Journal Article > Short ReportFull Text
Lancet Infect Dis. 2018 March 13; Volume 18 (Issue 9); DOI:10.1016/S1473-3099(18)30104-X
Cox HS, Hughes J, Black JM, Nicol MP
Lancet Infect Dis. 2018 March 13; Volume 18 (Issue 9); DOI:10.1016/S1473-3099(18)30104-X
Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management. We argue that a balance is required between the need to improve treatment access and the imperative to minimise resistance amplification and provide the highest standard of care, through a precision medicine approach. In tuberculosis, as in other diseases, we should aim to reduce the entrenched inequalities that manifest as different standards of care in different settings.
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Salaam-Dreyer Z, Streicher EM, Sirgel FA, Menardo F, Borrell S, et al.
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Rifampicin mono-resistant TB (RMR-TB, rifampicin resistance and isoniazid susceptibility) constitutes 38% of all rifampicin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rifampicin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rifampicin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p<0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (p<0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 μg/ml (range 0.125-1 μg/ml). The majority (215/230, 93.5%) of RMR-TB isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.
Journal Article > ResearchFull Text
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
Cox HS, Salaam-Dreyer Z, Goig GA, Nicol MP, Menardo F, et al.
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
BACKGROUND
South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.
METHODS
In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.
FINDINGS
The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).
INTERPRETATION
These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.
South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.
METHODS
In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.
FINDINGS
The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).
INTERPRETATION
These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.
Journal Article > ResearchFull Text
Lancet. 2011 April 19; Volume 377 (Issue 9776); DOI:10.1016/S0140-6736(11)60438-8
Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, et al.
Lancet. 2011 April 19; Volume 377 (Issue 9776); DOI:10.1016/S0140-6736(11)60438-8
BACKGROUND: The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings. METHODS: We assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2-3 sputum smears and 1-3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used. FINDINGS: We enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0-1), compared with 1 day (0-1) for microscopy, 30 days (23-43) for solid culture, and 16 days (13-21) for liquid culture. Median time to detection of resistance was 20 days (10-26) for line-probe assay and 106 days (30-124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39-81) to 5 days (2-8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures. INTERPRETATION: The MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment. FUNDING: Foundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2021 October 18; Volume 65 (Issue 11); e0036421.; DOI:10.1128/AAC.00364-21
Salaam-Dreyer Z, Streicher EM, Sirgel FA, Menardo F, Borrell S, et al.
Antimicrob Agents Chemother. 2021 October 18; Volume 65 (Issue 11); e0036421.; DOI:10.1128/AAC.00364-21
Rifampin monoresistance (RMR; rifampin resistance and isoniazid susceptibility) accounts for 38% of all rifampin-resistant tuberculosis (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) in a setting with high TB, RR-TB, and HIV burdens. Patient-level clinical data and stored RR Mycobacterium tuberculosis isolates from 2008 to 2017 with available whole-genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare RR-conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semiquantitative rifampin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.1 to 1.9) and diagnosis between 2013 and 2017 versus between 2008 and 2012 (aOR, 1.3; 95% CI, 1.1 to 1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR and MDR isolates were observed. Mutations associated with high-level RR were more commonly found among MDR isolates (811/889 [90.2%] versus 162/230 [70.4%] among RMR isolates; P < 0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR isolates versus 10/889 (1.1%) in MDR isolates (P < 0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 μg/ml (range, 0.125 to 1 μg/ml). The majority (215/230 [93.5%]) of RMR isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.
Journal Article > ResearchFull Text
Clin Infect Dis. 2020 January 9; Volume 71 (Issue 8); 1973-1976.; DOI:10.1093/cid/ciaa024
Sossen B, Broger T, Kerkhoff AD, Schutz C, Trollip AP, et al.
Clin Infect Dis. 2020 January 9; Volume 71 (Issue 8); 1973-1976.; DOI:10.1093/cid/ciaa024
Reducing diagnostic delay is key towards decreasing tuberculosis-associated deaths in people living with HIV. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.
Journal Article > ResearchFull Text
South Afr J HIV Med. 2022 September 27; Volume 23 (Issue 1); a1396.; DOI:10.4102/sajhivmed.v23i1.1396
Spies R, Schutz C, Ward A, Balfour A, Shey M, et al.
South Afr J HIV Med. 2022 September 27; Volume 23 (Issue 1); a1396.; DOI:10.4102/sajhivmed.v23i1.1396
BACKGROUND
Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death.
OBJECTIVES
We investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis.
METHOD
Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks.
RESULTS
Participants with microbiologically confirmed TB (n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07–3.29; P = 0.03).
CONCLUSION
Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.
Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death.
OBJECTIVES
We investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis.
METHOD
Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks.
RESULTS
Participants with microbiologically confirmed TB (n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07–3.29; P = 0.03).
CONCLUSION
Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.
Journal Article > ResearchFull Text
Lancet Child Adolesc Health. 2023 March 13; Online ahead of print; DOI:10.1016/S2352-4642(23)00004-4
Gunasekera KS, Marcy O, Muñoz J, Lopez-Varela E, Sekadde MP, et al.
Lancet Child Adolesc Health. 2023 March 13; Online ahead of print; DOI:10.1016/S2352-4642(23)00004-4
BACKGROUND
Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres.
METHODS
For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings.
FINDINGS
Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms.
INTERPRETATION
We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance.
Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres.
METHODS
For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings.
FINDINGS
Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms.
INTERPRETATION
We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance.
Journal Article > ResearchFull Text
J Clin Microbiol. 2022 February 16; Online ahead of print; jcm0236221.; DOI:10.1128/jcm.02362-21
Cox HS, Goig GA, Salaam-Dreyer Z, Dippenaar A, Reuter A, et al.
J Clin Microbiol. 2022 February 16; Online ahead of print; jcm0236221.; DOI:10.1128/jcm.02362-21
BACKGROUND
Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardised and based on limited drug susceptibility testing (DST). More individualised treatment with expanded DST access is likely to improve patient outcomes.
METHODS
To assess the potential of TB drug resistance prediction based on whole genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorise patients into a recommended regimen, either a standardised short regimen or a longer individualised regimen. Potential regimen changes were then described with the addition of WGS-derived DST.
FINDINGS
WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008-2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualised regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualisation.
INTERPRETATION
These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.
Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardised and based on limited drug susceptibility testing (DST). More individualised treatment with expanded DST access is likely to improve patient outcomes.
METHODS
To assess the potential of TB drug resistance prediction based on whole genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorise patients into a recommended regimen, either a standardised short regimen or a longer individualised regimen. Potential regimen changes were then described with the addition of WGS-derived DST.
FINDINGS
WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008-2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualised regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualisation.
INTERPRETATION
These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.
Journal Article > ResearchFull Text
PLOS Med. 2014 November 25; Volume 11 (Issue 11); e1001760.; DOI:10.1371/journal.pmed.1001760
Cox HS, Mbhele S, Mohess N, Whitelaw A, Muller O, et al.
PLOS Med. 2014 November 25; Volume 11 (Issue 11); e1001760.; DOI:10.1371/journal.pmed.1001760
BACKGROUND
Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.
METHODS AND FINDINGS
A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33-0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32-1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06-1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63-0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53-0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic.
CONCLUSIONS
These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants.
Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.
METHODS AND FINDINGS
A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33-0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32-1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06-1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63-0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53-0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic.
CONCLUSIONS
These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants.