Editorial Short-Course Chemotherapy of Tuberculosis Hail Britannia (and Friends)!
This issue of the AMERICAN REVIEW OF RESPIRAlORY DISEASE contains the two latest in a distinguished series of tuberculosis chemotherapy reports generated by the British Medical Research Council (BMRC) Thberculosisand Chest Diseases Unit and their colleagues from East Africa, Hong Kong, and Singapore. As one reads them, one must be impressed by the extraorindary beauty with which these studies complement prior BMRC reports. The authors should be acknowledged for their vision, tenacity, and genius. The modern era of tuberculosis treatment- short-course chemotherapy- began with the first East African/BMRC study (1), which demonstrated that the addition of rifampin to isoniazid and streptomycin allowed a dramatic curtailment (from 18months to 6 months) in the duration of drug therapy required to elicit cures in 95070 or more of patients, the consensus "gold standard." However, this first protocol had two drawbacks that limited its widespread application: (1) to assure all doses, the patients were hospitalized for the entire 6 months and (2) streptomycin injections were given daily for the entire period. Questions raised by these findings included whether some of the treatment could be given intermittently (to-potentiate supervised therapy) and whether streptomycin was really required to achieve satisfactory results. While these issues were being pondered, reports appeared from other BMRC studies to provide answers. The first Hong Kong group trial showed that 9-month twice or thrice weeklytreatments wereas effective as daily treatment with cure rates of 96070 (2); the second East Africa trial showed that deletion of streptomycin in the 6-month regimens raised relapse rates from 2 to 3 % to 7070 (3). The next layer of questions related to the particular roles of various agents. The second Hong Kong study showed a small but significant advantage of streptomycin over ethambutol during the late continu-
ation phase (4). The third East Africa group study demonstrated that, after an initial2-month intensivefour-drug phase, a 6-month course of isoniazid and thiacetazone yielded excellentresults - a substantial financial advantage because these are the two most economical agents in the anti-tuberculosis armamentarium (5). The third East Africa group study plus the second Singapore study (6), showed that when pyrazinamide was added to isoniazid, rifampin, and streptomycin during an initial 2-month daily phase of therapy, 99 to 100070 success rates could be achieved in just 6 months without the extended use of streptomycin. To plumb the question of how short could treatment be, the fourth East Africa study (7) and the second Singapore group study examined various combinations and rhythms of drugs for 4 months; these studies showed that no combination was adequate in this period. They also suggested that pyrazinamide need not be given for the entire duration of treatment. Having determined that 6 months was approximately the shortest duration of therapy that would yield the desired success rates, the next major question was how much of the therapy could be given intermittently. The third Hong Kong trial (8) decisively showed that 6 months of thrice weekly four-drug therapy was highly effective so long as isoniazid, rifampin, and pyrazinamide were among the four drugs; when pyrazinamide was omitted and ethambutol plus streptomycin were used, success rates at 5 yr fell from the range of 96 to 99070 to 90070 (9). An additional, highly significant finding of the third Hong Kong study was the efficacy of these regimens in cases involving initial resistance to isoniazid and/or streptomycin (8). Among the 127 such cases receiving pyrazinamide-containing regimens, there was only a 3 % relapse rate. In a world with an escalating prevalence of drug resistance, this information is of major significance. The two studies reported in this issue
further refine 6-month chemotherapy. The Hong Kong study (10), a variation on the 6-month thrice weeklyformat, addressed and answered these questions: (1) How long need we give pyrazinamide to achieve maximum benefit? The results indicate that with drug-susceptible disease 2 months is equal to 4 or 6. (2) Does streptomycin add to an isoniazid, rifampin, and pyrazinamide thrice weeklyregimen? They note that while there was not a significant difference (statistically), the only treatment failures occurred among the regimen minus the injectable drug; hence, the Hong Kong group continues to use streptomycin. (3) What is the efficacy and tolerance of a fixed-combination preparation of isoniazid, rifampin, and pyrazinamide (Rifaters; Gruppo Lepetit, Milan, Italy) during thrice weekly treatment? They conclude there is modestly better acceptance and comparable efficacy with the fixed-combination preparation. By contrast, in the Singapore study (11) the fixed-combination preparation (Rifater) given in an initial daily phase was significantly less effective than the same drugs given separately and in comparable doses. As in the new Hong Kong report, the Singapore trial indicates no significant contribution of streptomycin to an initial regimen of isoniazid, rifampin, and pyrazinamide (in this case daily not thrice weekly). A further contribution of this Singapore study was the demonstration that with drug-susceptible disease an initial daily, l-month, fourdrug phase was equal in efficacy to a 2-month phase. To summarize, BMRC scientists and their colleagues from around the world have conducted a series of studies over the past two decades that have generated an immense amount of highly instructive data that allows clinicians to select agents and regimens with the assurance of predictable efficacy and safety. These were not easy trials. Thousands of patients in diversecultures and settings were enrolled, treated, and monitored for tox697
698
EDITORIAL
icity; sputum specimens had to be sent to London for definitive susceptibility testing; and surveillance to determine efficacy required follow-up for 3 to 5 yr after completion of therapy. Although other groups have contributed significantly, there is no question that the major architects of this body of knowledge are the BMRC and colleagues. Although we have not reached the pinnacle of tuberculosis chemotherapy, we might stop at this point to reflect on these accomplishments and to applaud this remarkable coalition for one of the outstanding achievements of modern medicine. Well done!
MICHAEL D. ISEMAN, M.D. Chief, ClinicalMycobacteriology Service Division of Infectious Diseases National Jewish Center for Immunology and Respiratory Medicine Professor of Medicine University of Colorado School of Medicine Denver, CO JOHN A. SBARBARO, M.D. Professor of Medicine and Preventive Medicine University of Colorado School of Medicine Denver, CO
References 1. East African/British Medical Research Council Study. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977; 115:3-8. 2. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong: the results up to 30 months. Am Rev Respir Dis 1977; 115:727-32. 3. Second East African/British Medical Research Council Study. Second report. Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1976; 114:471-5. 4. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1978; 118:219-27. 5. Third East African/British Medical Research Council Study. Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1978; 118:39-48. 6. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of 6-month and 4-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir
Dis 1979; 119:579-85. 7. East African/British Medical Research Council. Controlled clinical trial of five short-course (4month) chemotherapy regimens in pulmonary tuberculosis. Second report of the fourth study. Am Rev Respir Dis 1981; 123:165-70. 8. Hong Kong Chest Service/British Medical Research Council. Controlled trial of four thriceweekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Lancet 1981; 1:171-4. 9. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987; 136:1339-42. 10. Hong Kong Chest Service/British Medical Research Council. Controlled trials of 2, 4, and 6 months of pyrazinamide in 6-month, three-timesweekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide: results at 30 months. Am Rev Respir Dis 1991; 143:700-6. 11. Singapore Tuberculosis Service/British Medical Research Council. Assessment of a daily combined preparation of isoniazid, rifampin, and pyrazinamide in a controlled trial of three 6-month regimens for smear-positive pulmonary tuberculosis. Am Rev Respir Dis 1991; 143:707-12.
This issue of the AMERICAN REVIEW OF RESPIRAlORY DISEASE contains the two latest in a distinguished series of tuberculosis chemotherapy reports generated by the British Medical Research Council (BMRC) Thberculosisand Chest Diseases Unit and their colleagues from East Africa, Hong Kong, and Singapore. As one reads them, one must be impressed by the extraorindary beauty with which these studies complement prior BMRC reports. The authors should be acknowledged for their vision, tenacity, and genius. The modern era of tuberculosis treatment- short-course chemotherapy- began with the first East African/BMRC study (1), which demonstrated that the addition of rifampin to isoniazid and streptomycin allowed a dramatic curtailment (from 18months to 6 months) in the duration of drug therapy required to elicit cures in 95070 or more of patients, the consensus "gold standard." However, this first protocol had two drawbacks that limited its widespread application: (1) to assure all doses, the patients were hospitalized for the entire 6 months and (2) streptomycin injections were given daily for the entire period. Questions raised by these findings included whether some of the treatment could be given intermittently (to-potentiate supervised therapy) and whether streptomycin was really required to achieve satisfactory results. While these issues were being pondered, reports appeared from other BMRC studies to provide answers. The first Hong Kong group trial showed that 9-month twice or thrice weeklytreatments wereas effective as daily treatment with cure rates of 96070 (2); the second East Africa trial showed that deletion of streptomycin in the 6-month regimens raised relapse rates from 2 to 3 % to 7070 (3). The next layer of questions related to the particular roles of various agents. The second Hong Kong study showed a small but significant advantage of streptomycin over ethambutol during the late continu-
ation phase (4). The third East Africa group study demonstrated that, after an initial2-month intensivefour-drug phase, a 6-month course of isoniazid and thiacetazone yielded excellentresults - a substantial financial advantage because these are the two most economical agents in the anti-tuberculosis armamentarium (5). The third East Africa group study plus the second Singapore study (6), showed that when pyrazinamide was added to isoniazid, rifampin, and streptomycin during an initial 2-month daily phase of therapy, 99 to 100070 success rates could be achieved in just 6 months without the extended use of streptomycin. To plumb the question of how short could treatment be, the fourth East Africa study (7) and the second Singapore group study examined various combinations and rhythms of drugs for 4 months; these studies showed that no combination was adequate in this period. They also suggested that pyrazinamide need not be given for the entire duration of treatment. Having determined that 6 months was approximately the shortest duration of therapy that would yield the desired success rates, the next major question was how much of the therapy could be given intermittently. The third Hong Kong trial (8) decisively showed that 6 months of thrice weekly four-drug therapy was highly effective so long as isoniazid, rifampin, and pyrazinamide were among the four drugs; when pyrazinamide was omitted and ethambutol plus streptomycin were used, success rates at 5 yr fell from the range of 96 to 99070 to 90070 (9). An additional, highly significant finding of the third Hong Kong study was the efficacy of these regimens in cases involving initial resistance to isoniazid and/or streptomycin (8). Among the 127 such cases receiving pyrazinamide-containing regimens, there was only a 3 % relapse rate. In a world with an escalating prevalence of drug resistance, this information is of major significance. The two studies reported in this issue
further refine 6-month chemotherapy. The Hong Kong study (10), a variation on the 6-month thrice weeklyformat, addressed and answered these questions: (1) How long need we give pyrazinamide to achieve maximum benefit? The results indicate that with drug-susceptible disease 2 months is equal to 4 or 6. (2) Does streptomycin add to an isoniazid, rifampin, and pyrazinamide thrice weeklyregimen? They note that while there was not a significant difference (statistically), the only treatment failures occurred among the regimen minus the injectable drug; hence, the Hong Kong group continues to use streptomycin. (3) What is the efficacy and tolerance of a fixed-combination preparation of isoniazid, rifampin, and pyrazinamide (Rifaters; Gruppo Lepetit, Milan, Italy) during thrice weekly treatment? They conclude there is modestly better acceptance and comparable efficacy with the fixed-combination preparation. By contrast, in the Singapore study (11) the fixed-combination preparation (Rifater) given in an initial daily phase was significantly less effective than the same drugs given separately and in comparable doses. As in the new Hong Kong report, the Singapore trial indicates no significant contribution of streptomycin to an initial regimen of isoniazid, rifampin, and pyrazinamide (in this case daily not thrice weekly). A further contribution of this Singapore study was the demonstration that with drug-susceptible disease an initial daily, l-month, fourdrug phase was equal in efficacy to a 2-month phase. To summarize, BMRC scientists and their colleagues from around the world have conducted a series of studies over the past two decades that have generated an immense amount of highly instructive data that allows clinicians to select agents and regimens with the assurance of predictable efficacy and safety. These were not easy trials. Thousands of patients in diversecultures and settings were enrolled, treated, and monitored for tox697
698
EDITORIAL
icity; sputum specimens had to be sent to London for definitive susceptibility testing; and surveillance to determine efficacy required follow-up for 3 to 5 yr after completion of therapy. Although other groups have contributed significantly, there is no question that the major architects of this body of knowledge are the BMRC and colleagues. Although we have not reached the pinnacle of tuberculosis chemotherapy, we might stop at this point to reflect on these accomplishments and to applaud this remarkable coalition for one of the outstanding achievements of modern medicine. Well done!
MICHAEL D. ISEMAN, M.D. Chief, ClinicalMycobacteriology Service Division of Infectious Diseases National Jewish Center for Immunology and Respiratory Medicine Professor of Medicine University of Colorado School of Medicine Denver, CO JOHN A. SBARBARO, M.D. Professor of Medicine and Preventive Medicine University of Colorado School of Medicine Denver, CO
References 1. East African/British Medical Research Council Study. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977; 115:3-8. 2. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong: the results up to 30 months. Am Rev Respir Dis 1977; 115:727-32. 3. Second East African/British Medical Research Council Study. Second report. Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1976; 114:471-5. 4. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1978; 118:219-27. 5. Third East African/British Medical Research Council Study. Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1978; 118:39-48. 6. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of 6-month and 4-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir
Dis 1979; 119:579-85. 7. East African/British Medical Research Council. Controlled clinical trial of five short-course (4month) chemotherapy regimens in pulmonary tuberculosis. Second report of the fourth study. Am Rev Respir Dis 1981; 123:165-70. 8. Hong Kong Chest Service/British Medical Research Council. Controlled trial of four thriceweekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Lancet 1981; 1:171-4. 9. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987; 136:1339-42. 10. Hong Kong Chest Service/British Medical Research Council. Controlled trials of 2, 4, and 6 months of pyrazinamide in 6-month, three-timesweekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide: results at 30 months. Am Rev Respir Dis 1991; 143:700-6. 11. Singapore Tuberculosis Service/British Medical Research Council. Assessment of a daily combined preparation of isoniazid, rifampin, and pyrazinamide in a controlled trial of three 6-month regimens for smear-positive pulmonary tuberculosis. Am Rev Respir Dis 1991; 143:707-12.
