An international co-operative investigation into thiacetazone (thioacetazone) side-effects

Abstract

In view of conflicting reports from different parts of the world, a study has been under-taken to determine the incidence of side-effects to thiacetazone in combined chemotherapy. It was conducted as a ‘double-blind’ controlled comparison of two regimens, streptomycin 1 g. daily with a daily tablet containing isoniazid 300 mg. plus thiacetazone 150 mg. (the STH regimen) and streptomycin 1 g. daily with a daily tablet of identical appearance containing isoniazid 300 mg. only (the SH regimen). In the main comparison the patients were treated for 8 weeks (8-week series) in 13 countries, Czechoslovakia, Cyprus, Turkey, Ghana, Kenya, Malawi, Nigeria, Rhodesia, South Africa, India, East and West Pakistan, Fiji and Hong Kong. In-patients were studied in all the countries, and in five of them, out-patients were also studied. In eight countries patients were treated for 16 weeks (16-week series). A total of 2,077 (1,045 STH, 1,032 SH) patients were admitted. After exclusions there were 1,002 STH and 987 SH patients for analysis in the 8-week series. Pre-treatment comparisons showed that, with few exceptions, in each country the distributions for sex, age, haemoglobin and weight were similar for the patients on the 2 regimens. During the 8-week period 21 (13 STH, 8 SH) patients died, 16 (10 STH, 6 SH) of tuberculosis. One (STH) patient died of hepatitis in the sixth week and an additional 2 (1 STH, 1 SH) patients died after 8 weeks with jaundice. Side-effects occurred in 214 (21·4%) of the STH patients compared with 77 (7·8%) of the SH patients, a statistically highly significant difference. The incidence of side-effects ranged from 0% on each regimen in Cyprus to 69% for the STH and 25% for the SH patients in Hong Kong. Treatment was not interrupted in 11·5% STH and 5·3% SH patients, was interrupted in 6·5% and 1·6%, and stopped in 3·4% and 0·9% respectively. Nausea or abdominal discomfort occurred in 4·0% STH and 1·6% SH patients, vomiting in 4·3% and 0·5%, and jaundice or hepatitis in 0·2% and 0·3% respectively. Flushing or itching occurred in 1·3% STH and 0·5% SH patients and rashes in 3·9% and 1·0% respectively. Dizziness or giddiness occurred in 9·6% STH and 2·9% SH patients, vertigo and ataxia in 2·3% and 0·7% and tinnitus and deafness in 1·1% and 0·0% respectively. Agranulocytosis occurred in 2 (STH) patients (both in Czechoslovakia; both recovered rapidly). Of the episodes of side-effects, 50% in the STH and 61% in the SH patients, commenced in the first 4 weeks, 45% and 60% respectively, lasted 6 days or less and 50% and 63% respectively, were mild. Of the 18 STH and 2 SH patients with cutaneous hypersensitivity leading to a major departure from treatment, there was confirmation that 9 (8 STH, 1 SH) had hypersensitivity to streptomycin, and 4 (3 STH, 1 SH) had hypersensitivity to the oral medicament. The incidence of side-effects in in-patients and out-patients was the same in Cyprus and Ghana, whereas in Turkey and Kenya there were more side-effects in in-patients and in Nigeria more in out-patients. There were 299 STH and 310 SH patients in the 16-week series (all were in the 8-week series also). During the 16-week period 8 (4 STH, 4 SH) patients died, 7 (3 STH, 4 SH) of tuberculosis and 1 (STH) with jaundice. Side-effects developed in the first 8 weeks in 25·1% STH and 11·0% SH patients compared with 7·0% and 5·5% respectively, in the second 8 weeks. Thus, the main differences between the regimens occurred in the first 8 weeks. The reasons for the differences between the countries in the reported incidence of side-effects have been discussed. © 1966, Published by Elsevier Ltd.. All rights reserved.