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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 Design and feasibility considerations for a phase 3 efficacy trial of the M72/AS01(2026-Jul-11) Dagnew AF; Noble R; Cinar A; Burhan E; Churchyard G; Fairlie L; Hanekom WA; Muyoyeta M; Mwandumba HC; Nduba V; Curran M; Schmidt ACBACKGROUND: M72/AS01 METHODS: We conducted event-driven simulations using lower bound (LB) of the two-sided 95% confidence interval (CI) for VE(D). For IGRA-positive participants, assumptions included 1:1 randomization, 9000 participants/arm, 0.4% TB incidence/year, 55% true VE(D), 5% dropout/year, and two-year enrollment. Enrollment irrespective of baseline IGRA status (mixed IGRA-status population) and IGRA-negative-only scenarios were explored to estimate sample sizes and trial duration. RESULTS: Simulations demonstrated that 110 events rule out a VE(D) 95% CI LB ≤10%, and 185 events rule out ≤25%, assuming ≥90% power and a true VE(D) of 55%. With 18,000 IGRA-positive participants, simulations projected a 90% probability of accruing 110 events within 3.5 to 4 years and 185 within 5.5 to 6 years. In the mixed IGRA-status population, few endpoints occurred among IGRA-negative participants, yielding insufficient power. Standalone VE(D) evaluation in IGRA-negative participants required large sample sizes (approximately 134,800) and prolonged timelines, indicating infeasibility. Accordingly, the selected primary objective of the phase 3 trial was to confirm VE(D) in IGRA-positive HIV-negative participants using LB of 95% CI for VE(D) > 10% after 110 events; secondary objectives include safety and immunogenicity in HIV-negative IGRA-positive; HIV-negative IGRA-negative; and HIV-positive individuals irrespective of IGRA status. CONCLUSIONS: An IGRA-positive-enriched, event-driven phase 3 trial is feasible to confirm VE(D) of M72/AS01Item Multicountry assessment of tongue swabs for tuberculosis using a common protocol for Xpert MTB/RIF Ultra testing: a prospective diagnostic accuracy study.(2026-May-14) de Vos M; Le H; Marcelo D; Ajide B; Alí-Francia KG; Borkman AL; Desravines R; Chang HT; Dowling W; Kamulegeya L; Marconi S; Moe CA; Rockman L; Shuma B; Christopher DJ; Hapeela N; Muyoyeta M; Nakiyingi L; Theron G; Ugarte-Gil C; Hung NV; Luong DV; Yu C; Alland D; Denkinger CM; Ellner J; Dorman SE; Kremer K; Manabe YC; Nahid P; Ruhwald M; Shah M; Penn-Nicholson A; Cattamanchi A; Bimba JSBACKGROUND: Despite advancements in tuberculosis diagnostics, many cases remain unconfirmed because of challenges in conventional sputum-based testing. This study aimed to evaluate the diagnostic accuracy of tongue swab sampling as a non-invasive alternative for tuberculosis diagnosis using Xpert MTB/RIF Ultra (Ultra). METHODS: We conducted a large-scale, multicountry, prospective diagnostic accuracy study of Ultra using tongue swabs in people with presumptive pulmonary tuberculosis. Participants were enrolled consecutively at primary health centres and hospitals across eight countries from June 26, 2023, to Feb 15, 2024, and the study was coordinated by three consortia. Eligible participants were individuals aged 12 years or older or 18 years or older, according to the consortium involved, with presumptive pulmonary tuberculosis or at least one risk factor for tuberculosis and a positive tuberculosis screening test at the select consortia. Standardised tongue swab collection and processing protocols were used in all countries. Sensitivity and specificity with 95% CI values were calculated against sputum liquid or solid culture (primary) and sputum Ultra (secondary) reference standards using Wilson's score method. Fisher's exact tests were used for subgroup comparisons, with p values < 0·05 considered statistically significant. FINDINGS: Among the 1844 participants included in the analysis, 389 tested positive and 1455 tested negative for pulmonary tuberculosis based on the primary sputum culture reference standard. 871 (47·2%) participants were female and 973 (52·7%) were male, with a mean age of 43 years (range 12-90). Among the 1844 participants, 399 (21·7%) were enrolled in Viet Nam, 166 (9·0%) in India, 427 (23·2%) in South Africa, 271 (14·7%) in the Philippines, 138 (7·5%) in Nigeria, 102 (5·5%) in Zambia, 175 (9·5%) in Uganda, and 166 (9·0%) in Peru. Tongue swab Ultra testing showed a sensitivity of 65·6% (95% CI 60·6-70·3) and specificity of 98·5% (95% CI 97·7-99·1) against the culture-based reference standard. Sensitivity estimates varied across collection centres and were higher in individuals without HIV than in those living with HIV (68·4% vs 50·0%; absolute difference 18·4 percentage points [95% CI 3·3-33·4]). When sputum Ultra was used as the reference standard, sensitivity was 75·4% (95% CI 69·0-78·8). Tongue swab Ultra showed higher sensitivity than sputum smear microscopy. Invalid or error result rates were variable and high at certain sites (range 0-16%). INTERPRETATION: Tongue swabs are a promising sample type for rapid diagnostic tests for tuberculosis, with moderate sensitivity and high specificity when Ultra was used as the reference standard. However, further research is needed to optimise protocols for Ultra testing and develop assays tailored to tongue swab specimens. Adoption of tongue swab-based molecular testing could expand tuberculosis diagnostics access, especially for populations unable to produce sputum, thus supporting global tuberculosis elimination goals. FUNDING: National Institute of Allergy and Infectious Diseases, United States Agency for International Development.Item Design and feasibility considerations for a phase 3 efficacy trial of the M72/AS01(2026-May-12) Dagnew AF; Noble R; Cinar A; Burhan E; Churchyard G; Fairlie L; Hanekom WA; Muyoyeta M; Mwandumba HC; Nduba V; Curran M; Schmidt ACBACKGROUND: M72/AS01 METHODS: We conducted event-driven simulations using lower bound (LB) of the two-sided 95% confidence interval (CI) for VE(D). For IGRA-positive participants, assumptions included 1:1 randomization, 9000 participants/arm, 0.4% TB incidence/year, 55% true VE(D), 5% dropout/year, and two-year enrollment. Enrollment irrespective of baseline IGRA status (mixed IGRA-status population) and IGRA-negative-only scenarios were explored to estimate sample sizes and trial duration. RESULTS: Simulations demonstrated that 110 events rule out a VE(D) 95% CI LB ≤10%, and 185 events rule out ≤25%, assuming ≥90% power and a true VE(D) of 55%. With 18,000 IGRA-positive participants, simulations projected a 90% probability of accruing 110 events within 3.5 to 4 years and 185 within 5.5 to 6 years. In the mixed IGRA-status population, few endpoints occurred among IGRA-negative participants, yielding insufficient power. Standalone VE(D) evaluation in IGRA-negative participants required large sample sizes (approximately 134,800) and prolonged timelines, indicating infeasibility. Accordingly, the selected primary objective of the phase 3 trial was to confirm VE(D) in IGRA-positive HIV-negative participants using LB of 95% CI for VE(D) > 10% after 110 events; secondary objectives include safety and immunogenicity in HIV-negative IGRA-positive; HIV-negative IGRA-negative; and HIV-positive individuals irrespective of IGRA status. CONCLUSIONS: An IGRA-positive-enriched, event-driven phase 3 trial is feasible to confirm VE(D) of M72/AS01Item Pulmonary Tuberculosis Detection with MiniDock MTB Using Swab Samples.(2026-Apr-30) Yerlikaya S; Chirwa M; Ajide B; Castro MDM; Ha H; Kato-Maeda M; Kisakye E; Marcelo D; Mochizuki T; Rockman L; Steadman A; Thangakunam B; Bimba JS; Christopher DJ; Muyoyeta M; Phan H; Theron G; Yu C; Kremer K; Phillips PPJ; Nahid P; Denkinger CM; Cattamanchi A; Andama ABACKGROUND: Improved diagnostic tools for tuberculosis that are suitable for use in peripheral health centers are essential for reducing the persistent gap between estimated and notified cases. The diagnostic accuracy and usability of the MiniDock MTB test for detecting pulmonary tuberculosis is unknown. METHODS: We conducted a prospective, cross-sectional study at outpatient centers in India, Nigeria, the Philippines, South Africa, Uganda, Vietnam, and Zambia. Patients 12 years of age or older with presumptive pulmonary tuberculosis were enrolled between September 12, 2024, and March 31, 2025. Assessment with MiniDock MTB was performed with sputum swabs and tongue swabs. Diagnostic accuracy was evaluated against a sputum-culture-based reference and as compared with sputum-smear microscopy and Xpert MTB/RIF Ultra assay. Usability was assessed with a system usability scale and direct observation. RESULTS: A total of 1380 participants were enrolled; 255 (18.5%) had human immunodeficiency virus infection and 226 (16.4%) had culture-confirmed tuberculosis. MiniDock MTB sensitivity was 85.7% (95% confidence interval [CI], 80.4 to 90.0) with sputum and 79.6% (95% CI, 73.8 to 84.7) with tongue swabs; specificity was greater than 97.5% for both. Results of sputum tests with MiniDock MTB closely matched those with Xpert MTB/RIF Ultra for sensitivity (difference, -2.8 percentage points; 95% CI, -6.0 to 0.5). MiniDock MTB had greater sensitivity than smear microscopy for tests of sputum (difference, 24.3 percentage points; 95% CI, 17.9 to 30.7) and tongue swabs (difference, 18.3 percentage points; 95% CI, 12.0 to 24.7). The test showed diagnostic accuracy that was consistent with World Health Organization (WHO) accuracy targets for near-point-of-care tuberculosis diagnostics (≥85% sensitivity for sputum and ≥75% for nonsputum and ≥98% specificity for both). The median score on the system usability scale (range, 0 to 100, with higher scores indicating better perceived usability) was 75 (interquartile range, 65 to 80), which indicated good usability. No adverse events related to the index test were reported. CONCLUSIONS: MiniDock MTB met WHO targets for diagnostic accuracy and usability for tuberculosis detection across diverse clinical settings. (Funded by the National Institutes of Health and others; Rapid Research in Diagnostics Development for TB Network and Assessing Diagnostics at Point-of-Care for Tuberculosis ClinicalTrials.gov numbers, NCT04923958 and NCT05941052.).Item Diagnostic Yield of Tongue Swab- Compared to Sputum-Based Molecular Testing for Tuberculosis in Four High-Burden Countries.(2026-Apr-30) Moe CA; Luswata RK; Barrameda AJ; Le H; Muzazu S; Crowder R; Andama AO; Denkinger CM; Muyoyeta M; Phan H; Cattamanchi A; Yu CBACKGROUND: Tongue swabs are a promising alternative specimen for tuberculosis (TB) diagnosis. Although test specificity exceeds 98%, sensitivity is lower than sputum-based molecular testing. We investigated whether the use of tongue swabs could increase sample availability, resulting in similar diagnostic yield. METHODS: In this cross-sectional study (July 2024-January 2025), we screened consecutive people with presumptive TB at health centers in the Philippines, Vietnam, Uganda, and Zambia. Participants were asked to provide tongue swabs and referred for routine sputum collection. Tongue swabs were tested in research laboratories using the MiniDock MTB Test (Guangzhou Pluslife Biotech Co., Ltd., China); sputum was tested using WHO-recommended molecular testing per national guidelines. We compared diagnostic yield, defined as proportion of positive test results among all participants, between tongue swab- and sputum-based molecular testing with a prespecified 3.0% non-inferiority margin. RESULTS: Of 1639 participants, 851 (51.9%) were female, 415 (25.3%) were diagnosed with HIV, and 132 (8.1%) were children <5 years. All provided tongue swabs, but only 1389 (84.7%) produced sputum. Diagnostic yield was 3.8% (63/1639) for tongue swabs and 4.1% (68/1639) for sputum-based (68/1639, 4.1%) molecular testing. The difference (0.3%, 95% CI -0.6 to +1.2) was within the prespecified non-inferiority margin. Results were consistent across countries and key subgroups (age, sex, and HIV status). CONCLUSIONS: Tongue swab-based molecular testing with MiniDock MTB achieved non-inferior diagnostic yield compared with sputum-based molecular testing. These findings support scale-up of swab-based platforms as a cost-efficient alternative, particularly where sputum collection is challenging or smear microscopy remains the primary diagnostic method.Item Tongue swab Xpert MTB/RIF Ultra testing for TB using a revised consensus protocol.(2026-Apr-27) Ajide B; Moe CA; Barrameda J; Chirwa M; Rockman L; de Haas P; de Vos M; Kato-Maeda M; Tasca B; Bimba J; Yu C; Denkinger CM; Kremer K; Nahid P; Cattamanchi A; Theron G; Muyoyeta MBACKGROUNDTongue swabs are a promising specimen type for TB diagnosis. In a previous study, using a consensus protocol, tongue swabs tested with Xpert MTB/RIF Ultra outperformed sputum smear microscopy, but a substantial proportion (6.1%) of results were non-actionable (e.g., invalid/error). We evaluated a revised protocol for tongue swab Xpert Ultra testing in four high-burden countries.METHODSParticipants aged ≥12 years with presumptive TB were enrolled from outpatient clinics in the Philippines, South Africa, Nigeria, and Zambia. Tongue swabs were processed using Sample Reagent (SR, Cepheid, USA) diluted 2:1 with phosphate buffer or phosphate-buffered saline and tested with Xpert Ultra. Diagnostic performance was assessed against culture-based microbiological reference standard and compared to sputum tests.RESULTSFrom March to November 2024, 1,168 participants were enrolled (median age 37 [IQR: 28-48] years; 46.7% female; 21.8% living with HIV; 18.5% culture-confirmed TB). The proportion of non-actionable tongue swab results was 5.6% overall, but <4% in all countries except South Africa (15.4%). Tongue swab sensitivity was 66.0% (95% CI: 59.0-72.5); specificity was 99.6% (95% CI: 98.9-99.9).CONCLUSIONThe revised protocol yielded low error rates at most sites and moderate sensitivity, supporting tongue swabs as an alternative specimen for Xpert Ultra testing when sputum is unavailable..Item Coverage of clinic-based TB screening in South Africa may be low in key risk groups.(2016-Mar-21) McCreesh N; Faghmous I; Looker C; Dodd PJ; Plumb ID; Shanaube K; Muyoyeta M; Godfrey-Faussett P; Ayles H; White RGThe South African Ministry of Health has proposed screening all clinic attendees for tuberculosis (TB). Amongst other factors, male sex and bar attendance are associated with higher TB risk. We show that 45% of adults surveyed in Western Cape attended a clinic within 6 months, and therefore potentially a relatively high proportion of the population could be reached through clinic-based screening. However, fewer than 20% of all men aged 18-25 years, or men aged 26-45 who attend bars, attended a clinic. The population-level impact of clinic-based screening may be reduced by low coverage among key risk groups.Item Diagnosed with TB in the era of COVID-19: patient perspectives in Zambia.(2020-Dec-21) Mwamba C; Kerkhoff AD; Kagujje M; Lungu P; Muyoyeta M; Sharma AINTRODUCTION: Delayed TB diagnosis and treatment perpetuate the high burden of TB-related morbidity and mortality in resource-constrained settings. We explored the potential of COVID-19 to further compromise TB care engagement in Zambia. METHODS: From April to May 2020, we purposefully selected 17 adults newly diagnosed with TB from three public health facilities in Lusaka, Zambia, for in-depth phone interviews. We conducted thematic analyses using a hybrid approach. RESULTS: The majority of participants were highly concerned about the impact of lockdowns on their financial security. Most were not worried about being diagnosed with COVID-19 when seeking care for their illness because they felt unwell prior to the outbreak; however, they were very worried about contracting COVID-19 during clinic visits. COVID-19 was perceived as a greater threat than TB as it is highly transmittable and there is no treatment for it, which provoked fear of social isolation and of death among participants in case they contracted it. Nonetheless, participants reported willingness to continue with TB medication and the clinic visits required to improve their health. CONCLUSION: The COVID-19 pandemic did not appear to deter care-seeking for TB by patients. However, messaging on TB in the era of COVID-19 must encourage timely care-seeking by informing people of infection control measures taken at health facilities.Item Clinical diagnosis of TB: lessons on misdiagnosis and overdiagnosis.(2025-Jun) Singini DS; Sanjase N; Kagujje M; Shatalimi J; Chisanga CP; Lupatali ZD; Phiri D; Tatila T; Olwit W; Kerkhoff AD; Muyoyeta MClinically diagnosed TB patients (n = 335) at two facilities in Lusaka, Zambia were re-evaluated within two weeks of diagnosis. This re-evaluation included sputum Xpert Ultra testing and expert reader interpretation of the chest x-rays (CXRs) used for initial diagnosis. Repeat Xpert Ultra detected TB in just 2.6% (n=6). Of the remaining patients (n=222), expert CXR re-interpretation classified 18.0% as normal; 36.0% as abnormal, consistent with TB; and 46.0% as abnormal, not consistent with TB. These findings suggest that clinical TB is frequently over diagnosed in those without detectable CXR abnormalities and misdiagnosed in those with abnormal CXRs: these abnormalities are likely due to other respiratory conditions. Such misdiagnosis leads to unnecessary treatment, failure to treat the true underlying condition and incorrect estimates of TB burden.Item Clinical and radiographic characteristics of presumptive tuberculosis patients previously treated for tuberculosis in Zambia.(2022) Mateyo K; Kerkhoff AD; Dunn I; Nteeni MS; Muyoyeta MBACKGROUND: Persistent respiratory symptoms and radiographic abnormalities are common among individuals previously treated for tuberculosis (TB) and may contribute to misdiagnosis and incorrect treatment when they seek care. We sought to determine if clinical and radiographic characteristics differed among previously treated, presumptive TB patients according to their current TB disease status. METHODS: Adults (>18 years of age) seeking care at a public health facility in Lusaka, Zambia were systematically evaluated for active TB using symptom screening and chest X-ray. All patients with presumptive TB submitted a sputum sample for microbiological TB testing. Patients who reported a prior history of TB treatment were included in the present analysis. 'Confirmed TB' was defined by the detection of TB using Xpert Ultra and/or liquid culture, while 'possible TB' was defined by the receipt of TB treatment without a positive Xpert Ultra or culture result. We evaluated the positive predictive value (PPV) of clinical symptoms and radiographic features for active TB alone and in combination. RESULTS: Of 740 presumptive TB patients, 144 (19%) had been previously treated for active TB. Of these, 19 (13%) patients had confirmed TB, 14 (10%) had possible TB, and 111 (77%) had no pulmonary TB. Overall, 119 (83%) patients had ≥1 current respiratory symptom-this did not differ according to current TB disease classification (95%, 93%, 79%; p = 0.23). Sixty-one patients (56%) had radiographic abnormalities suggestive of active TB and such findings were more common among patients with confirmed or possible TB compared to those without TB (93%, 71%, vs. 47%; p = 0.002). Most patients (n = 91, 83%) had at least one radiographic abnormality-no difference by current TB classification was observed (93%, 100%, 79%; p = 0.08). The PPV of any current respiratory symptom, active TB radiographic finding, or any radiographic abnormality for TB was 13% (95%CI: 7-21%), 21% (95%CI: 12-34) and 14% (95%CI: 9-23), respectively; combining clinical and radiographic characteristics did not significantly improve the PPV for active TB. CONCLUSIONS: Among presumptive TB patients previously treated for TB, respiratory symptoms and radiographic abnormalities were common and poorly differentiated those with current active TB from those without current active TB. Reliance on clinical and radiographic characteristics alone in this patient population may result in substantial overtreatment and therefore, microbiological investigations should be used to inform TB treatment decisions whenever possible.