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
- ItemDiagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralized high-throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance(Elsevier Ltd, 2021-09) Dippenaar, Anzaan; Derendinger, Brigitta; Dolby, Tania; Beylis, Natalie; Van Helden, Paul D.; Theron, Grant; Warren, Robin M.; De Vos, MargarethaObjectives To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug-resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods. Methods Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies. Results FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared with FluoroType MTBDR VER 2.0 (manual DNA extraction: 91.6% (294/321) versus 89.8% (291/324); p 0.4); automated DNA extraction: 92.1% (305/331) versus 87.7% (291/332); p 0.05)). FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance. Conclusions The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralized molecular drug susceptibility testing model.
- 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.
- ItemDifferential RD-1-specific IFN-γ host responses to diverse Mycobacterium tuberculosis strains in HIV-uninfected persons may be explained by genotypic variation in the ESX-1 region(Elsevier, 2020-04) Tomasicchio, Michele; Limberis, Jason; van der Merwe, Ruben; Jacobson, Rachael; Meldau, Richard; Theron, Grant; Nicol, Mark; Warren, Rob; Dheda, KeertanObjectives: Between-person variability in T-cell-specific interferon-gamma release assay (IGRA) responses and discordance between IGRA test formats are poorly understood. Methods: We evaluated the IFN-γ responses (QuantiFERON-TB Gold-In-Tube [QFT-GIT] and TSPOT-TB) stratified according to the Mycobacterium tuberculosis spoligotype of the culture isolate obtained from the same patients with confirmed active tuberculosis (n = 91). We further analysed differences within the RD-1-encoding ESX-1 region between the different strain types using whole genome sequencing. Results: In HIV-uninfected patients, TSPOT.TB and QFT-GIT IFN-γ responses were 5-fold (p < 0.01) and 2-fold higher (p < 0.05) for those infected with family 33 compared to the LAM strain (additionally, TSPOT.TB responses were 5.6-fold [p < 0.05] and 2.6-fold higher [p < 0.05] for the patients infected with the family 33 versus the X strain and Beijing versus the LAM strain, respectively). Multivariate analysis revealed that strain type (determined by spoligotyping) was independently associated with the magnitude of the IGRA response (varied by IGRA test type) and this is likely explained by variability in the ESX-1 region of Mycobacteriumtuberculosis (determined by next-generation sequencing). Conclusions: These data have implications for the understanding of between-person heterogeneity in IGRA responses, Mycobateriumtuberculosis-specific host immunity, and the discordance between different IGRA test formats.
- 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.
- ItemEffect of Xpert MTB/RIF on clinical outcomes in routine care settings : individual patient data meta-analysis(Elsevier, 2019-02) Di Tanna, Gian Luca; Khaki, Ali Raza; Theron, Grant; McCarthy, Kerrigan; Cox, Helen; Mupfumi, Lucy; Trajman, Anete; Mason, Peter; Bandason, Tsitsi; Durovni, Betina; Bara, Wilbert; Hoelscher, Michael; Clowes, Petra; Mangu, Chacha; Chanda, Duncan; Pym, Alexander; Mwaba, Peter; Cobelens, Frank; Nicol, Mark P.; Dheda, Keertan; Churchyard, Gavin; Fielding, Katherine; Metcalfe, John Z.Background: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. Methods: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. Findings Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68–1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65–1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60–0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I²<20% for the primary outcome). Interpretation Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact.
- 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.
- ItemPoint of care Xpert MTB/RIF versus smear microscopy for tuberculosis diagnosis in southern African primary care clinics : a multicentre economic evaluation(Elsevier, 2019-06-01) Pooran, Anil; Theron, Grant; Zijenah, Lynn; Chanda, Duncan; Clowes, Petra; Mwenge, Lawrence; Mutenherwa, Farirai; Lecesse, Paul; Metcalfe, John; Sohn, Hojoon; Hoelscher, Michael; Pym, Alex; Peter, Jonny; Dowdy, David; Dheda, KeertanBackground: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. Methods: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. Findings: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12–23·88] vs $28·03 [26·19–29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054–40 025) and was associated with an additional 24·3 treatment initiations ([–20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3–99·4]; $511 per same-day treatment), and 29·4 treatment completions ([–6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. Interpretation: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings.
- ItemXpert mycobacterium tuberculosis/rifampicin-detected rifampicin resistance is a suboptimal surrogate for multidrug-resistant tuberculosis in Eastern Democratic Republic of the Congo : diagnostic and clinical implications(Oxford University Press, 2020-06) Bisimwa, Bertin C.; Nachega, Jean B.; Warren, Robin M.; Theron, Grant; Metcalfe, John Z.; Shah, Maunank; Diacon, Andreas H.; Sam-Agudu, Nadia A.; Yotebieng, Marcel; Bulabula, André N. H.; Katoto, Patrick D. M. C.; Chirambiza, Jean-Paul; Nyota, Rosette; Birembano, Freddy M.; Musafiri, Eric M.; Byadunia, Sifa; Bahizire, Esto; Kaswa, Michel K.; Callens, Steven; Kashongwe, Zacharie M.Background Rifampicin (RIF) resistance is highly correlated with isoniazid (INH) resistance and used as proxy for multidrug-resistant tuberculosis (MDR-TB). Using MTBDRplus as a comparator, we evaluated the predictive value of Xpert MTB/RIF (Xpert)–detected RIF resistance for MDR-TB in eastern Democratic Republic of the Congo (DRC). Methods We conducted a cross-sectional study involving data from new or retreatment pulmonary adult TB cases evaluated between July 2013 and December 2016. Separate, paired sputa for smear microscopy and MTBDRplus were collected. Xpert testing was performed subject to the availability of Xpert cartridges on sample remnants after microscopy. Results Among 353 patients, 193 (54.7%) were previously treated and 224 (63.5%) were MTBDRplus TB positive. Of the 224, 43 (19.2%) were RIF monoresistant, 11 (4.9%) were INH monoresistant, 53 (23.7%) had MDR-TB, and 117 (52.2%) were RIF and INH susceptible. Overall, among the 96 samples detected by MTBDRplus as RIF resistant, 53 (55.2%) had MDR-TB. Xpert testing was performed in 179 (50.7%) specimens; among these, 163 (91.1%) were TB positive and 73 (44.8%) RIF resistant. Only 45/73 (61.6%) Xpert-identified RIF-resistant isolates had concomitant MTBDRplus-detected INH resistance. Xpert had a sensitivity of 100.0% (95% CI, 92.1–100.0) for detecting RIF resistance but a positive-predictive value of only 61.6% (95% CI, 49.5–72.8) for MDR-TB. The most frequent mutations associated with RIF and INH resistance were S531L and S315T1, respectively. Conclusions In this high-risk MDR-TB study population, Xpert had low positive-predictive value for the presence of MDR-TB. Comprehensive resistance testing for both INH and RIF should be performed in this setting.