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INT J TUBERC LUNG DIS 6(10):858–864 © 2002 IUATLD Frequency of recurrence among MDR-TB cases ‘successfully’ treated with standardised short-course chemotherapy G. B. Migliori,* M. Espinal,† I. D. Danilova,‡ V. V. Punga,§ M. Grzemska,† M. C. Raviglione† * WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, Tradate, Italy; † World Health Organization, Geneva, Switzerland; ‡ Ivanovo TB Dispensary, Ivanovo, § Central Tuberculosis Research Institute, Moscow, Russian Federation SUMMARY S E T T I N G : Ivanovo Oblast, Russian Federation, 300 km north-east of Moscow, where a pilot DOTS TB control programme was implemented in October 1995. O B J E C T I V E : To determine the frequency of TB recurrence among MDR (multidrug-resistant) patients who achieved treatment ‘success’ on standard short-course chemotherapy. M E T H O D S : All patients with MDR tuberculosis, defined as resistance to at least isoniazid and rifampicin, who were declared ‘cured’ or ‘treatment completed’, were identified using the district register and traced whenever possible. Eligible patients underwent medical examination and, if necessary, chest radiography, sputum smear examination, culture and susceptibility testing. If the patient had died, the relatives were interviewed to try to determine the reasons for death. R E S U L T S : Of 18 patients eligible for analysis, five (27.8%) were documented to have recurrence (two of seven patients resistant to HRSE, one of five patients resistant to HRS and two of six patients resistant to HR). Patients receiving the Category I regimen were more likely to relapse than those receiving the Category II regimen (40% vs. 12.5%). The median time to relapse was 8 months; 2.46 recurrences were observed in 100 person-months (3.17 in category I and 1.3 in Category II patients). C O N C L U S I O N S : The frequency of TB recurrence among MDR-TB patients declared ‘cured’ after short-course chemotherapy is high. Improvements in treatment success, after removal of programme-related pitfalls in the treatment delivery process, must incorporate methods for early detection of MDR, along with adequate treatment regimens including second-line drugs. Culturebased bacteriological confirmation at the end of treatment is recommended. K E Y W O R D S : tuberculosis; MDR; recurrence; Russia THE WORLD HEALTH ORGANIZATION (WHO) tuberculosis (TB) control strategy (the DOTS strategy), emphasises assessment of treatment results.1 According to guidelines published by the WHO and the IUATLD (International Union Against Tuberculosis and Lung Disease), a patient is defined as ‘successfully’ treated when the final outcome is ‘cured’ (bacteriological conversion at the end of treatment) or ‘treatment completed’ (documented treatment completion, but no evidence of sputum smear microscopy or culture conversion at the end of treatment).2 Multidrug-resistant (MDR) TB is considered a threat to TB control, as TB patients infected with MDR strains are difficult to cure, their treatment is expensive, and there are frequent severe adverse drug events.3,4 Previous reports suggest that standard shortcourse chemotherapy (SCC) achieves treatment ‘success’ in less than 60% of MDR-TB patients,5 compared to a success rate of more than 85% in patients with drug-susceptible TB. The concern is that even ‘cured’ (or ‘treatment completed’) patients may frequently relapse. However, no information is available on the chance of recurrence among patients with MDR-TB who have been treated and declared ‘cured’ with standard SCC. The aim of this study is to determine the proportion of MDR patients developing recurrent TB after achieving treatment ‘success’ with standard SCC. METHODS Setting A pilot DOTS TB control programme was implemented in Ivanovo Oblast in October 1995. Ivanovo Oblast is located 300 km north-east of Moscow. It has a population of 1.3 million people, and an economy based on industry (mainly textile) and agriculture. Deep economic recession and high inflation have Correspondence to: Dr Giovanni Battista Migliori, WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, via Roncaccio 16, 21049, Tradate (VA), Italy. Tel: (39) 0331 829404. Fax: (39) 0331 829402. e-mail: [email protected] Article submitted 1 March 2002. Final version accepted 26 June 2002. Recurrence of MDR-TB cases in Russia resulted in a rapid increase in unemployment, poverty, malnutrition and alcohol abuse, generating patient- and programme-related factors favouring spread of MDR-TB.6–9 At the time of the study, human immunodeficiency virus (HIV) infection was infrequent in this setting.6 WHO reports (available on request) show that the success rates achieved between the fourth quarter of 1995 and the first quarter of 1999 in sputum smear-positive cases ranged from 43.5% to 65.1%, with a high proportion of defaulters (from 6.3% to 24%) and failures (from 5.6% to 28.3%). In new cases, the prevalence of MDR ranged from 1.9% to 20% during this period. Prior to the implementation of the project, standard WHO training workshops were organised addressing project managers and medical and laboratory staff. A protocol to be used by all health staff participating in the project was jointly prepared by international WHO staff and consultants, and national staff from the Central Tuberculosis Research Institute, Moscow, and the Oblast TB Dispensary, Ivanovo. No incentives or enablers were provided to patients and health staff. Treatment cards, forms and registers for recording and reporting following WHO standards were made available in the Russian language.10 Sufficient antituberculosis drugs to cover the estimated annual burden of patients were provided to the TB units involved through the Oblast TB Dispensary (quality-proven triple fixed-dose combinations of isoniazid [H], rifampicin [R] and pyrazinamide [Z], and double combinations of R and H were provided free of charge by the then Marion-Merrel Dow; streptomycin [S] and ethambutol [E] were available from national sources). Organisation of control activities Diagnosis According to the protocol, detection of TB among symptomatic individuals self-referring to the health services was the main method of case finding. Microbiological examinations (acid-fast bacilli smear microscopy, culture and drug susceptibility testing) were coupled with chest radiography during the initial screening. Regular proficiency testing of the drug susceptibility tests carried out in a variety of local laboratories was organised by the laboratories of the Oblast TB Dispensary and the Central TB Research Institute, Moscow, as well as by laboratories belonging to the network of supranational reference laboratories in the WHO/IUATLD Global Project on Antituberculosis Drug Resistance Surveillance.11–13 Quality control for direct sputum smear examination was performed by blind re-reading of all positive and 10% of negative slides at Oblast level. The quality control process was evaluated by WHO experts during monitoring missions. Treatment Treatment was standardised into three categories of patients. The Category I regimen (new smear-positive 859 pulmonary TB and other newly diagnosed seriously ill patients with severe forms of TB) consisted of: 2 months of daily S, H, R and Z followed by 4 months of HR administered three times a week. The Category II regimen (relapse and failure smear-positive TB cases) consisted of: 2 months of daily SHRZE plus 1 month of HRZE followed by 5 months of HRE administered three times a week. The Category III regimen (new smear-negative pulmonary TB and other newly diagnosed patients not included in Category I) consisted of: 2 months of daily HRZ followed by 4 months of HR administered three times a week. Patients were given daily treatment during the intensive phase at the hospital. The intermittent continuation phase was designed to facilitate directly observed therapy (DOT) at Raion (county) level. In order to limit deviations from the standard treatment, the protocol did not include specific instructions on the management of drug-resistant cases. An ad hoc committee composed of senior staff was established at the Oblast TB Dispensary to decide when modifications of the treatment regimen were necessary. Definitions All definitions used were derived from published WHO recommendations.2,10,14–16 The main definitions were as follows: a ‘new case’ was a patient who had never received treatment for TB or who had taken anti-tuberculosis drugs for less than 4 weeks. A ‘cured’ patient was a patient whose sputum smears were negative on two occasions at the end of treatment or in the presence of a documented culture conversion during the continuation phase. ‘Treatment completed’ was recorded if there was documented treatment completion, but no sputum smear microscopy/culture conversion at the end of treatment. The ‘treatment success rate’ was defined as the sum of patients whose outcome was ‘cured’ and ‘treatment completed’ divided by the total number of patients registered for treatment, expressed as a percentage. Multidrug resistance was defined as resistance to at least H and R. For the purposes of this study, in the absence of restriction fragment length polymorphism (RFLP) analysis to distinguish true relapse from re-infection, the term ‘recurrence’ was used to indicate all cases who suffered a new episode of TB after having been considered ‘cured’ or after having completed a previous treatment regimen for the first disease episode. Search of patients All newly and previously treated culture positive patients with MDR-TB diagnosed in Ivanovo Oblast since the beginning of the pilot project (from October 1995 to March 1999) were identified using the computerised district register. MDR patients declared ‘cured’ and ‘treatment completed’ were identified, and whenever possible, traced by the physician in charge of 860 The International Journal of Tuberculosis and Lung Disease the Ivanovo Dispensary. Follow-up started in April 1999. Eligible patients underwent a medical examination and, if necessary (if they had cough, loss of weight, or any clinical reason to suspect recurrence of TB), chest radiography, sputum smear examination, culture and susceptibility testing. If the patient had died, the relatives were interviewed to try to determine the reasons for death (TB or other). Data analysis The data available on individual information on demographics, risk factors, bacteriology at diagnosis and during treatment, drug resistance, side effects, treatment prescribed and taken (including the number of doses) and treatment outcome were analysed by descriptive statistics. Kaplan-Meier survival curves were used to illustrate the recurrence-free periods observed during follow-up using SPSS 10.1 software (Statistical Package for Social Sciences, Chicago, IL, USA). Proportions were compared with the two-tailed 2 test (or Fisher’s exact test where appropriate) using Epi-Info (version 6.02, Centers for Disease Control and Prevention, Atlanta, GA). Mean values of continuous variables were compared using Student’s t-test for unpaired data. RESULTS The prevalence of MDR in Ivanovo in 1998 was 9% among newly diagnosed patients and 25.9 % among retreatment patients.11 Out of 76 MDR patients identified from the register in Ivanovo Oblast during the period October 1995 to March 1999, 21 had been declared ‘cured’ (bacteriologically confirmed) or ‘treatment completed’. Three patients could not be located, leaving 18 eligible for analysis (16 males and two females, mean age SD, 40.2 12.6 years, median 42 years). Eight were alcohol abusers, two were ex-prisoners and two had mental impairment (oligophrenia). Of the 18 patients, 10 were diagnosed as culturepositive/sputum smear-positive and eight were culturepositive/sputum smear-negative. All of these patients were hospitalised during the intensive phase of treatment at the Oblast TB Dispensary except for two (patients 1 and 2) who were admitted for the entire treatment period due to a psychiatric condition. All of the 18 patients were classified in the TB register as ‘cured’ after treatment with SCC (16 based on culture and two based on sputum smear results). The Kaplan-Meier curves describing the cumulative recurrence-free survival of MDR cases are summarised in the Figure. Overall, 2.46 recurrences were observed in 100 person-months (3.17 in Category I and 1.30 in Category II patients). Figure Cumulative recurrence-free survival during follow-up of 18 MDR-TB patients whose treatment outcome was ‘treatment success’. The median follow-up time (from the end of treatment to the time of evaluation) was 6.5 months (mean value SD, 11.3 10.1 months). In the patients with recurrence of their TB (see below) the median follow-up was 6 months (mean value SD, 11.2 10.6 months), while in patients without recurrence the median follow-up was 9 months (mean value SD, 11.6 10.0 months). Of the 18 patients, five had a recurrence: two (28.6%) of seven patients resistant to HRSE, one (20%) of five patients resistant to HRS, and two (33.3%) of six patients resistant to HR (Table 1). The mean time to recurrence was 10.4 10.7 months (median 8 months, range 1–28 months). All of the recurrent cases (all males) were confirmed by culture, except for one (patient n 3), who was diagnosed based on chest radiography and clinical findings; after completing a full re-treatment regimen the nodular infiltrate disappeared and there was significant clinical improvement. Data on the 13 patients who did not experience a recurrence of their TB are summarised in Table 2. At diagnosis, six had received Category I and seven Category II regimens. Six were new patients. Six patients had their treatment regimens modified once drug resistance was identified (Table 2). Patients n 8, 10, 11 and 12 underwent surgery in addition to drug treatment. Case n 10 had negative smear and culture results at months 3 and 5, while at the end of treatment only sputum smear examination was performed (three negative results). He had no recurrence after 7 months of follow-up. Case n 6 died in a car accident, and according to relatives was healthy at the time of death. The treatment length ranged from 6 to 11 months in Category I and from 8 to 16 months in Category II Recurrence of MDR-TB cases in Russia Table 1 N 861 Individual profiles of five ‘successfully’ treated MDR patients who had a recurrence of their tuberculosis Age (years) Sex Follow-up (months) New case WHO regimen Drug resistance Treatment Doses Doses duration Individualised Intensive Continuation (months) regimen phase phase Outcome 1 54 M 8 Yes Category I HRSE 6 No Mental impairment; after recurrence: C; SS; CXR (nodule); DST: susceptible; final outcome: Cured 2 49 M 1 Yes Category I HRSE 6 No Mental impairment; after relapse: C; SS; CXR (cavity); DST: HRSE; final outcome: died 3 39 M 12 Yes Category I HR 10 No Unemployed; after recurrence: C; SS; CXR (nodule); DST: negative; final outcome: tr. completed 4 40 M 9 No Category II HRS 9 No Alcohol abuse; after recurrence: C; SS; CXR (nodule); DST: negative; final outcome: cured 5 42 M 28 Yes Category I HR 6 No Alcohol abuse; after recurrence: C; SS; CXR (nodule); DST: RSE; final outcome: cured. 60 122 Cured 62 75 Cured 70 105 Cured 90 114 Cured 70 105 Cured MDR multidrug-resistant; WHO World Health Organization; M male; Category I/Category II regimens—see Methods section; H isoniazid; R rifampicin; S streptomycin; E ethambutol; positive result; negative result; C culture; SS sputum smear; CXR chest radiography; DST drug susceptibility testing. regimens. No significant differences were found comparing age, duration of follow-up, and number of doses of the intensive and continuation phases of treatment between the five MDR patients with and the 13 without TB recurrence. However, patients who received Category I regimens at the time of their first episode were more likely to have recurrent TB than those who received Category II regimens (4/10 [40%] vs. 1/9 ([12.5%], P NS). The treatment duration of the patients who had a recurrence was longer than for those who did not (P 0.05). DISCUSSION This observational study provides the first known evidence regarding longer-term outcome of TB patients Table 2 with MDR-TB considered as ‘cured’ after successful SCC: at least 27.8% of MDR patients declared ‘cured’ had recurrent TB. The study was performed in a setting characterised by a high prevalence of drug resistance. The results of the DOTS programme in the Oblast were generally sub-optimal, with a proportion of ‘successfully’ treated patients lower than 85%. In the period 1994–1996, among new patients, treatment success was 75% in pan-susceptible strains, 54% in patients with any resistance (but excluding MDR) and 11% in MDR patients.5 In a recent case-control study in Ivanovo Oblast performed between January 1996 and October 1998, a significant increase in MDR prevalence (from 3.8% to 9.4%) was observed among civilian patients who Individual profile of 13 ‘successfully’ treated MDR patients who had no recurrence of their tuberculosis Follow-up New Sex (months) case WHO regimen Treatment Drug duration resistance (months) N Age (years) 1 2 3 4 5 6 7 8 9 10 20 44 23 47 30 42 63 52 51 32 M M M M M M F M M M 4 6 6 6 28 12 20 37 5 7 Yes No No Yes Yes Yes Yes No No Yes Category I Category II Category II Category I Category I Category I Category I Category II Category II Category I HRS HRSE HR HRS HR HRSE HRSE HR HRS HRSE 11 8 10 11 8 6 6 12 11 15 11 50 M 4 No Category II HR 16 12 13 21 25 M F 6 4 No No Category II Category II HRSE HRS 12 12 Modified regimen No No Yes (intensive phase)* Yes (last month)† No No No No Yes (last month)‡ Yes (continuation phase)§ Yes (continuation phase)¶ No# Yes (continuation phase)** Doses Doses Intensive Continuation phase phase Outcome 60 90 90 60 60 60 60 80 90 60 171 111 152 74 114 120 90 163 107 276 Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured 90 120 Cured 142 120 140 237 Cured Cured MDR multidrug-resistant; WHO World Health Organization; H isoniazid; R rifampicin; S streptomycin; E ethambutol; Z pyrazinamide; M male; Category I/ Category II regimens—see Methods section. * Intensive phase: intravenous R and intramuscular H. † Last month: intravenous H. ‡ Last month: oral Z replaced H. § Last 2 months of continuation phase: HR from oral to intravenous intramuscular kanamycin. ¶ Surgery after one year of standard regimen; after surgery additional ethionamide. # Surgery performed after 6 months; regimen not modified. ** Last 3 months: kanamycin and ofloxacin added. 862 The International Journal of Tuberculosis and Lung Disease had never previously been treated, suggesting an increased circulation of MDR strains.6 To complicate matters, a high prevalence of alcohol abuse, previous incarceration, unemployment and history of homelessness were described among both drug-susceptible and drug-resistant TB patients.6 Although the phenomenon deserves further investigation, both patient-related (social factors linked to poverty and detention) and programme-related factors (sub-optimal co-ordination of TB control activities within and outside prisons; low staff salaries, leading to poor motivation impairing treatment delivery) have probably contributed to the spread of MDR strains within the community. The aim of this study was to identify the proportion of MDR patients previously deemed as ‘successfully’ treated who had recurrent TB. The assumption was that standard SCC could be inadequate to cure MDR-TB and result in an increased risk of relapse among patients who were apparently cured at the end of treatment. The study results indicate that the proportion of MDR-TB patients declared ‘cured’ who had recurrent TB is high, at at least 27.8%. Our study has several limitations. 1) The sample size was small and the follow-up period short. In an attempt to discourage the traditional long-term followup of all cases after cure, it was decided to perform the study by re-calling eligible patients, and patients were told to report if new symptoms occurred. 2) The 13 patients who had no recurrence when the assessment was done (except the case who died) still have a potential risk of relapse later, and thus the true proportion of recurrent TB cases may be higher than shown here. 3) The proficiency testing performed during the initial period of the study (1995–1997) did not strictly follow the principles of the WHO/ IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance.11–13 Hence, there is a risk of misinterpretation of drug susceptibility pattern. 4) The lack of RFLP analysis prevented any assessment of the reason for recurrence between exogenous reinfection and reactivation of a previous strain. A previous study has indicated that exogenous re-infection may be the leading cause of recurrence in some settings.17 5) In two patients (who were both sputum smear and culture-positive at diagnosis) the definition of ‘cure’ was based on three negative smear results, as culture was not done. It is possible that case n 3 (Table 1) had transient sputum smear-negative results, or that the quality of the sputum smear examination was poor. Clearly, the evaluation of the final outcome based on culture results, as performed in four out of five patients with recurrence and in 12 out of 13 cases without, is more reliable. Although Category I patients were more likely to have recurrent TB than those in Category II, statistical significance was not reached because of the limited number of cases. A previous study based on a large number of MDR patients treated by standard regimens demonstrated that Category I and II regimens are not adequate for the treatment of MDR patients, and, as expected, the proportion of success in MDR patients is related to the overall success rate among all cases.5 In the period 1995–1999, only first-line drugs were available in Ivanovo for the majority of patients. The use of standard Category I regimens is unlikely to guarantee that at least two, and preferably three drugs are active to prevent further development of drug resistance in MDR cases. Although prescribed to cases who did not develop recurrence (patients n 10 and 11), the addition of a single drug to a potentially failing regimen is to be considered a programmerelated pitfall. Further, four of 10 Category I patients had a treatment duration of longer than 9 months. In Russia it is common practice to treat TB cases until cavity closure is radiologically documented. The reason why some cases had no recurrence during the follow-up period can be explained by the following: 1) drugs were sufficient to achieve cure, especially among cases that were not resistant to all four drugs; 2) inconsistency between laboratory results and the in vivo action of the drugs; 3) partial resistance; and 4) the capacity of the immune system to guarantee an adequate response even with a relatively small contribution by drugs. There is evidence that properly designed regimens (including second-line drugs) can achieve higher success rates,18,19 although the cost per case cured is, at present, very high.20 However the recently established Green Light Committee has achieved a reduction in second-line drug prices of over 90%.21 Institution of appropriate treatment was the factor most strongly associated with a favourable outcome.18,19 It has been argued that the DOTS strategy alone is not sufficient to solve the problems of TB control in Russia.7 Others have called for action to resolve the Russian paradox of centralisation of TB services coupled with individualisation of casemanagement.8 The spread of MDR strains from the prison system, where monotherapy was the prevailing intervention for TB in the recent past due to lack of resources, is presently affecting the epidemiology of TB in the civilian population.8 In the absence of significant improvements, there is a high risk of not being able to control TB in this and other settings. The study results suggest that the present definition of treatment success2 is likely to overestimate the true results, at least among MDR cases. The Kaplan Meier analysis of cumulative recurrence-free survival indicates that the majority of events took place in the first 12 months of follow-up. A stricter use of a culturebased bacteriological monitoring at the end of treatment is necessary to define cure. In our study, 13 out of 18 MDR cases did not Recurrence of MDR-TB cases in Russia experience recurrence during follow-up (Table 2, Figure). Some of these patients might have acquired resistance to any first-line drugs to which their infecting strain was still susceptible.22–25 Adequate regimens with second-line drugs are crucial to improve patient outcome, although this approach could lead to the development of resistance to additional drugs if patients are not closely monitored to avoid drug mismanagement. As second-line drugs are the last resort to cure patients with MDRTB, both programme quality and patient compliance must be taken into consideration before initiating a similar approach. The use of adequate re-treatment regimens, including at least two, and preferably three, active second-line drugs, can reduce this risk. However, regimens containing second-line drugs must be used only after ensuring that programme-related pitfalls are minimised through implementation of quality DOTS programmes.22–25 Acknowledgements The authors wish to thank Dr Rosella Centis, WHO Collaborating Centre for Tuberculosis and Lung Diseases, for her invaluable help in data analysis, Dr Kenneth Castro, Division of Tuberculosis Elimination, CDC, Atlanta, for his useful comments on the manuscript, Dr N V Kutulina, Chief Mycobacteriology Laboratory, Ivanovo Dispensary for help in analysing laboratory data, and Dr A Morandi, University of Pavia, Italy, for the statistical analysis. The project was supported by the WHO through a grant from the United Kingdom. References 1 World Health Organization. WHO Framework for Effective Tuberculosis Control. WHO/TB/94.179: 1–13. Geneva: WHO, 1994. 2 Veen J, Raviglione M C, Rieder H L, et al. Standardised treatment outcome monitoring in Europe. Recommendations of a Working Group of WHO and IUATLD. Eur Respir J 1998; 12: 505–510. 3 Goble M, Iseman M D, Madsen L A, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Eng J Med 1993; 328: 527–532. 4 Mahmoudi A, Iseman M D. Pitfalls in the care of patients with tuberculosis. JAMA 1993; 270: 65–68. 5 Espinal M, Kim S J, Suarez P G, et al. Standard short-course chemotherapy for drug-resistant tuberculosis. Treatment outcome in 6 countries. JAMA 2000; 283: 2537–2545. 6 Danilova I, Stoyunin M, Repina E, et al. Primary multidrugresistant tuberculosis—Ivanovo Oblast, Russia. MMWR 1999; 48: 661–664. 863 7 Perelman M I. Tuberculosis in Russia. Int J Tuberc Lung Dis 2000; 4: 1097–1103. 8 Kimerling M E. The Russian equation: an evolving paradigm in tuberculosis control. Int J Tuberc Lung Dis 2000; 4 (Suppl 2): S160–S167. 9 Kimerling M E, Kluge H, Vezhnina N, et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999; 3: 451–453. 10 World Health Organization Tuberculosis Programme. Managing tuberculosis at district level. A training course. Modules A1–A12. Geneva: WHO, 1994. 11 World Health Organization, Communicable Diseases. Antituberculosis drug resistance in the world. Report. N2. Prevalence and trends. WHO/CDS/TB/2000.278: 1–253. Geneva: WHO, 2000. 12 World Health Organization. Anti-tuberculosis drug resistance in the world. The WHO/ IUATLD Global Project on antituberculosis drug resistance surveillance. WHO/TB/97.229: 1– 227. Geneva: WHO, 1997. 13 WHO/IUATLD Global Working Group on anti-tuberculosis drug resistant surveillance. Guidelines for surveillance of drug resistance in tuberculosis. WHO/TB/96.216: 1–36. Geneva: WHO, 1997. 14 Clancy L, Rieder H L, Enarson D A, Spinaci S. Tuberculosis elimination in the countries of Europe and other industrialized countries. Eur Respir J 1991; 4: 1288–1295. 15 Rieder H L, Watson J M, Raviglione M C, et al. Surveillance of tuberculosis in Europe. Eur Respir J 1996; 9: 1097–1104. 16 Migliori G B, Raviglione M C, Schaberg T, et al. Management of tuberculosis in Europe. Eur Respir J 1999; 14: 978–992. 17 Van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341: 1174–1179. 18 Park M, Davis A L, Schluger N W, et al. Outcome of MDR-TB patients, 1983–1993. Am J Respir Crit Care Med 1996; 153: 317–324. 19 Park S K, Kim C T, Song S D. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998; 2: 877–884. 20 Heymann S J, Brewer T F, Wilson M E, Fineberg H V. The need for global action against multidrug-resistant tuberculosis. JAMA 199; 281: 2138–2140. 21 Gupta R, Kim J Y, Espinal M A, et al. Public Health. Responding to market failures in tuberculosis control. Science 2001; 293: 1049–1051. 22 Spinaci S. Treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999; 3: 365. 23 Farmer P. Managerial successes, clinical failures. Bad news from Siberia. Int J Tuberc Lung Dis 1999; 3: 365–367. 24 Farmer P E, Bayona J, Becerra M, et al. The dilemma of MDRTB in the global era. Int J Tuberc Lung Dis 1998; 2: 869–876. 25 Farmer P E, Bayona J, Becerra M, et al. Multidrug-resistant tuberculosis and the need for biosocial perspectives. Int J Tuberc Lung Dis 2001; 5: 885–886. RÉSUMÉ Oblast d’Ivanovo, Fédération de Russie, à 300 km au nord-est de Moscou où un projet-pilote (Programme de Lutte contre la TB par le DOTS) a été mis en œuvre en octobre 1995. O B J E C T I F : Déterminer la fréquence de la rechute de TB parmi les patients à germes MR (multirésistance aux médicaments) qui avaient été traités avec succès par chimiothérapie standardisée de courte durée. CONTEXTE : Tous les patients atteints de tuberculose MR (définie comme une résistance au moins à l’égard de l’isoniazide et de la rifampicine) et qui ont été classés comme « guéris » ou « traitement achevé » ont été identifiés en utilisant le registre de district et recherchés lorsque c’était possible. Les patients éligibles ont subi un examen médical et, si nécessaire, un cliché thoracique, une bacilloscopie des expectorations, une culture et un test de MÉTHODES : 864 The International Journal of Tuberculosis and Lung Disease sensibilité. Si le patient était décédé antérieurement, les membres de la famille ont été interviewés de façon à tenter de déterminer les causes du décès. R É S U L T A T S : Sur 18 patients éligibles pour l’analyse, cinq (27,8%) ont été documentés comme ayant rechuté (deux des sept patients résistants à HRSE, un des cinq résistants à HRS et deux des six résistants à HR). Les patients ayant reçu un régime de catégorie I étaient plus susceptibles de rechute que ceux ayant reçu un régime de catégorie II (40% vs. 12,5%). La durée médiane jusqu’à la rechute était de 8 mois ; 2,46 rechutes ont été observées pour 100 mois-personne (3,17 chez les patients de catégorie I et 1,3 chez les patients de catégorie II). La fréquence de la rechute de TB parmi les patients TB-MR declarés comme « guéris » par une chimiothérapie de courte durée est élevée, même s’ils sont considérés comme guéris. Des améliorations dans les succès du traitement, après le retrait des pièges liés au programme dans le processus d’administration du traitement, doivent incorporer des méthodes pour la détection précoce de la MR en même temps que des régimes de traitement adéquats comportant des médicaments de deuxième ligne. Une confirmation basée sur la culture est recommandée à la fin du traitement. CONCLUSIONS : RESUMEN D E R E F E R E N C I A : Oblast de Ivanovo, Federación Rusa, a 300 km al noreste de Moscú, donde se implementó un proyecto piloto de Programa de Control de la Tuberculosis (TB) con DOTS, en octubre de 1995. O B J E T I V O : Determinar la frecuencia de la recaída de TB en los pacientes que presentan una multirresistencia a los medicamentos (MR), que habían sido tratados con éxito con una quimioterapia de corta duración. M É T O D O : Todos los pacientes con TB-MR (definida como resistente por lo menos a la isoniacida y a la rifampicina) que habían sido declarados « curados » o « tratamiento completado », fueron identificados gracias al registro de distrito y localizados cuando era posible. Los pacientes elegibles fueron sometidos a un examen médico y, cuando era necesario, a una radiografía de tórax, a una baciloscopia, a un cultivo de expectoración y a un test de sensibilidad. Si el paciente había fallecido previamente, los miembros de la familia eran entrevistados para tratar de determinar la causa del fallecimiento. R E S U L T A D O S : De 18 pacientes elegibles para análisis, cinco (27,8%) fueron documentados como habiendo MARCO tenido una recaída (dos de siete pacientes resistentes a HRSE, uno de cinco pacientes resistentes a HRS y dos de seis pacientes resistentes a HR). Los pacientes que recibieron un esquema de categoría I tenían más probabilidades de recaer que aquellos que recibieron un esquema de categoría II (40% vs. 12,5%). La mediana del tiempo de recaída fue de 8 meses ; 2,46 recaídas fueron observadas en 100 mesos-persona (3,17 en pacientes de categoría I y 1,3 en pacientes de categoría II). C O N C L U S I Ó N : La frecuencia de recaída en los pacientes con TB-MR declarados « curados » con una quimioterapia de corta duración es elevada, aun si son declarados como curados. Después de remover las trampas relacionadas con el programa, en el proceso de administración del tratamiento, los mejoramientos del éxito del tratamiento deben incorporar métodos de detección precoz de la MR, así como esquemas adecuados de tratamiento, incluyendo los fármacos de segunda línea. Una confirmación basada sobre la cultura es recomendada al fin del tratamiento.