I have been asked to review in 45 minutes all of

Transcription

1 The Chemotherapy of Pulmonary Tuberculosis: A Review Wallace Fox, M.D. I have been asked to review in 45 minutes all of the chemotherapy of tuberculosis! Of necessity I shall be brief and I shall therefore confine my remarks to some main issues and some issues of special inlerest. The reasons for failure of chemotherapy are: 1. prescribing inadequate regimens 2. drug toxicity 3. patients discharging themselves from treatment prematurely 4. patients continuing attending the treatment services, but a. stopping taking drugs b. becoming irregular in taking drugl 5. drug-resistant infection at start of chemotherapy It is now abundantly clear that(rovided inadequate regimens are not prescribed and drug toxicity is carefully managed (avoiding monotherapy, especially if prolonged, during sensitization courses), then the main reasons for failure of good regimens are points 3 and 4 above. Drugresistant infection at the start of chemotherany is now known to be relalively less important. This latter has been demonstrated in a controlled clinical trial in Hong Kong1 2 which was designed particularly to measure the influence of initial drug resistance on the overall therapeutic success when patients were treated with the classic, so-called 100 percent effective standard regimen, of streptomycin, PAS and isoniazid, followed by PAS and isoniazid:), Further evidence comes fi on(two surveys in East Africa3 4 in which an evaluation has been made of the results achieved by the routine treatment services when patients were receiving a triple regimen (STH) of streptomycin, thiacetazone and isoniazid, followed by th,iacetazone and isoniazid (Table 1). In Tanzania, the overall bacteriologic failure rate at one year in bacteriologically confirmed cases of pulmonary tuberculosis was 15 percent. Of this, at most 3 percent represented an inadequacy of the STH regimen (it is likely that an element of irregularity #{176}Director, Medical Research Council Tuberculosis and Chest Disease Unit, Brompton Hospital, London, England. Reprint requests: Dr. Fox, MRC Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fuiham Road, London SW36HP, England in the self-administration of thiacetazone plus isoniazid in the continuation phase contributed to this level of failure). An insufficient duration of the prescribed regimen due to the patient discontinuing collecting his chemotherapy prematurely (compounded, no doubt, by irregularity in taking the drugs in the period when the patient was still attending the treatment services) accounted for 9 percent of the failures. Finally, initial resistance to isoniazid accounted for the remaining 3 percent. Thus, the main reason for failure was undoubtedly irregularity in taking the prescribed regimen. The findings in Kenya for the same STH regimen in the 1974 survey are very similar. Indeed, the modern concept of a good regimen is, by definition, one that largel overcomes the influence of initial drug resistance.5) A measure of the frequency of the different causes of failure of standard chemotherapy in a technically advanced country was obtained in a survey of the management of therapy and the results achieved in patients in Scotland who were notified and brought under treatment in This year was chosen for the survey because he standard regimen (SPH) was still streptomycin, PAS and isoniazid daily followed by PAS and isoniazid in the continuation phase, given for a total duration of 18 months to two years. Considering antibacterial failures of chemotherapy (Table 2), of 770 patients, 1.9 percent died of active tuberculosis, 0.6 percent had their treatment changed for persisting sputum positivity, 1.7 percent had a bacteriologic relapse during chemo) Table 1-Estimated Percentages o/ Failures of Chemotherapy in Service Program and the Reasons (Patients with Bacteriologicaily-Con/lrmed Tuberculosis) Reasons for failure Tanzania 1969 % Kenya 1974 % Inadequacy of prescribed STH regimen 3 5 Insufficient duration of prescribed regimen 9 7 Initial resistance to isoniazid 3 3 All reasons Number of patients S = streptomycin; T = thiacetazone; H = isoniazid CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 785

2 ( Table 2-Antibacterial Failures of Chemotherapy (MRC 2-Year Follow-up of Pulmonary Tuberculosis in Types of failure &osland ( ))6 All failures No. % Died of tuberculosis * Still unfavorable status at 2 years Persistently positive sputum Bacteriologic relapse: 4.5 during chemotherapy after stopping chemotherapy J 2 Total patients assessed f patients who were diagnosed after death are included, this becomes 4.3 percent of 795 therapy and 0.3 percent more after stopping chemotherapy, making an overall failure rate of 4.5 percent. Although retreatment was undertaken and was effective in most patients, four still had an unfavorable bacteriologic status at two years. Nonbacteriologic reasons for failure are given in Table 3. Drug tqxicity necessitated a change of chemotherapy in 2.6 percent of patients. Initial drug resistance led the physician in charge to change the chemotherapy in 0.9 percent, but default in the first year was also a problem, for 4.7 percent of patients defaulted and were not traced even at the end of two years or later. A further 1.0 percent of patients refused to continue their chemotherapy or became very irregular in its self-administration and 2.3 percent more interrupted their chemotherapy for three or more months, although they returned before the end of the year. Overall, there were 11.4 percent of patients who represented failure of chemotherapy in nonbacteriologic terms. It is, of course, not known how many of the permanent defaulters failed to be cured, and so should have appeared in Table 2. Thus, there is excellent evidence that even in a technically ad- Table 3-Nonbacteriologic Failures of Chemotherapy (MRC 2-Year Follow-up of Pulmonary Tuberculosis in Type of failure Scotland Regimen changed for: drug toxicity initial drug resistance Default in first year: (a) permanent (b) refused chemotherapy or irregular selfadministration (c) returned after 3 months or more ( O)) All failures No. % 20 2, Unfavorable bacteriologic status at 2 years Total patients assessed 770 at least I 0 0? 1 0 Daily Intermittent Table 4-Standard Regimens (18 months - Initial daily phase 2-Years SPH SRH - SEll STH SPH SRH SEH STH Regimen Duration) Continuation phase - PH RH EH TH S2H, S2H2 E2H2 S2H2 Dosages of drugs S P-1O-12 R-450 or 600 mg g g E-l5 mg/kg T-150 mg mg S g H-15 mg/kg E-50 mg/kg S = streptomycin; P = PAS; H = isoniazid; R = rifampin; E = ethambutol; T thiacetazone vanced country with a well organized program, the then standard duration 100 percent effective regimen presej4ed a number of problems under service conditions.) Because of the adverse reactions, bulk and unpleasantness of PAS, this drug has jrgely been replaced in standard chemotherapy. (The main standard daily regimens, prescribed fr-18 months to two years, and the dosages of the drugs are summarized in Table 4. The daily triple drug phase is usually for up to three months. There is a degree of flexibility in the dosage schedules with one notable exception. The combination of thiacetazone plus isoniazid which is effective is thiacetazone 150 mg and isoniazid 300 mg daily in a single dose. Lowering the dose of isoniazid to 200 mg or of thiacetazone to 100 mg appreciably reduces the therapeutic effectiveness of the combination, especially the latter.7 Conversely, increasing the isoniazid dosage to140 mg in the combination confers no benefit.8 \ LTwo major developments in chemotherapy hae been directed at ensuring that the patient actually receives the full course as prescribed. These are: 1) fully supervised intermittent chemotherapy, and 2) shortening the duration of chemotherapy. In practice it has proved possible to combine the two approaches to produce short and largely, or even fully, intermittent regimens] Fuu,x SUPERVISED INTERM1TrENT CHEMOTHERAPY [Its advantages are: 1. it is therapeutically highly effective 2. it has lower chronic toxicity than daily regimens 3. it has lower cost 4. it avoids the undetected irregularity inherent in the self-administration of daily regimens 786 WALLACE FOX CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

3 Tuberculosis Table 5-Studies of Twice-weekly Regimens of Streptomycin plus High Dosage (15 mg/kg) Isoniazid in Primary Chemotherapy Initial daily Quiescent disease phase No. at 1 year Study (months) patients % Chemotherapy Centre, Madras (1964) Tuberculosis Chemotherapy Centre, Madras (1970) International Union Against Tuberculosis (1970) WHO Collaborating Centre for Tuberculosis Chemotherapy, Prague (1976)12 1 / (1971) (1976) Devi, S (Singapore) (1972) British Medical Research Council (1973) The standard most widely used intermittent regimen is a twice-weekly combination of streptomycin, 1 gm or 0.75 gm, plus isoniazid, 15 mg/kg bodyweight, per dose, the high dosage of isoniazid being very important. The regimen should he preceded, whenever possible, by a daily intensive phase of three drugs for up to three monthsjtable 5 hows the therapeutic results achieved witfi this regimen in a number of cpntrolled clinical trials of primary chemotherapy. /With no initial daily phase of triple chemotherapy hr with a one-month initial intensive phase, the quiescence rates at one year were above 90 percent. In a series of investigations in Prague, Singapore and Britain when the initial intensive phase with streptomycin, PAS and isoniazid was for six or more eeks, the regimen was almost uniform- 1successhit\ It is evidht from Table 6 that,jas with daily regixpens, the isoniazid inactivator status in patients on twice-weekly chemotherapy. when this is with streptomvcin plus isoniazid. is of no importance. but there is a suggestiqn that with PAS plus isoniazid or ethambutol plus isoniazid rapid inactivators respond less well than slow inactivators. It may well he that a longer initial intensive daily phase would eliminate the failures not only in slow but in rapid inactivatorstj In contrast, it will be seen that(nnceweeklyrgi mens (Table 7) there is a substantially lower success rate.in rapid inactivators of isoniazid, whether streptomycin plus isoniazid is being given, streptomycin plus isoniazid plus pyrazinamide, streptomycin plus isoniazid plus PAS, ethambutol plus isoniazid or rifampicin plus isoniazid. Nevertheless the evidence is that rifampicin cn largely, though not completely, eliminate the isoniazid deficiency in rapid acetylators of the drug even when the initial intensire phase with Xhree drugs is as short as two weeks Figure 1 shows(the serum curves of isoniazid after a 15 mg/kg dose of isoniazid by mouth. The concentration in rapid inactivators has fallen to the minimal inhibitory concentration (MIC) by about 14 hours com.pared with about 30 hours in slow inactivators. Thus, whereas the one exposure a week to isoniazid in slow inactivators is adequate for a high proportion to achieve a favorable response, rapid inactivators need two of their more limited exposures to achieve the same order of favorable response3 These findings have,jed to a practical procedure for managing patients n a large area of Czechoslovakia atiemts begm with an initial intensive phase of three drugs daily including streptomycin Table 6-Twice-weekly Regimens: Proportions of Patients with Favorable Therapeutic Response at Initial 12 MonthslC Acetylators Differdaily Slow Rapid ence phase Companion No. (A) (B) (A-B) Center (weeks) drug patients % % % Madras 2 PAS Madras 2 Ethambutol Madras 0 Streptomycin Prague 6 Streptomycin Prague 13 Streptomycin Britain 13 Streptomycin Singapore17 2 Rifampin Madras 4 Streptomycin Madras 4 S+PAS Table 7-Once-weekly Regimens: Proportions of Patients with Favorable Therapeutic Response at 12 Monthsls Madras 0 Streptomycin Madras 0 S+Pyrazinamide Madras 2 Ethambutol Prague 13 Streptomycin Singa pore Acetylators Initial Differdaily Slow Rapid ence phase Companion No. (A) (B) (A-B) Center (weeks) drugs patients % % % Rifampin CHEST, 76: -6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 787

4 20 Table 8-Comparison of Ethambutol/Isoniazid and Rifampin/Isoniazid Once a Week E a, p4 a C a a, CM MIC I I I PERIOD AFTER DOSE (HOURS SLOW Ficuax 1. Serum isoniazid concentrations after 15 mg/kg isoniazid by mouth. - and isoniazid and then, on the basis of the inactivation rate. slow inactivators are given continuation chemotherapy - with streptomycin plus high dosage isoniazid once a week and rapid inactivators streptomycin plus high dosage isoniazid twice a week. \ Standard duration intermittent regimens anil the drug dosages are set out in Table 4.{ A continuation combination particularly favored fn the USA is ethambutol plus isomazid twice a week. 19] Before leaving intermittent chemotherapy, there is, however, a further major point. (Table 8 summarizes the results of two studies onne year, 64- dose regimens in smear-positive, newly diagnosed disease: 1) following two weeks of daily streptomycin, ethambutol and isoniazid, a regimen of ethambutol plus isoniazid given once a week in the continuation phase, stopping at one year in Madras;2#{176} 2) following two weeks of daily streptomycin, rifampicin and isoniazid, a regimen of rifampicin plus isoniazid once a week in the continuation phase, stopping at one year in Singapore. 7 The overall failure rate (ie failures during chemotherapy and bacteriologic relapses after stopping chemotherapy) in the Madras ethambutol study (Table 8) was 66 percent (Tripathy, personal communication) and in the Singapore rifampicin study 7 percent. 7 This is striking evidence of the great potency of rifampicin, for the difference between the regimens is that one had 64 doses of rifampicin (600 mg per dose, both in the daily and once-weekly phases) and the other 64 doses of ethambutol (90 mg/kg per dose in the once-weekly phase), leading to a diffcrcncc l)etween the failure rates of the order of 60 pcrcint. We may conclude that rifampicin is a strikingly bactericidal drug and that the evidence is that, in contrast, ethambutol is only bacteriostatic, a point of relevance to short course chemotherapy also.) Failure during Relapse Overall chemo- after failure Regimen therapy stopping rate Study (1 year) % % % Madras (1979)* E,H, Singapore (1977) R,H, E = ethambutol; H = isoniazid; R rifampin *Tripathy SP (Personal communication) The organization of intermittent chemotherapy must be flexible and designed to meet the convenience of the patients. This means that the administration of the drug must be decentralized. The patients should be able to receive their directly supervised chemotherapy at facilities near their home, near their place of work, or en route to work, the facilities being selected for the convenience of the individual patient. The facilities which might be used include health centers, dispensaries, welfare clinics, hospitals, factory clinics, rural health units, special treatment stations (these may be set up on local market days in rural areas) and mobile services (these last are, however, expensive). The overall management of the patient, however, should remain in the hands of his physician. SHORT COURSE CHEMOTHERAPY Whereas in standard chemotherapy the drugs are selected with a view to preventing the emergence of drug resistance, in short-course chemotherapy the apjroach is different (Table 9). There are two key drug actions in short-course ch emotherapy. One is bactericidal activity, that is, killing dividing bacilli, which most of the antituberculosis drugs are able to do. The other is sterilizing activity, that is, killing the so-called persisters. bacilli which are scarcely metabolizing, much less dividing There is now a great deal of evidence from the laboratory, especially animal experimental work, summarized elsewhere, 1 and from studies in man, that Eifampicin and pyrazinamide have special abilities to eliminate persisters hut that isoniazid and, to a lesser extent streptomycin, also have steril- Table 9-Drug Actions in Short-Course Chemotherapy Bactericidal Activity Sterilizing Activity Killing dividing bacilli Bactericidal I drugs Killing persisters I Rifampin Pyrazinamide Isoniazid Streptomycin 788 WALLACE FOX CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

5 East Table 10-Role of Bacteriostatic Drugs, Thiacetazone (T) and Ethambutol (E), Given for 6 Months Study African! BMRC (1974)22.28 Hong Kong! BMRC (1978)26 Regimen SH SHT SHZ 2SHRE/S2H2E, 2SHRZ/S2H2Z, No. patients Culture negative at 2 months % For definition of a bbreviations see footnote to Table Bacterio- logic relapse % izing activity. Although the second phase of shortcourse chemotherapy is obviously one of sterilization, we believe that the elimination of persisters commences from the outset What, however, is the rol of bacteriostatic drugs in patients with drug-sensitive strains initially, for tli,py are not mentioned in this scheme? a study in East Africa of pulmonary disease in patients with sputum positive on smear examination (Table 10), streptomycin, isoniazid and thiacetazone (SHT) has been found to produce the same culture negativity rate (49 percent) at two months as streptomycin plus isoniazid (SH ).Culture-negativity at two months is an earlx index of the relative sterilizing activity of regimens, ps Professor Mitchison has pointed outf The bacteriologic relapse rate after stopping chemotherapy, the best index of sterilizing activity, was 29 percent in a two-year period for the two-drug combination and 22 percent for the thiacetazone regimen, a non-significant difference, also suggesting that the bacteriostatic drug, thiacetazone, made no contribution, or at most a very small contribution. In contrast, the addition of pyrazinamide in the SHZ regimen increased the culture-negativity rate at two months from 49 percent to 66 percent and reduced the bacteriologic relapse rate from 29 percent to 8 percent, evidence of the potent sterilizing role of pyrazinamide. In Hong Kong, too, streptomycin plus isoniazid plus pvrazi- namide given daily or three times a week were highly successful, andwhen given twice a week only marginally less so ) What is te role of ethambutol, also a bacteriostatic dmg?n one regimen in a study from Hong Kong #{176} (TabI 10) a two-month initial intensive (four-drug) phase with streptomycin, isoniazid, rifampicin and ethambutol (SHRE) was followed by streptomycin, isoniazid and ethambutol twice a week (S,H,E2). This was compared with a regimen which differed only in that pyrazinamide replaced ethambutol both in the daily (SHRZ) and intermittent phase (S,H,Zz). The culture-negativity rate at two months increased from 81 percent for the ethambutol regimen to 95 percent for the pyrazinamide regimen and the relapse rate in the year after stopping chemotherapy fell from 21 percent to 7 percent. (The two regimens were also compared for eight months, and the relapse rates after stopping chemotherapy were 10 percent and 4 percent, respectively.) Thus, pyrazinamide is again demonstrated to be a drug with potent sterilizing activity and the findings with the ethambutol regimen suggest that the ethambutol contributed nothing in either respect.) There has been no study of the role of PAS in short-course chemotherapy, but there is evidence from Hong Kong1 that PAS is most unlikely to be a drug of value in short course chemotherapy. It may be concluded that on current knowledge bacteriostatic drugs do not contribute to short course chemotherapy in patients with drug-sensitive infections. (They may, however, play their traditional role of preventing the emergence of further drug resistance in patients with an initially resistant strain.) \ (1 urthe evidence of the role of pyrazinamide is its inth.ience on the culture results at two months when added as a fourth drug to the potent combination of streptomycin, isoniazid and rifampicin (Table 11). In this Table it has been assumed, as mentioned earlier, that ethambutol has had no therapeutic effect in the Hong Kong study. It can be seen that pyrazinamide made a considerable and statistically significant difference to the culture-negativity rate at two months in all three studies.26 The influence of pyrazinamide on the relapse rates in these three studies is shown in Table 12. The findings from the,#{231}cond East African study 9 strongly suggest that (the addition of pyrazinamide in the first two months contributed to the low relapse rates in both regimens containing this drug see Table 8 of reference 30). Table 11-Additi1on of Pyrazinamide to SHR: Study Second East African! BMRC (1974)27 Third East African BMRC (1978)28 Second Hong Kong! BMRC (1978)26 Results at 2 Months Regimens SHR SHRZ SHR SHRZ SHRE SHRZ No. patients % culture negative at2 months P value For definition of abbreviation s see footn ote to Tabl e < <0.001 CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 789

6 Table 12-Influence of Addition of Pyrazinwnide on Relapse Rates in Short Course Regimens Study Regimens Duration (months) Favorable status at end of chemotherapy No. Bacteriologic relapses No. % P value Second SHR East African! 2SHRZ!TH BMRC Study (1976)29 2SHRZ!S2H2Z, Third East African! BMRC Study (1978)28 2SHR!TH 2SHRZ!TH j 0.08 Second Hong Kong! BMRC Study (1978)26 2SHRE!S2H2E2 6 2SHRZ/S2H2Z < j For definition of abbreviations see footnote to Table 4, There is surprisingly little difference between the three regimens, bearing in mind that in the first regimen the patients received streptomycin, isoniazid and rifampin throughout the last four months, whereas in the second regimen they received only thiacetazone and isoniazid, and the third regimen streptomycin, isoniazid and pyrazinamide twice a week. Further, in both the six- and eight-month comparison in the third East African study28 the relapse rates for the pyrazinamide-containing regimens were lower, although neither difference nor the overall difference attained statistical significance. In the second Hong Kong/BMRC study, 6 also of sixand eight-month durations, again the relapse rates on the pyrazinamide-containing regimen were lower, the difference for the six-month regimen and the verall difference attaining,, statistical significance) It may be concluded tha4 pyrazinamide is an important drug in short-course cemotherapy,\ Short-Course Chemotherapy in France and Britain 6The studies of Brouet and Roussel3 in France and the British Thoracic and Tuberculosis Association32 in Britain have consolidated the evidence on short-course chemotherapy (Table 13). In the French study, the initial intensive phase was for three months and in the British study for two months. Based on the findings, the BTTA has recommended the routine use in Britain of isoniazid plus rifampin daily for nine months with ethambutol for the first two months.)however it has been shown #{176} that reptomycin daily for six months added very little to isoniazid us rifampin given for six months and that ethambutol 1oes little or nothing in the short course chemotherapy of patients with initially sensitive organisms (Tables 11 and 12), making it very unlikely that either the streptomycin or the ethambutol made an important contribution to the success of the nine-month regimen based on isoniazid plus rifampinfurthermore, it is clear tha(very high levels of success can be achieved without he need to give rifampin all the way through (Tables 10 and 12). Moreover, intermittent regimens given throughout can be highly effective: for example, streptomycin, isonia.zid, rifampin and pyrazinamide, three times a week, followed by streptomycin, isoniazid and pyrazinamide twice a week, and they carry the advantages listed earlier. The nine-month daily regimen in current use in Table 13-Studies of Short-Course Chemotherapy in France and in Britain Bacteriologic Duration of Duration Total patients relapse follow-up Study Regimen (months) assessed (No.) (months) Brouet and SHR Roussel, 1977 HR EHR British Thoracic SHR and Tuberculosis HR Association, EHR For definition of abbreviations see footnote to Table 4. Results WALLACE FOX CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

7 Table 14-Bacteriologic Relapses After 4-month and 6-month Regimens 4-month regimens 6-month regimens East Africa34 Singapore35 Singapore35 Series Bacteriologic Patients relapse assessed % Patients assessed Bacteriologic relapse % Bacteriologic Patients relapse assessed % 2 SHRZ/HRZ SHRZ!HR SHRZ!HZ SHRZ!H For definition of abbreviations see footnote to Table 4 Britain is, therefore, clearly capable of being improved upon substantially and is not by any means the last word in short-course chemotherapo The Duration of Short Course Chemotherapy A key issue in short-course chemotherapy is to determine the shortest duration which will produce highly, or perhaps even uniformly, successful regimens, that is, with neither bacteriologic failures during chemotherapy nor bacteriologic relapse after stopping. wo studies of streptomycin, isoniazid and rifampin given daily for six months for sputum smear-positive pulmonary disease in East Africa yielded relapse rates of 3 percent2 and 2 percent, 9 respectively. In a classic pilot study of three-month regimens, Kreis and colleagues, reporting on spprnycinp1usisoniazid plus rifampin daily in 47 patients, had seven (15 percent) relapses and when the streptomycin was given daily and the isoniazid and rifampin three times a week, five (11 perceqt) of 44 patients relapsed.t should be noted thaiii both regimens the dosages of isoniazid (900 mg a dose) andrifampin (1200 mg a dose) were highj These findings suggested to my group that if the potent drug pyrazinamide were added in the initial phase and the chemotherapy prolonged to four months, a substantial improvement in therapeutic effectiveness might result. The findings of collaborative studies in East Africa 4 and in Singapore are given in Table 14. Ci East Africa, four regimens, all with streptomycin, isoniazid, rifampin and pyrazinamide daily for two months, were studied, all four regimens having a two-month continuation phase consisting of either isoniazid alone (H), or isoniazid and pyrazinamide (HZ), or isoniazid and rifampin (HR), or all three drugs (HRZ), a most interesting progression of drugs. In Singapore, the two regimens considered likely to be the best (with HRZ and HR in the continuation phase) were studied, and in case four) (months were too short, the regimens were also alloc#{227}tedfor six months, at random) CThe bacteriologic relapse rates in a year after stopping chemotherapy in East Africa were 14 percent and 11 percent for the regimens with rifampin throughout (HRZ and HR) and in six months after stopping chemotherapy in Singapore were 10 percent and 5 percent. These relapse rates with fourmonth regimens of potent drugs are disappointing. The next important point is that in East Africa when the continuation phase did not contain rifampin,i.he relapse rates were much higher, namely 28 percent for the HZ and 30 percent for the H regimens. Thus, there is evidence that rifampicin continued to make an important contribution in the two months of the continuation phase.jn contrast, there is no evidence that pvrazinamide contributed at all in the continuation phace when added to isoniazid and rifampicin, either in East Africa or in Singapore. Even more surprising, perhaps, is the finding that adding pyrazinamide to isoniazid (HZ) in the continuation phase in East Africa conferred no benefit over isoniazid alone (H). Thus, these findings suggest that pyrazinamide made its entire contribution in the first two months. sunnrg Professor Mitchison s hypothesis that pyrazinamide eliminates one bacterial population rapidly and that the population which rifampicin eliminates requires a longer period of exposure to that drug; (there are other possible explanations). Whether or not a longer period of exposure to rifampin than four months is especially beneficial remains to be established. ) TnxixN r OF SrAR-cAnvE PULMONARY DISEASE All the studies so far referred to have been conducted in patients with sputum positive for tubercle bacilli on direct smear examination, that is, they had large bacterial populations, most having extensive and cavitated pulmonary lesions. In practice, a high CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 191

8 Table 15-Proportion of Cases of Respiratory Tuberculosis Bacteriologically Confirmed Country Year % positive Finland West Germany Hungary Poland Costa Rica Guatemala Honduras Nicaragua Panama proportion of patients treated for active tuberculosis never have bacteriologic confirmation of the diagnosis, even on culture (Ta,le 15). As a generalization, it may be said that1 most countries, both developing and technically advanced, in at least half the patients with respiratory tuberculosis the dliagnosis is never confirmed bacteriologically and in some countries the proportion is as high as 70 percent or even higher. A collaborative investigation is currently being undertaken in Hong Kong in association with the BMRC groups and the Tuberculosis Research Centre, Madras, with reference bacteriology both in Madras and Professor Mitchison s laboratory in London. 6 To be eligible for admission to the study, patients had to be previously untreated, newly-diagnosed cases with active pulmonary disease on clinical and radiographic assessment and to have five consecutive negative direct smear examinations of the sputum, two undertaken in. Hong Kong and three in London. Of 1,072 patients with five such negative smears, 69L( 64 percent I had only negative culturesaiso, that is, although their disease was considered to be active clinically, the diagnosis was not confirmed bacteriologically, and percent) had one or more positive cultures. Of these latter, 31 percent had a fully drug-sensitive strainl\ Table 16-Bacteriologic Relapse in Patients with Drug.Sensitive Cultures on Admission, and with All Cultures Negative on Adnzission Culture Relapses by results on Patients 12 months admission Series assessed No. % Drug- 2SHRZ SHRZ SPH/S2H Selective chemotherapy All 2SHRZ cultures 3SHRZ negative SPH/S2H For definition of abbreviations see footnote to Table 4. nd 5 percent a strain resistant to isoniazid and/or streptomycin. The results in the patients with one or more positive cultures and a fully sensitive strain are shown in Table 16, upper half. Two short course re,gjniens, namely two months or three months of the four main drugs given daily, were compared at random with a standard 12-month regimen of streptomycin, PAS and isoniazid daily for three months followed by streptomycin plus high dosage isoniazid for nine months twice a week, a regimen in which every single dose was supervised. At 12 months (that is, ten months after stopping chemotherapy for the two-month series and nine months for the threemonth series) the bacteriologic relapse rates were 14 percent and 7 percent, respectively, compared with no failures among 83 patients who were on chemotherapy throughout the 12 months. These relapse rates are already unacceptably high, and may still increase with a longer period of follow-up, so that even the three-month regimen was not long enoug (Considering next the patients with five specimens n gative on smear and with all the culture reports negative also, the two-month and three-month regimens were again compared with the 12-month regimen (Table 16, lower half). In addition, however, there was a most important group, the selective chemotherapy group, in which the patients, who had been allocated to this group at random, were evaluated regularly by monthly bacteriology (both smear and culture) and by radiography. Treatment was started whenever a positive bacteriologic result was obtained, or if there were a clearcut radiographic deterioration. This group is particularly important epidemiologically, as it provides evidence of the proportion of patients who, beyond question, required chemotherapy for their disease. The breakdown rate to bacteriologic positivity in the 12 months was 34 percent for this group. In contrast, the relapse rate was 1 percent for each of the three chemotherapy regimens. This means that a relapse rate of the order of 30 percent had been prevented by both the short course regimens.) It is still too early to know what the final relapse rates with the short-course regimens will belln patients who are smear-positive initially, practiciiwill the relapses occur within a year after stopping chemotherapy. and the great majority within the first six months. \,However, the interval may be much longer in patie cits with very small bacterial populations at the outset. If such patients are left with viable residual populations, the number of organisms will be very small indeed and it may therefore be a considerable time before bacteria appear in the sputum. In view of this, we intend to follow-up the patients in this study for at least five years. 792 WALLACE FOX CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

9 Conclusions on the Duration of Short-Course Chemotherapy Considering all the evidence on the durtion of chemotherapy, it seems highly likely that we will have very effective regimens of six months duration for patients with smear-positive disease. Patients with. snutum consistently smear-negative, though culture-positive, will need a longer period of chemothrapv than three months. and it remains to be seen whether this will be four or five, or indeed, six months. In contrast, it may well be that for. patients with sputum consistently negative on smear and culture, three or even tw months of chemotherapy may prove to be adeqiiatejhowever, a longer period of follow-up of the current study in Hong Kong is necessary to clarify this point. It is important that other research groups undertake carefully designed studies of the treatment of patients with smear-negative disease. There is no doubt that a selective chemotherapy group is very important to establish the real risk of breakdown to bacteriologically positive disease since it cannot be assumed that the risk will be the same as in the patient population studied in Hong Kong. In many areas it may well be much lower, yet in others it could be even higher. Patients with Initial Drug Resistance There is no time to discuss the response of patients with initial drug resistance to short-course regimens. This has been referred to elsewhere. There is recent evidence that (tl regimen of streptomycin. isoniazid, rifampin and pyrazinamide for two months followed by rifampin and isoniazid in the continuation phase is particularly effective in the presence of initial drug resistap#{231}e. The effectiveness may be dependent on rifampin given throughout treatment. It may well be, however, that in addition the rifampicin and pyrazinamide in the initial intensive phase are together important because not only are these two potent sterilizing drugs, but initial drug resistance to either of them is very rare. Thus, the modem concept that a good regimen is by definition one that largely overcomes the influence of initial drug resistance, applies as much to short-course as to standard chemotherapy.] The Choice of Regimens for Short-course Chemotherapy Now I want to consider the choice of short-course chemotherapy regimens and the factors which influence the decisions as to which regimens to apply under program conditions (Table 17). From the well-known BTTA and French 1 studies it can be concluded thafrifampin plus isoniazid daily for nine months with ah initial two months of ethambutol or streptoniycin are, for allpractical purposes, 100 percent effective if taken regularly by the patients, but if terminated at six months they can cure 95 percent of pa.ticn. month, the success rates after eight or six months Table 17-The Potential Effectiveness of a Number of Short-Course Regimens in Drug-sensitive Infections Study BTTA French 2ERH/RH 2SRH/RH Regimen Duration (months) 9 or 8 6 % % % Singapore 2SRHZ/RH 99 East Africa RH (100) 95 East Africa 2SRHZ/TH East Africa 2SRHZ/S2H2Z Madras If pyazinamide is added in the first two months, as in Singapore, tp give a four-drug initial intensive phase. then a six-month rifampin plus isoniazid regimen is capable of achieving a cure in nearly but not quite every patient. When rifimpin pliic icn.. niaznfwas given daily for six months in East Afriea, it cured about 95 percent 9 of patientj and it is likely, on the evidence from Table 17d elsewhere, that this reginip would be 100 perent effective if given for nine months, even w.ithut a third drug in the initial intensive phase in drug sensitive infections. On the other hand, a study in East Africa (Table 12) suggests that if rifampin plus isoniazid is replaced by the convenient and very much cheaper daily thiacetazone plus isoniazid in the continuation plafter a four-drug initial intensive phase of two months. 100 percent success has been achieved with an eight-month duration and 90 percent with six months. ) Studies in East Africa and Madras 7 suggest thatafter the four-drug daily phase. where full supervision of an intermittent regimen in the continuation phase is possible, streptomycin plus isoniazid plus pvrazinamide twice a week can produce 100 percent success in perhaps even seven months (the Madras finding) and 95 percent success in six months. Jfh#{231}jnitial phase of this,xegirnen is shortened from two months to one East Africa 1SRHZ/S2H2Z East Africa 1SRHZ/TH Hong Kong S,R3H,Z3/S2H,Z, Hong Kong S3H3Z For definition of abbreviations see footnote to Table 4. CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 793

10 ,.treatment are somewhat If however, after a ope-month intensive four-drug phase. daily thiacetazone plus isoniazid is given in the continuation phase instead of the twice-weekly regimen, the success rates are about 10 percent lower. In Hong Kong, full supervision of every dose of drug is the normal practice throughout the chest service3a current study 6 has shown thacif the quantities of the four drugs for the initial two months intensive phase are spread over four months by giving them three times a week instead of daily, continuing with twiceweekly streptomycin plus isoniazid plus pyrazinamide, then an eight-month regimen is almost uniformly successful and a six-month regimen cures 95 percent of patients. Indeed, in Hong Kong a regimen of streptomycin plus isoniazid plus pyrazinamide three times a week for nine months cured 95 percent of palients. There is, therefore, a wide variety of choices and this list is by no means exhaustive, but it is based mainly on regimens from studies meeting the criteria of adequate numbers and an adequate period of observation. (The technically advanced countries content to use unsupervised chemotherapy, yet aiming to achieve 100 percent success (a paradoxic approach!) will choose, on current knowledge, a nine-month regimen with rifampin plus isoniazid daily throughout. The Singapore regimen may well prove to be equally effective, but within a period of six months. If the cast of d.riig is an important consideration, then the thiice may well be regimens with thiacetazone plus isoniazid or its equivalent (eg ethambutol plus isonizid) in the continuation phase. If. on the other hand, full supervision of every dose is the aim then, ikpendentnn.ihe cost of the regimenand the ability to organize full supervision, the choice might be an initial phase of two months or one month followed by intermittency. or else one of the regimens. intermjttent throughout. If the financial and organizational resources permit programs based on the longer durations shown in the Table, then the results are likely to be rather better when compared with sixmonth durations. If initial drug resistance is common, then there are advantages in choosing regimens with the longer durations of rifampin and which include pvrazinamide in the initial intensive phase Each country must decide its own,,.policy of chemotherapy under program conditions.lthe choice might be to apply two regimens, one fully supervised throughout for urban conditions and another suitable for self-administration, for use especially in rural areas. \ The levels of effectiveness in Table 17 are based on patients with smear-positive disease and drugsensitive infections. The success rate in patients with Table 18-Implications of Short-Course Chemotherapy under Program Conditions 1. Total quantity of drug used is less: (a) Less chronic drug toxicity (h) The cost is lower 2. Total delivery of health services to the patients is curtailed 3. More efforts can be concentrated on ensuring: (a) Patient attendance (b) That the patient remains on chemotherapy 4. Patients who abscond early are less likely to relapse 5. Routine follow-up after the end of chemotherapy can be abandoned smear-negative culture-positive and smear-negative culture-negative disease may well be higher than those in this Table, possibly even when the duration is shorter than six months. The Advantages of Short-Course Chemotherapy There are a number of advantages of short-course regimens applied under program conditions summarized in Table 18. It is often not appreciated, however, that short-course chemotherapy is not a new system of chemotherapy requiring special organizational arrangements. When ambulatory chemotherapy was demonstrated to be as effective as sanatorium treatment, this was a new system of chemotherapy and its introduction required the development of good ambulatory outpatient supervision. Similarly, when fully supervised intermittent chemotherapy was introduced, this too required reorganization of the outpatient services to ensure the effective delivery of the intermittent regimens. In contrast, the only difference between short-course chemotherapy and standard chemotherapy is that it is given for a shorter period. It requires no special reorganization of the services. The patient is offered a quicker cure and as long as this vital point and its advantages to the patient and the family are adequately explained to them and as long as the supervisory staff also fully appreciate the effectiveness of a short-course cure and its advantages, no other special feature is involved. The organization of effective short-course chemotherapy, like standard duration chemotherapy, means improving the organization of chemotherapy programs and this must not be overlooked. There is, however, a risk that if short-course chemotherapy programs are organized as badly as many standard duration programs, then what they actually achieve in practice will not nearly approach their potential success rates. It is vital to apply short-course chemotherapy in an efficient organizational framework, just as it was for standard 794 WALLACE FOX CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

11 chemotherapy, both daily and intermittent. Indeed, the importance of the organizational aspects of chemotherapy programs cannot be overemphasized. REFERENCES 1 Hong Kong TB Treatment Services/British Medical Research Council: A study in Hong Kong to evaluate the role of pretreatment susceptibility tests in the selection of regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 106:1-22, Hong Kong TB Treatment Services/British Medical Research Council: A study in Hong Kong to evaluate the role of pretreatment susceptibility tests in the selection of regimens of chemotherapy for pulmonary tuberculosis. Second report. Tubercie 55: , East African/British Medical Research Council Co-operative Investigation: Tuberculosis in Tanzania: a follow-up of a national sampling survey of drug resistance and other factors. Tubercle 58:55-78, East African/British Medical Research Council Co-operative Investigation: Tuberculosis in Kenya: Follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. Tubercle 60: , Fox W: The modern management and therapy of pulmonary tuberculosis. Proc Roy Soc Med 70:4-15, Heffernan JF, Nunn AJ, Peto J, et a!: A two-year followup of a national sample survey of new cases of respiratory tuberculosis notified in Tubercle 57: , East African/British Medical Research Council Co-operative Investigation: Isoniazid with thiacetazone in the treatment of pulmonary tuberculosis in East Africa-Second Investigation. Tubercie 44: , East African/British Medical Research Council Co-operative Investigation: Isoniazid with thiacetazone (thioacetazone) in the treatment of pulmonary tuberculosis in East Africa-fourth investigation: The effect of increasing the dosage of isoniazid. Tubercle 47: , Tuberculosis Chemotherapy Centre, Madras: A concurrent comparison of intermittent (twice-weekly) isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull Wld HIth Org 31: , Tuberculosis Chemotherapy Centre, Madras: A controlled comparison of a twice-weekly and three onceweekly regimens in the initial treatment of pulmonary tuberculosis. Bull Wid Hlth Org 43: , International Union Against Tuberculosis: A controlled trial of three regimens of self-administered and supervised chemotherapy for pulmonary tuberculosis. Bull hit Un Tuberc 44:9-53, WHO Collaborating Centre for Tuberculosis Chemotherapy, Prague: A study of two twice-weekly and a once-weekly continuation regimen of tuberculosis chemotherapy, including a comparison of two durations of treatment. 1. First report: The results at 18 months. Tubercle 57:45-48, WHO Collaborating Centre for Tuberculosis Chemotherapy, Prague: A comparative study of daily and twiceweekly continuation regimens of tuberculosis chemotherapy including a comparison of two durations of sanatorium treatment. Bull Wid Hlth Org 45: , Devi S: A controlled comparison of self-administered versus supervised treatment in Singapore. Bull mt Un Tuberc 47:15-21, British Medical Research Council: Co-operative controlled trial of a standard regimen of streptomycin, PAS and isoniazid and three alternative regimens of chemotherapy in Britain. Tubercle 54:99-129, Ellard GA: Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis. Clin Pharmacol Ther 19: , Singapore Tuberculosis Service/British Medical Research Council: Study of rifampicin plus high dosage (15 mg/kg body weight) isoniazid twice a week or once a week, following 2 weeks of streptomycin plus isoniazid plus rifampicin. Am Rev Respir Dis 116: , Fox W: The John Barnwell Lecture. Changing concepts in the chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 97: , Sbarbaro JA, Hudson LD: High dose ethambutol: an oral alternate for intermittent chemotherapy. Am Rev Respir Dis 110:91-94, Tripathy SP: A controlled comparison of daily, twiceweekly and once-weekly chemotherapy with ethambutol plus isoniazid in the treatment of newly-diagnosed pulmonary tuberculosis. In Symposium on Rifanipicin in Tuberculosis Treatment, Helsinki, 1974, pp Fox W, Mitchison DA: State of the art. Short course chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 111: , East African/British Medical Research Council Co-operative Investigation: Controlled clinical trial of short course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet 1: , East African/British Medical Research Council Co-operative Investigation: Controlled clinical trial of 4 short course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 2: , Hong Kong TB Treatment Service/British Medical Research Council: Controlled trial of 8-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Tubercle 56:81-96, Hong Kong TB Treatment Service/British Medical Research Council: Controlled trial of 6-month 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 115: , 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 118: , Second East African/British Medical Research Council Study: Controlled clinical trial of four short-course (6- month) regimens of chemotherapy for the treatment of pulmonary tuberculosis. Lancet 2: , East African/British Medical Research Council Co-operative Investigation: Controlled clinical trial of four short course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 118:39-48, Second East African/British Medical Research Council Study: Controlled clinical trial of four short-course (6- month) regimens of chemotherapy for the treatment of CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT CHEMOTHERAPY OF PULMONARY TUBERCULOSIS 195