Arthralgia in South Indian patients with pulmonary tuberculosis during treatment with pyrazinamide and rifampicin

Arthralgia was the major adverse reaction encountered in a clinical trial of the treatment of pulmonary tuberculosis with three short-course regimens containing pyrazinamide in South Indian patients. The first regimen was of rifampicin, streptomycin, isoniazid and pyrazinamide given daily for three months; the second was of the same four drugs daily for three months followed by streptomycin, isoniazid and pyrazinamide twice-weekly for two months, and the third was the same as the second except that rifampicin was not administered. Arthralgia was reported in 36% of 353 rifampicin patients and 66% of 179 non-rifampicin patients, a highly significant difference (p<0.001). The onset of arthralgia was mostly during the first two months of chemotherapy. The knees were affected in about 90% followed by the ankles in about 50% of the patients with arthralgia, and about 60% of these patients had one or more of the signs, swelling, tenderness and limitation of joint movement. Chemotherapy was modified in 10 rifampicin and 15 non-rifampicin patients; the rest of the patients were managed with symptomatic treatment with analgesics. There was a two to three fold increase in serum uric acid concentrations by the end of the first month and the concentrations were more or less stationary throughout the rest of the daily phase of treatment. The mean concentration during the daily phase of treatment in patients with arthralgia (0.482 mmoles/litre) was similar to that in those without arthralgia (0.484 mmoles/litre), while that in the rifampicin patients (0.476 mmoles/litre) was significantly lower (p=0.03) than that in the non-rifampicin patients (0.495 mmoles/litre)

Toxicity of pyrazinamide, administered once weekly in high dosage, in tuberculous patients*

The success of a twice-weekly regimen of streptomycin plus isoniazid, reported earlier from the Tuberculosis Chemotherapy Centre, Madras, prompted an investigation at the Centre of various once-weekly regimens of chemotherapy. In this context, a pilot study was undertaken in 19 patients to assess the toxicity of high-dosage pyrazinamide (70 mg/kg of body-weight), when administered once weekly, together with isoniazid (14 mg/kg of body-weight) and streptomycin (1 g), for at least 6 months. Serial estimations of SGOT and SGPT activity, urine tests for urobilin and bilirubin and haematological investigations were undertaken at frequent intervals. None of the patients showed any clinical evidence of hepatotoxicity; however, there was a slight and transient elevation in aminotransferase activity, probably of a non-specific nature, at 2 weeks. These findings are encouraging for the use of high-dosage pyrazinamide in once-weekly regimens of chemotherapy

Influence of HLA-DR and -DQ phenotypes on tuberculin reactive status in pulmonary tuberculosis patients

Setting: HLA and tuberculin status in pulmonary tuberculosis patients. Tuberculosis Research Centre, Indian Council of Medical Research, Madras, India. Objective: To elucidate the role of HLA-class-II genes/gene products on tuberculin reactivity in pulmonary tuberculosis patients. Design: Serological determination of HLA-DR and -DQ antigens was carried out in 62 healthy control subjects and 146 pulmonary tuberculosis patients. The tuberculin reaction pattern of pulmonary tuberculosis patients to PPD was studied and the role of HLA-DR and -DQ antigens (class-II gene products) on tuberculin reaction was analysed. Results: HLA-DR and -DQ antigens did not influence high, medium and low tuberculin reaction dramatically in active pulmonary tuberculosis patients. However, a heterozygous combination of various HLA-DR antigens influenced the tuberculin reaction. Conclusion: The HLA-genetic make up (heterozygous combination) of the individual may influence the tuberculin reaction pattern in pulmonary tuberculosis

Attack rate of tuberculosis in a 5-year period among close family contacts of tuberculous patients under domiciliary treatment with isoniazid plus PAS or isoniazid alone*

This report from the Tuberculosis Chemotherapy Centre, Madras, considers the risk, over a 5-year period, to close family contacts of sputum-positive patients treated at home for 1 year with a standard regimen of isoniazid plus PAS or one of 3 regimens of isoniazid alone. The attack rate of tuberculosis in the contacts did not appear to be influenced by the treatment received by the patients in the first year or by the duration in the 5-year period for which the patients had (1) positive sputum smears, (2) positive cultures, or (3) isoniazid-resistant cultures. Further, over half the cases of tuberculosis developed in the first year, many of these being in the first 3 months. These findings confirm the conclusions reached from an earlier study, namely, that the major risk to the contacts is from exposure to the infectious patient before diagnosis, and that the risks from the other possible sources of infection (the patient during treatment and the urban environment of Madras) are, in comparison, small

Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin, and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculous meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16–39 % in children with tuberculous meningitis, 10 % in patients with spinal tuberculosis (non-surgical cases), and 2–8 % in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11 % of 317 slow acetylators and 1 % of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39 %) was higher than that with 12 mg/kg (16 %), and appreciably lower in patients given rifampicin twice-weekly (5 %) rather than daily (21 %). There was no indication that pyrazinamide contributed to the hepatic toxicity

Treatment of pulmonary tuberculosis patients treated with short course chemotherapy regimens in South India - 5-year follow-up

A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1 % of 126 R/5, 4.0 % of 124 R/7 and 6.7 % of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment

A controlled comparison of cycloserine plus ethionamide with cycloserine plus thiacetazone in patients with active pulmonary tuberculosis despite prolonged previous chemotherapy

Twenty-seven patients with chronic pulmonary tuberculosis who had failed to respond to two previous chemotherapeutic regimens were allocated to treatment with cyctoserine plus ethionamide (14 patients), or with cycloserine plus thiacetazone (13 patients). All had isoniazid-resistant strains and all but one had streptomycin-resistant strains at the start of the study. At the end of a year nine of 14 patients in the ethionamide series compared with three of 13 in the thiacetazone series had bacteriologically quiescent disease, one and three, respectively, had bacteriologically active disease; during the year, two patients (one in each series) deteriorated and had their chemotherapy changed and two patients (both on thiacetazone) died of tuberculosis. The difference in the proportions of unfavourable response attained statistical significance. There was one case of peripheral neuropathy due to ethionamide. Definite toxicity to thiacetazone was not observed. One of nine patients excluded from the main analysis had had intractable vomiting due to cycloserine

A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India*

This report is the last of a series of nine publications from the Tuberculosis Chemotherapy Centre, Madras, concerning various aspects of an investigation of the role of ambulatory chemotherapy for pulmonary tuberculosis. It presents the attack rates of tuberculosis over a 5-year period of follow-up of close family contacts of patients, all of whom were treated for one year with isoniazid plus PAS, half (selected at random) in sanatorium and half at home. The incidence of active tuberculosis and of tuberculous infections was no greater in the contacts of patients treated at home than in the contacts of patients treated in sanatorium, either in the first year or over the subsequent four years. The major risk to the contacts resulted from exposure to the patient before diagnosis. These findings reaffirm that close family contacts of patients treated at home were at no additional risk of developing tuberculosis, provided the patients received effective chemotherapy. Finally, this study has shown that it is possible in South India to obtain extremely good co-operation from a group of families over a period of several years