A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial) (preprint)

ABSTRACT Background Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results 52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% ‘possible’ or 25% ‘probable’. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) ( p=0 . 083 ). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 ( p=0 . 04 ), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms. Conclusions High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit. SUMMARY In this phase 2a randomised control trial we demonstrate that high-doserifampicin and adjunctive linezolid is safe in adult HIV-associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with aspirin, in relation to benefit on morbidity and mortality.

The effect of the COVID-19 lockdown on mental health care use in South Africa: an interrupted time series analysis (preprint)

AimsIn March 2020, South Africa introduced a lockdown in response to the COVID-19 pandemic, entailing the suspension of all non-essential activities and a complete ban of tobacco and alcohol sales. We studied the effect of the lockdown on mental health care utilisation rates in private-sector care in South Africa. MethodsWe did an interrupted time series analysis using insurance claims from January 1, 2017, to June 1, 2020 of beneficiaries 18 years or older from a large private sector medical aid scheme. We calculated weekly outpatient consultation and hospital admission rates for organic mental disorders, substance use disorders, serious mental disorders, depression, anxiety, other mental disorders, any mental disorder, and alcohol withdrawal syndrome. We calculated adjusted odds ratios (OR) for the effect of the lockdown on weekly outpatient consultation and hospital admission rates and the weekly change in rates during the lockdown until June 1, 2020. Results710,367 persons were followed up for a median of 153 weeks. Hospital admission rates (OR 0.38; 95% CI 0.33-0.44) and outpatient consultation rates (OR 0.74; 95% CI 0.63-0.87) for any mental disorder decreased substantially after the lockdown and did not recover to pre-lockdown levels until June 1, 2020. Health care utilisation rates for alcohol withdrawal syndrome doubled after the introduction of the lockdown, but the statistical uncertainty around the estimates was large (OR 2.24; 95% CI 0.69-7.24). ConclusionsReduced mental health care contact rates during the COVID-19 lockdown likely reflect a substantial unmet need for mental health services with potential long-term consequences for mental health patients and their families. Steps to ensure access and continuity of mental health services during future lockdowns should be considered.