INTENSE-TBM PROJECT
BACKGROUND
Tuberculosis (TB) remains a global health problem. In 2017, an estimated 10 million new cases and 1.6 million deaths occurred due to tuberculosis [1]. The most lethal and disabling form of TB is tuberculous meningitis (TBM), with an estimated 100,000 new cases occurring per year, representing around 6% of extra pulmonary TB cases [2, 3]. HIV prevalence in patients with tuberculosis is 36% in the African region and up to 60% in South Africa [1]. TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-positive individuals with drug resistant TB strains [1, 3], with death occurring most frequently in the first 2 weeks after diagnosis.
Amongst TBM survivors, 50% are disabled due to neurological sequelae [4, 5].
TBM deaths and neurological sequelae are in large part due to stroke and cerebral vasculitis. A clinically focal neurological deficit in TBM can occur in up to 20% of patients whereas infarctions are revealed in 13–35% of Computerized Tomography (CT) scans and up to 57% in Magnetic Resonance Imaging (MRI) scans. In autopsy 22–56% of patients are shown to have cerebral infarction [6]. The reversibility and long-term impact of these neurological complications remain unknown.
LIMITATION OF CURRENT TREATMENT
Anti-TB treatment before the onset of coma is the strongest predictor of TBM survival [2]. The treatment of drug-susceptible TBM is based on regimens used against pulmonary tuberculosis, which probably result in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood–brain barrier penetration. The optimal combination, dose, frequency and duration of anti-TB drugs have yet to be determined. The current WHO recommended first line treatment for TBM includes a four-drug regimen for two months orally (rifampicin 10 mg/kg/d, isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d, streptomycin or ethambutol 20 mg/kg/d plus corticosteroids) then rifampicin and isoniazid for 7-10 months [9].
This treatment has remained unchanged for decades despite its relatively poor efficacy.
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New anti-TB drugs are now becoming available but are not expected to contribute to the management of TBM. It is unfortunate that the three drugs which are the closest to wide clinical use – bedaquiline, delamanid and pretomanid – are highly protein-bound and thus unlikely to have free penetration into cerebrospinal fluid. The risk of increased side effects limits the potential for increasing their dose [10]. The literature therefore justifies the need for a new and improved treatment [11, 12].
The management of TBM in HIV-infected people is even more challenging given the severe prognosis and frequent complications related to the Central Nervous System Immune Reconstitution Inflammatory Syndrome (IRIS) and drug-drug interactions between rifampicin and antiretroviral drugs [13].
HYPOTHESIS AND POTENTIALS BENEFIT OF INTERVENTIONS
INTENSE-TBM hypothesizes that a new treatment strategy including high dose rifampicin and linezolid, in addition to standard dose of isoniazid, pyrazinamide, and ethambutol, herein referred to as the “INTENSE-TBM regimen”, will reduce mortality in TBM HIV-infected and uninfected patients. Furthermore, it is hypothesized that addition of aspirin, a “host-directed therapy” could also reduce mortality and limit neurological complications and disability. This will be tested in a randomized controlled factorial clinical trial comparing an intensified TB regimen using generic TB drugs (high dose rifampicin, isoniazid, linezolid, pyrazinamide, ethambutol) – with or without the addition of aspirin – with the WHO standard TBM treatment. In addition, INTENSE-TBM will assess the effect of the interventions on the incidence of IRIS after ART initiation with DTG, and the pharmacological interactions between high dose rifampicin and DTG among HIV-TBM co-infected patients.
[1] World Health Organization. Global tuberculosis report 2018. https://www.who.int/tb/publications/global_report/en/.
[2] Wilkinson RJ, Rohlwink U, Misra UK, van Crevel R, Mai NTH, Dooley KE, et al. Tuberculous meningitis. Nat Rev Neurol. 2017;13:581-98.
[3] Gomes T, Reis-Santos B, Bertolde A, Johnson JL, Riley LW, Maciel EL. Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model. BMC Infect Dis. 2014;14:9.
[4] Tenforde MW, Mokomane M, Leeme TB, Tlhako N, Tsholo K, Chebani T, et al. Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study. Lancet Infect Dis. 2019;19:740-9.
[5] Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculous meningitis in HIV-infected and non-infected patients: comparison of cerebrospinal fluid findings. Int J Tuberc Lung Dis. 2009;13:269-71.
[6] Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculous meningitis in HIV-infected patients: drug susceptibility and clinical outcome. AIDS. 2007;21:373-4.
[7] Misra UK, Kalita J, Maurya PK. Stroke in tuberculous meningitis. J Neurol Sci. 2011;303:22-30.
[8] Lai RPJ, Meintjes G, Wilkinson RJ. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin Immunopathol. 2016;38:185-98.
[9] World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care (2017 update). 2017.
[10] Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013;12:999-1010.
[11] Donald PR. Chemotherapy for Tuberculous Meningitis. N Engl J Med. 2016;374:179-81.
[12] Global Alliance for TB drug development. Handbook of antituberculosis agents: introduction. In Edinburgh; 2008.
OBJECTIVES
Reduction of TBM mortality and neurological impairment
The primary objective of INTENSE-TBM is to reduce the mortality and neurological complications and sequellae of TBM in adults and adolescents with or without HIV co-infection in sub-Saharan Africa (SSA). This is investigated via a clinical trial in four SSA countries to evaluate the efficacy of an intensified TB treatment regimen – the “INTENSE-TBM regimen “ – including high-dose rifampicin and linezolid (repurposed drug), with the addition of aspirin (not as yet used for TBM). This intensified TB treatment is expected to reduce mortality by at least 30% and minimize disability.
Management of TBM-HIV coinfection
The objective of the INTENSE-TBM “co-infection” study is to improve the management of TBM-HIV coinfection by implementing a prospective study nested within the clinical trial to assess the incidence and aetiology of severe Immune Reconstitution Inflammatory Syndrome (IRIS) after anti-retroviral treatment initiation with dolutegravir (DTG). Diagnostic and management procedures are developed for safe and effective management of patients with HIV infection and improvement of the understanding of IRIS in TBM-HIV coinfection.
Microbiological tests
The INTENSE-TBM microbiological study undertakes Mycobacterium tuberculosis microbiological diagnosis and sensitivity to first line drugs in each clinical site or country. M tuberculosis strains are also evaluated for second line drugs and linezolid sensitivity, and in vitro for synergy studies.
PK-PD study
The INTENSE-TBM PK-PD study assesses the pharmacological interactions between high dose rifampicin and the other anti-TB drugs and between high dose rifampicin and dolutegravir (DTG) in HIV-infected patients by drawing 24h curves of plasma rifampicin, linezolid and (for HIV positive individuals) DTG concentrations. It is performed in 40 voluntary adult patients: 20 (10 HIV-positive, 10 HIV-negative) in the WHO TBM treatment group and 20 (10 HIV-positive, 10 HIV-negative) in the Intensified TBM treatment group.
Disability in TBM
The overall objective of the INTENSE-TBM neurological study is to provide a comprehensive assessment of TBM-related disability that is used to compare the overall impact of the different trial intervention strategies on participants’ lives. The following components of TBM-related disability are considered: neurological disability, cognitive impairment, functional impairment and functional and social participation limitations. Neuropathy and depressive symptoms are also assessed.
Capacity building
INTENSE-TBM aims to strengthen the potential of the participating clinical sites to carry out clinical research both in terms of practices (Good Clinical Practices & Infection control) and know-how, but also infrastructure. These life-long skills and developments will have long standing impact upon standards of care in hospitals throughout sub-Saharan Africa and will facilitate further research beyond INTENSE-TBM.