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The CIDRZ Research Repository serves as an open-access archive for peer-reviewed publications, conference papers, and other scholarly outputs from CIDRZ researchers. Our goal is to promote the dissemination of knowledge and support evidence-based public health initiatives.
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Item 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.(2024) Székely, Rita; Sossen, Bianca; Mukoka, Madalo; Muyoyeta, Monde; Nakabugo, Elizabeth; Hella, Jerry; Nguyen, Hung V.; Ubolyam, Sasiwimol; Chikamatsu, Kinuyo; Macé, Aurelien; Vermeulen, Marcia; Centner, Chad M.; Nyangu, Sarah; Sanjase, Nsala; Sasamalo, Mohamed; Dinh, Huong T.; Ngo, The A.; Manosuthi, Weerawat; Jirajariyavej, Supennee; Mitarai, Satoshi; Nguyen, Nhung V.; Avihingsanon, Anchalee; Reither, Klaus; Nakiyingi, Lydia; Kerkhoff, Andrew D.; MacPherson, Peter; Meintjes, Graeme; Denkinger, Claudia M.; Ruhwald, MortenThere 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).Item Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.(2024-Jul) Broger, Tobias; Marx, Florian M. ; Theron, Grant ; Marais, Ben J ; Nicol, Mark P.; Kerkhoff, Andrew D.; Nathavitharana, Ruvandhi; Huerga, Helena; Gupta-Wright, Ankur; Kohli, Mikashmi ; Nichols, Brooke E. ; Muyoyeta, Monde; Meintjes, Graeme; Ruhwald, Morten; Peeling, Rosanna W. ; Pai, Nitika P. ; Pollock, Nira R.; Pai, Madhukar; Cattamanchi, Adithya; Dowdy, David W.; Dewan, Puneet; Denkinger, Claudia M.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.Item 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.(2024-Aug-15) Hoffmann, Christopher J.; Herce, Michael E.; Chimoyi, Lucy; Smith, Helene J.; Tlali, Mpho; Olivier, Cobus J. ; Topp, Stephanie M.; Muyoyeta, Monde; Reid, Stewart E.; Hausler, Harry; Charalambous, Salome; Fielding, KatherineBACKGROUND: 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.Item A Prospective Evaluation of the Diagnostic Accuracy of the Point-of-Care VISITECT CD4 Advanced Disease Test in 7 Countries.(2025-Feb-04) Gils, Tinne; Hella, Jerry; Jacobs, Bart K.M.; Sossen, Bianca; Mukoka, Madalo; Muyoyeta, Monde; Nakabugo, Elizabeth; Nguyen, Hung Van; Ubolyam, Sasiwimol; Macé, Aurélien; Vermeulen, Marcia; Nyangu, Sarah; Sanjase, Nsala; Sasamalo, Mohamed; Dinh, Huong T.; Ngo, The A.; Manosuthi, Weerawat; Jirajariyavej, Supunnee; Denkinger, Claudia M. ; Nguyen, Nhung V.; Avihingsanon, Anchalee; Nakiyingi, Lydia; Székely, Rita; Kerkhoff, Andrew D.; MacPherson, Peter; Meintjes, Graeme; Reither, Klaus; Ruhwald, MortenBACKGROUND: CD4 measurement is pivotal in the management of advanced human immunodeficiency virus (HIV) disease. VISITECT CD4 Advanced Disease (VISITECT; AccuBio, Ltd) is an instrument-free, point-of-care, semiquantitative test allowing visual identification of 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, people with HIV ≥18 years old were prospectively recruited in 7 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 CD4 ≤ 200 cells/ µL were evaluated. RESULTS: Among 1604 participants, the median flow cytometry CD4 was 367 cells/µL (interquartile range, 128-626 cells/µL) and 521 (32.5%) had CD4 ≤ 200 cells/µL. VISITECT sensitivity was 92.7% (483/521; 95% confidence interval [CI], 90.1%-94.7%) and specificity was 61.4% (665/1083; 95% CI, 58.4%-64.3%). For participants with CD4 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. Clinical Trials Registration. NCT04089423.Item The accuracy of point-of-care C-Reactive Protein as a screening test for tuberculosis in children.(2024) Kagujje, Mary; Nyangu, Sarah; Maimbolwa, Minyoi M.; Shuma, Brian; Sanjase, Nsala; Chungu, Chalilwe ; Kerkhoff, Andrew D.; Creswell, Jacob; Muyoyeta, MondeSystematic screening for TB in children, especially among those at high risk of TB, can promote early diagnosis and treatment of TB. The World Health Organization (WHO) recently recommended C-Reactive Protein as a TB screening tool in adults and adolescents living with HIV (PLHIV). Thus, we aimed to assess the performance of point-of-care (POC) CRP as a screening tool for TB in children. A cross-sectional study was conducted at 2 primary health care facilities in Lusaka, Zambia between September 2020 -August 2021. Consecutive children (aged 5-14 years) presenting for TB services were enrolled irrespective of TB symptoms. All participants were screened for the presence of TB symptoms and signs, asked about TB contact history, and undertook a POC CRP test, chest X-ray, and sputum Xpert MTB/RIF Ultra test. The accuracy of CRP (≥10 mg/L cutoff) was determined using a microbiological reference standard (MRS) and a composite reference standard (CRS). Of 280 children enrolled and with complete results available, the median age was 10 years (IQR 7-12), 56 (20.0%) were HIV positive, 228 (81.4%) had a positive WHO symptom screen for TB, 62 (22.1%) had a close TB contact, and 79 (28.2%) had a positive CRP POC test. Five (1.8%) participants had confirmed TB, 71 (25.4%) had unconfirmed TB, and 204 (72.3%) had unlikely TB. When the MRS was used, the sensitivity of CRP was 80.0% (95%CI: 28.4-99.5%) and the specificity was 72.7% (95%CI: 67.1-77.9%). When the CRS was used, the sensitivity of CRP was 32.0% (95%CI: 23.3% - 42.5%), while the specificity was 74.0% (95%CI: 67.0% - 80.3%). Using the CRS, there were no statistically significant differences in sensitivity and specificity of CRP in the HIV positive and HIV negative individuals. Among children in Zambia, POC CRP had limited utility as a screening tool for TB. There remains a continued urgent need for better tools and strategies to improve TB detection in children.Item Urine-Xpert Ultra for the diagnosis of tuberculosis in people living with HIV: a prospective, multicentre, diagnostic accuracy study.(2024-Dec) Sossen, Bianca; Székely, Rita; Mukoka, Madalo; Muyoyeta, Monde; Nakabugo, Elizabeth; Hella, Jerry; Van Nguyen, Hung; Ubolyam, Sasiwimol; Erkosar, Berra; Vermeulen, Marcia; Centner, Chad M.; Nyangu, Sarah; Sanjase, Nsala; Sasamalo, Mohamed; Dinh, Huong T.; Ngo, The A.; Manosuthi, Weerawat; Jirajariyavej, Supunnee; Nguyen, Nhung V.; Avihingsanon, Anchalee; Kerkhoff, Andrew D.; Denkinger, Claudia M.; Reither, Klaus; Nakiyingi, Lydia; MacPherson, Peter; Meintjes, Graeme; Ruhwald, MortenBACKGROUND: Diagnostic delays for tuberculosis are common, with high resultant mortality. Urine-Xpert Ultra (Cepheid) could improve time to diagnosis of tuberculosis disease and rifampicin resistance. We previously reported on lot-to-lot variation of the Fujifilm SILVAMP TB LAM. In this prespecified secondary analysis of the same cohort, we aimed to determine the diagnostic yield and accuracy of Urine-Xpert Ultra for tuberculosis in people with HIV, compared with an extended microbiological reference standard (eMRS) and composite reference standard (CRS) and also compared with Determine TB LAM Ag (AlereLAM, Abbott). METHODS: In this prospective, multicentre, diagnostic accuracy study, we recruited consecutive inpatients and outpatients (aged ≥18 years) with HIV from 13 hospitals and clinics in seven countries (Malawi, South Africa, Tanzania, Thailand, Uganda, Viet Nam, and Zambia). Patients with no isoniazid preventive therapy in the past 6 months and fewer than three doses of tuberculosis treatment in the past 60 days were included. Reference and index testing was performed in real time. The primary outcome of this secondary analysis was the diagnostic yield and accuracy of Urine-Xpert Ultra compared with the eMRS and CRS. Diagnostic accuracy was compared with AlereLAM and diagnostic yield was compared with both AlereLAM and Sputum-Xpert Ultra. This study was registered with ClinicalTrials.gov, NCT04089423, and is complete. FINDINGS: Between Dec 13, 2019, and Aug 5, 2021, 3528 potentially eligible individuals were screened and 1731 were enrolled, of whom 1602 (92·5%) were classifiable by the eMRS (median age 40 years [IQR 33-48], 838 [52·3%] of 1602 were female, 764 [47·7%] were male, 937 [58·5%] were outpatients, 665 [41·5%] were inpatients, median CD4 count was 374 cells per μL [IQR 138-630], and 254 [15·9%] had microbiologically confirmed tuberculosis). Against eMRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 32·7% (95% CI 27·2-38·7) and 30·7% (25·4-36·6) and specificities were 98·0% (97·1-98·6) and 90·4% (88·7-91·8), respectively. Against CRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 21·1% (95% CI 17·6-25·1), and 30·5% (26·4-34·9), and specificities were 99·1% (98·3-99·6) and 95·1% (93·5-96·3), respectively. The combination of Sputum-Xpert Ultra with AlereLAM or Urine-Xpert Ultra diagnosed 202 (77·1%) and 204 (77·9%) of 262 eMRS-positive participants, respectively, in incompletely overlapping groups; combining all three tests diagnosed 214 (81·7%) of 262 eMRS-positive participants INTERPRETATION: Urine-Xpert Ultra could offer promising clinical utility in addition to AlereLAM and Sputum-Xpert Ultra. In inpatient settings where both AlereLAM and Urine-Xpert Ultra are possible, both should be offered to support rapid diagnosis and treatment. FUNDING: Global Health Innovative Technology Fund, KfW Development Bank, Commonwealth of Australia represented by the Department of Foreign Affairs and Trade, and the Netherlands Enterprise Agency.Item Prospective Multi-Site Validation of AI to Detect Tuberculosis and Chest X-Ray Abnormalities.(2024-Oct) Kazemzadeh, Sahar; Kiraly, Atilla P.; Nabulsi, Zaid; Sanjase, Nsala; Maimbolwa, Minyoi ; Shuma, Brian; Jamshy, Shahar; Chen, Christina; Agharwal, Arnav; Lau, Charles T.; Sellergren, Andrew; Golden, Daniel; Yu, Jin; Wu, Eric; Matias, Yossi; Chou, Katherine ; Corrado, Greg S.; Shetty, Shravya ; Tse, Daniel; Eswaran, Krish; Liu, Yun; Pilgrim, Rory; Muyoyeta, Monde; Prabhakara, ShruthiBACKGROUND: Using artificial intelligence (AI) to interpret chest X-rays (CXRs) could support accessible triage tests for active pulmonary tuberculosis (TB) in resource-constrained settings. METHODS: The performance of two cloud-based CXR AI systems - one to detect TB and the other to detect CXR abnormalities - in a population with a high TB and human immunodeficiency virus (HIV) burden was evaluated. We recruited 1978 adults who had TB symptoms, were close contacts of known TB patients, or were newly diagnosed with HIV at three clinical sites. The TB-detecting AI (TB AI) scores were converted to binary using two thresholds: a high-sensitivity threshold and an exploratory threshold designed to resemble radiologist performance. Ten radiologists reviewed images for signs of TB, blinded to the reference standard. Primary analysis measured AI detection noninferiority to radiologist performance. Secondary analysis evaluated AI detection as compared with the World Health Organization (WHO) targets (90% sensitivity, 70% specificity). Both used an absolute margin of 5%. The abnormality-detecting AI (abnormality AI) was evaluated for noninferiority to a high-sensitivity target suitable for triaging (90% sensitivity, 50% specificity). RESULTS: Of the 1910 patients analyzed, 1827 (96%) had conclusive TB status, of which 649 (36%) were HIV positive and 192 (11%) were TB positive. The TB AI's sensitivity and specificity were 87% and 70%, respectively, at the high-sensitivity threshold and 78% and 82%, respectively, at the balanced threshold. Radiologists' mean sensitivity was 76% and mean specificity was 82%. At the high-sensitivity threshold, the TB AI was noninferior to average radiologist sensitivity (P<0.001) but not to average radiologist specificity (P=0.99) and was higher than the WHO target for specificity but not sensitivity. At the balanced threshold, the TB AI was comparable to radiologists. The abnormality AI's sensitivity and specificity were 97% and 79%, respectively, with both meeting the prespecified targets. CONCLUSIONS: The CXR TB AI was noninferior to radiologists for active pulmonary TB triaging in a population with a high TB and HIV burden. Neither the TB AI nor the radiologists met WHO recommendations for sensitivity in the study population. AI can also be used to detect other CXR abnormalities in the same population.Item Designing community-based strategies to reach non-household contacts of people with tuberculosis in Lusaka, Zambia: a rapid qualitative study among key stakeholders.(2024) Kerkhoff, Andrew D.; Foloko, Marksman; Kundu-Ng'andu, Evelyn; Nyirenda, Herbert; Jabbie, Zainab; Syulikwa, Mainza; Mwamba, Chanda; Kagujje, Mary; Muyoyeta, Monde; Sharma, AnjaliBACKGROUND: In high-burden settings, most tuberculosis (TB) transmission likely occurs outside the home. Our qualitative study in Zambia explored the acceptability and preferences for designing TB active case finding (ACF) strategies to reach non-household contacts of people with TB. METHODS: We conducted 56 in-depth interviews with persons with TB ( RESULTS: All participants felt that TB was an important issue in their community and that new detection strategies were needed. A "social-network strategy" was perceived as acceptable and feasible, where participants noted it was a caring act and could facilitate early diagnosis. For a "venue-based strategy," most participants suspected TB transmission occurred at bars/taverns due to heavy alcohol use and prolonged time spent in crowded spaces; churches and betting halls were also commonly mentioned locations. Nearly all owners/leaders and patrons/attendees of bars, churches, and betting halls expressed acceptance of a venue-based strategy. They also indicated an interest in participating, citing many benefits, including increased TB knowledge/awareness, early diagnosis, convenience, and possibly reduced transmission, and recommended that the strategy incorporate sensitization, consent, volunteerism, and respectful, confidential, private services. For both strategies, most participants preferred the use of and being approached by trained peer TB survivors to facilitate ACF, given their prior TB patient experience and trust among community members. CONCLUSION: Stakeholders found social-network and venue-based TB-ACF strategies highly acceptable, recognizing their potential benefits for individuals and the broader community. Future research should evaluate the feasibility and effectiveness of TB ACF strategies for reaching non-household contacts.Item Point-of-Care Urine Ethyl Glucuronide Testing to Detect Alcohol Use Among HIV-Hepatitis B Virus Coinfected Adults in Zambia.(2018-Jul) Vinikoor, Michael J.; Zyambo, Zude; Muyoyeta, Monde; Chander, Geetanjali; Saag, Michael S.; Cropsey, KarenIn an HIV-hepatitis B virus (HIV-HBV) coinfection cohort in Zambia, we piloted a qualitative point-of-care (POC) test for urine Ethyl glucuronide (uEtG), assessed concordance between uEtG and alcohol use disorders identification test-consumption (AUDIT-C), and identified epidemiological factors associated with underreporting (defined as uEtG-positivity with last reported drink > 7 days prior). Among 211 participants (40.8% women), there were 44 (20.8%) lifetime abstainers, 32 (15.2%) former drinkers, and 135 (64.0%) current drinkers, including 106 (50.2%) with unhealthy drinking per AUDIT-C. Eighty-seven (41.2%) were uEtG-positive including 64 of 65 (98.5%) who drank ≤ 3 days prior and 17 of 134 (12.7%) underreported, all of whom admitted to recent drinking when results were discussed. uEtG was moderately concordant with AUDIT-C. Past drinking (versus lifetime abstinence) and longer time on antiretrovirals (≥ 12 months) were associated with underreporting. These data support further use of POC alcohol biomarkers in HIV and hepatitis research and clinical settings.Item Coordinating the prevention, treatment, and care continuum for HIV-associated tuberculosis in prisons: a health systems strengthening approach.(2018-Nov) Herce, Michael E.; Muyoyeta, Monde; Topp, Stephanie M.; Henostroza, German; Reid, Stewart E.PURPOSE OF REVIEW: To advance a re-conceptualized prevention, treatment, and care continuum (PTCC) for HIV-associated tuberculosis (TB) in prisons, and to make recommendations for strengthening prison health systems and reducing HIV-associated TB morbidity and mortality throughout the cycle of pretrial detention, incarceration, and release. RECENT FINDINGS: Despite evidence of increased HIV-associated TB burden in prisons compared to the general population, prisoners face entrenched barriers to accessing anti-TB therapy, antiretroviral therapy, and evidence-based HIV and TB prevention. New approaches, suitable for the complexities of healthcare delivery in prisons, have emerged that may address these barriers, and include: novel TB diagnostics, universal test and treat for HIV, medication-assisted treatment for opioid dependence, comprehensive transitional case management, and peer navigation, among others. SUMMARY: Realizing ambitious international HIV and TB targets in prisons will only be possible by first addressing the root causes of the TB/HIV syndemic, which are deeply intertwined with human rights violations and weaknesses in prison health systems, and, second, fundamentally re-organizing HIV and TB services around a coordinated PTCC. Taking these steps can help ensure universal access to comprehensive, good-quality, free and voluntary TB/HIV prevention, treatment, and care, and advance efforts to strengthen health resourcing, staffing, information management, and primary care access within prisons.