Elsevier

The Lancet

Volume 360, Issue 9332, 17 August 2002, Pages 528-534
The Lancet

Articles
Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial

https://doi.org/10.1016/S0140-6736(02)09742-8Get rights and content

Summary

Background

Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week.

Methods

We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drugsusceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat.

Findings

1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9·2%) in those on rifapentine once a week, and 28/502 (5·6%) in those given rifampicin twice a week (relative risk 1·64, 95% CI 1·04–2·58, p=0·04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2·8, 95% CI 1·7–4·6); cavitation on chest radiography (3·0, 1·6–5·9); being underweight (3·0, 1·8–4·9); bilateral pulmonary involvement (1·8, 1·0–3·1); and being a non-Hispanic white person (1·8, 1·1–3·0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1·34; 0·83–2·18; p=0·23). Of participants without cavitation, rates of failure/relapse were 6/210 (2·9%) in the once a week group and 6/241 (2·5%) in the twice a week group (relative risk 1·15; 95% CI 0·38–3·50; p=0·81). Rates of adverse events and death were similar in the two treatment groups.

Interpretation

Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Introduction

Short-course treatment with a regimen containing rifampicin is highly effective for cure of tuberculosis.1, 2 Directly-observed treatment with rifampicin prevents acquired drug resistance, increases cure rates, and reduces incidence of secondary cases of tuberculosis.3 Treatment with a rifampicin-containing regimen can be given twice a week after an initial daily phase, which greatly simplifies treatment and facilitates directly-observed therapy.4 Although less frequent dosing (eg, once a week) would further facilitate therapy, treatment once a week with isoniazid and rifampicin is not sufficiently effective, and a substantial proportion of patients receiving this regimen have various adverse reactions, including thrombocytopenia and flu-like syndrome.5

Rifapentine is a rifamycin derivative with excellent activity against Mycobacterium tuberculosis in vitro and in animals.6, 7 Rifapentine has a longer half-life in serum than rifampicin (10–15 h8 vs 2–3 h9), and therefore could be effective for treatment of tuberculosis once a week. Compared with the standard regimen twice a week, treatment once a week during the continuation phase would reduce by 30% the number of contacts needed between patient and provider of directly-observed treatment. We did a randomised, open-label, multicentre trial to compare the once a week rifapentine-based treatment with the standard twice a week rifampicinbased treatment in the last 4 months (continuation phase) of a 6-month regimen for patients with pulmonary tuberculosis.

Section snippets

Patients

Patients 18 years of age or older, who were HIV-negative with pulmonary tuberculosis confirmed by culture from a respiratory specimen, were assessed for inclusion in the study. Patients were excluded if their isolate was resistant to 1·0 mg/L isoniazid or 1·0 mg/L rifampicin on solid media. Other exclusion criteria were intolerance to study drugs, tuberculosis of the central nervous system or bones or joints, silicosis, pregnancy or breastfeeding, or the following abnormal laboratory values:

Results

1004 HIV-seronegative patients were enrolled between April, 1995, and November, 1998; follow-up ended in March, 2001. Table 1 shows characteristics of patients at randomisation. Regimens used during the intensive phase were similar for both treatment groups. Patients randomised to rifapentine were more likely to have cavitary disease on chest radiography and to be positive by sputum smear or sputum culture at the end of the intensive phase of therapy.

31 (6%) of 502 patients who received

Discussion

We have shown that 600 mg rifapentine plus 900 mg isoniazid once a week is safe and effective for continuation phase treatment of pulmonary tuberculosis. In the unadjusted analysis, treatment once a week with rifapentine and isoniazid was less effective at prevention of failure/relapse than treatment twice a week with rifampicin and isoniazid (9·2% vs 5·6%). Two risk factors—cavitation and positive sputum culture—were unequally distributed between treatment groups (table 1), and this occurrence

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