A prospective evaluation of the diagnostic accuracy of the point-of-care VISITECT CD4 Advanced Disease test in seven countries.

BACKGROUND: CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT® CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or >200 cells/µl from finger-prick or venous blood. METHODS: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated. RESULTS: Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128-626) cells/µl and 521 (32.5%) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7% (483/521, 95% CI 90.1-94.7%) and specificity was 61.4% (665/1083, 95% CI 58.4-64.3%). For participants with a CD4 between 0-100, 101-200, 201-300, 301-500, and >500 cells/µl, VISITECT misclassified 4.5% (95% CI 2.5-7.2%), 12.5 (95% CI 8.0-18.2%), 74.1% (95% CI 67.0-80.5%), 48.0% (95% CI 42.5-53.6%), and 22.6% (95% CI 19.3-26.3%), respectively. CONCLUSIONS: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated.

Engagement of private health care facilities in TB management in Lusaka district of Zambia: lessons learned and achievements.

BACKGROUND: Globally, at least 3 million TB patients are missed every year. In Zambia, the TB treatment coverage increased from 66% in 2020 to 92% in 2022. Involvement of all levels of health care service delivery is critical to finding all the missing TB patients. METHODS: A survey was undertaken in 15 private facilities in Lusaka district of Zambia using a structured tool administered by project team and a district health team member. Data collected during the survey was analysed and results were used to determine the type of TB services that were offered as well as barriers and enablers to TB service provision. This was followed by a set of interventions that included; training and mentorship on active case finding and systematic TB screening, increased diagnostic capacity, provision of national recording and reporting tools and provision of TB medication through linkage with the National TB program (NTP). We report findings from the baseline survey and changes in presumptive TB identification and notification following interventions. RESULTS: Major barriers to TB service delivery were the high cost of TB diagnostic testing and treatment in facilities where services were not supported by the National TB program; the mean cost was 33 (SD 33) and 93 (SD 148) for GeneXpert testing and a full course of treatment respectively. Pre-intervention, presumptive TB identification appeared to increase monthly by 4 (P = 0.000, CI=[3.00-5.00]). The monthly trends of presumptive TB identification during the intervention period increased by 5.32 (P = 0.000, [CI 4.31-6.33. Pre-intervention, the notification of TB appeared to decrease every month by -4.0 (P = 0.114, CI=[-9.00-0.10]) followed by an immediate increase in notifications of 13.94 TB patients (P = 0.001, CI [6.51, 21.36] in the first month on intervention. The monthly trends of notification during the intervention period changed by 0.34 (P = 0.000 [CI 0.19-0.48]). Private facility contribution to TB notification increased from 3 to 7%. CONCLUSION: Engagement and inclusion of private health facilities in TB service provision through a systems strengthening approach can increase contribution to TB notification by private health facilities.

Knowledge, attitudes, and practices towards childhood tuberculosis among healthcare workers at two primary health facilities in Lusaka, Zambia.

BACKGROUND: Zambia is among the 30 high-burden countries for tuberculosis (TB), Human Immunodeficiency Virus (HIV)-associated TB, and multi-drug resistant/rifampicin resistant TB with over 5000 children developing TB every year. However, at least 32% of the estimated children remain undiagnosed. We assessed healthcare workers' (HCWs) knowledge, attitudes, and practices (KAP) towards childhood TB and the factors associated with good KAP towards childhood TB. METHODS: Data was collected at two primary healthcare facilities in Lusaka, Zambia from July to August 2020. Structured questionnaires were administered to HCWs that were selected through stratified random sampling. Descriptive analysis was done to determine KAP. A maximum knowledge, attitude, and practice scores for a participant were 44, 10, and 8 points respectively. The categorization as either "poor" or "good" KAP was determined based on the mean/ median. Logistic regression analysis was performed to assess the associations between participant characteristics and KAP at statistically significant level of 0.05%. RESULTS: Among the 237 respondents, majority were under 30 years old (63.7%) and were female (72.6%). Half of the participants (50.6%) were from the outpatient department (OPD) and antiretroviral therapy (ART) clinic, 109 (46.0) had been working at the facility for less than 1 year, 134 (56.5%) reported no previous training in TB. The median/mean KAP scores were 28 (IQR 24.0-31.0), 7 (IQR = 6.0-8.0) and 5 points (SD = 1.9) respectively. Of the participants, 43.5% (103/237) had good knowledge, 48.1% (114/237) had a good attitude, and 54.4% (129/237) had good practice scores on childhood TB. In the multivariate analysis, clinical officers and individuals with 1-5 years' work experience at the facility had higher odds, 2.61 (95% CI = 1.18-5.80, p = 0.018) and 3.09 (95% CI = 1.69-5.65, p = 0.001) of having good attitude respectively, and medical doctors had 0.17 lower odds (95% CI = 0.18-5.80, p = 0.018) of good childhood TB practice. Other participant characteristics didn't show a significant association with the scores. CONCLUSION: The study found suboptimal levels of knowledge, attitude, and practices regarding childhood TB among HCWs. Targeted programmatic support needs to be provided to address the above gaps.

The Incidence and Risk Factors for Enterotoxigenic E. coli Diarrheal Disease in Children under Three Years Old in Lusaka, Zambia.

This study aimed to estimate the incidence and risk factors for Enterotoxigenic Escherichia coli (ETEC) diarrhea. This was a prospective cohort study of children recruited in a household census. Children were enrolled if they were 36 months or below. A total of 6828 children were followed up passively for 12 months to detect episodes of ETEC diarrhea. Diarrheal stool samples were tested for ETEC using colony polymerase chain reaction (cPCR). Among the 6828 eligible children enrolled, a total of 1110 presented with at least one episode of diarrhea. The overall incidence of ETEC diarrhea was estimated as 2.47 (95% confidence interval (CI): 2.10-2.92) episodes per 100 child years. Children who were HIV-positive (adjusted Hazard ratio (aHR) = 2.14, 95% CI: 1.14 to 3.99; p = 0.017) and those whose source of drinking water was public tap/borehole/well (aHR = 2.45, 95% CI: 1.48 to 4.06; p < 0.002) were at increased risk of ETEC diarrhea. This study found that children whose mothers have at least senior secondary school education (aHR = 0.49, 95% CI: 0.29 to 0.83; p = 0.008) were at decreased risk of ETEC diarrhea. Our study emphasizes the need for integrated public health strategies focusing on water supply improvement, healthcare for persons living with HIV, and maternal education.

Reaching for 90:90:90 in Correctional Facilities in South Africa and Zambia: Virtual Cross-Section of Coverage of HIV Testing and Antiretroviral Therapy During Universal Test and Treat Implementation.

BACKGROUND: People in correctional settings are a key population for HIV epidemic control. We sought to demonstrate scale-up of universal test and treat in correctional facilities in South Africa and Zambia through a virtual cross-sectional analysis. METHODS: We used routine data on 2 dates: At the start of universal test and treat implementation (time 1, T1) and 1 year later (time 2, T2). We obtained correctional facility census lists for the selected dates and matched HIV testing and treatment data to generate virtual cross-sections of HIV care continuum indicators. RESULTS: In the South African site, there were 4193 and 3868 people in the facility at times T1 and T2; 43% and 36% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 1803 (43%) and 1386 (36%) had known HIV status, 804 (19%) and 845 (21%) were known to be living with HIV, and 60% and 56% of those with known HIV were receiving antiretroviral therapy (ART). In the Zambian site, there were 1467 and 1366 people in the facility at times T1 and T2; 58% and 92% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 857 (59%) and 1263 (92%) had known HIV status, 277 (19%) and 647 (47%) were known to be living with HIV, and 68% and 68% of those with known HIV were receiving ART. CONCLUSIONS: This virtual cross-sectional analysis identified gaps in HIV testing coverage, and ART initiation that was not clearly demonstrated by prior cohort-based studies.

Expanding molecular diagnostic coverage for tuberculosis by combining computer-aided chest radiography and sputum specimen pooling: a modeling study from four high-burden countries.

Background: In 2022, fewer than half of persons with tuberculosis (TB) had access to molecular diagnostic tests for TB due to their high costs. Studies have found that the use of artificial intelligence (AI) software for chest X-ray (CXR) interpretation and sputum specimen pooling can each reduce the cost of testing. We modeled the combination of both strategies to estimate potential savings in consumables that could be used to expand access to molecular diagnostics. Methods: We obtained Xpert testing and positivity data segmented into deciles by AI probability scores for TB from the community- and healthcare facility-based active case finding conducted in Bangladesh, Nigeria, Viet Nam, and Zambia. AI scores in the model were based on CAD4TB version 7 (Zambia) and qXR (all other countries). We modeled four ordinal screening and testing approaches involving AI-aided CXR interpretation to indicate individual and pooled testing. Setting a false negative rate of 5%, for each approach we calculated additional and cumulative savings over the baseline of universal Xpert testing, as well as the theoretical expansion in diagnostic coverage. Results: In each country, the optimal screening and testing approach was to use AI to rule out testing in deciles with low AI scores and to guide pooled vs individual testing in persons with moderate and high AI scores, respectively. This approach yielded cumulative savings in Xpert tests over baseline ranging from 50.8% in Zambia to 57.5% in Nigeria and 61.5% in Bangladesh and Viet Nam. Using these savings, diagnostic coverage theoretically could be expanded by 34% to 160% across the different approaches and countries. Conclusions: Using AI software data generated during CXR interpretation to inform a differentiated pooled testing strategy may optimize TB diagnostic test use, and could extend molecular tests to more people who need them. The optimal AI thresholds and pooled testing strategy varied across countries, which suggests that bespoke screening and testing approaches may be needed for differing populations and settings. Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00081-2.

Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosis in people living with HIV demonstrates lot-to-lot variability.

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).

Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.