A controlled comparison of two fully supervised once-weekly regimens in the treatment of newly diagnosed pulmonary tuberculosis

Abstract

Four hundred and fifteen patients with pulmonary tuberculosis were admitted to a controlled study of a year's treatment, on an out-patient basis, with one of the following two fully supervised regimens: • SH/SHOW. Streptomycin 1 g or 0·75 g plus isoniazid 400 mg administered daily for the first four weeks, followed by streptomycin in the same dosage plus isoniazid 13 mg/kg or 17 mg/kg body-weight, administered once a week for the rest of the year. Pyridoxine 6 mg was incorporated in every dose of isoniazid. • SPH/SPHOW. Streptomycin, isoniazid and pyridoxine in the same dosages as in the SH/SHOW regimen, plus sodium PAS 6 g throughout the year, all the drugs being administered daily for the first four weeks and once a week for the rest of the year. The regimen, the streptomycin dosage and the once-weekly isoniazid dosage were allocated at random for each patient. The main analyses in this report concern 359 newly-diagnosed patients (181 SH/SHOW, 178 SPH/SHHOW) with cultures sensitive to isoniazid and streptomycin on admission. About 90 per cent of the patients had cavitated disease and a positive sputum smear on admission, and 40 per cent were rapid inactivators of isoniazid. The condition on admission was similar for the two series. Two patients (both SH/SHOW) died of tuberculosis and four (all SH/SHOW) had their chemotherapy changed on account of radiographic or clinical deterioration in the presence of a positive sputum. At one year, 85 per cent of the SH/SHOW and 87 per cent of the SPH/SHHOW patients were classified as having a favourable response, mainly on the basis of culture results at 10, 11 and 12 months. Among those who had an unfavourable response, approximately half had responded well initially but had a bacteriological relapse by one year. Considerable or exceptional radiographic improvement was shown by about three-fourths of the patients in each series, and cavitation had disappeared in about half. Resistance to isoniazid was observed at one year in 8 per cent of the SH/SHOW and 5 per cent of the SPH/SPHOW patients, and resistance to streptomycin in 8 per cent and 2 per cent, respectively. It is concluded that the addition of PAS to the SH/SHOW regimen did not confer an appreciable benefit. Slow inactivators of isoniazid responded considerably better than rapid inactivators, the proportions with a favourable response at 1 year being 93 per cent and 72 per cent respectively in the SH/SHOW and 95 per cent and 76 per cent respectively in the SPH/SPHOW series. The relative insufficiency of isoniazid in the rapid inactivators was manifested by less efficient elimination of isoniazid-sensitive organisms and greater frequency of streptomycin resistance. The duration of coverage with a bacteriostatic concentration of isoniazid (0·2 μg/ml) following a once-weekly dose and the total exposure to isoniazid (expressed as the area under the time-concentration curve) were substantially higher in the slow inactivators (30–34 hours; 85–111 units) than in the rapid inactivators (14–15 hours; 36–51 units). The peak concentration in the former, however, was only 22 per cent higher than that in the latter, the difference being of the same order as that between SPH/SPHOW and SH/SHOW patients, and isoniazid high-dosage (17 mg/kg) and low-dosage (13 mg/kg) patients. These findings suggest that response to once-weekly chemotherapy with isoniazid is largely determined by the duration of coverage and the total exposure to isoniazid. Streptomycin 0·75 g (approximately 20 mg/kg body-weight) was therapeutically as effective as 1 g and less toxic. The isoniazid dosage of 17 mg/kg in the once-weekly phase appeared to be slightly more effective than the dosage of 13 mg/kg, but only in rapid inactivators.