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EARLY BACTERICIDAL ACTIVITY OF HIGH-DOSE ISONIAZID AGAINST MULTIDRUG-RESISTANT TB
Kelly E. Dooley1, Sachiko Miyahara2, Florian von Groote-Bidlingmaier3, Xin Sun2, Richard Hafner4, Susan L. Rosenkranz5, Eric Nuermberger1, Laura E. Moran6, Kathleen Donahue5, Susan Swindells7, Andreas H. Diacon3
1Johns Hopkins University School of Medicine, Baltimore, MD,2Harvard University, Boston, MA, USA,3TASK Applied Science, Cape Town, South Africa,4DAIDS, NIAID, Bethesda, MD, USA,5Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA,6Social & Scientific Systems, Silver Spring, MD, USA,7University of Nebraska Medical Center, Omaha, NE, USA
High-dose isoniazid (INH) may be useful in treating multidrug-resistant tuberculosis (MDR-TB), particularly when INH resistance is mediated by inhA mutations. Although the World Health Organization (WHO) recommends 'high-dose' INH as part of the new shorter MDR-TB regimen, the optimal dose and its efficacy are not established.
AIDS Clinical Trials Group (ACTG) A5312 is a Phase 2A randomized, open-label trial in which individuals with smear-positive pulmonary MDR-TB with INH resistance mediated by an inhA mutation (Group 1) were randomized to receive INH doses of 5, 10 or 15 mg/kg daily for 7 days. Controls with drug-sensitive TB (Group 2) received the standard INH dose of 5 mg/kg/day. Sputum cultures were collected daily, beginning at baseline. The early bactericidal activity of INH, estimated as the average daily change in log10 colony forming units (CFU) on solid media (EBACFU0-7) or average daily change in time to positivity (TTP) in hours on liquid media (EBATTP0-7) over 7 days of treatment was estimated using nonlinear mixed effects models. Safety data were collected from study entry through Day 21.
59 participants (43 in Group 1, 16 in Group 2) were enrolled, all in South Africa. The majority (73%) were men, median age was 32 years, 20% were HIV co-infected, and 88% had cavitary lung disease. 58/59 (98%) completed study treatment (one withdrew consent in the 15 mg/kg arm). Eight participants had 9 grade 3 (and no grade 4) adverse events (fever, pain, dyspnea, pneumothorax (2), anemia (4)), all unrelated or unlikely to be related to study drugs. Mean EBACFU0-7 in Group 1 at doses of 5, 10 and 15 mg/kg was 0.07, 0.17 and 0.22 log10CFU/mL/day, respectively; and in Group 2 was 0.16 log10CFU/mL/day (Figure). Mean EBATTP0-7 in Group 1 (5, 10, 15 mg/kg doses) was 3, 7, 11 hours/day, and in Group 2 was 10 hours/day (Figure). Median minimal inhibitory concentrations in 90 patients screened for study participation were 1 mg/L for inhA-mutated and 0.2 mg/L for drug-sensitive strains.
INH had substantial EBA against Mycobacterium tuberculosis strains with inhA mutations among patients with MDR-TB, provided it was dosed at 10-15 mg/kg, supporting WHO recommendations for high-dose INH in this population. Activity at these doses was similar to the standard 5 mg/kg dose in drug-sensitive TB. Longer-term tolerability, plus efficacy of high-dose INH against strains with katG mutations require further study.