Dataset Information

Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial.

ABSTRACT:

Rationale

High-dose isoniazid is recommended in short-course regimens for multidrug-resistant TB (MDR-TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown.

Objective

Define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations.

Methods

AIDS Clinical Trials Group A5312 is a Phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10 or 15 mg/kg daily for 7 days (inhA group), and controls with drug-sensitive TB received standard dose (5 mg/kg/day). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity of isoniazid was estimated as the average daily change in log10 colony forming units on solid media (EBACFU0-7) or as time to positivity in liquid media in hours (EBATTP0-7) using nonlinear mixed effects models.

Measurements and main results

Fifty-nine participants, 88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive and 41 with isoniazid mono-resistant or MDR TB, were enrolled at one site in South Africa. Mean EBACFU0-7 at doses of 5, 10 and 15 mg/kg in the inhA group was 0.07, 0.17 and 0.22 log10CFU/mL/day, respectively, and 0.16 log10CFU/mL/day in controls. EBATTP0-7 patterns were similar. There were no drug-related Grade >3 adverse events.

Conclusions

Isoniazid 10-15 mg/kg daily had similar activity against TB strains with inhA mutations as 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.

SUBMITTER: Dooley KE

PROVIDER: S-EPMC7258626 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:Isoniazid-resistant, rifampin susceptible tuberculosis (INHR-TB) is the most common form of drug resistant TB globally. Treatment of INHR-TB with standard first-line therapy is associated with high rates of multidrug resistant TB (MDR-TB). We modelled the potential impact of INHR-TB detection and appropriate treatment on MDR-TB prevalence. METHODS:A decision analysis model was developed to compare three different strategies for the detection of TB (AFB smear, Xpert MTB/RIF, and Line-Probe Assays (LPA)), combined with appropriate treatment. The population evaluated were patients with a globally representative prevalence of newly diagnosed, drug-susceptible (88.6%), isoniazid-resistant (7.3%), and multidrug resistant (4.1%) pulmonary TB. Our primary outcome was the proportion of patients with MDR-TB after initial attempt at diagnosis and treatment within a 2-year period. Secondary outcomes were the proportion of i) individuals with detected TB who acquired MDR-TB ii) individuals who died after initial attempt at diagnosis and treatment. RESULTS:After initial attempt at diagnosis and treatment, LPA combined with appropriate INHR-TB therapy resulted in a lower proportion of prevalent MDR-TB (1.61%; 95% Uncertainty Range (UR: 2.5th and 97.5th percentiles generated from 10 000 Monte Carlo simulation trials) 1.61-1.65), when compared to Xpert (1.84%; 95% UR 1.82-1.85) and AFB smear (3.21%; 95% UR 3.19-3.26). LPA also resulted in fewer cases of acquired MDR-TB in those with detected TB (0.35%; 95% UR 0.34-0.35), when compared to Xpert (0.67%; 95% UR 0.65-0.67) and AFB smear (0.68%; 95% UR 0.67-0.69). The majority of acquired MDR-TB arose from the treatment of INHR-TB in all strategies. Xpert-based strategies resulted in a lower proportion of death (2.89%; 95% UR 2.87-2.90) compared to LPA (2.93%; 95% UR 2.91-2.94) and AFB smear (3.21%; 95% UR 3.19-3.23). CONCLUSION:Accurate diagnosis and tailored treatment of INHR-TB with LPA led to an almost 50% relative decrease in acquired MDR-TB when compared with an Xpert MTB/RIF strategy. Continued reliance on diagnostic and treatment protocols that ignore INHR-TB will likely result in further generation of MDR-TB.