Browsing by Author "Theron, Grant"
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- ItemAn automated tuberculosis screening strategy combining X-ray-based computer-aided detection and clinical information(Springer Nature, 2016) Melendez, Jaime; Sanchez, Clara; Philipsen, Rick H. H. M.; Maduskar, Pragnya; Dawson, Rodney; Theron, Grant; Dheda, Keertan; Van Ginneken, BramLack of human resources and radiological interpretation expertise impair tuberculosis (TB) screening programmes in TB-endemic countries. Computer-aided detection (CAD) constitutes a viable alternative for chest radiograph (CXR) reading. However, no automated techniques that exploit the additional clinical information typically available during screening exist. To address this issue and optimally exploit this information, a machine learning-based combination framework is introduced. We have evaluated this framework on a database containing 392 patient records from suspected TB subjects prospectively recruited in Cape Town, South Africa. Each record comprised a CAD score, automatically computed from a CXR, and 12 clinical features. Comparisons with strategies relying on either CAD scores or clinical information alone were performed. Our results indicate that the combination framework outperforms the individual strategies in terms of the area under the receiving operating characteristic curve (0.84 versus 0.78 and 0.72), specificity at 95% sensitivity (49% versus 24% and 31%) and negative predictive value (98% versus 95% and 96%). Thus, it is believed that combining CAD and clinical information to estimate the risk of active disease is a promising tool for TB screening.
- ItemBedaquiline microheteroresistance after cessation of tuberculosis treatment(Massachusetts Medical Society, 2019-05-30) De Vos, Margaretha; Wiggins, Kristin B.; Derendinger, Brigitta; Reuter, Anja; Dolby, Tania; Burns, Scott; Schito, Marco; Engelthaler, David M.; Metcalfe, John; Theron, Grant; Van Rie, Annelies; Posey, James; Warren, Rob; Cox, HelenENGLISH ABSTRACT: Bedaquiline improves survival among persons with multidrug-resistant tuberculosis (MDR-TB).1 We report the case of a 65-year-old South African man who was negative for human immunodeficiency virus and in whom MDR-TB was diagnosed in 2013 (resistant to rifampin and isoniazid; phenotypically susceptible to a fluoroquinolone and amikacin). A baseline radiograph showed changes consistent with bilateral tuberculosis with left apex cavitation. He started standardized treatment that included moxifloxacin, pyrazinamide, kanamycin, ethionamide, isoniazid, and terizidone. After initial sputum culture conversion (at month 3) and clinical improvement, the patient again became culture-positive, and bilateral cavitation developed. After detection of phenotypic resistance to fluoroquinolones (at month 6), his treatment was revised (at month 8) to include high-dose isoniazid, ethambutol, pyrazinamide, terizidone, linezolid, paraaminosalicylic acid, and kanamycin (Figure 1 and the Supplementary Appendix, available with the full text of this letter at NEJM.org). Bedaquiline was added 22 days later and was administered for 6 months.2 The patient remained culture-positive (treatment failure), and treatment was stopped 15 months after revision of the regimen. The patient died 7 months later.
- ItemCost-effectiveness of Xpert MTB/RIF and investing in health care in Africa(Elsevier, 2014-10) Dheda, Keertan; Theron, Grant; Welte, AlexThe Xpert MTB/RIF assay is an accurate test for the diagnosis of tuberculosis when an adequate sputum sample can be obtained; even in smear-negative tuberculosis the sensitivity is about 67%.1, 2 Although the assay turnaround time is under 2 h, depending on the health-care setting, time to tuberculosis treatment can be 2 weeks or more in a substantial number of patients.3 The technology has now been endorsed by WHO as a frontline test for tuberculosis in populations where there is a high incidence of HIV.4 Indeed, several countries in Africa are rolling out Xpert MTB/RIF.5 However, for expanded and sustained uptake, governments and policy makers require information about the cost-effectiveness of the technology to allow for appropriate planning and allocation of health-care resources. Cost-effectiveness must be balanced against affordability and sustainability. Thus, although the diagnostic accuracy of the technique is not in doubt, questions remain about the cost-effectiveness of the technology given that the overall number of patients treated for tuberculosis can remain unchanged6 and given the high rates of empirical treatment in resource-poor health-care settings.7
- ItemThe diagnostic accuracy of the MTBDRplus and MTBDRsl assays for drug-resistant TB detection when performed on sputum and culture isolates(Springer Nature, 2016) Tomasicchio, Michele; Theron, Grant; Pietersen, Elize; Streicher, Elizabeth M.; Stanley-Josephs, Danielle; Van Helden, Paul; Warren, Rob; Dheda, KeertanAlthough molecular tests for drug-resistant TB perform well on culture isolates, their accuracy using clinical samples, particularly from TB and HIV-endemic settings, requires clarification. The MTBDRplus and MTBDRsl line probe assays were evaluated in 181 sputum samples and 270 isolates from patients with culture-confirmed drug-sensitive-TB, MDR-TB, or XDR-TB. Phenotypic culture-based testing was the reference standard. Using sputum, the sensitivities for resistance was 97.7%, 95.4%, 58.9%, 61.6% for rifampicin, isoniazid, ofloxacin, and amikacin, respectively, whereas the specificities were 91.8%, 89%, 100%, and 100%, respectively. MTBDRsl sensitivity differed in smear-positive vs. smear-negative samples (79.2% vs. 20%, p < 0.0001 for ofloxacin; 72.9% vs. 37%, p = 0.0023 for amikacin) but not by HIV status. If used sequentially, MTBDRplus and MTBDRsl could rule-in XDR-TB in 78.5% (22/28) and 10.5% (2/19) of smear-positive and smear-negative samples, respectively. On culture isolates, the sensitivity for resistance to rifampicin, isoniazid, ofloxacin, and amikacin was 95.1%, 96.1%, 72.3% and 76.6%, respectively, whereas the specificities exceeded 96%. Using a sequential testing approach, rapid sputum-based diagnosis of fluoroquinolone or aminoglycoside-resistant TB is feasible only in smear-positive samples, where rule-in value is good. Further investigation is required in samples that test susceptible in order to rule-out second-line drug resistance.
- ItemDrug-associated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa(Public Library of Science, 2013-05-07) Shean, Karen; Streicher, Elizabeth M.; Pieterson, Elize; Symons, Greg; Van Zyl Smit, Richard; Theron, Grant; Lehloenya, Rannakoe; Padanilam, Xavier; Wilcox, Paul; Victor, Tommie C.; Van Helden, Paul D.; Groubusch, Martin; Warren, Robin M.; Badri, Motasim; Dheda, KeertanBackground: Treatment-related outcomes in patients with extensively drug-resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce. Methods: Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1–2 = mild to moderate; and grade 3–5 = severe (drug stopped, life-threatening or death)]. Findings: 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ∼50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3–5) vs. grade 0–2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient). Conclusion: Drug-associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre-treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB.
- ItemExtract from used Xpert MTB/ RIF Ultra cartridges is useful for accurate second-line drug-resistant tuberculosis diagnosis with minimal rpoB-amplicon cross-contamination risk(Nature Research (part of Springer Nature), 2020) Venter, Rouxjeane; Minnies, Stephanie; Derendinger, Brigitta; Tshivhula, Happy; De Vos, Margaretha; Dolby, Tania; Ruiters, Ashley; Warren, Robin M.; Theron, GrantXpert MTB/RIF Ultra (Ultra) detects Mycobacterium tuberculosis and rifampicin resistance. Follow-on drug susceptibility testing (DST) requires additional sputum. Extract from the diamond-shaped chamber of the cartridge (dCE) of Ultra’s predecessor, Xpert MTB/RIF (Xpert), is useful for MTBDRsl-based DST but this is unexplored with Ultra. Furthermore, whether CE from non-diamond compartments is useful, the performance of FluoroType MTBDR (FT) on CE, and rpoB cross-contamination risk associated with the extraction procedure are unknown. We tested MTBDRsl, MTBDRplus, and FT on CEs from chambers from cartridges (Ultra, Xpert) tested on bacilli dilution series. MTBDRsl on Ultra dCE on TB-positive sputa (n = 40) was also evaluated and, separately, rpoB amplicon cross-contamination risk . MTBDRsl on Ultra dCE from dilutions ≥103 CFU/ml (CTmin <25, >“low semi-quantitation”) detected fluoroquinolone (FQ) and second-line injectable (SLID) susceptibility and resistance correctly (some SLIDs-indeterminate). At the same threshold (at which ~85% of Ultra-positives in our setting would be eligible), 35/35 (100%) FQ and 34/35 (97%) SLID results from Ultra dCE were concordant with sputa results. Tests on other chambers were unfeasible. No tubes open during 20 batched extractions had FT-detected rpoB cross-contamination. False-positive Ultra rpoB results was observed when dCE dilutions ≤10−3 were re-tested. MTBDRsl on Ultra dCE is concordant with isolate results. rpoB amplicon cross-contamination is unlikely. These data mitigate additional specimen collection for second-line DST and cross-contamination concerns.
- ItemGenoType MTBDRsl assay for resistance to second-line anti-tuberculosis drugs(Cochrane, 2016-09-08) Theron, Grant; Peter, Jonny; Richardson, Marty; Warren, Rob; Dheda, Keertan; Steingart, Karen R.Background: Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of aWorld Health Organization process to develop updated guidelines for using MTBDRsl. Objectives: To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance.
- ItemMycobacterial genomic DNA from used Xpert MTB/RIF cartridges can be utilised for accurate second-line genotypic drug susceptibility testing and spoligotyping(Nature, 2017) Venter, Rouxjeane; Derendinger, Brigitta; De Vos, Margaretha; Pillay, Samantha; Dolby, Tanya; Simpson, John; Kitchin, Natasha; Ruiters, Ashley; Van Helden, Paul D.; Warren, Robin M.; Theron, GrantXpert MTB/RIF (Xpert) is a widely-used test for tuberculosis (TB) and rifampicin-resistance. Second-line drug susceptibility testing (DST), which is recommended by policymakers, typically requires additional specimen collection that delays effective treatment initiation. We examined whether cartridge extract (CE) from used Xpert TB-positive cartridges was, without downstream DNA extraction or purification, suitable for both genotypic DST (MTBDRplus, MTBDRsl), which may permit patients to rapidly receive a XDR-TB diagnosis from a single specimen, and spoligotyping, which could facilitate routine genotyping. To determine the limit-of-detection and diagnostic accuracy, CEs from dilution series of drug-susceptible and -resistant bacilli were tested (MTBDRplus, MTBDRsl). Xpert TB-positive patient sputa CEs (n = 85) were tested (56 Xpert-rifampicin-susceptible, MTBDRplus and MTBDRsl; 29 Xpert-rifampicin-resistant, MTBDRsl). Spoligotyping was done on CEs from dilution series and patient sputa (n = 10). MTBDRplus had high non-valid result rates. MTBDRsl on CEs from dilutions ≥103CFU/ml (CT ≤ 24, >“low” Xpert semiquantitation category) was accurate, had low indeterminate rates and, on CE from sputa, highly concordant with MTBDRsl isolate results. CE spoligotyping results from dilutions ≥103CFU/ml and sputa were correct. MTBDRsl and spoligotyping on CE are thus highly feasible. These findings reduce the need for additional specimen collection and culture, for which capacity is limited in high-burden countries, and have implications for diagnostic laboratories and TB molecular epidemiology.
- ItemMycobacterial genomic DNA from used Xpert MTB/RIF cartridges can be utilised for accurate secondline genotypic drug susceptibility testing and spoligotyping(Springer Nature, 2017-11-01) Venter, Rouxjeane; Derendinger, Brigitta; De Vos, Margaretha; Pillay, Samantha; Dolby, Tanya; Simpson, John; Kitchin, Natasha; Ruiters, Ashley; Van Helden, Paul D.; Warren, Robin M.; Theron, GrantENGLISH ABSTRACT: Xpert MTB/RIF (Xpert) is a widely-used test for tuberculosis (TB) and rifampicin-resistance. Second-line drug susceptibility testing (DST), which is recommended by policymakers, typically requires additional specimen collection that delays effective treatment initiation. We examined whether cartridge extract (CE) from used Xpert TB-positive cartridges was, without downstream DNA extraction or purification, suitable for both genotypic DST (MTBDRplus, MTBDRsl), which may permit patients to rapidly receive a XDR-TB diagnosis from a single specimen, and spoligotyping, which could facilitate routine genotyping. To determine the limit-of-detection and diagnostic accuracy, CEs from dilution series of drug-susceptible and -resistant bacilli were tested (MTBDRplus, MTBDRsl). Xpert TB-positive patient sputa CEs (n = 85) were tested (56 Xpert-rifampicin-susceptible, MTBDRplus and MTBDRsl; 29 Xpert-rifampicin-resistant, MTBDRsl). Spoligotyping was done on CEs from dilution series and patient sputa (n = 10). MTBDRplus had high non-valid result rates. MTBDRsl on CEs from dilutions ≥103CFU/ml (CT ≤ 24, >“low” Xpert semiquantitation category) was accurate, had low indeterminate rates and, on CE from sputa, highly concordant with MTBDRsl isolate results. CE spoligotyping results from dilutions ≥103CFU/ml and sputa were correct. MTBDRsl and spoligotyping on CE are thus highly feasible. These findings reduce the need for additional specimen collection and culture, for which capacity is limited in high-burden countries, and have implications for diagnostic laboratories and TB molecular epidemiology.