Frequently Asked Questions (FAQs)

The interim guidance is based on results of an international phase 3 clinical trial sponsored by CDC’s Tuberculosis Trials Consortium and conducted in collaboration with the National Institutes of Health-sponsored AIDS Clinical Trials Group. The article, “Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis,” published in the New England Journal of Medicine (NEJM), details findings from Study 31/A5349 – an international, randomized, controlled, open-label, phase 3 noninferiority clinical trial. It demonstrated that a shorter four-month daily treatment regimen with high-dose rifapentine and moxifloxacin is as effective as (noninferior to) the standard daily six-month regimen in curing drug-susceptible TB disease. This was the first successful shorter treatment regimen for drug-susceptible TB disease identified in almost 40 years. The clinical trial was recognized as one of the NEJM’s 2021 Notable Articles. The “Notable Articles” are selected by NEJM editors as the most meaningful in changing medical practice and improving patient care.

Yes, the study’s patient population is representative of adults and adolescents with drug-susceptible pulmonary TB disease in the United States. The large sample size of the trial allowed inclusion of patients with different extent and severity of TB disease and inclusion of subgroups that are relevant to U.S. patients and their co-morbidities.

Participants were followed-up in the trial for 18 months after randomization. Recent analysis confirmed that a 4-month regimen had noninferior efficacy at 18 months compared to the standard 6-month control regimen.

The substitution of these two drugs (i.e., rifapentine for rifampin, and moxifloxacin for ethambutol) in the standard 6-month RIPE regimen (i.e., rifampin, isoniazid, pyrazinamide, and ethambutol) made it possible to reduce the duration of treatment for drug-susceptible pulmonary tuberculosis to four months.

Interim guidance issued by CDC means the evidence is new or evolving. This guidance is based on an international phase 3 clinical trial (Study 31/A5349), preclinical/animal evidence, prior clinical trial findings, and pharmacokinetic and pharmacodynamic modeling. This is the first guidance published for U.S. healthcare providers about the use of the 4-month rifapentine-moxifloxacin regimen. CDC is the appropriate agency to draft such guidance as the sponsor of Study 31/A5349 and as the agency with authority for TB control and elimination efforts in the United States. Official American Thoracic Society/CDC/Infectious Diseases Society of America guidelines for the treatment of drug-susceptible TB disease in the United States were last updated in 2016, replacing prior guidelines published in 2003. Interim guidance in response to Study 31/A5349 is needed before the next major revision of TB treatment guidelines.

Testing of sputum specimens should be attempted, however, testing of other respiratory specimens is acceptable. If the sputum sample is not optimal for molecular testing (e.g., low bacillary load), referral of an isolate of Mycobacterium tuberculosis should be considered for baseline molecular susceptibility testing.

Sputum collection is not an activity specific to use of this regimen alone. Collection of sputum specimens should be attempted for all patients undergoing treatment for TB disease. If the patient does not produce sputum, other respiratory specimens are acceptable. All health care settings where patients with possible TB disease receive care should establish and follow a TB infection control program. Cough-inducing and aerosol-generating procedures should be performed using environmental controls and appropriate personal protective equipment. Refer to TB Infection Control in Health Care Settings.

Sputum induction with hypertonic saline is an acceptable method to collect sputum.

Specimens obtained from other diagnostic procedures, such as bronchoscopy with bronchoalveolar lavage and biopsy, can be considered for testing in patients who are unable to produce sputum; however, a less invasive procedure such as sputum induction should generally be attempted before obtaining specimens via bronchoscopy.

To rapidly identify drug resistance, it is advisable to assess for mutations associated with resistance to isoniazid, rifampin (as a proxy for rifapentine), pyrazinamide, and fluoroquinolones from a respiratory specimen obtained at baseline. Isolates also can undergo molecular testing for detecting mutations associated with resistance. Phenotypic drug susceptibility testing should be performed on a baseline isolate.

State and local public health laboratories as well as CDC’s Tuberculosis Elimination Laboratory can assist with identifying laboratories to perform fluoroquinolone drug susceptibility testing.

If resistance to any drug in the 4-month rifapentine-moxifloxacin regimen is demonstrated by either molecular or phenotypic drug susceptibility testing, the 4-month rifapentine-moxifloxacin regimen should be discontinued. Expert consultation through state or local TB control office or the TB Centers of Excellence for Training, Education, and Medical Consultation may be obtained for choosing appropriate TB treatment regimens in case of drug resistance.

Molecular testing of sputum or isolate at baseline allows for quicker results to facilitate more rapid changes in treatment if warranted. Reliance on phenotypic DST alone takes longer for results and could lead to delays in appropriate treatment for patients with drug-resistant TB disease.

The reason to include phenotypic testing for fluroquinolones is because some molecular methods (depending on sensitivity) can miss heteroresistance (subpopulations of cells with increased antibiotic resistance when compared with the susceptible main population), which is common for fluoroquinolone resistance. Depending on the molecular method used, phenotypic methods may be more sensitive for this purpose.

Patients found to have fluoroquinolone resistance were not followed in the clinical trial. If fluoroquinolone resistance is identified, the 4-month rifapentine-moxifloxacin regimen should be discontinued, and patients should be treated according to drug susceptibility testing profile and patient’s individual characteristics. For further information, refer to Treatment to Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

The clinical trial protocol had an inclusion criterion for potassium only (serum or plasma potassium level greater than or equal to 3.5 mEq/L). Calcium and magnesium levels were not tested in the trial. When a patient has abnormal test results at baseline, the physician should consider the risks and benefits of using the 4-month rifapentine-moxifloxacin regimen, accounting for possible cardiac conduction abnormalities and underlying heart disease.

Baseline ECG is not routinely recommended for all patients starting this 4-month rifapentine-moxifloxacin regimen. Patient co-morbidities and potential drug-drug interactions should be evaluated. Prolonged QT syndrome, which is generally asymptomatic, is a contraindication to the 4-month rifapentine-moxifloxacin regimen.

There are no prospective randomized trials that clearly define the role of TDM for anti-TB drugs. As such, opinions vary regarding the utility of TDM. For further information, refer to Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

Differences in baseline evaluations for patients treated with the 4-month rifapentine-moxifloxacin regimen as compared to the standard 6-month regimen are summarized in the Evaluation and Testing Considerations for Drug-susceptible Pulmonary TB Treatment Regimens table.

In the clinical trial, there was no upper limit for weight for participants. Some experts recommend therapeutic drug monitoring in patients with obesity that are not responding to treatment. Healthcare providers should consider all aspects of the patient in initiating and monitoring the 4-month rifapentine-moxifloxacin regimen.

The clinical trial did not have an upper age limit. Healthcare providers should consider a patient’s comorbidities in initiating and monitoring 4-month rifapentine-moxifloxacin regimen.

Yes, the clinical trial enrolled 83 participants with diabetes. Among trial participants with diabetes, there was no significant difference in efficacy and safety outcomes between the 4-month rifapentine-moxifloxacin regimen and the control regimen.

The 4-month rifapentine-moxifloxacin regimen can be used in adolescents aged 12-17. Analysis indicated that adolescents had numerically similar safety and efficacy outcomes in the rifapentine-moxifloxacin arm compared to the control regimen (although numbers of participants were small). The 4-month rifapentine-moxifloxacin regimen was not studied in and is not recommended for children younger than 12 years old.

The 4-month rifapentine-moxifloxacin regimen is not recommended for pregnant and breastfeeding patients. A pregnancy test should be conducted for people of reproductive potential before starting the 4-month rifapentine-moxifloxacin regimen.

Rifapentine is not recommended for pregnant people or people who expect to become pregnant during TB treatment because its safety during pregnancy has not been established. The use of fluoroquinolones is generally avoided in pregnancy. Pyrazinamide is generally avoided in pregnancy.

For further information, refer to Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

CDC does not recommend the 4-month rifapentine-moxifloxacin regimen for people who have most types of suspected or documented extrapulmonary TB. Patients with miliary and disseminated TB were not included in the trial. An alternate regimen should be considered if disseminated disease is identified after regimen is initiated. For further information, refer to Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

CDC recommends [PDF – 233 KB] using directly observed therapy (DOT) at least 5 days a week for the duration of the 4-month rifapentine-moxifloxacin regimen.

CDC recommends video DOT (vDOT) as an equivalent alternative to in-person DOT for patients on treatment for TB.

The State TB Control Offices and TB Centers of Excellence for Training, Education, and Medical Consultation can provide additional assistance and support in treating people with TB disease.

Healthcare providers should carefully review a patient’s clinical history, concurrent medications, social determinants of health (e.g., stable housing, food access, regular access to medical care) and risk factors for adverse drug reactions in making the decision to use this regimen. Food insecurity should be screened for (and resources provided as needed) at every encounter as the 4-month rifapentine-moxifloxacin regimen should be taken with food. Housing and income insecurity should also be considered to ensure retention in TB care.

Yes. By law, all TB cases must be reported to the local health department. TB programs can also help private or hospital providers to minimize any challenges related to medication procurement, directly observed therapy, infection control, and contact investigations. Healthcare providers seeking clinical consultation should contact their state or local TB control office or the TB Centers of Excellence for Training, Education, and Medical Consultation.

Drug-drug interactions for people with HIV and TB can be complex and should be considered before initiating treatment. Only patients receiving efavirenz, rather than protease inhibitors or integrase inhibitors, were studied. For further information, refer to Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Healthcare providers seeking clinical consultation should contact their state or local TB control office or the TB Centers of Excellence for Training, Education, and Medical Consultation.

No. All patients should receive flat rifapentine dosing of 1200 mg. The 4-month rifapentine-moxifloxacin regimen should not be used in persons with weight less than 40 kg.

The clinical trial did not detect concerning health risks related to use of moxifloxacin. There was no clinical evidence of increased risk of cardiotoxicity, although electrocardiographic monitoring was not a required component of the study. However, careful safety monitoring should be incorporated into clinical use of the 4-month rifapentine-moxifloxacin regimen given the difficulty of detecting robust signals of rare events in clinical trials. For further information, refer to Supplementary Appendix Supplement to: Dorman SE, Nahid P, Kurbatova E, et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis.

Only moxifloxacin was evaluated in the clinical trial as part of 4-month rifapentine- moxifloxacin regimen. Currently, there are no data regarding fluoroquinolone substitution in the 4-month rifapentine-moxifloxacin regimen, so CDC does not recommend substituting other fluoroquinolones for moxifloxacin in this regimen.

CDC and the National Tuberculosis Controllers Association (NTCA) work with the U.S. Food and Drug Administration (FDA) to monitor drug shortages. Information on current drug shortages is available from FDA. TB programs can report shortages using a form available on the National Tuberculosis Controllers Association website. Shortages can also be reported to FDA directly by e-mail (drugshortages@fda.hhs.gov) or telephone (240) 402-7770.