Elsevier

The Lancet

Volume 353, Issue 9167, 29 May 1999, Pages 1843-1847
The Lancet

Early Report
Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid

https://doi.org/10.1016/S0140-6736(98)11467-8Get rights and content

Summary

Background

Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001.

Methods

Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of fourdrug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods.

Findings

71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twiceweekly isoniazid/rifampin group (log rank x2=0·69 p=0·41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0·05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 mL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0·03) and concomitant therapy with antifungal agents (75% vs 9%, p=0·006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date.

Interpretation

Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIVseropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Introduction

Rifapentine is a cyclopentyl-substituted rifamycin with excellent activity against Mycobacterium tuberculosis1 in animal studies and early clinical trials.2, 3, 4, 5 Rifapentine's long serum half-life (10–15 h, compared with 2–3 h for rifampin6), suggests the possibility of once-weekly treatment. The US Public Health Service organised Study 22 to assess the use of once weekly isoniazid and rifapentine in the last 4 months of standard 6-month short-course tuberculosis therapy (the continuation phase). Compared with a standard twice-weekly 6-month regimen, this regimen would reduce by 28% the number of contacts required between patient and provider of directly observed therapy (DOT).

Enrollment of HIV-seropositive people stopped when acquired rifamycin monoresistance occurred in four of 36 people treated with once-weekly isoniazid and rifapentine (the subject of this report). The trial of HIVseronegative people completed enrollment in October, 1998, and follow-up will continue until 2001. However, relying principally upon data from another trial among HIV-seronegative patients, the US Food and Drug Administration granted accelerated approval to rifapentine in mid-1998. Because rifapentine will probably soon be available in other countries we believe it important to share our experience with rifapentine in HIV-infected tuberculosis patients.

Rifampin (rifampicin) is the key drug in modern tuberculosis regimens. Resistance has been welldescribed but generally occurs in the setting of resistance to isoniazid and other antituberculosis drugs. However, isolated resistance to rifampin is increasingly recognised, and patients with HIV-related tuberculosis seem to be at increased risk.7 Because there appears to be substantial cross-resistance among rifampin, rifabutin, and rifapentine, this form of resistance is better termed “rifamycin monoresistance”.8 Mycobacterial resistance to rifamycins poses a serious challenge to the treatment of tuberculosis. Our study offers insights into the possible mechanisms of acquired rifamycin monoresistance.

Section snippets

Patients

Study 22 is a randomised, open-label multicentre comparison of two regimens in the continuation phase of short-course tuberculosis therapy. All patients received standard four-drug therapy during the first 8–10 weeks (induction phase), with daily, twice-weekly, or thrice-weekly isoniazid, rifampin, pyrazinamide, and ethambutol. If daily therapy was given throughout induction, the patient had to have received at least 40 DOT doses and at least 45 total doses of daily therapy to be eligible; if

Results

Enrolment began in April, 1995. By early 1997, four rifamycin monoresistant relapses had occurred among HIV-seropositive patients randomly assigned weekly rifapentine/isoniazid, and the Data and Safety Monitoring Board, CDC, and the investigators decided not to enrol any more HIV-seropositive patients. Those still taking once-weekly isoniazid/rifapentine were switched to isoniazid, rifampin, and ethambutol, and treatment was extended to 9 months.

The trial enrolled 71 HIV-seropositive patients.

Discussion

The four cases of acquired rifamycin monoresistance among HIV-infected tuberculosis patients randomly assigned once-weekly isoniazid/rifapentine led to the closure of the HIV-seropositive arm of Study 22. Drug resistance rarely develops in patients with initially drug-susceptible strains who are treated with modern DOT regimens13, 14 even among patients who are non-compliant.15 Rifamycin monoresistance is very uncommon.7 Given the critical role of rifamycins in short-course chemotherapy, the

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