As part of a large-scale international cooperative investigation into the side effects of thioacetazone-containing regimens in the treatment of tuberculosis, an evaluation has been made of the variation in the frequency of side effects between different countries and between different centres in the same country and of the likely reasons for this variation. In 3 countries patients of different racial origin were under observation in the same hospital. Over a 12-week period of treatment there was considerable variation between the countries and centres in the overall frequency of side effects and of those leading to a major departure from prescribed treatment, the variation being similar for the two thioacetazone-containing regimens and for the streptomycin plus isoniazid control regimen, though at a lower level for the latter. In Malaysia, Singapore, and Trinidad, where different racial groups were under treatment, there was no clear indication that race was an important factor in explaining the differences between countries, except for cutaneous side effects in Trinidad and possibly in Malaysia.It is concluded that the differences in the frequency of side effects to thioacetazone-containing regimens probably result from variation in the closeness of supervision of patients, in the recording and interpretation of side effects, and in environmental factors including the previous use of other medicaments or exposure to sensitizing substances.
BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.