Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries.

CONTEXT: No large-scale study has investigated the impact of multidrug-resistant tuberculosis (TB) on the outcome of standard short-course chemotherapy under routine countrywide TB control program conditions in the World Health Organization's (WHO) directly observed treatment short-course strategy for TB control. OBJECTIVE: To assess the results of treatment with first-line drugs for patients enrolled in the WHO and the International Union Against Tuberculosis and Lung Disease's global project on drug-resistance surveillance. DESIGN AND SETTING: Retrospective cohort study of patients with TB in the Dominican Republic, Hong Kong Special Administrative Region (People's Republic of China), Italy, Ivanovo Oblast (Russian Federation), the Republic of Korea, and Peru. PATIENTS: New and retreatment TB cases who received short-course chemotherapy with isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin between 1994 and 1996. MAIN OUTCOME MEASURE: Treatment response according to WHO treatment outcome categories (cured; died; completed, defaulted, or failed treatment; or transferred). RESULTS: Of the 6402 culture-positive TB cases evaluated, 5526 (86%) were new cases and 876 (14%) were retreatment cases. A total of 1148 (20.8%) new cases and 390 (44.5%) retreatment cases were drug resistant, including 184 and 169 cases of multidrug-resistant TB, respectively. Of the new cases 4585 (83%) were treated successfully, 138 (2%) died, and 151 (3%) experienced short-course chemotherapy failure. Overall, treatment failure (relative risk [RR], 15.4; 95% confidence interval [CI], 10.6-22.4; P<.001) and mortality (RR, 3.73; 95% CI, 2.13-6.53; P<.001) were higher among new multidrug-resistant TB cases than among new susceptible cases. Even in settings using 100% direct observation, cases with multidrug resistance had a significantly higher failure rate than those who were susceptible (9/94 [10%] vs 8/1410 [0.7%]; RR, 16.9; 95% CI, 6.6-42.7; P<.001). Treatment failure was also higher among patients with any rifampicin resistance (n=115) other than multidrug resistance (RR, 5.48; 95% CI, 3.04-9.87; P<.001), any isoniazid resistance (n=457) other than multidrug resistance (RR, 3. 06; 95% CI, 1.85-5.05; P<.001), and among patients with TB resistant to rifampicin only (n=76) (RR, 5.47; 95% CI, 2.68-11.2; P<.001). Of the retreatment cases, 497 (57%) were treated successfully, 51 (6%) died, and 124 (14%) failed short-course chemotherapy treatment. Failure rates among retreatment cases were higher in those with multidrug-resistant TB, with any isoniazid resistance other than multidrug resistance, and in cases with TB resistant to isoniazid only. CONCLUSIONS: These data suggest that standard short-course chemotherapy, based on first-line drugs, is an inadequate treatment for some patients with drug-resistant TB. Although the directly observed treatment short-course strategy is the basis of good TB control, the strategy should be modified in some settings to identify drug-resistant cases sooner, and to make use of second-line drugs in appropriate treatment regimens. JAMA. 2000;283:2537-2545

[Molecular characteristics of multiresistant clinical strains of Mycobacterium tuberculosis isolated in Russia]. / Molekuliarnaia kharakteristika polirezistentnykh klinicheskikh shtammov Mycobacterium tuberculosis iz Rossii.

The efficiency of tuberculosis control programs is largely determined by methods for rapid diagnosis of the agent. In comparison with the traditional methods, new molecular technologies for characterization of mycobacteria appear to be more promising, because the result can be obtained in almost no time. Sixty-five strains of M. tuberculosis isolated in various regions of Russia were investigated. Drug resistance and strain appurtenance of this sample were determined by classical (absolute concentrations method, IS6110-RFLP) and modern molecular genetic methods (detection of mutations in rpo B gene, DRE-PCR). The spectrum of mutations of the rpoB gene associated with rifampicin resistance was evaluated by direct sequencing. Mutations involving codons 531 (62.7%), 526 (18.6%), and 516 (10.2%) of rpoB gene predominated in the studied sample. The studied strains were discriminated into 52 individual strains by IS6110-RFLP and DRE-PCR typing. Analysis of the resultant genetic variants showed the predominance of M. tuberculosis family W. The efficiency of combined approach to screening for M. tuberculosis is discussed.

[Detection and characteristics of rpoB gene mutations in rifampicin-resistant clinical strains of M. tuberculosis]. / Detektsiia i kharakteristika mutatsii v gene rpoB rezistentnykh k rifampitsinu klinicheskikh shtammov M. tuberculosis.

The resistance of M. tuberculosis to rifampicin, one of the key agents used in the treatment of tuberculosis is due to point mutations in the rpoB gene encoding for the B-subunit of PNA polymerase. Based on the detection of such mutations, genotypic determinations of rifampicin resistance is a serous alternative to routine microbiological assays that take much more time. Nevertheless, the efficiency of genotypic methods largely depends how completely the resistance-associated mutations are studied and characterized. It is shown that the types and detection rates of certain rpoB mutations can greatly vary in the Mycobacterium strains spread in different geographical regions. By applying the approach based on the direct sequencing of PCR with rpoB gene fragments, the present paper analyzed 48 rifampicin-sensitive and 52 rifampicin-resistant clinical M. tuberculosis strains provided by Moscow tuberculous control facilities. Mutations responsible for rifampicin resistance were detected in 51 (98%) of the 52 resistant strains. The mutations involving codons 531 (46%), 526 (23%), and 516 (23%) of the rpoB gene were proved to be dominant. An unusual double mutation combining the replacement of F by L in codon 514 and previously uncharacterized methionine deletion in the position 515 was detected in the single investigated strain. The efficiency of the employed approach for rapid diagnosis of rifampicin-resistant M. tuberculosis strains is discussed.

[DOTS strategy and its application in Russia]. / Strategiia DOTS i ee rasprostranenie v Rossii.

Leading principles of DOTS strategy for Russia are outlined. It has been introduced in Russia since 1994 in Ivanovo, Tomsk Regions, Mary El Republic. New territories (Leningrad and Arkhangelsk Regions) have recently joined the project. Methods of detecting bacillary patients, scheme of chemotherapy for different tuberculosis patients and of bacteriological and x-ray follow-up control are presented. Positive aspects of the program are analyzed as well as causes of its insufficient benefit under conditions of Russian Federation.

[Diagnosis, clinical picture and treatment policy in acute progressive forms of pulmonary tuberculosis under present-day epidemiological conditions]. / Diagnostika, klinika i taktika lecheniia ostroprogressiruiushchikh form tuberkuleza legkikh v sovremennykh épidemiologicheskikh usloviiakh.

Among 103 examinees, the most common clinical type was caseous pneumonia (45.6%), progressive fibrocavernous tuberculosis (20.4%), infiltrative caseous pneumonia (17.5%), disseminated tuberculosis (16.5%). Progression was characterized by cavern formation in 91.1% of patients, with large and giant caverns containing nonspecific microbes forming in 79.6%. All the patients were found to isolate bacteria and 93.5% showed their excess. Drug-resistant microbes were identified in 62.1% of patients; polydrug resistance was seen in 37.5%. Chemotherapy was performed at the first stage by using 5 drugs: isoniazid, rifampicin, pyrazinamide, ethambutol plus kanamycin or amikacin. A combination of reserve drugs, including prothionamide, ofloxacin (ciprofloxacin) amikacin, pyrazinamide, and ethambutol, was used in patients with polyresistance. Symptomatic and pathogenetic therapies should aim at correcting complications and concomitant abnormalities. Following 6 months, 80% of patients stopped isolating bacteria, the process became stable and they could be prepared for planned surgical treatment. In 20% of cases, the process was progressive and it required salvage operations.

Cost-effectiveness analysis of tuberculosis control policies in Ivanovo Oblast, Russian Federation. Ivanovo Tuberculosis Project Study Group.

Many of the current tuberculosis control programmes in the Russian Federation are based on costly strategies which are underfunded and use long, individualized treatment regimens. This article compares, using a cost-effectiveness analysis, the new WHO strategy implemented in the Ivanovo Oblast (case-finding among symptomatic patients (SCF) and shorter regimens) and the old strategy (active screening of the asymptomatic population (ACF) and longer regimens). The cost per case cured was calculated at different levels of cure rate (45-95%) using three scenarios to describe the new WHO strategy (use of WHO-recommended regimens and three options at increasing rates of admission) and a fourth scenario to describe the old strategy (all patients admitted for the whole treatment and longer regimens). The cost per case detected was determined by calculating the following: yield of the new and old strategy (number of examinations necessary to diagnose one case); cost of the diagnostic process; multiplying yield per cost according to the three scenarios describing the new WHO strategy and a fourth scenario describing the old strategy. In the Ivanovo Oblast the cost per case cured, at 85% cure rate level, ranged from US$ 1197 (new strategy, scenario 1 without food) to US$ 6293 (old strategy, scenario 4) the cost per case detected ranged from US$ 1581 (new strategy, scenario 1) to US$ 4000 (old strategy, scenario 4). Significant savings can result from shifting towards the new WHO strategy. Decision-makers and health administrators should be responsible for re-investing the financial and human resources mobilized by the adoption of cost-effective strategies within the TB control programme.

[Clinical and epidemiological aspects of controlled short-term chemotherapy]. / Klinicheskie i épidemiologicheskie aspekty kontroliruemoi khimioterapii ukorochennoi dlitel'nosti.

The current aspects of controlled short-term chemotherapy are reviewed. The efficiency and mechanism of action of various agents are evaluated, with emphasis laid on their effects of mycobacterial population, including drug-resistant Mycobacteria tuberculosis. Treatment of new cases isolating M. tuberculosis is shown to be a priority under the present epidemiological conditions, which stopped the spread of infection in the human community and reduces the infection and disease rates. The programmes of controlled chemotherapy in different patients recommended by the WHO and the International Tuberculosis and Pulmonary Diseases Control Union are analyzed. This leads to the conclusion that the programmed chemotherapy with clear identification of groups of patients and well-defined drug combinations, the fixed duration of treatment and the calculated required doses for therapy can drastically reduce tuberculosis morbidity and mortality rates drastically.

[Cost benefit of detection and treatment patients with tuberculosis in Ivanovo region, Russian Federation]. / Stoimost' vyiavleniia i lecheniia bol'nykh tuberkulezom v Ivanovskoi oblasti Rossiiskoi Federatsii.

To execute the tuberculosis control programme in the Ivanovo Region, the authors calculated the cost of detection of a tuberculosis case at patients' referrals to a therapeutical-and-prophylactic institution for medical aid and during prophylactic X-ray fluographic examinations and the cost of tuberculosis cure while treating the patient at a hospital in the intensive treatment phase (2-3 months) and in the outpatient setting or at a day hospital by the intermittent method in the continued treatment phase. The costs calculated were compared with those obtained by early approaches. The cost of detection of a tuberculosis case was 1580.8 for referrals in 1996 and 4000 for X-ray fluographic prophylactic examinations. The costs of hospital tuberculosis cure (85% cure rates) only in the intensive treatment phase (for 2-3 months) and outpatient intermittent treatment (for 2-4 months) with and without meals were 2415.34 and 2142.17 respectively. If the efficiency is equal, the introduction of new approaches to organizing the detection and treatment tuberculosis cases may save 3877.7 for each cured tuberculosis case and 2419.2 for each patient detected.

[Tuberculosis: yesterday, today, tomorrow]. / Tuberkulez vchera, segodnia i zavtra.

The historical aspects of phisiology are briefly outlined. The main factors that promote the prevalence of tuberculosis are characterized. The present-day tuberculosis epidemiological situation makes one to correct antituberculous measures and with the use of new investigations and developments to improve the identification of patients with tuberculosis, primarily those with contagious types of the disease, to introduce the currently available short-term regimens of 2-stage drug therapy, to design novel agents and depot formulations of the well known ones. Further investigations are required to search for a new tuberculosis vaccine.

[Sociomedical aspects of detection and treatment of patients with tuberculosis under present conditions]. / Mediko-sotsial'nye aspekty vyiavleniia i lecheniia bol'nykh tuberkulezom v sovremennykh usloviiakh.

By analyzing the present-day tuberculosis epidemiological situation in the country and sociomedical characteristics of new cases, the authors present methods for detecting and treating patients, which are of paramount importance for today. Of the most significance is the need to promptly identify patients with strains on their referral to the general somatic hospitals for complaints by using 3-multiple sputum bacterioscopy for Mycobacterium tuberculosis by the Ziehl-Neelsen method. The vital problem is also to change chemotherapeutical regimens as more severe progressive types of the disease require more active treatment in the first months after detection especially in the cohort of socially disadapted persons.

[Role and significance of structural, metabolic and functional disorders of mononuclear phagocytes in pathogenesis of caseous pneumonia]. / Rol' i znachenie strukturno-metabolicheskikh i funktsional'nykh naryshenii fagotsitarnoi sistemy v patogeneze kazeoznoi pnevmonii.

Comprehensive clinical, X-ray, cytochemical, morphological, biochemical, and immunological studies of 14 patients with caseous pneumonia have provided evidence that significant structural, metabolic, and functional disorders of mononuclear phagocytes (MNP) play a leading role in the pathogenesis of acute tuberculosis. Structural and metabolic disorders of macrophages and monocytes in patients with caseous pneumonia result from impaired mitochondrial oxidation and glycolysis, aggregation and latinization of the membranes of lysosomes, release of their contents into the cytosol with damages to intracellular structures and the cellular membrane itself. This is also suggested by a drastic rise in the production of prostaglandins E2 and F2 alpha, prostaglandins E2 in particular, in the supernatants of cultured monocytes (100 nM). This is determined as the membrane-damaging effect of MNP due to the toxic action of rapidly multiplying mycobacterial population not only in the lung, but even in blood. MNP structural and metabolic disturbances are an equivalent to their lowered functional activity, as evidenced by a considerable deficiency of synthesis of intracellular and secretory pools of interleukin I and by a fall in their migrational and adhesive activities, two thirds of macrophages having signs of dystrophy and cytolysis. On entering the specific inflammatory area of the lung, these cells abundantly disintegrate. Their destruction leads to the elaboration of enzymes, prostaglandins, and other biologically active agents, which promotes the occurrence of extensive caseously destructive changes and creates conditions for rapid multiplication of mycobacteria.

Serodiagnosis of tuberculosis: detection of mycobacterial antibodies and antigens.

SETTING: The diagnosis of tuberculosis is based primarily on identification of mycobacteria and on clinical evidence. Recently, serological studies have been widely used experimentally as a diagnostic approach. OBJECTIVE: The aim of our study was to optimize serodiagnosis of tuberculosis by detecting mycobacterial antigens and antibodies in sera from patients with lung tuberculosis, non-related diseases and healthy controls. DESIGN: Mycobacterium tuberculosis H37Rv was disintegrated by pressure. Cell walls were extracted with 3 M KCL and were subjected to gel filtration in Toyopearl gel. Immune sera were prepared by immunization of rabbits with cell wall material. Anti H37Rv antibodies were purified by affinity chromatography. The reagents obtained were used to detect serum antibodies and antigens (following immune complex dissociation) using ELISA. RESULTS: Using fraction 6 of cell wall extract, antibodies were detected in 72.2% of TB patients; there were no positive reactions in control subjects. By use of affinity-purified antibodies, antigens were detected in 77.1% of TB patients, 10% of patients with unrelated diseases and 6.7% of healthy controls. CONCLUSION: Effective serodiagnosis of tuberculosis can be achieved only by combining detection of both circulating antibodies and antigens using highly specific purified reagents and immune complex-dissociated sera.

[Genomic polymorphism in Mycobacterium tuberculosis strains]. / Issledovanie genomnogo polimorfizma shtammov Mycobacterium tuberculosis.

Different genomic fingerprinting techniques (universal probes, such as rRNA genes, phage M13 DNA, IS 6110 probe) have been used to investigate the genomic polymorphism of Mycobacterium tuberculosis strains isolated in different geographical regions of Russia and in some CIS countries. As shown with the use of these techniques and a specially developed PCR-mediated system for genetic typing, M.tuberculosis strains are genotypically heterogeneous in regions with a sporadic level of tuberculosis morbidity and genotypically homogeneous in regions with elevated morbidity and mortality levels. The evaluation of the effectiveness of the genetic typing of M.tuberculosis with the use of different genomic fingerprinting techniques has made it possible to propose the optimum 3-stage scheme for the differentiation of M.tuberculosis strains: (1) the typing of all isolated strains of the PCR-mediated test system; (2) the typing of several selected M.tuberculosis strains with the use of 1S 6110 probe (2-3 strains of each detected PCR-RFLP [correction of PLRF] genotypes); (3) the typing of M.tuberculosis strains, containing 1 copy of 1S 6110 or not containing such sequence, with the use of probes (phage M13 DNA) detecting hypervariable sequences in M.tuberculosis genomes.

[Efficacy of chemotherapy of pulmonary tuberculosis drug-resistant m.tuberculosis]. / Effektivnost' khimioterapii tuberkuleza legkikh s lekarstvenno-ustoichivymi mikbakteriiami.

M. tuberculosis examined in 717 patients with pulmonary tuberculosis appeared resistant to chemotherapy in 67.2% of cases. Whereas chronic patients developed drug resistance (DR) as secondary DR in 90.2% of cases, new cases with DR (50.1% of the examinees) seemed to be infected with drug-resistant M. tuberculosis. 2-stage chemotherapy with 4-5 drugs terminates bacterial discharge within first 3 months of treatment in the majority of the patients, especially if early correction of chemotherapy is used by the results of early determination M. tuberculosis drug sensitivity.

[Dynamics of isolation of mycobacterium tuberculosis during 2-stage standard chemotherapy]. / Dinamika vydeleniia mikobakterii tuberkuleza pri 2-etapnoi standartnoi khimioterapii.

Two-stage standard chemotherapy was performed in 149 newly detected patients with pulmonary tuberculosis, by isolating Mycobacteria. Within the first 2 months, the patients received 4 drugs: isoniazid, rifampicin, pyrazinamide, streptomycin or ethambutol. Treatment with two agents (isoniazid and rifampicin) was continued for 4 months. Mycobacterial isolation was stopped in 104 patients after 2 months of treatment, in other 26 after 3 months, which amounts to 80.2%. Higher therapeutical results were observed in patients who had isolated Mycobacteria resistant to 1 and even 2 drugs.