct a systematic search of peer-reviewed and grey literature published in English language and with no date limitation. A systematic search was conducted on PubMed, Embase, CINAHL, and the Cochrane library. The initial search identified 231 records considered for inclusion in this review. Twelve duplicate records were removed. The remaining 219 records were screened by title and abstract of which 165 records were excluded and 54 records were selected for full-text review. A further 16 records were excluded due to a lack of relevance or the unavailability of the full text article. Finally, 38 were charted and analysed thematically., Results: Thirty-eight studies were included. These comprised a range of different models to integrate NCD and HIV care in the region, reflecting differences in health system environments, and disease epidemiology. The studies provide a variety of evidence that integration of HIV and NCD care can be feasible and can improve clinical effectiveness and identify barriers and facilitators to integration and task shifting. The review confirms that integrated HIV and NCD care services is by-and-large feasible, being both clinically effective and cost-effective., Conclusion: The review may inform the understanding of how best to develop an integrated model of care service by reducing barriers to uptake, linkage and retention in HIV, diabetes and hypertension treatment in SSA countries., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

The October 2020 Global TB report reviews TB control strategies and United Nations (UN) targets set in the political declaration at the September 2018 UN General Assembly high-level meeting on TB held in New York. Progress in TB care and prevention has been very slow. In 2019, TB remained the most common cause of death from a single infectious pathogen. Globally, an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV. Adults accounted for 88% and children for 12% of people with TB. The WHO regions of South-East Asia (44%), Africa (25%), and the Western Pacific (18%) had the most people with TB. Eight countries accounted for two thirds of the global total: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%). Only 30% of the 3.5 million five-year target for children treated for TB was met. Major advances have been development of new all oral regimens for MDRTB and new regimens for preventive therapy. In 2020, the COVID-19 pandemic dislodged TB from the top infectious disease cause of mortality globally. Notably, global TB control efforts were not on track even before the advent of the COVID-19 pandemic. Many challenges remain to improve sub-optimal TB treatment and prevention services. Tuberculosis screening and diagnostic test services need to be ramped up. The major drivers of TB remain undernutrition, poverty, diabetes, tobacco smoking, and household air pollution and these need be addressed to achieve the WHO 2035 TB care and prevention targets. National programs need to include interventions for post-tuberculosis holistic wellbeing. From first detection of COVID-19 global coordination and political will with huge financial investments have led to the development of effective vaccines against SARS-CoV2 infection. The world now needs to similarly focus on development of new vaccines for TB utilizing new technological methods., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Although HIV continues to have a high prevalence among adults in sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCD) such as diabetes and hypertension is increasing rapidly. There is an urgent need to expand the capacity of healthcare systems in SSA to provide NCD services and scale up existing chronic care management pathways. The aim of this study was to identify key components, outcomes, and best practice in integrated service provision for the prevention, identification and treatment of HIV, hypertension and diabetes., Methods: An international, multi stakeholder e-Delphi consensus study was conducted over two successive rounds. In Round 1, 24 participants were asked to score 27 statements, under the headings 'Service Provision' and 'Benefits of Integration', by importance. In Round 2, the 16 participants who completed Round 1 were shown the distribution of scores from other participants along with the score that they attributed to an outcome and were asked to reflect on the score they gave, based on the scores of the other participants and then to rescore if they wished to. Nine participants completed Round 2., Results: Based on the Round 1 ranking, 19 of the 27 outcomes met the 70% threshold for consensus. Four additional outcomes suggested by participants in Round 1 were added to Round 2, and upon review by participants, 22 of the 31 outcomes met the consensus threshold. The five items participants scored from 7 to 9 in both rounds as essential for effective integrated healthcare delivery of health services for chronic conditions were improved data collection and surveillance of NCDs among people living with HIV to inform integrated NCD/HIV programme management, strengthened drug procurement systems, availability of equipment and access to relevant blood tests, health education for all chronic conditions, and enhanced continuity of care for patients with multimorbidity., Conclusions: This study highlights the outcomes which may form key components of future complex interventions to define a model of integrated healthcare delivery for diabetes, hypertension and HIV in sub-Saharan Africa., (© 2021. The Author(s).)

Introduction: East Africa countries (Tanzania, Kenya, and Uganda) are among tuberculosis high burdened countries globally. As we race to accelerate progress towards a world free of tuberculosis by 2035, gaps related to screening and diagnosis in the cascade care need to be addressed., Methods: We conducted a three-year (2015-2017) retrospective study using routine program data in 21 health facilities from East Africa. Data abstraction were done at tuberculosis clinics, outpatient departments (OPD), human immunodeficiency virus (HIV) and diabetic clinics, and then complemented with structured interviews with healthcare providers to identify possible gaps related to integration, screening, and diagnosis of tuberculosis. Data were analyzed using STATA™ Version 14.1., Results: We extracted information from 49,454 presumptive TB patients who were registered in the 21 facilities between January 2015 and December 2017. A total of 9,565 tuberculosis cases were notified; 46.5% (4,450) were bacteriologically confirmed and 31.5% (3,013) were HIV-infected. Prevalence of tuberculosis among presumptive pulmonary tuberculosis cases was 17.4%. The outcomes observed were as follows: 79.8% (7,646) cured or completed treatment, 6.6% (634) died, 13.3% (1,270) lost to follow-up or undocumented and 0.4% (34) treatment failure. In all countries, tuberculosis screening was largely integrated at OPD and HIV clinics. High patient load, weak laboratory specimen referral system, shortage of trained personnel, and frequent interruption of laboratory supplies were the major cited challenges in screening and diagnosis of tuberculosis., Conclusion: Screening and diagnostic activities were frequently affected by scarcity of human and financial resources. Tuberculosis screening was mainly integrated at OPD and HIV clinics, with less emphasis on the other health facility clinics. Closing gaps related to TB case finding and diagnosis in developing countries requires sustainable investment for both human and financial resources and strengthen the integration of TB activities within the health system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed., Methods: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations., Results: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities., Conclusion: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes., (© 2021. The Author(s).)

Background: The potential shift of major causes of febrile illnesses from malaria to non-malarial febrile illnesses, including arboviral diseases such as chikungunya and dengue, is of concern. The last outbreaks of these infections were reported in 2018 and 2019 for chikungunya in Zanzibar and dengue in Dar es Salaam. We conducted a cross-sectional study that involved serological testing of stored blood samples from the blood banks in Temeke Referral Hospital in Dar es Salaam and the National Blood Bank Unit in Zanzibar. The samples were collected from Zanzibar and Dar es Salaam donors in May and June 2020, respectively. A total of 281 samples were included in the study, and their demographic information extracted from the registers. The samples were then transported to Muhimbili University of Health and Allied Sciences at the Microbiology Laboratory. They were subjected to an indirect ELISA to detect IgG and IgM against dengue and chikungunya viruses., Results: Seropositive IgM samples from Dar es Salaam were 3/101 (2.97%) for chikungunya and 1/101 (0.9%) for dengue, while samples from Zanzibar were all IgM negative for both viruses. Chikungunya IgG seropositivity was significantly higher (p ≤ 0.05) in Dar es Salaam 21/101 (21.2%) than Zanzibar 22/180 (12.2%). There was no difference in dengue IgG seropositivity between Dar es Salaam 44/101 (43.5%) and Zanzibar 68/180 (37.8%). Similarly, dual IgG seropositivity for both dengue and chikungunya viruses were not different between Dar es Salaam 13/101 (12.9%) and Zanzibar 11/180 (6.1%)., Conclusion: Detection of IgM for dengue and chikungunya in Dar es Salaam indicates recent or ongoing transmission of the two viruses in the absence of a reported outbreak. These findings suggest the possibility of transmission of the two infections through blood transfusion. Detection of IgG antibodies for dengue and chikungunya viruses might be contributed by both; the ongoing infections and residual responses caused by preceding infections in the country. Results from blood banks may represent the tip of the iceberg. Further studies are needed to gain insight into the actual burden of the two diseases in Tanzania., (© 2021. The Author(s).)

Pediatric extrapulmonary tuberculosis (EPTB) is a diagnostic challenge. A new immunochemistry based MPT64 antigen detection test has shown improved sensitivity compared to current laboratory tests. The aim of this study was to implement and validate the test performance in a resource limited African setting. Presumptive pediatric (0-18 y) EPTB patients were prospectively enrolled at Mbeya Zonal Referral Hospital, and followed to the end of treatment or until a final diagnosis was reached. Specimens from suspected sites of infection were subject to routine diagnostics, GeneXpert MTB/RIF assay and the MPT64 test. The performance of the tests was assessed using mycobacterial culture as well as a composite reference standard. 30 patients were categorized as TB cases, 31 as non-TB cases and 2 were uncategorized. In the TB group, the three most common infections were adenitis (30%), peritonitis (30%) and meningitis (20%). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the MPT64 test was 92%, 88%, 87%, 92% and 90%, respectively. Mortality was equally high among TB/non-TB cases (23% vs 21%), and malnutrition was the main comorbidity among TB cases. The MPT64 test was implementable in the routine diagnostics in a low-resource setting and improved the diagnosis of pediatric EPTB., (© 2021. The Author(s).)

The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2021. The Authors.)

With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for <14 days compared with those on ART for >14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described., Methods: Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation., Results: Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6-1.2; P  = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8-1.32; P  = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART., Conclusions: In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Low-income and middle-income countries are struggling to manage growing numbers of patients with chronic non-communicable diseases (NCDs), while services for patients with HIV infection are well established. There have been calls for integration of HIV and NCD services to increase efficiency and improve coverage of NCD care, although evidence of effectiveness remains unclear. In this review, we assess the extent to which National HIV and NCD policies in East Africa reflect the calls for HIV-NCD service integration., Methods: Between April 2018 and December 2020, we searched for policies, strategies and guidelines associated with HIV and NCDs programmes in Burundi, Kenya, Rwanda, South Sudan, Tanzania and Uganda. Documents were searched manually for plans for integration of HIV and NCD services. Data were analysed qualitatively using document analysis., Results: Thirty-one documents were screened, and 13 contained action plans for HIV and NCDs service integration. Integrated delivery of HIV and NCD care is recommended in high level health policies and treatment guidelines in four countries in the East African region; Kenya, Rwanda, Tanzania and Uganda, mostly relating to integrating NCD care into HIV programmes. The increasing burden of NCDs, as well as a move towards person-centred differentiated delivery of services for people living with HIV, is a factor in the recent adoption of integrated HIV and NCD service delivery plans. Both South Sudan and Burundi report a focus on building their healthcare infrastructure and improving coverage and quality of healthcare provision, with no reported plans for HIV and NCD care integration., Conclusion: Despite the limited evidence of effectiveness, some East African countries have already taken steps towards HIV and NCD service integration. Close monitoring and evaluation of the integrated HIV and NCD programmes is necessary to provide insight into the associated benefits and risks, and to inform future service developments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class' purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted M. tuberculosis killing of -0.17 (95% confidence interval [CI] -0.23 to -0.12) for the injectable bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI -1.05 to -0.20) log 10 eCFU/ml for the injectable bedaquiline-containing regimen ( P  = 0.019), -0.35 (95% CI -0.65 to -0.13) log 10 eCFU/ml for the all-oral bedaquiline-based regimen ( P  = 0.054), and -0.29 (95% CI -0.78 to +0.22) log 10 eCFU/ml for the RHZE regimen ( P  = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside., (Copyright © 2021 Mbelele et al.)

Among 472 patients with human immunodeficiency virus-associated cryptococcal meningitis, 16% had severe visual loss at presentation, and 46% of these were 4-week survivors and remained severely impaired. Baseline cerebrospinal fluid opening pressure ≥40 cmH 2 O (adjusted odds ratio [aOR], 2.56; 95% confidence interval [CI], 1.36-4.83; P = .02) and fungal burden >6.0 log 10 colonies/mL (aOR, 3.01; 95% CI, 1.58-5.7; P = .003) were independently associated with severe visual loss., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Diagnosis of pulmonary tuberculosis remains grim, especially in resource-limited settings. Low quality of sputum, particularly among seriously ill, HIV/AIDS, and pediatric patients might result in missing the diagnosis. This study evaluated the performance of GeneXpert MTB/RIF for the detection of pulmonary tuberculosis on stool specimens as an alternative to respiratory specimens., Methods: A cross-sectional study design was used to evaluate the performance of GeneXpert MTB/RIF to detect TB in stool specimens from presumptive TB patients. Sputum culture on Lowenstein-Jensen media was used as the gold standard. Recruitment of patients into the study was conducted in 12 selected health facilities in Tanzania. Two sputa and a stool specimen were collected from each study participant. Both sputa and stool samples were tested at their respective study sites of collection using GeneXpert, and their respective portions shipped to the Central Tuberculosis Reference Laboratory for testing by stool GeneXpert and sputum culture in the LJ media. Statistical analysis was performed using STATA software version 14.1., Results: A total of 590 presumptive tuberculosis patients were enrolled in this study. Their median age was 35 years (IQR = 21-47 years). More than half (57.5%, n = 339) of the study participants, were males. Children aged below 15 years constituted 17.6% (n = 104) of the study participants. A total of 75 tuberculosis cases were detected by sputum culture. The sensitivity and specificity of Stool GeneXpert conducted at CTRL was 84% (95% CI: 81.0-87.0%), and 93.4% (CI: 98.5-99.9%) respectively. The overall sensitivity and specificity of stool GeneXpert at the peripheral laboratories was 63.0% (95% CI: 47.8-76.1) and 76.7% (95% CI: 72.1-81.4), respectively., Conclusion: Findings from this study suggest that stool is a potential alternative to respiratory specimen for use in routine diagnosis of tuberculosis, especially when obtaining a respiratory specimen is challenging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Published by Elsevier Ltd.)

Competing Interests: Competing interests: None declared.

Background: Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented., Methods: At the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann-Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis., Results: We enrolled 51 human immunodeficiency virus-negative children (median age, 5.3 years [range, 0.75-14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the "old" dosages, those who received the "revised" WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001)., Conclusions: Among this cohort of human immunodeficiency virus-negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain., Methods: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER., Results: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved., Conclusions: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility, which are associated with the development of aneuploidy. The implications of this phenomenon for pharmacodynamics of fluconazole for cryptococcal meningitis are poorly understood. The pharmacodynamics of fluconazole were studied using a hollow-fiber infection model (HFIM) and a well-characterized murine model of cryptococcal meningoencephalitis. The relationship between drug exposure and both antifungal killing and the emergence of resistance was quantified. The same relationships were further evaluated in a recently described group of patients with cryptococcal meningitis undergoing induction therapy with fluconazole at 800 to 1,200 mg/day. The pattern of emergence of fluconazole resistance followed an "inverted U." Resistance amplification was maximal and suppressed at ratios of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC ( f AUC:MIC) of 34.5 to 138 and 305.6, respectively. Emergence of resistance was observed in vivo with an f AUC:MIC of 231.4. Aneuploidy with duplication of chromosome 1 was demonstrated to be the underlying mechanism in both experimental models. The pharmacokinetic (PK)-pharmacodynamic model accurately described the PK, antifungal killing, and emergence of resistance. Monte Carlo simulations from the clinical pharmacokinetic-pharmacodynamic model showed that only 12.8% of simulated patients receiving fluconazole at 1,200 mg/day achieved sterilization of the cerebrospinal fluid (CSF) after 2 weeks and that 83.4% had a persistent subpopulation that was resistant to fluconazole. Fluconazole is primarily ineffective due to the emergence of resistance. Treatment with 1,200 mg/day leads to the killing of a susceptible subpopulation but is compromised by the emergence of resistance. IMPORTANCE Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy., (Copyright © 2019 Hope et al.)

Background: Despite effort to diagnose tuberculosis (TB) in the Human Immunodeficiency Virus (HIV) infected population, 45% of adults with HIV that had a previously unknown reason for death, demonstrated TB was the cause by autopsy examination. We aimed to assess the clinical outcomes of implementation a new algorithm for diagnosis and treatment of tuberculosis (TB) related sepsis among PLHIV presenting with life-threatening illness., Methods: This study is a prospective cohort conducted in three-referral hospitals in Kilimanjaro, recruited 97 PLHIV from February through June 2018. Patients provided urine and sputum samples for testing lateral flow - lipoarabinomannan (LF-LAM) and Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) assays, respectively. Anti-TB was prescribed to patients with positive LF-LAM or Xpert MTB/RIF or received broad-spectrum antibiotics but deteriorated., Results: Of 97 patients, 84 (87%) provided urine and sputa, and 13 (13%) provided only urine. The mean age (95% confidence interval) was 40 (38-43) years and 52 (54%) were female. In 84 patients, LF-LAM increased TB detection from 26 (31%) by Xpert MTB/RIF to 41 (55%) by both tests. Of 97 patients, 69 (71%) prescribed anti-TB, 67% (46/69) and 33% (23/69) had definitive and probable TB respectively. Sixteen (16.5%) patients died, of which one died before treatment, 73% (11/15) died within 7 days of admission. The 30-day survival was similar in both treatment groups (log rank = 0.1574). Mortality was significantly higher among hospitalized patients compared to outpatients (P ≤ 0.027)., Conclusion: Implementation of new algorithm increased TB case detection in patients that could have been missed by Xpert MTB/RIF assay. Survival of PLHIV with confirmed or probable TB was comparable to those of PLHIV that were treated with broad-spectrum antibiotics alone. Further work should focus on the optimal timing and content of the immediate antimicrobial regimen for sepsis among PLHIV in TB-endemic settings., Competing Interests: None

Background: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses., Methods: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done., Results: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved., Clinical Trials Registration: ISRCTN45035509., Conclusions: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

This qualitative study assessed the knowledge and beliefs surrounding fever syndrome among adult febrile patients seeking health care in Kilombero, Tanzania. From June 11 to July 13, 2014, 10% of all adult (≥ 15 years) febrile patients enrolled in the larger syndromic study, who presented with an axillary temperature ≥ 37.5°C and symptom onset ≤ 5 days prior, were randomly selected to participate in an in-depth physician-patient interview, informed by Health Belief Model constructs. Interviews were audio recorded, translated, and transcribed. Transcripts were coded using NVivo Version 11.1, and the thematic content was analyzed by two separate researchers. Blood and nasopharyngeal/oralpharyngeal specimens were collected and analyzed using both acute febrile illness and respiratory TaqMan Array Cards for multipathogen detection of 56 potential causative agents. A total of 18 participants provided 188 discrete comments. When asked to speculate the causative agent of febrile illness, 33.3% cited malaria and the other 66.6% offered nonbiomedical responses, such as "mosquitoes" and "weather." Major themes emerging related to severity and susceptibility to health hazards included lack of bed net use, misconceptions about bed nets, and mosquito infestation. Certain barriers to treatment were cited, including dependence on traditional healers, high cost of drugs, and poor dispensary services. Overall, we demonstrate low concurrence in speculations of fever etiology according to patients, clinicians, and laboratory testing. Our findings contribute to the important, yet limited, base of knowledge surrounding patient risk perceptions of febrile illness and underscore the potential utility of community-based participatory research to inform disease control programs.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To make an informed viewpoint on the usefulness of Tuberculin Skin test (TST) compared to Interferon Gamma Release Assays (IGRAs) for diagnosis of Latent TB Infection (LTBI) in different geographical settings., Methods: We reviewed the current literature on TST compared to IGRA, including national implementation of WHO LTBI recommendations and retrospective data over the past 7 years at the National Institute for Infectious Diseases "L. Spallanzani" as indirect indicator of usage of both tests under actual programmatic conditions., Results: Current national guidelines vary considerably, reflecting the uncertainty and rapidly evolving evidence about the potential use of these tests. Data from Institute "L. Spallanzani" showed IGRA concordance in TST positive subjects only in 54.74% of subjects, while there was strong concordance between two tests in TST negative subjects (93.78%)., Conclusion: Neither IGRAs nor TST can distinguish active TB from LTBI. TST will continue to be clinically useful in low and high TB endemic areas until more accurate and predictive tests will become available. Clinical judgment remains fundamental in choosing between IGRA/TST tests and interpreting their results., (Copyright © 2019. Published by Elsevier Ltd.)