The 4-Month Isoniazid, Rifapentine, Moxifloxacin, and Pyrazinamide Treatment Regimen for Drug-Susceptible Pulmonary Tuberculosis: A Word of Caution

To the Editor:

We are grateful for the updated joint American Thoracic Society/CDC/Infectious Diseases Society of America/European Respiratory Society guidelines on the treatment of drug-susceptible and drug-resistant tuberculosis (TB) (1) by Saukkonen and colleagues. This has been a highly anticipated publication and is a testament to the outstanding work accomplished by the multidisciplinary panel and research teams providing evidence-based support for these updated recommendations.

The new 4-month combination regimen of isoniazid (INH), rifapentine, moxifloxacin, and pyrazinamide (PZA) (HPMZ) for the treatment of drug-susceptible pulmonary TB provides for a shortened duration compared with the 6-month program of rifampin, INH, PZA, and ethambutol (RIPE) and is a compelling option for both patients and TB programs alike (2). As providers and public health programs operationalize this regimen, however, there are important considerations that are not captured in the new guideline.

The HPMZ regimen requires a high pill burden for the patient. Rifapentine is dispensed in 150-mg tablets, and thus the 1,200-mg recommendation requires eight pills daily. When combined with INH (B6), PZA, and moxifloxacin, the entire regimen totals 13–15 pills per day during the first 2 months and 11 pills daily (after discontinuing PZA) for the subsequent 2 months. This is a notable increase compared with the RIPE regimen, which includes 7–12 pills in the intensive phase and 3–4 in the continuation phase of treatment. The volume of pills in the HPMZ regimen may adversely impact patient preference, tolerance, and compliance. Indeed, comparatively high rates of patient intolerance to HPMZ have already been reported (3). To the extent that these factors are mitigated by directly observed therapy, the new regimen may place an additional burden on public health programs, many of which already face resource and personnel shortfalls.

Daily treatment with rifapentine places additional pressure on drug supply sustainability within the United States, as the authors of the guideline note. There have already been both national and regional shortages, and rifapentine remains listed by the U.S. Food and Drug Administration as an ongoing shortage (4). Therefore, it will be imperative that patients started on HPMZ have access to sustainable rifapentine supplies to complete treatment. Supply pressures may also directly impact local and state public health departments using the 12-week INH-rifapentine (3HP) (5) and require decisions about prioritizing or rationing rifapentine use for latent TB infection (72 tablets per course) versus treatment of active TB disease with the new 4-month regimen (952 tablets per course). The HPMZ regimen may also be more expensive for public health departments than standard RIPE treatment, and the consequential impacts on limited budgets will need to be assessed.

The inclusion of moxifloxacin necessitates confirming fluoroquinolone (FQ) drug susceptibility testing (DST) of the Mycobacterium tuberculosis isolate, as advised in the guidelines. Many mycobacterial laboratories, however, do not routinely perform FQ DST as part of their first-line drug panel for M. tuberculosis. The laboratory may need to be contacted to add moxifloxacin DST when the regimen is being considered, and some labs may need to develop further capacity for FQ testing or identify protocols for forwarding samples to referral laboratories with that capacity.

Despite these considerations, the 4-month program including rifapentine and moxifloxacin can be an attractive treatment option for patients who are unable or unwilling to complete a 6-month treatment duration. Such patients may include nonresidents or other patients departing the United States within 6 months, those incarcerated with a short duration remaining on their sentence, and patients waiting for select medical treatments (organ transplantation, elective surgery, immunosuppression) that favor completion of TB therapy as quickly as possible. Having multiple options to treat TB helps ensure more favorable patient outcomes through individualized care, but this is a word of caution that the 4-month HPMZ may not be for everyone.