Abstract
Background: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory. Methods: This multicentre cohort study was done in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status. Findings: We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment. Interpretation: Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis. Funding: National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 298-307 |
| Number of pages | 10 |
| Journal | The Lancet Infectious Diseases |
| Volume | 19 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2019 |
ASJC Scopus subject areas
- Infectious Diseases
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In: The Lancet Infectious Diseases, Vol. 19, No. 3, 03.2019, p. 298-307.
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}
TY - JOUR
T1 - Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries
T2 - a multicentre cohort study
AU - International epidemiology Databases to Evaluate AIDS (IeDEA) consortium
AU - Zürcher, Kathrin
AU - Ballif, Marie
AU - Fenner, Lukas
AU - Borrell, Sonia
AU - Keller, Peter M.
AU - Gnokoro, Joachim
AU - Marcy, Olivier
AU - Yotebieng, Marcel
AU - Diero, Lameck
AU - Carter, E. Jane
AU - Rockwood, Neesha
AU - Wilkinson, Robert J.
AU - Cox, Helen
AU - Ezati, Nicholas
AU - Abimiku, Alash'le G.
AU - Collantes, Jimena
AU - Avihingsanon, Anchalee
AU - Kawkitinarong, Kamon
AU - Reinhard, Miriam
AU - Hömke, Rico
AU - Huebner, Robin
AU - Gagneux, Sebastien
AU - Böttger, Erik C.
AU - Egger, Matthias
AU - Chammartin, Frédérique
AU - Boettger, Erik C.
AU - Abimiku, Alash'le
AU - Wenzi, Landry
AU - Tabala, Martine
AU - Warren, Robin
AU - Streicher, Elizabeth
AU - Carter, E. Jane
AU - Zamudio, Carlos
AU - Sohn, Annette
AU - Petersen, Tor
AU - Kasipong, Naruporn
AU - N'Guessan, Kouassi
N1 - Funding Information: We thank all sites that participated in this survey and the patients whose data were used in this study. We are grateful to the Tuberculosis Working Group of IeDEA for helpful discussions, and to the reviewers for their thoughtful comments. We also thank all regional data centres that contributed to the coordination of the study. This research was supported by the Swiss National Science Foundation (grant numbers 153442, 310030_166687 and 174281), the National Institutes of Allergy and Infectious Diseases (NIAID) under award numbers U01 AI096299, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, U01 AI096186, and U01 AI069923, and the Swiss National Center for Mycobacteria, University of Zurich, Switzerland. RJW is supported by the Francis Crick Institute (grant number 10218), which is funded by the Wellcome Trust, Cancer Research UK, and Research Councils UK. RJW also receives support from the Wellcome Trust (104803 and 203135). HC is supported by a Wellcome Trust fellowship and reports grants from UK Medical Research Council and the National Research Foundation of South Africa. SG is supported by the Swiss National Science Foundation (310030_166687, IZRJZ3_164171, IZLSZ3_170834, and CRSII5_177163), the European Research Council (309540-EVODRTB) and SystemsX.ch. KK was supported by the National Research University Program, Office of the Higher Education Commission, Bangkok, Thailand. Funding Information: The results of this multicentre cohort study of patients treated for drug-resistant or drug-susceptible tuberculosis in seven high tuberculosis burden countries show that the accuracy of drug susceptibility testing in routine care was moderate, with discordant results from local drug susceptibility testing compared with phenotypic drug susceptibility testing in a reference laboratory in about 20% of patients. Discordant results led to inadequate treatment and contributed to the excess mortality associated with drug-resistant tuberculosis. As expected, mortality was highest in patients with pre-XDR or XDR tuberculosis and higher in patients who were under-treated than in those who were adequately treated. Patients with pan-susceptible tuberculosis who were over-treated also had higher mortality than did those who were adequately treated, although the difference was not significant. It is possible that over-treated patients had worse adherence and were at higher risk of adverse drug effects than were adequately treated patients. To our knowledge, this is the first study to assess the accuracy of drug susceptibility testing in real-world, routine settings and to examine the impact of inaccurate results on mortality. Our findings support the recent call for a precision medicine approach to the treatment of drug-resistant tuberculosis, guided by detailed molecular drug susceptibility testing done locally, to replace the standardised, empirical combination regimens used in many low-income and middle-income countries with a high tuberculosis burden. 25 At present, WHO recommends that “Xpert MTB/RIF be used as an initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB”, 26 based on a Cochrane review of test accuracy studies in adults with suspected rifampicin resistance or MDR tuberculosis. 27 In line with this recommendation, Xpert MTB/RIF was the most commonly used test in our study sites. The Cochrane review reported a pooled sensitivity of 95%, based on 17 studies and 555 patients with rifampicin-resistant strains. 27 The pooled specificity was 98%. We examined the accuracy of drug susceptibility testing strategies at the level of the local laboratories in high-burden countries, in routine care settings, rather than by examining a single test. Our estimates of sensitivity and specificity, for detection of any drug resistance, were lower overall (90·8% and 84·3%), and lower for Xpert MTB/RIF (79·5% and 97·1%) and for culture (93·1% and 71·6%), indicating that drug susceptibility testing is less accurate in routine settings than in test accuracy studies. 27 There are concerns about both false-negative and false-positive Xpert MTB/RIF test results, and a policy of confirmatory testing has been introduced in South Africa and Brazil. 28,29 The discordant drug susceptibility test results that potentially led to under-treatment of drug-resistant tuberculosis (false negative for resistance) were mainly based on locally done cultures, Xpert MTB/RIF tests, or a combination of the two. Notably, the recently developed Xpert MTB/RIF Ultra assay has been shown to improve detection of rifampicin resistance. 30 Culture-based tests dominated discordance that potentially led to over-treatment, whereas Xpert MTB/RIF dominated in the category of discordance with unclear clinical significance. Some discordance could be explained by mixed infections, heteroresistance, or minority resistant populations. 31,32 LPAs were rarely used in our study, possibly because they have been widely replaced by Xpert MTB/RIF, which is easier to use and provides results in a shorter time. Additionally, LPAs have suboptimal accuracy for isoniazid resistance, and WHO recommends that culture-based drug susceptibility testing for isoniazid should still be used, particularly in patients with suspected MDR tuberculosis in whom the LPA result does not detect isoniazid resistance. 33 In one case, the local laboratory detected resistance to ethambutol but this could not be confirmed in the reference laboratory: drug susceptibility testing is challenging for ethambutol and less reproducible. 34 Data about treatment outcomes in drug-resistant tuberculosis are scarce, particularly for sub-Saharan Africa. A systematic review of treatment outcomes in patients with MDR tuberculosis included data on mortality among adults from seven studies done in sub-Saharan Africa, six in South Africa and one in Lesotho. 35 In these studies, mortality during tuberculosis treatment ranged from 12·4% in patients with MDR tuberculosis treated in a referral hospital in the Western Cape, South Africa, 36 to 45·8% in a study of patients with XDR tuberculosis from three South African provinces. 37 Our results extend these data to other countries in the region and also provide data for Peru and Thailand. Our study confirms the poor outcome in patients with isoniazid monoresistant tuberculosis who are treated with first-line regimens (as recommended by WHO during the study period 38 ), in line with a study from Durban, South Africa, 39 and a systemic review and meta-analysis. 40 Mortality in patients with monoresistant tuberculosis, especially isoniazid-resistant tuberculosis, was higher than in patients with MDR tuberculosis. This might be due to the treatment of almost all patients with isoniazid monoresistant tuberculosis with first-line regimens, whereas most patients with MDR tuberculosis received second-line treatment. WHO has updated its guidelines recommending the inclusion of fluoroquinolones in the treatment of isoniazid monoresistant tuberculosis. 41 Chance is another explanation: few patients had monoresistant tuberculosis and in the analysis of mortality the confidence intervals of the odds ratios for monoresistant and MDR tuberculosis overlapped widely. In patients with HIV co-infection, treatment of drug-resistant tuberculosis is challenging for several reasons, including poorer absorption of drugs, 42 the risk of immune reconstitution inflammatory syndrome, 43 and interactions between antiretroviral and second-line tuberculosis drugs. 44–46 In contrast to previous studies from South Africa, which reported higher mortality at the end of treatment in HIV-positive patients with MDR tuberculosis compared with HIV-negative patients with MDR tuberculosis, 36,47 we found no association with HIV infection, although the confidence intervals were wide. The median CD4 cell count of HIV-positive patients was considerably higher in our study (192 cells per μL) than in the South African studies, 36,47 which might explain the discrepant results. A study from Lesotho 48 also found little evidence for a difference in mortality between HIV-positive patients (median CD4 cell count 185 cells per μL) and HIV-negative patients. Finally, for patients with XDR tuberculosis, treatment outcomes have been uniformly poor in previous studies, irrespective of HIV status. 37 Our study has several limitations. We sampled eligible patients within strata defined by drug resistance and HIV infection, and therefore could not estimate the incidence or prevalence of drug-resistant tuberculosis in HIV-positive or HIV-negative patients. In previous studies, HIV infection has not been consistently associated with drug resistance, 28 but it is clear that in regions with a high burden of HIV, the majority of patients with MDR tuberculosis will have HIV co-infection. 28 Although we initially exceeded the planned sample size, about a quarter of patients had to be excluded from analyses of drug susceptibility, mainly because of contamination or insufficient growth of cultures, and about a third were excluded from the analysis of mortality outcomes, mainly because vital status was unknown at database closure. The reference laboratory tested resistance against six drugs, and we would have missed resistance against other drugs used, such as kanamycin, ethionamide, or levofloxacin. Furthermore, the presence of different subpopulations of M tuberculosis in isolates tested at the local sites versus the reference laboratory might have introduced variability in phenotypic or molecular drug susceptibility testing. 49 In conclusion, our study shows that the accuracy of drug susceptibility testing in routine care in high-burden countries was inadequate and that inaccurate results led to inadequate treatment and contributed to the excess mortality associated with drug-resistant tuberculosis. Our results support the notion that access to rapid molecular drug susceptibility testing of first-line and second-line drugs at treatment initiation is required to improve outcomes in patients with MDR tuberculosis and pre-XDR/XDR tuberculosis. 28 Whole-genome sequencing is the most promising approach to reach this goal, but much work remains to be done to make this approach feasible and affordable in low-income and middle-income countries. 28 In particular, direct testing of sputum samples should become routine to circumvent lengthy mycobacterial cultures. 40 A standardised approach for the interpretation of mutations conferring drug resistance has been developed. 50 In the meantime, the capacity for the phenotypic and molecular drug susceptibility testing recommended by WHO should be increased to ensure the most adequate treatment of drug-resistant tuberculosis in these settings. Contributors KZ, MB, and ME wrote the first draft of the paper, which was reviewed by all authors and revised on the basis of the comments received by co-authors. MB coordinated data and strain collection across study sites. ECB and PMK supervised drug susceptibility testing at the Swiss National Center for Mycobacteria, which were done by RHö. HC, JG, OM, MY, LD, EJC, NR, RJW, NE, AGA, JC, AA, and KK supervised drug susceptibility testing at the local laboratory and the collection of clinical data. ME and KZ did statistical analyses. All authors approved the final version of the manuscript. Declaration of interests AA has received honoraria fees from Jensen-Cilag, Gilead, and Bristol-Myers Squibb. All other authors declare no competing interests. Acknowledgments We thank all sites that participated in this survey and the patients whose data were used in this study. We are grateful to the Tuberculosis Working Group of IeDEA for helpful discussions, and to the reviewers for their thoughtful comments. We also thank all regional data centres that contributed to the coordination of the study. This research was supported by the Swiss National Science Foundation (grant numbers 153442 , 310030_166687 and 174281 ), the National Institutes of Allergy and Infectious Diseases (NIAID) under award numbers U01 AI096299 , U01 AI069919 , U01 AI069924 , U01 AI069911 , U01 AI069907 , U01 AI096186 , and U01 AI069923 , and the Swiss National Center for Mycobacteria, University of Zurich, Switzerland. RJW is supported by the Francis Crick Institute (grant number 10218 ), which is funded by the Wellcome Trust, Cancer Research UK, and Research Councils UK. RJW also receives support from the Wellcome Trust ( 104803 and 203135 ). HC is supported by a Wellcome Trust fellowship and reports grants from UK Medical Research Council and the National Research Foundation of South Africa. SG is supported by the Swiss National Science Foundation ( 310030_166687 , IZRJZ3_164171 , IZLSZ3_170834 , and CRSII5_177163 ), the European Research Council ( 309540-EVODRTB ) and SystemsX.ch. KK was supported by the National Research University Program, Office of the Higher Education Commission, Bangkok, Thailand. Publisher Copyright: © 2019 Elsevier Ltd
PY - 2019/3
Y1 - 2019/3
N2 - Background: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory. Methods: This multicentre cohort study was done in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status. Findings: We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment. Interpretation: Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis. Funding: National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.
AB - Background: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory. Methods: This multicentre cohort study was done in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status. Findings: We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment. Interpretation: Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis. Funding: National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.
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UR - http://www.scopus.com/inward/citedby.url?scp=85062024718&partnerID=8YFLogxK
U2 - 10.1016/S1473-3099(18)30673-X
DO - 10.1016/S1473-3099(18)30673-X
M3 - Article
C2 - 30744962
AN - SCOPUS:85062024718
SN - 1473-3099
VL - 19
SP - 298
EP - 307
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 3
ER -