Drug Resistance

DRAMATIC Phase 2 Duration Randomized MDR-TB Treatment Trial

  • Investigator: C. Robert Horsburgh
  • Funding Source: National Institute of Allergy and Infectious Diseases

Multidrug-resistant tuberculosis (MDR-TB) was estimated to occur in 600,000 people in 2017. The roll-out of the GeneXpert™ test has generated a substantial increase in the demand for MDR-TB treatment. However, current MDR-TB treatment regimens take 9 months or longer to complete and have substantial toxicity. Therefore, a shorter, less toxic treatment regimen is needed. We have developed an innovative Phase 2 study design (“duration-randomization”) to identify the shortest effective treatment duration. In this design, participants are randomized to four durations of treatment from the shortest to the longest likely effective duration. The results are then analyzed together to determine the optimal treatment duration. In the proposed multicenter, randomized, partially blinded, four-arm, phase 2 DRAMATIC Trial (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical Trial) we will examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks. Aim 1: To identify the optimal duration of an experimental MDR-TB treatment regimen consistent with a successful treatment outcome. Aim 2: To describe the relationship between baseline prognostic risk strata and successful treatment outcome. Aim 3: To establish that the rRNA synthesis ratio, a novel biologic marker based on M. tb precursor rRNA, is associated with relapse at the individual-level across the range of durations studied in the trial. Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of TB control programs to treat the growing number of patients.


Impact of delayed second‐line drug resistance testing on clinical outcomes and genetic mutations in rifampin‐resistant tuberculosis

  • Investigator: Tara Bouton
  • Funding Source: ASTMH/Burroughs-Wellcome Fund

Impact of HIV on the frequency and evolution of compensatory mutations in drug resistant tuberculosis

  • Investigator: Tara Bouton
  • Funding Source: Providence/Boston Center for Aids Research (CFAR)

Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT)

  • Investigator: C. Robert Horsburgh
  • Funding Source: National Institute of Allergy and Infectious Diseases

Tuberculosis (TB) is a leading causes of global mortality. Nearly one-third of the world’s population is infected with M. tuberculosis, an estimated 10.4 million new cases of TB develop annually, and 1.4 million persons die from the disease. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB has exacerbated the threat to public health and created a renewed sense of urgency to control the disease. Treatment of MDR-TB leads to emergence of additional drug resistance in 6-20% of patients on treatment. We propose to investigate the causes of emergence of mycobacterial drug resistance in an observational cohort study, the Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT) Study. In the PREEMPT study, we will enroll 400 patients with MDR-TB in India and Brazil over a 24-month period and follow them prospectively for 3 years. The proposal has the following Specific Aims: Aim 1: To determine whether low serum antimycobacterial drug concentrations contribute to the emergence of drug resistance in MDR TB patients, and whether HIV seropositivity is a risk factor for low serum drug concentrations and/or the emergence of resistance. Aim 2: To determine the contribution of increased DNA mutation (caused either by an intrinsic property of the M. tuberculosis strain or by FQ treatment) to clinical emergence of drug resistance in patient isolates. Aim 3: To determine whether mutations responsible for drug resistance can be detected early during treatment, when an intervention to prevent XDR-TB might be possible.