TBTC 31 – 4 month TB regimen
Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.
Dorman SE, Nahid P, Kurbatova EV, et al.; AIDS Clinical Trials Group; Tuberculosis Trials Consortium.
N Engl J Med. 2021 May 6;384(18):1705-1718. [Full text]
The mainstay of therapy for susceptible Mycobacterium tuberculosis (MTb) has been 6 months of rifampin, isoniazid, pyrazinamide, and ethambutol, or RIPE. Rifapentine is a cyclopentyl derivative of rifampin that also has activity against MTb but has a longer half-life, increasing the duration of exposure to rifamycins while still only dosed once daily. Moxifloxacin has activity against MTb, and regimens including moxifloxacin accelerate culture clearance [1] but have been insufficient to shorten therapy from 6 to 4 months [2]. In TBTC 31, the AIDS Clinical Trials Group and Tuberculosis Trials Consortium attempted to demonstrate non-inferiority of a 4 month MTb regimen containing rifapentine and moxifloxacin.
Patient population and Design
Patients were recruited from 34 clinical sites in 13 countries to this open-label, phase 3, randomized, controlled. Anyone 12 years of age or older that had newly diagnosed pulmonary tuberculosis, confirmed on culture to be susceptible to isoniazid, rifampin, and fluoroquinolones was eligible. Participants were required to have at least one sputum specimen that was positive for acid-fast bacilli on smear or positive for M. tuberculosis on a rapid nucleic acid amplification test (Xpert MTB). Those with HIV were required to have a CD4 T-cell count of ≥ 100 cells /mL3 and were enrolled to evaluate drug–drug interactions between rifapentine and efavirenz.
The participants were randomly assigned in a 1:1:1 ratio to a standard RIPE regimen (control), or a rifapentine regimen with or without moxifloxacin. Randomization was stratified according to trial site, presence of cavitation on chest radiography at baseline, and HIV status.
The RIPE control regimen was 8 weeks of daily RIPE followed by 18 weeks of daily rifampin and isoniazid. The rifapentine regimen was 8 weeks of daily rifapentine + IPE followed by 9 weeks of daily rifapentine and isoniazid. The rifapentine+moxifloxacin regimen replaced ethambutol with moxifloxacin for the first 8 weeks and was followed by 9 weeks of daily rifapentine, isoniazid, and moxifloxacin.
Rifapentine dosing was 1200 mg daily, 1 hour after food ingestion while rifampin was administered on an empty stomach. Moxifloxacin was dosed at 400 mg daily.
Outcomes
The primary efficacy outcome was survival free of tuberculosis at 12 months after randomization and was coded as favorable, unfavorable, or not assessable for each participant.
- Favorable status: was alive and free of tuberculosis at 12 months and had either an MTb negative sputum culture at 12 months or was unable to produce sputum.
- Unfavorable status: had MTb–positive cultures from two sputum specimens obtained at or after week 17, died or was withdrawn from the trial or lost to follow-up, had an MTb–positive culture when last seen, or received additional treatment for tuberculosis.
- Not assessable: Did not meet an ‘unfavorable outcome’ and did not attend the 12 month visit, had a change in treatment because of pregnancy, died from a cause unrelated to tuberculosis, received additional treatment for tuberculosis after exogenous reinfection (genomically verified).
The primary safety outcome was an adverse event of grade 3 or higher according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Liver toxicity was a concern.
Results
A total of 2343 participants were enrolled, 768 in the RIPE control group, 791 in the rifapentine–moxifloxacin group, and 784 in the rifapentine group. Only 194 were co-infected with HIV while 1703 had cavitation on chest radiography
An unfavorable outcome occurred in 15.5% of the rifapentine–moxifloxacin group and 14.6% of the RIPE control group (△1%; 95% CI, −2.6 to 4.5). This met non-inferiority.
In contrast, the rifapentine regimen was not non-inferior to the RIPE control regimen (△3%; [95% CI, −0.6 to 6.6]).
No difference in grade ≥3 adverse events was noted between the rifapentine–moxifloxacin group and the RIPE control group (18.8% [159 participants] vs. 19.3% [159]; △−0.6%; 95% CI, −4.3 to 3.2) while it was lower in the rifapentine group (14.3%, △−5.1 percentage points; 95% CI, −8.7 to −1.5). All-cause mortality was similar between treatment regimens. Liver toxicity was nearly similar between groups though serum bilirubin was more frequently elevated ≥3×ULN in the rifapentine–moxifloxacin group (see table below).
| Variable | Control (N=825) | Rifapentine–Moxifloxacin (N=846) | Rifapentine (N=835) |
| ALT or AST level ≥5×ULN — no. (%) | 24 (2.9) | 16 (1.9) | 13 (1.6) |
| ALT or AST level ≥10×ULN — no. (%) | 9 (1.1) | 4 (0.5) | 5 (0.6) |
| Serum total bilirubin level ≥3×ULN — no. (%) | 8 (1.0) | 28 (3.3) | 20 (2.4) |
| Hy’s law (ALT or AST level ≥3×ULN + serum total bilirubin level ≥2×ULN) — no. (%) | 7 (0.8) | 10 (1.2) | 8 (1.0) |
Discussion
TBTC 31 is the first study to show a 4 month regimen, in this case one that includes rifapentine and moxifloxacin instead of rifampin and ethambutol, is non-inferior to the traditional 6 month RIPE regimen for MTb. Four months of rifapentine without moxifloxacin, like other moxifloxacin regimens for MTb [2] are not non-inferior to 6 months of RIPE. Although HIV patients were included, they were only a small portion (8%, 194 pts). Therefore, there may still be insufficient supporting evidence to shorten MTb treatment in HIV co-infection.
A regimen that is shorter by 2 months may improve adherence and take some burden off of directly observed therapy administration, though that delivery infrastructure would still be required. That rifapentine dosing (after meals) differs from rifampin could conversely complicate implementation and adherence. Rifapentine is also more costly than rifampin [3], especially important in the developing world that carries most of the MTb burden. Finally, while the rifapentine and moxifloxacin regimen was not clearly shown to be more hepatotoxic, there was a hint of increasing bilirubin providers should be alert to.
Regardless, at least there is a regimen that can be given over a shorter 4 month period, dispelling the dogma that 6 months is always required. Perhaps other short regimens will be discovered, either even shorter, more cost effective, and/or more accessible. Ongoing work in this arena is needed for the nearly 10 million cases of MTb annually worldwide, with this study a huge step forward.
| F: Follow up | 18 months |
| R: Randomization | 1:1:1 stratified by trial site, cavitation on CXR at baseline, and HIV status |
| I: Intention to treat | No*. ITT results were reported separately from the main results in the assessable population |
| S: Similar at baseline | Yes |
| B: Blinding | No, open-label |
| E: Equal treatment | Presumed, but not explicitly discussed |
| S: Source (funding) | CDC and others |
- Burman WJ, Goldberg S, Johnson JL, et al.; Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006 Aug 1;174(3):331-8.
- Gillespie SH, Crook AM, McHugh TD, et al.; REMoxTB Consortium. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1577-87.
- Rubin EJ, Mizrahi V. Shortening the Short Course of Tuberculosis Treatment. N Engl J Med. 2021 May 6;384(18):1764-1765.
