Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: A prospective cohort study

Tracy Dalton, Peter Cegielski, Somsak Akksilp, Luis Asencios, Janice Campos Caoili, Sang Nae Cho, Vladislav V. Erokhin, Julia Ershova, Ma Tarcela Gler, Boris Y. Kazennyy, Hee Jin Kim, Kai Kliiman, Ekaterina Kurbatova, Charlotte Kvasnovsky, Vaira Leimane, Martie Van Der Walt, Laura E. Via, Grigory V. Volchenkov, Martin A. Yagui, Hyungseok Kang

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Background: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. Methods: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. Findings: Among 1278 patients, 43·7 showed resistance to at least one second-line drug, 20·0 to at least one second-line injectable drug, and 12·9 to at least one fluoroquinolone. 6·7 of patients had XDR tuberculosis (range across study sites 0·8-15·2). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. Interpretation: Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. Funding: US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare.

Original languageEnglish
Pages (from-to)1406-1417
Number of pages12
JournalThe Lancet
Issue number9851
StatePublished - Oct 2012
Externally publishedYes

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This large, prospective study of resistance to second-line drugs for MDR tuberculosis shows comprehensively that the prevalence of resistance is high (43·7%), and that the risk of XDR tuberculosis (6·7%) in the eight countries studied is worrying. The prevalence of drug resistance correlates with the time that second-line drugs have been available in each country. They had been available for 10 years or less in Thailand (7 years), the Philippines (9 years), and Peru (10 years), and these countries had the lowest rates of resistance. By contrast, South Korea and Russia had the longest histories of availability (more than 20 years) and the highest rates of resistance. Other practices, including criteria for treatment, admission to hospital, directly observed therapy, and drug procurement, should be assessed to find out whether they affect resistance rates. WHO data showed that 5·4% of patients with MDR tuberculosis had XDR tuberculosis. 2 In our population, 6·7% had XDR tuberculosis. This higher rate might be due at least partly to differences in laboratory procedures. We tested all three second-line injectable agents for this study, but most countries test one or two, which could underestimate the burden of XDR tuberculosis. The same may be said for fluoroquinolones. The prevalence values we found show some differences from and similarities to country-specific surveillance data from WHO. Fluoroquinolone resistance was 26·1% in Estonia, 14·0% in Latvia, and 12·6% in South Africa, and 30·6%, 15·6%, and 14·2% in WHO data. For XDR tuberculosis, however, although the rates for South Africa are similar (10·6% vs 10·5%), those for Estonia and Latvia were lower in our study (6·5% vs 12·5% and 8·0% vs 14·8%, respectively). 2 Thus, prevalence of resistance to second-line drugs in the three countries was not likely to be artificially increased because of the two-culture criterion. Another study of MDR tuberculosis in Estonia showed a similar rate of 5·2% for XDR tuberculosis. 17 Few studies have been done of resistance to second-line drugs, probably because of low capacity for laboratory testing. 1 Previous studies have reported prevalence of 23% in South Korea and of 6% in Peru for XDR tuberculosis among patients with MDR tuberculosis treated at tertiary referral hospitals. 6,18 In these countries we showed 15% and 6% prevalence, respectively. A study done in Thailand before XDR tuberculosis was defined found that 9% of patients with MDR tuberculosis had resistance to a fluoroquinolone and 5% to kanamycin. 19 These values are similar to those in our study. Previous treatment for MDR tuberculosis with a second-line drug was the strongest risk factor for resistance, which is consistent with previous reports. 6,20 Patients being in hospital at enrolment was also strongly associated with resistance, possibly because of nosocomial transmission or disease severity. Women had greater prevalence of fluoroquinolone resistance than men, and thereby greater risk of XDR tuberculosis, which is consistent with the findings of a study done in South Korea. 6 By contrast, HIV-infected patients were less likely than other patients to have resistance to fluoroquinolones, but in other studies HIV infection has been a strong risk factor for XDR tuberculosis. 20 Unlike fluoroquinolones, resistance to second-line injectables was associated with social factors, including imprisonment, unemployment, alcohol abuse, and smoking. Social factors should be taken into account in the management of tuberculosis. Panel Research in context Systematic review We searched PubMed with the search term “(tuberculosis OR TB) AND (extensive drug resistance OR XDR OR second-line drug resistance OR fluoroquinolone resistance OR kanamycin resistance OR amikacin resistance OR capreomycin resistance) AND (epidemiology OR prevalence OR risk factors)”. The search identified 568 publications. Of these, 85 articles contained original data on the epidemiology of drug-resistant tuberculosis, including information on resistance to second-line drugs. The remainder were reviews, editorials, letters, studies focused on treatment and treatment outcomes, phylogenetic and transmission studies, and case reports or small case series. Interpretation Of 85 articles on the epidemiology of resistance to second-line drugs, 60 were retrospective reviews based on medical records or laboratory records at tertiary referral hospitals, specialised tuberculosis hospitals, and mycobacteriology reference laboratories, and data had been recorded previously for other purposes. Thus, they reflected highly selected groups of patients and did not represent the general population. Seven reports based on national or multinational surveillance systems included little information about risk factors because they were limited to routinely captured data. With one exception, South Korea, susceptibility testing for second-line drugs is not done routinely, and, therefore, resistance data are not routinely captured by surveillance systems. 16 studies focused on specific classes of second-line drugs (usually fluoroquinolones) or on extensively drug-resistant tuberculosis, but did not assess individual drugs. Seven publications focused narrowly on specific groups such as prisoners, miners, health-care workers, people with HIV infection, and migrants and another seven phylogenetic analyses focused on transmission dynamics, including contact investigations, and on molecular characterisation of specific DNA mutations associated with phenotypic resistance to specific individual drugs. These 85 papers represented little geographical overlap with our study— 72 (85%) reported data from countries or regions not included in this study, and design limitations in ten of the remaining 13 reports meant little population crossover. Thus, our report adds prospective, population-based data from many locations not previously studied that include detailed information on risk factors related to resistance to individual drugs as well as drug combinations, according to centralised laboratory testing. PETTS had important limitations. The prospective gathering of data under programmatic conditions led to some variability between sites in the information available. Differences in demographic, social, and clinical risk factors might be related to the extent of missing data for specific variables. Data collection was based on medical records, where some features are not routinely recorded and we could not acquire the data. However, of the variables that applied to all patients, only six had more than 10% of data missing. Data from Masan, South Korea, were extracted from a separate study that was being done in collaboration with the US National Institutes of Health and, therefore, we used their data collection instrument, which included all variables except years of education and number of children. 6 When we expanded the enrolment criteria in November 2005, Estonia, Latvia, and Masan, South Korea, were close to their enrolment targets and maintained the original protocol of requiring a second positive culture per patient. South Africa began enrolling patients with one culture, but only shipped samples for those with a second positive culture to CDC. The rest of the sites changed protocols and required only a baseline positive culture. This difference might have contributed to country-specific differences. The patients tested might not have been representative of the larger populations of adults with pulmonary MDR tuberculosis in the study countries to the extent that the prevalence of drug resistance among enrolled patients differed from that in patients who were not enrolled. We could not assess how representative our patient cohorts were because we did not collect demographic and medical information for eligible patients who were not enrolled. The enrolment rates at some centres were low owing to circumstances not related to the study, such as changes in personnel. Finally, the results are not generalisable to the world as a whole because India and China—the countries with the highest numbers of tuberculosis cases—did not participate. India and China had pilot projects for MDR tuberculosis approved by the Green Light Committee, but not until 3 and 4 years, respectively, after PETTS started. Population-based data on resistance to second-line drugs in these two countries are limited. In China's 2007 national drug resistance survey, 27·4% (95% CI 23·1–32·1) of cases of MDR tuberculosis tested for resistance to second-line drugs showed fluoroquinolone resistance and 7·2% of patients (4·9–10·2) had XDR tuberculosis. 2 In India, a 2006 population-based survey of tuberculosis drug resistance in Gujarat State reported fluoroquinolone resistance in 24·1% of cases (18·5–30·3) and XDR tuberculosis in 3·2% (1·2–6·6). 2 In both surveys, fluoroquinolone resistance was near the high end of the range of values in our study. The prevalence of XDR tuberculosis in China was slightly higher than the average value in our study, but in Gujarat State, India, it was similar to the lower values in our study. Other reports from China and India have been based on retrospective reviews of cases at specialised tuberculosis referral centres that happened to have drug-susceptibility results for second-line drugs and are not representative of the general population. 21–24 As a large, multicentre, collaborative study, PETTS also has strengths. All drug-susceptibility testing was done in one reference laboratory with standard, quality-controlled methods, which eliminated variability intrinsic to phenotypic testing in multiple laboratories. Additionally, the study was designed to provide data within defined criteria that were representative for the populations served by the participating programmes. Five of the participating countries had projects approved by the Green Light Committee in place at the time of the study and, therefore, were representative of other countries with approved projects. Of the countries without approved projects, one was a high-income and two were upper-middle-income countries and would not be representative of the worldwide situation, especially for low-income countries. Nevertheless, our country-specific results can be extrapolated to guide in-country policy for laboratory capacity and for designing effective treatment recommendations for MDR tuberculosis. PETTS continues, and follow-up isolates are being tested to investigate the frequency of and risk factors for acquired resistance to second-line drugs in patients with MDR tuberculosis. The effect of the Green Light Committee initiative in combating acquired resistance to second-line drugs, the timing of acquired resistance, and the role of specific genetic mutations in different regions of the world are also being assessed. This online publication has been corrected. The corrected version first appeared at on September 4, 2012 Contributors PC and Katherine Tan designed the initial study proposal. TD, PC, JCC, JE, Alison Taylor, Katherine Tan, EK, CK, Melanie Wolfgang, Carmen Contreras, and Joey Lancaster contributed to the study design, database development, data collection, monitoring, training, data analysis, and data interpretation. TD and Lois Diem did the drug-susceptibility testing at the Centers for Disease Control and Prevention. Michael Chen provided statistical consultation. SA, JCC, MTG, BYK, HJK, KK, VL, GVV, MAY, Rattanawadee Akkslip, Wanpen Wattanaamornkiet, Jaime Bayona, Carmen Contreras, Seonyoung Min, Tatiana Khorosheva, Elena Kyryanova, Thelma Tupasi, Ingrida Sture, Tiina Kummik, Tatiana Kuznetsova, and Tatiana Somova were responsible for patients' enrolment and treatment at the study centres. LA, LEV, Wanlaya Sitti, Sofia Andreevskaya, Larisa Chernousova, Elea Larionova, Tatyana Smirnova, Alena Vorobyeva, Isdore Shamputa, Jeanette Brand, Eunjin Cho, Seok Yong Eum, Hyun Kyung Kwak, Jongseok Lee, Evgenia Nemtsova, Grace Egos, Chang-ki Kim, Inga Norvaisa, Girts Skenders, Klavdia Levina, Gloria Yale, Gustavo Pariona, Carmen Suarez, and Eddy Valencia were responsible for local laboratory testing and shipping cultures to the Centers for Disease Control and Prevention. All authors contributed to data collection, study coordination, and critical revision of the paper. Conflicts of interest We declare that we have no conflicts of interest. Global PETTS Investigators and coauthors (continued from page 1) Rattanawadee Akksilp, Wanlaya Sitti, and Wanpen Wattanaamornkiet, Office of Disease Prevention and Control Region 7, Ubon Ratchatani, Thailand; Sofia N Andreevskaya, Larisa N Chernousova, Olga V Demikhova, Elena E Larionova, Tatyana G Smirnova, Irina A Vasilieva, and Alena V Vorobyeva, Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russian Federation; Clifton E Barry III, Ying Cai, and Isdore C Shamputa, National Institute for Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA; Jaime Bayona and Carmen Contreras, Socios en Salud Sucursal, Lima, Peru; Cesar Bonilla and Oswaldo Jave, Ministry of Health, National TB Strategy, Lima, Peru; Jeannette Brand, Joey Lancaster, and Ronel Odendaal, Medical Research Council, Pretoria, South Africa; Michael P Chen, Lois Diem, Beverly Metchock, Kathrine Tan, Allison Taylor and Melanie Wolfgang, Centers for Disease Control and Prevention, Division of TB Elimination, Atlanta, GA, USA; Eunjin Cho, Seok Yong Eum, Hyun Kyung Kwak, Jiim Lee, Jongseok Lee, and Seonyeong Min, International Tuberculosis Research Center, Masan and Yonsei University College of Medicine, Seoul, South Korea; Irina Degtyareva, Evgenia S Nemtsova, Tatiana Khorosheva, and Elena V Kyryanova, Orel Oblast Tuberculosis Dispensary, Orel, Russian Federation; Grace Egos, Ma Therese C Perez, and Thelma Tupasi, Tropical Disease Foundation, Manila, Philippines; Soo Hee Hwang, National Masan Tuberculosis Hospital, Masan, South Korea; Chang-ki Kim, Su Young Kim, and Hee Jeong Lee, Korean Institute of Tuberculosis, Seoul, South Korea; Liga Kuksa, Inga Norvaisha, Girts Skenders, and Ingrida Sture, State Agency, Infectology Centre of Latvia, Tuberculosis and Lung Disease Clinic, Riga, Latvia; Tiina Kummik, Tartu University Hospital, Tartu, Estonia; Tatiana Kuznetsova and Tatiana Somova, Vladimir Oblast Tuberculosis Dispensary, Vladimir, Russian Federation; Klavdia Levina, North Estonia Regional Hospital, Tallinn, Estonia; Gustavo Pariona and Gloria Yale, Lima City Health District Reference Laboratory, Lima, Peru; Carmen Suarez, Lima East Health District Reference Laboratory, Lima, Peru; Eddy Valencia, National Tuberculosis Reference Laboratory, Lima, Peru; and Piret Viiklepp, National Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia. Acknowledgments The findings and conclusions in this Article are those of the authors and do not necessarily represent the views of the US CDC. We thank the patients who gave their time and energy to contribute to this study and the doctors, nurses, and microbiologists at each of the enrolment sites for their contributions to this work. We thank the people in the following countries and organisations for support and contributions: Centers for Disease Control and Prevention Division of Tuberculosis Elimination, US Agency for International Development, National Institute of Allergy and Infectious Diseases, North Estonia Regional Hospital, Tartu University Hospital, Estonia National Tuberculosis Registry, Estonia National Institute for Health Development, State Agency Infectology Centre of Latvia, Riga Tuberculosis and Lung Disease Clinic, Lima Ciudad and Lima Este Health Districts and reference laboratories, Philippines Tropical Disease Foundation, Orel and Vladimir Oblast Tuberculosis Dispensaries, Central Tuberculosis Research Institute of the Russian Academy of Medical Sciences, South Africa Medical Research Council, KwaZulu-Natal King George V Hospital, Klerksdorp Hospital, Witbank Specialised Tuberculosis Hospital, Jose Pearson Hospital, Korean Institute of Tuberculosis, National Masan Tuberculosis Hospital, Thai Office of Disease Prevention and Control, and WHO in Switzerland, Denmark, Peru, and Russia. We also thank medical and nursing staff in the Ubon Ratchathani, Srisaket, Sakon Nakon, Yasothon Provinces, Thailand.


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