A randomised trial of clinical outcomes for patients with drug-resistant tuberculous meningitis (TBM) underscores that new diagnostic tools and treatments for the disease are critically needed, a study led by A Dorothee Heemskerk at the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam and the Nuffield Department of Medicine, University of Oxford has found.
The study found early identification of drug-resistance and intensified treatment to be pivotal in improving survival chances of people with the disease, the most fatal form of TB, that also is among the most difficult to detect. Even with treatment, the disease kills about a third of patients who have it the authors note.
Accounting for only about 5% of all cases of tuberculosis outside the lungs, tuberculous meningitis is most common in countries with limited health resources, and in children under four years old, but has risen among adults with the spread of HIV. Still no optimal treatment for drug-resistant tuberculous meningitis has been identified, or investigated.
Researchers randomised patients from two hospitals in Ho Chi Minh, Vietnam to standard or intensified treatment, that depended on the drug resistance identified in cerebrospinal fluid. They found significantly higher survival rates among patients whose disease was resistant to isoniazid who were given additional doses of rifampicin, particularly among those who were not also HIV-infected.
The finding is important, researchers write, because tuberculosis that is resistant to treatment with isoniazid is increasing, and associated with poorer outcomes.
Identifying the drug resistance early is essential they note, but while the World Health Organisation recommends the Xpert MTB test for initial testing of cerebrospinal fluid for patients with tuberculous meningitis, the test does not currently detect isoniazid resistance.
Abstract
Background: Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment.
Methods: We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression.
Results: Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00–11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11–2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15–.76], P = .01) in INH-R TBM.
Conclusions: Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored.
Authors
A Dorothee Heemskerk, Mai Thi Hoang Nguyen, Ha Thi Minh Dang, Chau Van Vinh Nguyen, Lan Huu Nguyen, Thu Dang Anh Do, Thuong Thuy Thuong Nguyen, Thao Thi Phuong Le, Bang Duc Nguyen, Maxine Caws, Guy E Thwaites
[link url="http://sciencespeaksblog.org/2017/06/26/study-early-intensified-treatment-boosted-drug-resistant-tb-meningitis-survival-but-detection-remains-challenged/"]ScienceSpeaks material[/link]
[link url="https://academic.oup.com/cid/article/65/1/20/3796242/Clinical-Outcomes-of-Patients-With-Drug-Resistant"]Clinical Infectious Diseases abstract[/link]