The relative merits of a fully supervised twice weekly regimen of Streptomycin and INH (SHtW) and an unsupervised daily regimen of INH and Thioacetazone (TH) in routine programme conditions in an urban area are compared in terms of acceptability and response to treatment at one year. Of the 474 newly diagnosed sputum positive cases at Lady Willingdon TB Demonstration & Training Centre, Bangalore during 1968-69, 134 were allocated to SHtW regimen and 189 to TH regimen. All others who were unwilling to take the allocated regimen or were excretors of bacilli resistant to INH and or SM were analysed as a subsidiary group.

About 25% of the patients allocated to SHtW regimen expressed unwillingness to start treatment on account of unsuitability of working hours and or distance. Refusal to TH regimen was negligible (5%). As regards drug acceptability after start of treatment, while the duration of treatment taken was similar for both the regimens, the level of drug intake achieved by the SHtW patients was lower compared with TH patients i.e., 31.3% of the SHtW patients and 56.1% of TH patients took more than 80% of treatment. If concealed irregularity among TH patients is taken into consideration, it is likely that the drug intake among TH patients would be similar to the drug intake among SHtW patients. The acceptability was therefore almost similar among SHtW and TH patients. Very low level (28%) of treatment completion was achieved by SHtW patients. With TH regimen, 46% had made 10 or more monthly collections during 12 months. Among the SHtW patients there was greater irregularity in the later months which was not apparent among TH patients. However, the favourable response among patients on SHtW and on TH regimen was 68% and 60% respectively. Deaths among SHtW patients were 4%, 13.5% among TH patients, the difference being statistically significant. The response was directly related to the level of drug collection or supervised consumption. The large proportion of the patients who stopped treatment prematurely, continued to remain positive with drug sensitive organisms, if initially they were so. In the subsidiary group there were 62 patients who were excretors of drug resistant organisms. They were treated with drugs to which their organisms were resistant and nearly 30% of these patients had negative culture at the end of one year.

It is concluded that (i) SHtW regimen was superior to TH as it prevented deaths and showed better bacteriological conversion among patients with level 3 & 4 of treatment and (ii) treatment organization is the most important factor in obtaining better results in routine chemotherapy with available drug regimens.

The effect of specific anti TB drugs on patients having smear negative radiologically positive pulmonary tuberculosis (suspect cases), was studied in Lady Willingdon Tuberculosis Demonstration & Training Centre (LWTDTC), Bangalore during 1975 & 1976. The main objective was to know the proportion of suspect cases treated under the programme requiring the specific treatment with anti TB drugs. A total of 457 suspect cases were randomly allocated to one of the two regimens; 228 patients were treated with INH + Thioacetazone (TH) and 229 with calcium gluconate (Placebo) regimens, for one year. The placebo group allowed a concurrent comparison of status of suspect cases without any specific treatment. After the intake, sputum examination by direct smear, culture for M.tuberculosis and sensitivity for drugs as well as X-ray examinations were carried out at 0, 2nd, 4th, 6th, 9th and 12th month of treatment.

Among the 228 patients on TH, 103 (45.2%) were real suspect cases, 83 (36.4%) sputum positive and remaining 42 non- tubercular. Similarly, out of the 229 patients on placebo regimen, 110 (48%) were real suspect cases, 61 (26.5%) sputum positive and 58 non- tubercular. The effect of treatment was measured by observing the incidence of bacteriologically positive or radiologically active disease from among the real suspect cases of the two groups. At the end of the treatment period, 12.6% of TH group and 29.7% of placebo group were broken down, the difference being statistically significant. Further, an element of self healing was also observed, as about 40% of patients in placebo group showed either clearance of lesions or continuing regression which could be due to self healing or the lesion being non- tubercular in nature. About 30% of the 457 patients at the start of the study were real cases of tuberculosis who under the programme were missed and 20% broke down with bacteriological positive or progress to radiologically active disease when treatment was not offered. Thus, nearly 50% of the suspect cases diagnosed in the programme required anti TB treatment and for those requiring treatment, perhaps TH is not sufficient, as 12.6% broke down in spite of treatment. It would be appropriate to treat suspect cases both from the clinical and epidemiological point of view after taking due precautions to remove non- tubercular cases by doing repeat sputum examination.

A controlled clinical trial of the three Short Course Chemotherapy (SCC) regimens was carried out at the Lady Willingdon State Tuberculosis Centre, Bangalore and Tuberculosis Research Centre, Madras with the collaboration of National Tuberculosis Institute, Bangalore. The regimens were (1) R3: (rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (3RSHZ); (2) R5: same as regimen R3, followed by streptomycin, isoniazid, pyrazinamide twice weekly for 2 months (3RSHZ/2S2H2Z2); (3) Z5: same as regimen R5 but without rifampicin (3SHZ/2S2H2Z2). Newly diagnosed tuberculosis patients who were aged 12 years or more had no history of previous treatment and two sputum cultures positive for M.tuberculosis were taken to the study and allocated at random to one of the above stated three regimens. The patients were given supervised chemotherapy as out patients. Sputum specimens were examined by fluorescent microscopy, culture by modified Petroff's method, tested for sensitivity to INH, rifampicin, streptomycin and ethambutol. The follow up was done by sputum smear and culture examination at the end of every month for 2 years. The distribution of various pre treatment characteristics like age, sex, and initial sensitivity status were similar in the three series. At the end of 3 months, of the 455 patients on R3, and R5 series, 96% with drug sensitive organism became culture negative and of 235 on Z5 series 93% became culture negative. For R5 and Z5 series favourable response at the end of chemotherapy were 96%, 99% and 97% respectively. In all, 6 patients (3 R3 & 3 Z5) were classified as having unfavourable response. At the end of 24th month from the date of start of treatment, 20% of the 200 patients on R3, 4% of 187 patients on R5 and 13% of 199 patients on Z5 had bacteriological relapse. The difference between R3 and Z5 series was highly significant. (p = 0.00001). The relapse rates in R3 & Z5 series were significantly higher than that in R5. Of the 57 patients with initial drug resistance organisms in R3 and R5 series combined 4 had an unfavourable response to treatment compared with 13 of 26 in the Z5 series (p = 0.0001). Of the 4 patients with an unfavourable response in R3 and R5 series combined, resistance to rifampicin emerged in 2 patients. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of Z5 patients (p = 0.00001). However, chemotherapy was modified in only 5 and 12% respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p = 0.0001).

The fate of patients with isoniazid (H) resistant pulmonary tuberculosis, treated with 3 different Short Course Chemotherapy regimens (Regimen A-1 SHRZ/7TH, Regimen B-2SHR/6TH, Regimen C-2EHR/4H2R2) was examined in two sequential studies. One hundred H resistant patients belonging to two groups-one without history of previous treatment(core group) and second with history of previous treatment >=15 days (non-core group), were followed up at the end of 12th, 15th and 24th/36th month of chemotherapy. Bacteriological favourable response among patients in the core group at the end of chemotherapy with Regimen A, B and C were 65.2% of 23 patients, 50% of l8 patients, and 57.1% of 18 patients respectively. The response among patients in the non-core group were 27.3% with Regimen A and 52.6% with Regimen B.

At the end of 24/36th month of chemotherapy, 62.5% patients in the core group and 2 out of 7 in the non-core group on regimen A and 68.7% patients on regimen C in the core group and 5 out of 15 in the core group and 41.7% in the non-core group on regimen B were culture negative. The relapses were significantly high in regimen B & C in comparison with regimen A. Thus, of the total 100 patients, 99.3% were eligible for examination (1 died during chemotherapy), 67 were examined and of them 37 (62.7%) were culture negative, 22 positive and 8 were dead. The development of drug resistance to rifampicin was directly related to the duration of its use.

Even though BCG has been in use for last 60 years, it has always been the subject of controversy, as several scientific studies done all over the world showed the protective value of BCG varying from 0 percent to 80. Because of the controversy over its protective effect and its extensive use in India it was felt necessary to undertake further field trials, wherein all shortcomings of previous trials could be eliminated. The Government of India took the decision to undertake a BCG trial in India. In 1968, the study was carried out in Chingleput district in Tamil Nadu, where no BCG vaccination was previously offered. The objective of the study were to obtain i) precise estimate of the protective effect of BCG vaccination against tuberculosis in the non-infected, ii) effect of BCG vaccination in persons already infected and iii) protective effect of different strains of BCG and iv) epidemiological data on tuberculosis in the community. The entire population of 3,60,000 persons were registered during a period of two and a half years of intake. All the persons aged one month and above were randomly divided into three main groups. One group vaccinated with the Madras vaccine, the second with Paris vaccine and the third with Placebo. At the same time all persons were tested with tuberculin, those above 10 years and above were X-rayed and those having X-ray shadows were examined by direct smear and culture. The study population was systematically and intensively followed up by X-ray and sputum examinations to diagnose all the new cases occurring in the community. The protective effect of BCG vaccination is defined as the proportionate reduction in the occurrence of new cases among the vaccinated, initially tuberculin negatives as compared to a similar but unvaccinated group. The protective effect was studied among individuals who were not previously infected, who had no tuberculosis at the time of vaccination and who were either vaccinated or left unvaccinated. The results of 7½ years of follow up showed that the number of new cases that occurred among the group vaccinated by either of the vaccines or from the unvaccinated group were similar. This showed that BCG vaccination did not offer any protection against tuberculosis of the lung. The epidemiological characteristics of the population were high prevalence and incidence of tuberculosis infection and disease and high prevalence of non- specific sensitivity. The risk of manifest disease for this recently infected was relatively small, as most of the new cases occurred among those who were tuberculin positive at the time of intake and not from those who were not infected then. Implications : Several expert committees appointed both by the authorities in India and by the WHO have examined all the procedures followed up in the study and came to the conclusion that the study had been meticulously carried out and vaccine used in the trial were the best available ones. The implications of this study was 'should BCG vaccination be given up in India?' Yet another committee appointed jointly by ICMR and the WHO went into the epidemiological aspects of the causation of tuberculosis under Indian conditions and concluded that BCG may not protect against tuberculosis of lung which occurs mostly in adults; it could provide substantial protection against childhood form of tuberculosis such as tubercular meningitis, tuberculosis of bones & joints etc. The protective effect of BCG against these forms of tuberculosis was not studied in Chingleput Trial. In India BCG vaccination is recommended to be given at an early age preferably before the end of the first year after birth.