Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection

Abstract

Rationale: Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less.

Objectives: To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens.

Methods: Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment.

Measurements and main results: M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide.

Conclusions: In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.

Figures

Figure 1.

Scheme of the treatment efficacy experiment. D0 = initiation of treatment; rBCG = immunization with rBCG30 12 weeks before treatment (W−12); TB = low-dose challenge with Mycobacterium tuberculosis 6 weeks before treatment (W−6). End points were lung colony-forming unit counts at Week 2 (W2), Week 4 (W4), Week 6 (W6), and Week 8 (W8) of treatment and culture-positive relapse rates assessed 3 months after completing treatment for 4, 6, and 8 weeks.

Figure 2.

M. tuberculosis CFU counts in (A) lungs and (B) spleens after low-dose aerosol infection with M. tuberculosis in nonimmunized, Bacille Calmette-Guérin (BCG) Tice-immunized, and rBCG30-immunized mice in lungs. Diamonds = nonimmunized; squares = Tice BCG-immunized; triangles = rBCG30-immunized.

Figure 2.

M. tuberculosis CFU counts in (A) lungs and (B) spleens after low-dose aerosol infection with M. tuberculosis in nonimmunized, Bacille Calmette-Guérin (BCG) Tice-immunized, and rBCG30-immunized mice in lungs. Diamonds = nonimmunized; squares = Tice BCG-immunized; triangles = rBCG30-immunized.