CONTROLLED CLINICAL TRIAL OF FOUR SHORT-COURSE (6-MONTH) REGIMENS OF CHEMOTHERAPY FOR TREATMENT OF PULMONARY TUBERCULOSIS

1100 lous

therapy. Close monitoring of liver function and lung radiography is clearly mandatory in all patients receiving B.C.G. The following were found at necropsy: granulomatous disease; relatively small metastases with limited distribution in patients 2, 8, and 10 ; and splenomegaly in all five patients who came to necropsy. Splenomegaly is in keeping with stimulation of the reticuloendothelial system; however, lymphadenopathy was not seen. The spleens of two patients contained metastases. This organ is not a common site of secondary spread, and the possibility that immune stimulation makes the spleen more susceptible to tumour growth must be considered. Opinions differ on the value of tests of immunological function as a guide to selection of patients for B.c.G. therapy and as monitors of progress. Some workers describe the prognosis as poor in patients anergic to P.P.D. or D.N.C.B.,23,24 while others find no significant difference in prognosis between the positive and negative responders.25 From our own study it seems that demonstrable tumour-direced immunity may indicate those patients most likely to respond to stimulation. Of the three patients who did not respond to treatment, two showed no inhibition of leucocyte migration by tumour-derived materials before immune stimulation. The four patients who received chlorambucil in association with antitumour antibody were concurrently receiving B.c.G. therapy, and the part played by the individual components of this combination is difficult to assess. Doubt has been expressed by Rubens 26 as to whether chlorambucil and immunoglobulins do bind in vivo, but Davies and O’Neill 27 have suggested that even without a physical or chemical bond the two materials given simultaneously act

synergistically. Investigations of B.c.G. therapy should certainly continue, but taking into account its potential and actual hazards. Further studies are urgently needed to determine the ideal doses of B.c.G. organisms, the most effective type of B.c.G. preparation, the best route of administration, and the frequency of immunological stimulation required to produce optimum results. Ideally, non-living biological stimulants or synthetic agents will be developed, reducing at least The identificasome of the problems encountered. tion of patients likely to benefit from immune stimulation should also be carefully considered, the best results to date being obtained when patients capable of being made clinically tumour-free were treated.12,19 The answers to many of these questions will best and most rapidly come from cooperative studies. Trials of immune stimulation in melanoma are in progress under the control of the melanoma cooperative group of the European Organisation for Research on Treatment of Cancer, the World Health Organisation Melanoma Reference Centre, and various cooperative groups in the U.S.A. We thank the following colleagues who referred patients to Mr R. A. Hall, York; Mr T. Gibson and Mr I. A. McGregor, Canniesburn Hospital; Dr R. A. Kell, Victoria Infirmary; Prof. 1. Donald and Dr H. R. Chandrachud, Western Infirmary; and Mr D. C. Miln of Stobhill General Hospital, Glasgow. Prof. J. R. Anderson and Prof. J. A. Milne provided considerable support and encouragement. Dr Klaus Neelsen us:

and Howard Thomas kindly assisted in the preparation 0: chlorambucil-associated antisera. This study was conducted with the assistance of grants from the Secretary of State for Scotland and the McMillan Research Funds of the University of

Glasgow. Requests for reprints should be addressed to A. J. C.. Pathology Department, Western Infirmary, Glasgow Gll 6NT REFERENCES

M., Gutterman, J. U., Mavligit, G. M., Burgess, M. A., Hersh, McBride, C. M. Proceedings of International Symposium on Immunological Reactions to Melanoma Antigens, Hannover, 1974 (in the press). 2. Lewis, M. G. Lancet, 1967, ii, 921. 3. Morton, D. L., Malmgren, R. A., Holmes, E. C., Ketcham, A. S. Surgery, 1968, 64, 233. 4. Lewis, M. G., Ikonopisov, R. L., Nairn, R. C., Phillips, T. M., Fairley, G. H., Bodenham, D. C., Alexander, P. Br. med. J. 1969, iii, 547. 5. Currie, G. A., Lejeune, F., Fairley, G. H. ibid. 1971, ii, 305. 6. Hellström, I., Hellström, K. E., Sjögren, H. O., Warner, G. A. Int. J. Cancer, 1971, 7, 1. 7. Cochran, A. J., Spilg, W. G. S., Mackie, R. M., Thomas, C. E. Br. med. J. 1972, iv, 67. 8. Lewis, M. G. Rev. Inst. Pasteur, Lyon, 1971, 4, 309. 9. Currie, G. A. Br. J. Cancer, 1973, 28, suppl. 1, 153. 10. Mathé, G., Amiel, J. L., Schwarzenberg, L., Schneider, M., Caftan, A., Schlumberger, J. R., Hayat, M., de Vassal, F. Lancet, 1969, i, 697. 11. Morton, D. L., Eilber, F. R., Malmgren, R. A., Wood, W. C. Surgery, 1970, 68, 158. 12. Bluming, A. Z., Vogel, C. L., Ziegler, J. L., Mody, N., Kanye, G. E.

1.

Ann. int. Med. 1972, 76, 405. 13. Crowther, D., Powles, R. L., Bateman, C. J. T., Beard, M. E. J., Gauci, C. I., Wrigley, P. F. M., Malpas, J. S., Fairley, G. H., Scott, R. B. Br. med. J. 1973, i, 131. 14. Ghose, T., Nigam, S. P. Cancer, 1972, 29, 1398. 15. Cochran, A. J., Mackie, R. M., Thomas, C. E., Grant, R. M., Cameron-Mowat, D. E., Spilg, W. G. S. Br. J. Cancer, 1973, 28, suppl. 1, 77. 16. Ross, C. E., Cochran, A. J., Hoyle, D. E., Grant, R. M., Mackie, R. M. Lancet, 1973, ii, 1087. 17. Coulson, A. S., Chalmers, D. G. ibid. 1964, i, 468. 18. Sandilands, G. P., Gray, K., Cooney, A., Browning, J. D., Grant, R. M., Anderson, J. R., Dagg, J. H., Lucie, N. ibid. 1974, i, 903. 19. Takasugi, M., Klein, E. Transplant, 1970, 9, 219. 20. Gutterman, J. U., Mavligit, G., McBride, C., Frei, E., Freireich, E. J., Hersh, E. M. Lancet, 1973, i, 1208. 21. Hunt, J. S., Silverstein, M. J., Sparks, F. C., Haskell, C. M., Pilch, Y. H., Morton, D. L. ibid. p. 820. 22. Gormsen, H. Acta path. microbiol. scand. 1955, suppl. 111, 117. 23. Baker, M. A., Taub, R. N. Lancet, 1973, i, 1118. 24. Morton, D. L. in Scientific Foundations of Surgery (edited by C. Wells, J. Kyle, and J. E. Dunphy). London, 1974. 25. Chetravorty, R. C., Curutcher, H. P., Coppolle, F. S., Park, C. M., Blaylock, W. K., Lawrence, W. Surgery, 1973, 5, 730. 26. Rubens, R. D. Lancet, 1974, i, 498. 27. Davies, D. A. L., O’Neill, G. J. Br. J. Cancer, 1973, suppl. 1, 285.

CONTROLLED CLINICAL TRIAL OF FOUR SHORT-COURSE (6-MONTH) REGIMENS OF CHEMOTHERAPY FOR TREATMENT OF PULMONARY TUBERCULOSIS SECOND MEDICAL

EAST

AFRICAN/BRITISH

RESEARCH

COUNCIL

STUDY

A comparison has been made between four 6-month regimens. One consisted of streptomycin plus isoniazid plus rifampicin, the second of isoniazid and rifampicin, the third and fourth, both with an initial intensive phase for 2 months, of four drugs (streptomycin, isoniazid. rifampicin, and pyrazinamide), followed in the third by thiacetazone plus isoniazid daily and in the fourth by streptomycin plus isoniazid plus pyrazinamide twice a week. At 6 months, only 3 of 734 patients were classified as having an unfavourable response Summary

1101

also very little drug toxicity. The bacteriobetween 6 and 12 months were relapse-rates logical 5% of 170 patients on the two-drug combination, 2% of 166 on the three-drug combination, 6% of 180 patients on the regimen with thiacetazone plus isoniazid in the continuation phase, and 4% of 161 patients on the regimen with intermittency in the continuation phase. Most of the relapses occurred by 9 months, and all except 1 of the 31 patients who relapsed did so with drug-sensitive organisms. It is concluded that all the regimens were effective, that the streptomycin in the triple regimen has not made an important contribution to therapeutic success, and that reducing the rifampicin to 2 months has left effective regimens even when followed in the continuation phase by a standard daily regimen or a twiceweekly intermittent regimen. There

was

Introduction IN a previous large-scale cooperative investigation in East Africa and Zambia it was found that two 6-month regimens of daily chemotherapy-namely, streptomycin plus isoniazid plus rifampicin, and streptomycin plus isoniazid plus pyrazinamide, especially the former-were both very effective in the treatment of newly diagnosed extensive smear-positive pulmonary tuberculosis in African patients.-’ Thus, apart from early deaths in gravely ill patients, there were only 4 (3%) relapses in 152 patients on the rifampicin regimen and 13 (8 %) relapses in 153 patients on the pyrazinamide regimen in a 2-year period of follow-up after stopping chemotherapy-a difference which is statistically significant at the 5 %

level. When the early findings from this study became available a second investigation was planned to investigate, firstly, whether the streptomycin in the rifampicin regimen had contributed appreciably to its therapeutic success or whether, in practice, this depended solely on the action of the two bactericidal drugs, isoniazid and rifampicin. Secondly, it was decided to explore a daily initial intensive phase of four drugs for 2 months, including rifampicin and pyrazinamide, followed by the standard daily continuation regimen of thiacetazone plus isoniazid, which is widely used in Africa. Since there was reason to believe that an intermittent regimen in the continuation phase might also prove effective,4 this was investigated as well. The results up to 12 months are reported here. Plan and Conduct of Selection

Study

of Patients Eligible patients were Africans, aged 15 years or more, with previously untreated extensive pulmonary tuberculosis, believed to be of recent origin, with sputum positive for tubercle bacilli, who were considered to be cooperative and who lived within reach of a follow-up clinic. Patients were ineligible if they had extrapulmonary tuberculosis requiring additional treatment, or non-tuberculous disease contraindicating the use of any of the antituberculosis drugs under study, or if they were in very poor general condition. Allocation of Treatment A patient was allocated, by opening the next in a series ’

of consecutively numbered sealed envelopes provided for each centre, to one of the following four 6-month regimens :

(1) SHR.-Streptomycin sulphate 1 g. intramuscularly, with isoniazid 300 mg. plus rifampicin 450 mg. for patients weighing less than 50 kg. (" light") or 600 mg. for heavier (" heavy ") patients, together in a single dose orally, once daily for 6 months. (2) HR.-The above regimen for 6 months but omitting

streptomycin. (3) SHRZ/TH.-Streptomycin sulphate 1 g. intramuscularly, with isoniazid 300 mg. plus rifampicin 450 mg. for light patients or 600 mg. for heavy patients, plus pyrazinamide 15g. for light and 2 g. for heavy patients, together in a single dose orally for 2 months, followed by thiacetazone 150 mg. plus isoniazid 300 mg. in a single tablet daily taken orally for 4 months.

(4) SHRZ/S2H2Z2.—The initial four-drug regimen as above for 2 months, followed by streptomycin sulphate 1 g. intramuscularly with isoniazid 600 mg. for light and 900 mg. for heavy patients, plus pyrazinamide 3 g. for light and 4 g. for heavy patients, twice weekly for 4 months. (The dosage of isoniazid and pyrazinamide for the twice-weekly phase was based on the patient’s weight at 2 months.) In order to ensure the regular supervised administration of every dose the patients were given their chemotherapy in hospital for the full 6 months. From 6 months onwards all patients were provided with tablets of calcium lactate, to be taken orally once daily, to encourage regular attendance for the monthly follow-up examinations. Pretreatment Investigations The pretreatment investigations included a chest radiograph, smear and culture examinations of three specimens of sputum, and sensitivity tests to streptomycin, isoniazid, and rifampicin on two of them. For the SHRZ/S2H2Z2 regimen only, the isoniazid inactivation rate was estimated in London by determining the ratio of acetylisoniazid to acid-labile isoniazid excreted in a urine specimen collected between 23 and 24 hours after an oral dose of 600 mg. isoniazid in a slow-release matrix formulation (Smith and Nephew HS 82).5

Investigations During Treatment At the monthly examination the

physician

recorded de-

partures from the prescribed regimen and any-evidence of drug intolerance. Two sputum specimens were collected

monthly from 1 to 6 months and a single specimen monthly thereafter, for examination by direct smear and culture. Sensitivity tests were undertaken on one positive culture each month when available, from the third month onwards. At 6 and 12 months a chest radiograph was taken. To supervise drug-taking for all the regimens while the patient was being treated, a specimen of urine was collected at randomly selected intervals and tested in the central laboratories for acetylisoniazid by the method of Eidus and Hamilton.6 To ensure that the patients were not receiving isoniazid from unofficial sources after the completion of their 6-month course, a specimen obtained at each subsequent monthly outpatient attendance was also tested.

Change of Chemotherapy The bacteriological response of larly reviewed and the physician at

each patient was reguthe centre was informed if the response was unfavourable and a change of chemotherapy or retreatment was indicated. Chemotherapy could also be changed by the physician if there was clearcut radiographic deterioration in the presence of a positive sputum, or on account of drug toxicity. Except in cases of clinical urgency, a change was preceded by discussion with the East African Tuberculosis Investigation Centre.

1102

Bacteriological

Procedures

CONDITION* AND BACTERIAL CONTENT OF SPUTUM ON ADMISSION TO TREATMENT

TABLE II-RADIOGRAPHIC

Smears and Cultures Details of the procedures for smear and culture examination of the sputum and methods for identifying mycobacteria isolated have been described previously.7-10 The examinations were carried out in the central laboratories in Nairobi, Kampala, and Dar es Salaam.

Sensitivity Tests For the first 2 months of the study all sensitivity tests done at the Kampala laboratory. Subsequently they were centralised at the Nairobi laboratory. They were examined by the absolute concentration method used in recent M.R.C. studies.11 The concentrations of rifampicin were 4, 8, 16, 32, 64, and 128 µg. per ml.

were

Definitions of Bacterial Resistance "

Growth " has been defined as 20 or more colonies. The definitions of resistance used in this report are: 0.2 ug. per ml. and rifampicin and during treatment. If one of the pretreatment cultures was drug-sensitive and the other resistant the patient was classified as having a resistant strain. For streptomycin the pretreatment definition was growth on 16 µg. per ml. on either of the two specimens tested, or growth on 8 µg. per ml. on both. During treatment the definition was growth on 8 µg. per ml. on a single specimen. For isoniazid

growth

on

growth

64 µg. per

on

ml., both pretreatment

Intake A total of 953 patients was submitted from 35 centres in East Africa and Zambia between July 3, 1972, and Aug. 1, 1973 (427 from Kenya, 164 from Uganda, 298 from Tanzania, 64 from Zambia).

Exclusions In all, 158 patients were excluded from the main analysis on account of pretreatment factors (table i). Pretreatment sensitivity tests were not available for 70; 78 had a resistant strain (42 isoniazid-resistant, 23 streptomycinresistant, 13 both isoniazid and streptomycin resistant), and for 10 there were miscellaneous reasons. During the TABLE I-EXCLUSIONS FROM THE MAIN ANALYSIS

*

Radiographs not available for 10 SHRZ/S.H.Z.) patients.

44

(12 SHR,

7

HR, 15 SHRZ/TH,

Defined in ref. 12. $Defined in ref. 13. § Direct smear result of first specimen.

first 6 months a further 61 patients were excluded. 30 had an excessive interruption of chemotherapy due to non-cooperation; 13 had insufficient bacteriology to assess the response; there were 8 deaths (see below); and 10 were excluded for miscellaneous reasons, including 1 patient who had chemotherapy changed on account of

drug toxicity. Deaths Of the 8 deaths (2 SHR, 1 HR, 4 SHRZ/TH, 1 SHRZ/ 1 SHR patient died of tuberculosis in the 3rd week. 3 patients had fatal hæmoptyses—the 2nd SHR patient in the 6th week, an SHRZ/TH patient in the 4th week, and an SHRZ/S2H2Z2 patient in the 4th month (this patient had been culture-negative at 2 and 3 months). The remaining 4 (1 HR, 3 SHRZ/TH) patients died from non-tuberculous causes (the HR patient of renal failure and the others of carcinoma of the pancreas, perforated duodenal ulcer, and malaria). 2 of these 4 patients had survived more than 3 months and had quiescent disease at the time of death.

S2H2Z2),

Condition

on

Admission

majority (62%) of the patients were male (range 58-66% for the four series), over three-quarters (76%) of the patients were aged less than 35 years (range 73-79%), and the average weight was 47-6 kg. (range 472-.480 kg.). Radiographically the disease was class:fied as extensive or gross in 50% of the patients (table nB The

and moderate or extensive cavitation was present in 77-% A positive result on direct smear examination of the first sputum specimen was obtained from 96% of the patient. Thus, nearly all the patients had advanced disease. Further, the distributions of the factors on admission for a’.: four series were very similar.

Results FIRST

Culture Results At 2 months the

6

highest

MONTHS

rate

of culture negativy

1103 TABLE III—CULTURE RESULTS (BASED ON FIRST OR ONLY SPECIMEN AT EACH MONTH)

Subsequently, the cultures were negative at 7 and 8 months, there was no specimen at 9 months and cultures were positive with sensitive strains at 10 and 11 months; hence the patient was re-treated. The other SHRZ/S2H2Z2 patient had positive cultures (4 of 6 specimens) at 4, 5, and 6 months with drug-sensitive strains. This patient, who was culture-positive at 7 months, continued on his regimen for 6 weeks after 6 months and was subsequently culture-negative, except for a single colony at 10 months.

Drug-resistant Strains Apart from the 3 patients classified as failures referred to above, there was a total of 71 positive cultures with sensitivity test results, from 4 to 6 months, to isoniazid, streptomycin, and rifampicin. Only 6 resistant strains were obtained during the period. 2 (both HR) patients had a strain resistant to isoniazid, 3 (1 HR, 1 SHRZ/TH, 1 SHRZ/S2H2Z2) had a strain resistant to streptomycin, and 1 (SHRZ/ TH) had a strain resistant to isoniazid and to rifampicin. All but 1 of the cultures grew ten colonies or

less.

Adverse Reactions to Drugs Of the 953 patients submitted to the study, after 10 exclusions, of whom 8 did not even start treatment, 943 were available for analysis of adverse reactions.

was achieved in the two regimens with the initial intensive four-drug phase of SHRZ-namely, 82% of 347 compared with 70 % for the SHR and 64% for the HR patients (P=0.006 for the comparison of the SHRZ and SHR results). At 3 months the difference had disappeared, and the rates of culture negativity remained high and similar for all four regimens up to 6 months. Thus, the regimens with the initial intensive phase had an advantage at 2 months in the speed with which they had eliminated drug-sensitive tubercle bacilli. Among patients with results positive either by smear or by culture, smear-positive but culturenegative results at 2 months were obtained for 44 % of 115 SHRZ patients-a higher proportion than the 19% of 62 SHR patients (P=0.0001) or the 30% of 89 HR patients (P=0.06).

(table III)

Status of Patients at 6 Months The status of the patients at 6 months, based on the culture results (usually 6) obtained from 4 to 6 months, is set out in table iv. Only 3 (1 HR, 2 SHRZ/S2H2Z2) patients amongst the 734 were classified as failures of chemotherapy. The HR patient had all four specimens culture-positive at 4 and 5 months with strains resistant to isoniazid but sensitive to rifampicin; at 6 months both specimens were culture-negative. The patient then absconded and was subsequently found to have died of "enteritis" in the 12th month, there being no further information on the activity of the tuberculosis. Urine tests suggested that she might have been irregular in her drug taking. 1 SHRZ/S2H2Z2 patient had all four specimens scantily culture-positive at 4 and 5 months, but with drugsensitive strains, and was culture-negative at 6 months.

In all, 22 had episodes, 5 (2%) of 237 SHR, 6 (3 % ) of 237 HR, 3 (1 %) of 239 SHRZ/TH, and 8 (3 %) of 230 SHRZ/S2H2Z2 patients. 14 (4 SHR, 4 HR, 6 SHRZ/S2H2Z2) patients required only symptomatic treatment. Of the remaining 8 patients, 3 had one or more drugs terminated and 5 had interruptions of chemotherapy of 7 days or more. 1 SHR patient had all 3 drugs terminated because of jaundice in the lst month, and 2 SHRZ/ TH patients had the thiacetazone plus isoniazid tablets stopped because of rashes-1 in the 3rd and the other in the 4th month. 2 HR patients developed jaundice in the 1st month (following a blood transfusion in 1)-1 had rifampicin interrupted for 20 days, and the other both drugs for 32 days. 1 SHRZ/TH patient developed giddiness in the lst month which led to an interruption of streptomycin for 14 days. 1 of 2 SHRZ/S2H2Z2 patients had isoniazid interrupted for 8 days in the 2nd month because of paraesthesia, TABLE IV-STATUS AT 6 MONTHS (BASED ON CULTURES AT AND 6 MONTHS)

4, 5,

1104 and the other all three drugs for 7 days (two intermittent doses) in the 3rd month, because of arthralgia and giddiness.

6 MONTHS AND BACTERIOLOGICAL RELAPSE MONTHS 7-12 IN PATIENTS WITH PRETREATMENT DRUGRESISTANT STRAINS

TABLE VI-STATUS AT IN

BACTERIOLOGICAL RELAPSE IN THE SECOND 6 MONTHS

There were 731 (181 SHR, 182 HR, 191 SHRZ/ TH, 177 SHRZ/S2H2Z2) patients who had a favourable or doubtful status at 6 months. Of these, the following 54 have been excluded: 3 who died of nontuberculous causes, 2 who continued chemotherapy beyond 6 months in error, 32 who defaulted, and 17 who had insufficient bacteriology in the last 3 months for accurate assessment of their progress up to 12 months. Bacteriological relapse, defined as 2 or more positive cultures in any 3-month period in the second 6 months, is presented in table v. The analysis has been restricted to patients who had culture results at at least 2 of the last 3 months of the year. Bacteriological relapse occurred in 2% of 166 SHR patients, 5% of 170 HR, 6% of 180 SHRZ/TH, and 4% of TABLE V-BACTERIOLOGICAL RELAPSE FROM 6 TO 12 MONTHS (BASED ON PATIENTS WITH A FAVOURABLE OR DOUBTFUL STATUS AT 6 MONTHS)

both rapid inactivators. Of the 6 patients on the regimen who relapsed after stopping chemotherapy and for whom results were available, 3 were rapid and 3 slow inactivators. Thus, the acetylator phenotype did not influence the response to treatment with

were

SHRZ/S2H2Z2-

’

PATIENTS

WITH PRETREATMENT DRUG-RESISTANT STRAINS

Of 78

patients with drug-resistant strains before (table I), there remain, after exclusions, 71 for analysis (table VI). Of 39 patients with pretreatment isoniazid resistance, 37 had a favourable or

treatment

By the definition of relapse adopted, have relapsed at 12 months.

161

no

patient in this analysis could

SHRZ/S2H2Z2 patients, non-significant differ-

ences.

total of 616 patients with a favourable status at 6 months (all cultures negative at 4, 5, and 6 months), who were assessed for the 6 months of follow-up, 25 (4%) relapsed, compared with 6 (10%) with a doubtful status at 6 of 61 patients (P>0.1) months (1 or 2 positive cultures at 4, 5, or 6 months).

Of

a

Month

of Relapse

The month of the first positive culture of the bacteriological relapse is set out in table v. 22 of the 31 relapses occurred within 3 months of stopping

chemotherapy. Drug Sensitivity of the Strain All the patients who relapsed did so with organisms fully sensitive to isoniazid, streptomycin, and rifampicin, except 1 HR patient with organisms resistant to isoniazid. INFLUENCE OF ISONIAZID INACTIVATION

The

proportions of rapid and slow inactivators of isoniazid, based on a random sample of 107 patients on the SHRZ/S2H2Z2 regimen, were 44% and 56%, respectively. The 2 patients on this regimen who were classified as failures of chemotherapy at 6 months

doubtful status at 6 months. All of these 37 were assessed up to 12 months, there being 7 relapses; 4 of the 7 were among 10 patients on the SHRZ/TH regimen. In contrast, there were no failures at 6 months among 20 patients with streptomycinresistant strains pretreatment and no relapses amongst the 18 followed up to a year. Of 12 patients with a pretreatment strain resistant to both isoniazid and streptomycin, 8 had a favourable or doubtful status at 6 months, 2 of the 8 patients assessed up to a year having a bacteriological relapse. Thus streptomycin resistance alone was of no prognostic importance. resistance to isoniazid alone carried a relatively unfavourable prognosis, and the prognosis for resistance to both drugs was worse.

Discussion The results up to 12 months of this second study have already carried our knowledge and understanding of short-course chemotherapy much further. As in the first study,1-3 there were a few early tuberculous deaths, indicative of a limitation of even the most potent regimens in desperately ill patien:5. These patients apart, all four regimens were very effective in the first 6 months, there being only:= failures of chemotherapy amongst the total of ’_ patients on the four regimens. Of these failures. :

1105

examples of exceptionally slow sputum conversion, as drug resistance did not emerge. The 3rd were

may not have ingested all her medicament. relapse-rates in the first 6 months after stopping chemotherapy are low for all four regimens, ranging from 2% to 6%, none of the differences being statistically significant. It is unlikely that the longterm relapse-rates will become even as much as double these figures since most of the relapses so far encountered, namely, 22 of the total of 31, occurred in the first 3 months after chemotherapy was stopped, so already there is evidence that the cases are tailing off. This finding is in keeping with those of the earlier study in which 58 % of the relapses in a 2-year period of follow-up occurred in the first 3 months after chemotherapy was stopped, increasing to 84% at the end of the second 3 months.2,3 Another point in common between the current and the earlier study is that practically all the relapses encountered occurred with fully sensitive organisms. Thus relapse, when it occurs, is not due to the emergence of drug resistance, but is due to the multiplication of residual sensitive tubercle bacilli in the lungs, and their reappearance in the sputum, usually soon after chemotherapy is stopped. Finally, drug toxicity was not a problem even with the regimens with four drugs for the first 2 months, despite the fact that pyrazinamide, rifampicin, and isoniazid (all potentially hepatotoxic) were given together. Amongst the questions this study was designed to answer is whether the streptomycin in the triple-drug SHR regimen makes an important contribution to the level of therapeutic success which the regimen achieves. The relapse-rate in the two-drug HR regimen of 9 (5%) of 170 patients is close to that of the SHR regimen, 4 (2%) of 157 patients. It suggests that the addition of the streptomycin daily for 6 months did not greatly contribute to the prevention of relapse. The four-drug initial intensive phase of streptomycin, isoniazid, rifampicin, and pyrazinamide for 2 months in the two SHRZ regimens proved to be particularly effective in eliminating sensitive bacilli. At 2 months the culture negativity rate of the combination was 82% compared with 70% for the SHR regimen (P=0006) and 64% for the HR regimen. The proportion of smear-positive culture-negative specimens was also higher in the four-drug regimen than in either the SHR or HR regimens. Further, both had low relapse-rates-6 % for the regimen with thiacetazone plus isoniazid in the continuation phase, and 4% for the regimen with twice-weekly chemotherapy in the continuation phase. Thus, two regimens with an initial intensive phase that both reduces the duration of rifampicin and the daily streptomycin injections to 2 months have proved effective in this study. It should not, however, be assumed that the removal of streptomycin from these regimens would necessarily leave effective regimens, just because there is evidence suggesting that the removal of streptomycin from the SHR regimen probably had only a small

patient The

,

.

;

,

effect. The finding that a twice-weekly regimen, albeit in the continuation phase in the present study, is successful had been predicted by us on the basis of results

a study in the Tuberculosis Chemotherapy Centre, Madras.* In that study the rate of culture negativity in the early months of treatment-that is, the speed of elimination of sensitive tubercle bacilliwas virtually identical for three regimens even although one consisted of streptomycin plus high dosage (15 mg. per kg. body-weight) isoniazid twice a week, a second of streptomycin plus high dosage isoniazid once a week, and the third of streptomycin plus moderate dosage (8 mg. per kg.) isoniazid daily for a month followed by streptomycin plus high dosage isoniazid once a week. Our knowledge of intermittent short-course chemotherapy will be carried a stage further by a study in Hong Kong under-

from

taken in association with the Tuberculosis Treatment Services, the preliminary results of which will soon be reported. In that study three regimens of streptomycin plus isoniazid plus pyrazinamide, given daily or 3 times a week or twice a week from the start of treatment, are being compared. The advantages of supervised intermittent regimens 14 are now well documented. It is clear that the development of effective intermittent short-course regimens (especially if this is from the outset or after a short initial intensive phase) could have far-reaching effects on chemotherapy programmes. We have suggested earlier that the effective elimination of sensitive tubercle bacilli depends on the preThe sence in a regimen of two bactericidal drugs.-’ bactericidal drugs which we have studied so far are isoniazid, rifampicin, and streptomycin plus pyrazinamide, which latter two drugs, as pointed out by Mitchison,15 can together be regarded as forming a single bactericidal drug active against the entire bacterial population irrespective of the pH. However, as discussed elsewhere,16 this hypothesis conflicts with experimental evidence. It seems more probable that both rifampicin and pyrazinamide may make special contributions in short course regimens, rifampicin by its ability to kill bacilli even when growth occurs for a very short period of time and pyrazinamide because of its effect on organisms whose growth is limited by an acid environment. Since these drugs act on different organisms within the bacterial population, bactericidal synergism would occur. In evaluating short-course chemotherapy, especially for application in developing countries, an important group of patients are those with strains resistant to isoniazid and/or streptomycin on admission to treatment. A considerable amount of information has now been obtained on their response whilst on shortcourse regimens of chemotherapy and on subsequent relapse. The failure-rate up to 1 year based on the current and earlier study has been estimated for the effective short-course regimens-namely, the four regimens of the present study, and the regimen of streptomycin, isoniazid, and pyrazinamide studied in the first investigation.16 The overall failure-rate at 1 year is of the order of 5 % in the presence of streptomycin resistance alone, 20% in the presence of isoniazid resistance alone, and 50% in the presence of double drug resistance. The difference in failure rates in patients with initial resistance to isoniazid alone and to isoniazid and streptomycin could be because streptomycin in combination with rifampicin

1106 can

substitute

to a

considerable

extent

for the loss of

isoniazid, or, alternatively, it may be due to a lower proportion of isoniazid resistant organisms in initial resistance to isoniazid (usually primary) alone, than to both drugs (sometimes undisclosed acquired). Thus, substantial proportions of patients achieve and maintain quiescent disease even in the presence of initial drug resistance. In this respect the regimens compare not unfavourably with the standard regimen of streptomycin, isoniazid, and P.A.S. when given for the usual 18

to

24 months17,18

INHIBITION OF GASTRIN AND GASTRIC-ACID SECRETION BY GROWTH-HORMONE RELEASE-INHIBITING

HORMONE S. R. BLOOM Middlesex Hospital, London W1

M. O. THORNER C. H. MORTIMER G. M. BESSER St. Bartholomew’s

Finally, there is every reason to believe that, low as the relapse-rates in the present study are, they might have been even lower, and conceivably absent, had chemotherapy been prolonged for even a short period - perhaps only a month or two. Further information on this point will be forthcoming from the study in Hong Kong in which patients have been allocated at random

to

either 6

or

9 months’ duration of chemo-

therapy. The following East African hospitals and laboratories operated in this investigation:

co-

In Kenya-District Hospitals at Bungoma, Embu, Kericho, Kiambu, Meru, Msambweni, Murang’a; Provincial Hospitals at Kakamega, Kisumu, Machakos, Nyeri; Port Reitz Chest and Infectious Diseases Hospital, Mombasa; and the Infectious Diseases Hospital, Nairobi. The Kenya Tuberculosis Laboratory, Nairobi. In Tanzania—Muhimbili Hospital, Dar es Salaam; Kibongoto Hospital, Sanya Juu; Kola Ndoto Hospital, Shinyanga; Bombo and Infectious Diseases Hospitals, Tanga; Turiani Hospital, Turiani; District Hospital at Lushoto; Government Hospitals at Kahama, Korogwe, Morogoro; Regional Hospitals at Dodoma, Tabora; and the V.I. Lenin Hospital, Zanzibar. The Central Pathology Laboratory, Dar es Salaam. In Uganda-District

Hospitals at Fort Portal, Jinja, Lira, Kabale, Masaka, Mbarara, Soroti, and Tororo. The Ministry of Health Bacteriological Unit, Kampala. In Zambia-Government Hospital, Kabwe; Kafue Gorge Hospital and Lusaka Chest Clinic.

The valuable cooperation of the physicians in these hospitals, and of the medical assistant, nursing, radiological, health assistant, secretarial, and administrative staff, is greatly appreciated. Full acknowledgements to them will be given elsewhere. The continued support and cooperation of the Chief Medical Officers of Kenya, Tanzania, Uganda, and Zambia are again gratefully

acknowledged. The coordinating centres were the East African Medical Research Council, Tuberculosis Investigation Centre, Nairobi; the Medical Research Council Tuberculosis and Chest Diseases Unit, London, where the report was written; and the Medical Research Council Unit for Laboratory Studies of Tuberculosis, London. Messrs Gruppo Lepetit of Milan and Messrs Ciba Geigy of Basle generously provided as a free gift all the rifampicin used in this investigation. Requests for reprints should be addressed to the Director, Medical Research Council Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fulham Road, London SW3 6HP, or to the Director, East African Tuberculosis Investigation Centre, P.O. Box 47855, Nairobi, Kenya.

Hospital, London EC1A 7BE

A. GOMEZ-PAN V. M. ROY Royal Victoria Infirmary, Newcastle upon Tyne R. HALL

St.

R. C. G. RUSSELL Mary’s Hospital, London W2

D. H. COY

A. T. KASTIN A. V. SCHALLY Veterans Administration Hospital and Tulane University, School of Medicine, New Orleans, Louisiana, U.S.A. The hypothalamic polypeptide growthhormone release-inhibiting hormone (G.H.-R.I.H.) inhibited gastrin release in all subjects studied. In normal subjects and in patients with acromegaly during a standard food stimulus a G.H.R.I.H. infusion completely suppressed gastrin release, and immediately after the infusion was stopped gastrin levels rose sharply to exceed control values. Two patients with pernicious anæmia demonstrated a rapid fall in plasma-gastrin during G.H.-R.I.H. infusion, and in a patient with Zollinger-Ellison syndrome a 20-minute G.H.-R.I.H. infusion greatly lowered plasmagastrin concentrations and almost totally suppressed

Sum ary

gastric-acid production. Introduction THE

polypeptide growth-hormone release-inhibiting

hormone (G.H.-R.I.H. or somatostatin) has been shown to be a potent inhibitor of growth-hormone release and also to block thyroid-stimulating-hormone release

after administration of thyroid-stimulating-hormone releasing factor.1 Partial suppression of basal prolactin release has also been reported.2 Later studies have demonstrated a remarkable inhibition of the a andB cells of the pancreas, since both glucagon and insulin release are blocked, leading to a fall in glucose in

REFERENCES

African/British Medical Research Council Investigation: Lancet, 1972, i, 1079. East African/British Medical Research Council Investigation: Second Report. ibid. 1973, i, 1331. East African/British Medical Research Council Investigation: Third Report. ibid. 1974, ii, 237. Tuberculosis Chemotherapy Centre, Madras. Bull. Wld Hlth Org. 1970, 43, 495. Ellard, G. A., Gammon, P. T., Tiitinen, H. Unpublished. Eidus, L., Hamilton, E. J. Am. Rev. resp. Dis. 1964, 89, 587. East African/British Medical Research Council Thiacetazone/ Diphenylthiourea Investigation. Tubercle, 1960, 41, 399. Allen, B., Baker, F. J. Mycobacteria: Isolation, Identification and Sensitivity Testing. London, 1968.

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