Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis – United States, 2022

On May 5, 2021, CDC’s Tuberculosis Trials Consortium and the National Institutes of Health (NIH)–sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB and provides implementation considerations for this treatment regimen.

Background

Standard treatment for culture-positive TB requires ≥6 months of antibiotics (2). Shorter, effective TB treatments could enable more rapid cure and improve patient quality of life. Sponsored by CDC and conducted in collaboration with the NIH-sponsored ACTG, Study 31/A5349 (https://clinicaltrials.gov/ct2/show/NCT02410772external icon) was an international, open label, phase 3 noninferiority clinical trial that randomized 2,516 participants at 34 clinical sites in 13 countries. The trial confirmed that a 4-month daily treatment regimen containing high-dose RPT and MOX, as well as INH and PZA, is as effective as (noninferior to) the standard daily 6-month regimen in curing drug-susceptible TB (1).

Methods

CDC developed this interim guidance, based on evidence from Study 31/A5349, preclinical and animal evidence, previous clinical trial findings, pharmacokinetic and pharmacodynamic modeling (1,3–6), and CDC expert opinion regarding considerations for implementation of the new 4-month daily treatment regimen in the United States. A systematic review framework was not applicable because this regimen has not been compared in other studies. A CDC writing group reviewed the evidence and drafted guidance for comments from external TB subject matter experts and for presentation for public comment. Comments were addressed by developing content to be published at https://www.cdc.gov/tb/topic/treatment/tbdisease.htm.

Rationale and Evidence

Clinical practice guidelines for treatment of drug-susceptible TB in the United States were published in 2016 (2). This interim guidance updates 2016 guidelines by recommending and providing implementation considerations for a novel 4-month daily treatment regimen, based on high-dose daily RPT with MOX, INH, and PZA (1) as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB. The regimen is intended for administration in settings where mycobacterial cultures, molecular and phenotypic drug susceptibility testing (DST), radiographic studies and other diagnostic tools, infrastructure for adverse event monitoring, patient-centered clinical care, and coordination with public health for case management are available.

Recommendation for Use of the 4-month Rifapentine-Moxifloxacin Regimen

CDC recommends the 4-month RPT-MOX regimen for treating patients aged ≥12 years with body weight ≥40 kg with pulmonary TB caused by organisms that are not known or suspected to be drug-resistant and who have no contraindications to this regimen. The 4-month daily treatment regimen consists of an intensive phase composed of 8 weeks of daily treatment with RPT, MOX, INH, and PZA, followed by a continuation phase of 9 weeks of daily treatment with RPT, MOX, and INH (Table 1). Anti-TB drugs should be administered once daily with food, 7 days per week, for a total of 119 treatment doses; similar to the standard 6-month regimen, at least 5 of 7 weekly doses should be administered under direct observation (2). The 4-month regimen can be used in persons with an HIV infection who have CD4 counts ≥100 cells/μL and are receiving or planning to initiate efavirenz as part of their antiretroviral therapy (ART) regimen in the absence of any other known drug-drug interactions between antituberculosis and antiretroviral medications.

Considerations. The 4-month daily treatment regimen was not studied in, and CDC does not recommend this regimen for, the following patient groups: body weight <40 kg; age <12 years; pregnant or breastfeeding; most types of suspected or documented extrapulmonary TB infection (see exceptions below); history of prolonged QT syndrome or concurrent use of one or more QT-prolonging medications (in addition to MOX); patients receiving medications with known clinically relevant drug-drug interactions with RPT, MOX, INH, or PZA; or patients infected with a baseline Mycobacterium tuberculosis isolate known or suspected to be resistant to INH, PZA, rifampin (RIF), or fluoroquinolones.

The 4-month daily treatment regimen was not studied in, and CDC recommends that clinical consultation be obtained to determine if this regimen is an acceptable treatment option for, patient groups with increased risk for M. tuberculosis resistance to any drug in the regimen, including persons who received >5 doses of treatment directed against TB in the preceding 6 months, who received >5 doses of latent tuberculosis infection treatment in the preceding 6 months, or who received >5 doses of treatment with any one or more of the following drugs for any reason (e.g., urinary tract infection or pneumonia) in the preceding 30 days: INH, RIF, rifabutin, RPT, PZA, or any fluoroquinolone. Other patient groups for whom clinical consultation is recommended include those with serum or plasma alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal or total bilirubin >2.5 times the upper limit of normal, or with preexisting advanced liver disease; renal insufficiency or end-stage renal disease, or with serum or plasma creatinine level >2 times the upper limit of normal; plasma potassium level <3.5 mEq/L; who have types of extrapulmonary TB that are likely to be paucibacillary, not pose a substantial risk for death or disability, and not require prolonged treatment (i.e., pleural or lymph node TB); or for whom a specimen was unable to be submitted for any M. tuberculosis resistance testing before initiating treatment.

The 4-month daily treatment regimen was not studied in patients with a negative sputum culture, but who in the judgment of the clinician likely represent paucibacillary or low mycobacterial burden pulmonary TB disease. A 4-month regimen for smear-negative, culture-negative, noncavitary TB exists in the 2016 CDC guidelines (2), and CDC recommends that the 4-month RPT-MOX regimen may also be used unless patients are in one of the nonrecommended patient groups listed above.

Baseline and follow-up evaluations. Microbiology, laboratory, and clinical assessments are recommended before starting and during treatment with the 4-month daily regimen (Table 2). A respiratory specimen for acid-fast bacilli smear microscopy and culture should be obtained at baseline and at monthly intervals during treatment until two consecutive specimens are negative on culture. Baseline molecular drug-susceptibility testing for rapid identification of mutations associated with resistance to at least INH, PZA, RIF, and fluoroquinolones is advisable. Phenotypic DST should follow with a panel to include at least RIF (as surrogate for RPT), INH, PZA, and MOX as the preferred fluoroquinolone. CDC’s Tuberculosis Elimination Laboratory (TBLab@cdc.gov) can assist identifying laboratories to perform this testing for TB programs that intend to implement the 4-month daily treatment regimen.

Duration and definition of completion of therapy. The 4-month daily treatment regimen is considered complete based on the total number of doses taken (119). Recommended treatment duration is independent of any cavitation on baseline chest radiograph. Intensive phase doses (56) should be administered within 70 days from treatment initiation, and continuation phase doses (63) should be administered within 84 days from intensive phase completion, so that the regimen is completed within 5 months. If these targets are not met, the patient should be considered to have interrupted therapy and be managed as described in TB treatment guidelines (2). Confirmation of continued susceptibility to all drugs in the 4-month daily treatment regimen is required before restarting this regimen.

Poor treatment response and treatment failure or discontinuation. Patients with any positive culture at completion of 2 months of therapy, with or without ongoing symptoms, should be carefully evaluated to identify the cause of delayed response (2). Mycobacterial isolates obtained after 2 months should be sent to a reference laboratory for DST. If drug resistance to INH, RIF, PZA, or any fluoroquinolone is detected by any testing method (i.e., phenotypic or molecular) in baseline or follow-up specimens, the 4-month regimen should be stopped, and patients should be started on an appropriate treatment regimen that accounts for the identified drug-resistance pattern (7). Patients who become pregnant while on treatment should receive clinical consultation regarding whether to stop the 4-month daily treatment regimen and be treated with an alternative regimen that is considered safer for pregnant persons (2).

Discussion

The 4-month RPT-MOX regimen is a treatment option for patients aged ≥12 years with drug-susceptible pulmonary TB. Additional studies are needed to understand the pharmacokinetics and efficacy of the 4-month daily treatment regimen in patients for whom this regimen is not currently recommended, including young children, persons who are pregnant, patients with extrapulmonary TB, and patients with an HIV infection who are taking non-efavirenz–based antiretroviral therapy. Clinicians should carefully review a patient’s clinical history, concurrent medications, social determinants of health, and risk factors for adverse drug reactions when making the decision to use this regimen.

Although neither RPT nor MOX has a labeling indication for a 4-month treatment of TB disease in the United States, RPT is recommended in U.S. guidelines as part of a preferred treatment regimen to prevent TB in persons with latent tuberculosis infection (8), and MOX is recommended as a drug for TB treatment (2). Available formulations of RPT, a key drug in the 4-month regimen, and of RIF, a key drug in standard 6-month TB treatment, have recently been found to contain low levels of nitrosamines.* More information about nitrosamines in these and other pharmaceuticals is available from the Food and Drug Administration (https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medicationsexternal icon).

Health care providers seeking clinical consultation should contact their state, tribal, local, and territorial health department TB programs (https://www.tbcontrollers.org/community/statecityterritory/external icon) or the CDC-funded TB Centers of Excellence for Training, Education, and Medical Consultation (https://www.cdc.gov/tb/education/tb_coe/). CDC has information for health care providers and patients at https://www.cdc.gov/tb/topic/treatment/tbdisease.htm. CDC and other organizations will monitor the implementation of this interim guidance and update TB clinical guidelines as necessary.