Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial.

BACKGROUND: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes. METHODS: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample. FINDINGS: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50). INTERPRETATION: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

The aetiology and antimicrobial resistance of bacterial maternal infections in Sub-Saharan Africa-a systematic review and meta-analysis.

BACKGROUND: Understanding the aetiological organisms causing maternal infections is crucial to inform antibiotic treatment guidelines, but such data are scarce from Sub-Saharan Africa (SSA). We performed this systematic review and meta-analysis to address this gap. METHODS: Microbiologically confirmed maternal infection data were collected from PubMed, Embase, and African Journals online databases. The search strategy combined terms related to bacterial infection, pregnancy, postnatal period, observational studies, SSA. Exclusion criteria included colonization, asymptomatic infection, and screening studies. Pooled proportions for bacterial isolates and antimicrobial resistance (AMR) were calculated. Quality and completeness of reporting were assessed using the Newcastle-Ottawa and STROBE checklists. FINDINGS: We included 14 papers comprising data from 2,575 women from four sources (blood, urine, surgical wound and endocervical). Mixed-growth was commonly reported at 17% (95% CI: 12%-23%), E. coli from 11%(CI:10%-12%), S. aureus from 5%(CI: 5%-6%), Klebsiella spp. at 5%(CI: 4%- 5%) and Streptococcus spp. at 2%(CI: 1%-2%). We observed intra-sample and inter-sample heterogeneity between 88-92% in all meta-analyses. AMR rates were between 19% -77%, the highest with first-line beta-lactam antibiotics. Convenience sampling, and limited reporting of laboratory techniques were areas of concern. INTERPRETATION: We provide a comprehensive summary of microbial aetiology of maternal infections in SSA and demonstrate the paucity of data available for this region. We flag the need to review the current local and international empirical treatment guidelines for maternal bacterial infections in SSA because there is high prevalence of AMR among common causative bacteria. FUNDING: This research was supported by the NIHR-Professorship/NIHR300808 and the Wellcome-Strategic-award /206545/Z/17/Z. TRIAL REGISTRATION: Prospero ID CRD42021238515.

Impact of Community-Wide Tuberculosis Active Case Finding and Human Immunodeficiency Virus Testing on Tuberculosis Trends in Malawi.

BACKGROUND: Tuberculosis case-finding interventions are critical to meeting World Health Organization End TB strategy goals. We investigated the impact of community-wide tuberculosis active case finding (ACF) alongside scale-up of human immunodeficiency virus (HIV) testing and care on trends in adult tuberculosis case notification rates (CNRs) in Blantyre, Malawi. METHODS: Five rounds of ACF for tuberculosis (1-2 weeks of leafleting, door-to-door enquiry for cough and sputum microscopy) were delivered to neighborhoods ("ACF areas") in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighborhoods in Blantyre City ("non-ACF areas") provided a non-randomized comparator. We analyzed TB CNRs from January 2009 until December 2018. We used interrupted time series analysis to compare tuberculosis CNRs before ACF and after ACF, and between ACF and non-ACF areas. RESULTS: Tuberculosis CNRs increased in Blantyre concurrently with start of ACF for tuberculosis in both ACF and non-ACF areas, with a larger magnitude in ACF areas. Compared to a counterfactual where pre-ACF CNR trends continued during ACF period, we estimated there were an additional 101 (95% confidence interval [CI] 42 to 160) microbiologically confirmed (Bac+) tuberculosis diagnoses per 100 000 person-years in the ACF areas in 3 and a half years of ACF. Compared to a counterfactual where trends in ACF area were the same as trends in non-ACF areas, we estimated an additional 63 (95% CI 38 to 90) Bac + diagnoses per 100 000 person-years in the same period. CONCLUSIONS: Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre.

Effects of Coronavirus Disease Pandemic on Tuberculosis Notifications, Malawi.

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.

Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis.

BACKGROUND: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). METHODS AND FINDINGS: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. CONCLUSIONS: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. TRIAL REGISTRATION: clinicaltrials.gov NCT03519425.

Durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease with a Bayesian analysis of prevalence survey and notification data.

BACKGROUND: Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking. METHODS: We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods. RESULTS: Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4-8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2-11.2) for men and 8.1 months (95% CrI: 6.2-10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6-7.9) for men and 3.5 months (95% CrI: 1.3-6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3-3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0-12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%). CONCLUSION: Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.

Pattern of abnormalities amongst chest X-rays of adults undergoing computer-assisted digital chest X-ray screening for tuberculosis in Peri-Urban Blantyre, Malawi: A cross-sectional study.

BACKGROUND: The prevalence of diseases other than tuberculosis (TB) detected during chest X-ray screening is poorly described in sub-Saharan Africa. Computer-assisted digital chest X-ray technology is available for TB screening and has the potential to be a screening tool for non-communicable diseases as well. Low- and middle-income countries are in a transition period where the burden of non-communicable diseases is increasing, but health systems are mainly focused on addressing infectious diseases. METHODS: Participants were adults undergoing computer-assisted chest X-ray screening for tuberculosis in a community-wide tuberculosis prevalence survey in Blantyre, Malawi. Adults with abnormal radiographs by field radiographer interpretation were evaluated by a physician in a community-based clinic. X-ray classifications were compared to classifications of a random sample of normal chest X-rays by radiographer interpretation. Radiographic features were classified using WHO Integrated Management for Adult Illnesses (IMAI) guidelines. All radiographs taken at the screening tent were analysed by the Qure.ai qXR v2.0 software. RESULTS: 5% (648/13,490) of adults who underwent chest radiography were identified to have an abnormal chest X-ray by the radiographer. 387 (59.7%) of the participants attended the X-ray clinic, and another 387 randomly sampled normal X-rays were available for comparison. Participants who were referred to the community clinic had a significantly higher HIV prevalence than those who had been identified to have a normal CXR by the field radiographer (90 [23.3%] vs. 43 [11.1%] p-value < 0.001). The commonest radiographic finding was cardiomegaly (20.7%, 95% CI 18.0-23.7). One in five (81/387) chest X-rays were misclassified by the radiographer. The overall mean Qure.ai qXR v2.0 score for all reviewed X-rays was 0.23 (SD 0.20). There was a high concordance of cardiomegaly classification between the physician and the computer-assisted software (109/118, 92.4%). CONCLUSION: There is a high burden of cardiomegaly on a chest X-ray at a community level, much of which is in patients with diabetes, heart disease and high blood pressure. Cardiomegaly on chest X-ray may be a potential tool for screening for cardiovascular NCDs at the primary care level as well as in the community.

Tuberculosis diagnosis cascade in Blantyre, Malawi: a prospective cohort study.

BACKGROUND: Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. METHODS: A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. RESULTS: Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02-5.06), increasing age (aOR:1.02, 95%CI:1.01-1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45-7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8-12/day). CONCLUSIONS: Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.

Disparities in access to diagnosis and care in Blantyre, Malawi, identified through enhanced tuberculosis surveillance and spatial analysis.

BACKGROUND: A sizeable fraction of tuberculosis (TB) cases go undiagnosed. By analysing data from enhanced demographic, microbiological and geospatial surveillance of TB registrations, we aimed to identify modifiable predictors of inequitable access to diagnosis and care. METHODS: Governmental community health workers (CHW) enumerated all households in 315 catchment areas during October-December 2015. From January 2015, government TB Officers routinely implemented enhanced TB surveillance at all public and private TB treatment registration centres within Blantyre (18 clinics in total). This included collection from registering TB patients of demographic and clinical characteristics, a single sputum sample for TB microscopy and culture, and geolocation of place of residence using an electronic satellite map application. We estimated catchment area annual TB case notification rates (CNRs), stratified by microbiological status. To identify population and area-level factors predictive of CHW catchment area TB case notification rates, we constructed Bayesian spatially autocorrelated regression models with Poisson response distributions. Worldpop data were used to estimate poverty. RESULTS: In total, the 315 CHW catchment areas comprised 753,489 people (range 162 to 13,066 people/catchment area). Between 2015 and 2017, 6077 TB cases (61% male; 99% HIV tested; 67% HIV positive; 55% culture confirmed) were geolocated, with 3723 (61%) resident within a CHW catchment area. In adjusted models, greater distance to the nearest TB registration clinic was negatively correlated with TB CNRs, which halved for every 3.2-fold (95% CI 2.24-5.21) increase in distance. Poverty, which increased with distance from clinics, was negatively correlated with TB CNRs; a 23% increase (95% CI 17-34%) in the mean percentage of the population living on less than US$2 per day corresponded to a halving of the TB case notification rates. CONCLUSIONS: Using enhanced surveillance of TB cases in Blantyre, we show an ecological relationship consistent with an 'inverse care law' whereby poorer neighbourhoods and those furthest from TB clinics have lower relative CNRs. If confirmed as low case detection, then pro-poor strategies to facilitate equitable access to TB diagnosis and treatment are required.

The Effect of Real-Time Medication Monitoring-Based Digital Adherence Tools on Adherence to Antiretroviral Therapy and Viral Suppression in People Living With HIV: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Universal antiretroviral therapy (ART) has led to improved treatment outcomes in persons living with HIV. Adherence to ART is required to achieve viral suppression. Real-time medication monitoring (RTMM)-based digital adherence tools (DATs) could be effective in improving ART adherence and viral suppression in persons living with HIV. OBJECTIVES: The primary and secondary objectives of this review were to assess the effect of RTMM-based DATs on improving ART adherence and viral load suppression. METHODS: We searched MEDLINE, Embase, and Global Health for publications published through October 11, 2022. Narrative synthesis and random effects meta-analyses were conducted to synthesize the results. RESULTS: Of 638 papers identified, 8 were included. Six studies were randomized controlled trials (RCTs), and 2 were cohort studies. Two studies, an RCT in China (mean adherence: 96.2% vs 89.1%) and a crossover cohort study in Uganda (mean adherence: 84% vs 93%), demonstrated improved ART adherence. No studies demonstrated improved viral suppression. In the meta-analyses, we estimated that RTMM-based digital adherence tools had a statistically insignificant small positive effect on ART adherence and viral suppression with a standardized mean difference of 0.1922 [95% CI: -0.0268 to 0.4112, P-value: 0.0854] and viral suppression with an odds ratio of 1.3148 [95% CI: 0.9199 to 1.8791, P-value: 0.1331]. CONCLUSIONS: Our meta-analyses found that RTMM-based DATs did not have a significant effect on ART adherence and viral suppression. However, due to few published studies available, heterogeneity of target populations, intervention designs, and adherence measurement instruments, more data are required to provide conclusive evidence.

Suppression of host gene expression is associated with latent TB infection: a possible diagnostic biomarker.

The World Health Organization End TB strategy aims for a 90% reduction of tuberculosis (TB) incidence by 2035. Systematic testing and treatment of latent TB infection (LTBI) among contacts of active TB patients is recommended as one of the ways to curtail TB incidence. However, there is a shortage of tools to accurately diagnose LTBI. We assessed the appropriateness of whole blood host transcriptomic markers (TM) to diagnose LTBI among household contacts of bacteriologically confirmed index cases compared to HIV negative healthy controls (HC). QuantiFERON-TB Gold Plus Interferon gamma release assay (IGRA) and reverse-transcriptase quantitative PCR were used to determine LTBI and quantify TM expression respectively. Association between TM expression and LTBI was evaluated by logistic regression modelling. A total of 100 participants, 49 TB exposed (TBEx) household contacts and 51 HC, were enrolled. Twenty-five (51%) TBEx individuals tested positive by IGRA, and were denoted as LTBI individuals, and 37 (72.5%) HC were IGRA-negative. Expression of 11 evaluated TM was significantly suppressed among LTBI compared to HC. Out of the 11 TM, ZNF296 and KLF2 expression were strongly associated with LTBI and successfully differentiated LTBI from HC. Paradoxically, 21 (49%) TBEx participants who tested IGRA negative exhibited the same pattern of suppressed TM expression as IGRA positive (LTBI-confirmed individuals). Results suggest that suppression of gene expression underlies LTBI and may be a more sensitive diagnostic biomarker than standard-of-care IGRA.

Utility of Cerebrospinal Fluid Unstimulated Interferon-Gamma (IRISA-TB) as a Same-Day Test for Tuberculous Meningitis in a Tuberculosis-Endemic, Resource-Poor Setting.

Background: Tuberculous meningitis (TBM) mortality is high and current diagnostics perform suboptimally. We evaluated the diagnostic performance of a DNA-based assay (GeneXpert Ultra) against a new same-day immunodiagnostic assay that detects unstimulated interferon-gamma (IRISA-TB). Methods: In a stage 1 evaluation, IRISA-TB was evaluated in biobanked samples from Zambia (n = 82; tuberculosis [TB] and non-TBM), and specificity in a South African biobank (n = 291; non-TBM only). Given encouraging results, a stage 2 evaluation was performed in suspected TBM patients from Zimbabwe and Malawi (n = 668). Patients were classified as having definite, probable or possible TBM, or non-TBM based on their microbiological results, cerebrospinal fluid (CSF) chemistry, and whether they received treatment. Results: In the stage 1 evaluation, sensitivity and specificity of IRISA-TB were 75% and 87% in the Zambian samples, and specificity was 100% in the South African samples. In the stage 2 validation, IRISA-TB sensitivity (95% confidence interval [CI]) was significantly higher than Xpert Ultra (76.2% [55.0%-89.4%] vs 25% [8.9%-53.3%]; P = .0048) when trace readouts were considered negative. Specificity (95% CI) was similar for both assays (91.4% [88.8%-93.4%] vs 86.9% [83.4%-89.8%]). When the Xpert Ultra polymerase chain reaction product was verified by sequencing, the positive predictive value of trace readouts in CSF was 27.8%. Sensitivity of IRISA-TB was higher in human immunodeficiency virus (HIV)-infected versus uninfected participants (85.8% vs 66.7%). Conclusions: As a same-day rule-in test, IRISA-TB had significantly better sensitivity than Xpert Ultra in a TB/HIV-endemic setting. An immunodiagnostic approach to TBM is promising, and further studies are warranted.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

Spatial distribution and characteristics of women reporting cervical cancer screening in Malawi: An analysis of the 2020 to 2021 Malawi Population-based HIV Impact Assessment survey data.

BACKGROUND: Malawi has one of the highest incidence and mortality rates of cervical cancer in the world. Despite a national strategic plan and the roll-out of VIA and screen-and-treat services, cervical cancer screening coverage in Malawi remains far below the national target.Using a nationally representative sample of women enumerated in the Malawi Population-based Impact Assessment (MPHIA) survey we estimated the prevalence and spatial distribution of self-reported cervical cancer screening as a proxy for uptake in Malawi. METHODS: MPHIA was a nationally representative household survey in Malawi, targeting adults aged 15 and above, that employed a cross-sectional, two-stage, cluster design. The primary aim of MPHIA was to assess the regional prevalence of viral load suppression and the progress towards achieving the UNAIDS 95-95-95 goals among adults aged 15 and above. The survey was carried out between January 2020 and April 2021. Prevalence of self-reported cervical cancer screening by different characteristics was estimated accounting for the survey design using the Taylor series approach. We used univariable and multivariable logistic regression approaches to examine associations between the prevalence of cervical cancer screening and demographic characteristics. FINDINGS: A total of 13,067 adult (15 years and older) female individuals were surveyed during the MPHIA 2020 to 2021 survey, corresponding to a weighted total of 5,604,578. The prevalence of self-reported cervical cancer screening was 16.5% (95% CI 15.5-18.0%), with women living with HIV having a higher prevalence of 37.8% (95% CI 34.8-40.9) compared to 14.0% (95% CI 13.0-15.0) in HIV negative women. The highest prevalence of screening was reported in the Southwest zone (SWZ) (24.1%, 95% CI 21.3-26.9) and in major cities of Blantyre (25.9%, 95% CI 22.9-29.0), and Lilongwe (19.6%, 95% CI 18.0-21.3). Higher self-reported screening was observed in women who resided in urban regions ((22.7%; 95% CI 21.4-24.0) versus women who resided in rural areas (15.2%; 95% CI 14.0-16.8). Cervical cancer screening was strongly associated with being HIV positive (aOR 2.83; 95% CI 2.29-3.50), ever having been pregnant (aOR 1.93; 95% CI 1.19-3.14), attaining higher education level than secondary education (aOR 2.74; 95% CI 1.67-4.52) and being in the highest wealth quintile (aOR 2.86; 95% CI 2.01-4.08). INTERPRETATION: The coverage of cervical cancer screening in Malawi remains low and unequal by region and wealth/education class. Current screening efforts are largely being focussed on women accessing HIV services. There is need for deliberate interventions to upscale cervical cancer screening in both HIV negative women and women living with HIV.

Tuberculosis Immunoreactivity Surveillance in Malawi (Timasamala)-A protocol for a cross-sectional Mycobacterium tuberculosis immunoreactivity survey in Blantyre, Malawi.

Tuberculosis (TB) transmission and prevalence are dynamic over time, and heterogeneous within populations. Public health programmes therefore require up-to-date, accurate epidemiological data to appropriately allocate resources, target interventions, and track progress towards End TB goals. Current methods of TB surveillance often rely on case notifications, which are biased by access to healthcare, and TB disease prevalence surveys, which are highly resource-intensive, requiring many tens of thousands of people to be tested to identify high-risk groups or capture trends. Surveys of "latent TB infection", or immunoreactivity to Mycobacterium tuberculosis (Mtb), using tests such as interferon-gamma release assays (IGRAs) could provide a way to identify TB transmission hotspots, supplementing information from disease notifications, and with greater spatial and temporal resolution than is possible to achieve in disease prevalence surveys. This cross-sectional survey will investigate the prevalence of Mtb immunoreactivity amongst young children, adolescents and adults in Blantyre, Malawi, a high HIV-prevalence city in southern Africa. Through this study we will estimate the annual risk of TB infection (ARTI) in Blantyre and explore individual- and area-level risk factors for infection, as well as investigating geospatial heterogeneity of Mtb infection (and its determinants), and comparing these to the distribution of TB disease case-notifications. We will also evaluate novel diagnostics for Mtb infection (QIAreach QFT) and sampling methodologies (convenience sampling in healthcare settings and community sampling based on satellite imagery), which may increase the feasibility of measuring Mtb infection at large scale. The overall aim is to provide high-resolution epidemiological data and provide new insights into methodologies which may be used by TB programmes globally.

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries.

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5-94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those without HIV (61·0%, 51·6-69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF).

Sequential and parallel testing for microbiological confirmation of tuberculosis disease in children in five low-income and middle-income countries: a secondary analysis of the RaPaed-TB study.

BACKGROUND: Despite causing high mortality worldwide, paediatric tuberculosis is often undiagnosed. We aimed to investigate optimal testing strategies for microbiological confirmation of tuberculosis in children younger than 15 years, including the yield in high-risk subgroups (eg, children younger than 5 years, with HIV, or with severe acute malnutrition [SAM]). METHODS: For this secondary analysis, we used data from RaPaed-TB, a multicentre diagnostic accuracy study evaluating novel diagnostic assays and testing approaches for tuberculosis in children recruited from five health-care centres in Malawi, Mozambique, South Africa, Tanzania, and India conducted between Jan 21, 2019, and June 30, 2021. Children were included if they were younger than 15 years and had signs or symptoms of pulmonary or extrapulmonary tuberculosis; they were excluded if they weighed less than 2 kg, had received three or more doses of anti-tuberculosis medication at time of enrolment, were in a condition deemed critical by the local investigator, or if they did not have at least one valid microbiological result. We collected tuberculosis-reference specimens via spontaneous sputum, induced sputum, gastric aspirate, and nasopharyngeal aspirates. Microbiological tests were Xpert MTB/RIF Ultra (hereafter referred to as Ultra), liquid culture, and Löwenstein-Jensen solid culture, which were followed by confirmatory testing for positive cultures. The main outcome of this secondary analysis was categorising children as having confirmed tuberculosis if culture or Ultra positive on any sample, unconfirmed tuberculosis if clinically diagnosed, and unlikely tuberculosis if neither of these applied. FINDINGS: Of 5313 children screened, 975 were enrolled, of whom 965 (99%) had at least one valid microbiological result. 444 (46%) of 965 had unlikely tuberculosis, 282 (29%) had unconfirmed tuberculosis, and 239 (25%) had confirmed tuberculosis. Median age was 5·0 years (IQR 1·8-9·0); 467 (48%) of 965 children were female and 498 (52%) were male. 155 (16%) of 965 children had HIV and 110 (11%) children had SAM. 196 (82%) of 239 children with microbiological detection tested positive on Ultra. 110 (46%) of 239 were confirmed by both Ultra and culture, 86 (36%) by Ultra alone, and 43 (18%) by culture alone. 'Trace' was the most common semiquantitative result (93 [40%] of 234). 481 (50%) of 965 children had only one specimen type collected, 99 (21%) of whom had M tuberculosis detected. 484 (50%) of 965 children had multiple specimens collected, 141 (29%) of whom were positive on at least one specimen type. Of the 102 children younger than 5 years with M tuberculosis detected, 80 (78%) tested positive on sputum. 64 (80%) of 80 children who tested positive on sputum were positive on sputum alone; 61 (95%) of 64 were positive on induced sputum, two (3%) of 64 were positive on spontaneous sputum, and one (2%) was positive on both. INTERPRETATION: High rates of microbiological confirmation of tuberculosis in children can be achieved via parallel sampling and concurrent testing procedures. Sample types and choice of test to be used sequentially should be considered when applying to groups such as children younger than 5 years, living with HIV, or with SAM. FUNDING: European and Developing Countries Clinical Trials Partnership programme, supported by the EU, the UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung, the German Center for Infection Research, and Beckman Coulter.

The diagnostic performance of Xpert MTB/RIF Ultra on Pericardial, Pleural and Ascitic cohort study fluids for diagnosis of extra-pulmonary Tuberculosis at a referral hospital in Malawi.

Background: Extra-pulmonary tuberculosis (EPTB) accounts for 15% of the 1.4 million patients with TB notified in 2019. EPTB carries a high risk of mortality and so early diagnosis and treatment are important to reduce this risk. Diagnosis of EPTB in low- and middle-income countries is challenging. This study investigated the diagnostic performance of Xpert MTB Ultra for the diagnosis of EPTB (pericardial, pleural, and ascitic fluid) in adults at a referral hospital in Malawi. Methods: Adults with suspected extra-pulmonary TB were screened for evidence of extra-pulmonary fluid and tested for TB using Xpert MTB Ultra, mycobacterial culture, and a Focused Abdominal Sonography in HIV-associated TB (FASH scan). The diagnostic performance of the Xpert MTB Ultra was compared to mycobacterial culture and a composite reference standard defined as a positive FASH scan or a positive mycobacterial culture or a clinical TB diagnosis (constitutional symptoms not otherwise explained with response to empirical TB treatment). Results: There were 174 patients recruited: 99/174 (57%) pleural, 70/174 (40%) ascitic and 5/174 (3%) pericardial. Overall, 10/174 (6%) had bacteriologically confirmed TB and 30/174 (17%) were started on TB treatment based on a positive FASH scan or a clinical TB diagnosis. The sensitivity and specificity of Xpert ultra compared to culture was 83% (95%CI:36%-100%) and 98% (95%CI:94%-99%), respectively. Compared to the composite reference standard, the sensitivity of Xpert Ultra was 17% (95%CI:7%-34%) and specificity was 98% (95%CI:94%-100%). Conclusion: Xpert MTB Ultra provides good diagnostic performance on pleural, pericardial and ascitic fluid with reference to mycobacterial culture. Improved EPTB diagnostic tests are required to improve patient outcomes. We recommend larger multi-centre studies to corroborate our findings.

Interventions to reduce deaths in people living with HIV admitted to hospital in low- and middle-income countries: A systematic review.

People living with HIV (PLHIV) admitted to hospital have a high risk of death. We systematically appraised evidence for interventions to reduce mortality among hospitalised PLHIV in low- and middle-income countries (LMICs). Using a broad search strategy with terms for HIV, hospitals, and clinical trials, we searched for reports published between 1 Jan 2003 and 23 August 2021. Studies of interventions among adult HIV positive inpatients in LMICs were included if there was a comparator group and death was an outcome. We excluded studies restricted only to inpatients with a specific diagnosis (e.g. cryptococcal meningitis). Of 19,970 unique studies identified in search, ten were eligible for inclusion with 7,531 participants in total: nine randomised trials, and one before-after study. Three trials investigated systematic screening for tuberculosis; two showed survival benefit for urine TB screening vs. no urine screening, and one which compared Xpert MTB/RIF versus smear microscopy showed no difference in survival. One before-after study implemented 2007 WHO guidelines to improve management of smear negative tuberculosis in severely ill PLHIV, and showed survival benefit but with high risk of bias. Two trials evaluated complex interventions aimed at overcoming barriers to ART initiation in newly diagnosed PLHIV, one of which showed survival benefit and the other no difference. Two small trials evaluated early inpatient ART start, with no difference in survival. Two trials investigated protocol-driven fluid resuscitation for emergency-room attendees meeting case-definitions for sepsis, and showed increased mortality with use of a protocol for fluid administration. In conclusion, ten studies published since 2003 investigated interventions that aimed to reduce mortality in hospitalised adults with HIV, and weren't restricted to people with a defined disease diagnosis. Inpatient trials of diagnostics, therapeutics or a package of interventions to reduce mortality should be a research priority. Trial registration: PROSPERO Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019150341.

The effect of a customised digital adherence tool on HIV treatment outcomes in young people living with HIV (YPLHIV) in Blantyre, Malawi: a protocol for a randomised controlled trial.

BACKGROUND: People living with HIV (PLHIV) have to take lifelong antiretroviral treatment, which is often challenging. Young people living with HIV (YPLHIV) have the lowest viral load suppression rates in Malawi and globally, mostly due to poor treatment adherence. This is a result of complex interactions of multiple factors unique to this demographic group. The use of digital health interventions, such as real-time medication monitor (RTMM)-based digital adherence tools (DATs), could improve ART adherence in YPLHIV and subsequently improve viral load suppression which in turn could lead to reduced HIV-associated morbidity and mortality. AIM: To provide the evidence base for a digital adherence intervention to improve treatment outcomes in YPLHIV on ART. OBJECTIVES: 1. The primary objective is to determine the efficacy of a customised DAT compared to the standard of care in improving ART adherence in YPLHIV. 2. The secondary objective is to determine the efficacy of the customised DAT compared to the standard of care in improving viral load suppression in YPLHIV. METHODOLOGY: This will be a parallel open-label randomised control controlled two-arm trial in which non-adherent YPLHIV in selected ART facilities in Blantyre will be randomised in a 1:1 ratio to a customised DAT and standard care arms and followed up for 9 months. The primary outcome is the proportion adherent at 9 months (> = 95% by pill count), and the secondary outcome is the proportion with viral load suppressed at 9 months (< 200 copies/ml). DISCUSSION: There is a paucity of good quality evidence on effective digital health interventions to improve ART adherence and viral load suppression in YPLHIV globally and particularly in HIV high-burden settings like Malawi. This study will provide good-quality evidence on the effectiveness of a customised DAT in improving ART adherence and viral load suppression in this important demographic. TRIAL REGISTRATION: The trial has been registered in the Pan African Clinical Trials Registry number: PACTR202303867267716 on 23 March 2023 and can be accessed through the following URL: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=25424 . All items from the WHO Trial Registration Data Set are described in this manuscript.