HIV – associated tuberculous meningitis: finding better diagnosis and treatment

Fiona Cresswell is a medical doctor with a specialisation in HIV and sexual health and has been based in Uganda since 2016 working with the meningitis research team at the Infectious Diseases Institute (IDI), Kampala and the Clinical Research Department at London School of Hygiene and Tropical Medicine. Her PhD research focused on finding better diagnostics and treatments for HIV-associated tuberculous meningitis, the most severe form of TB, which carries a greater than 50% case fatality in Uganda. Fiona was supervised by Professor Alison Elliott during her Wellcome-funded PhD, which she completed in March 2021. Her goal as a researcher is to improve the outcomes of advanced HIV disease through better management of opportunistic infections and HIV infection in African settings. “I feel this is an important area to tackle. Despite the incredible rollout of antiretroviral therapy, HIV/AIDS is still being the leading cause of death in some countries. Brain infections (due to a fungus called Cryptococcus) and TB being the two biggest killers of people living with HIV,” noted Dr. Fiona Cresswell.

In collaboration with University of Minnesota and University of California San Francisco they conducted a prospective observational study in adults presenting with suspected meningitis to Kiruddu National Referral Hospital and Mbarara Regional Referral Hospital to examine the diagnostic performance of both high- and low-technology novel assays on cerebrospinal fluid (CSF, the fluid that bathes the brain and spinal cord). This included two nucleic acid amplification approaches (Xpert MTB/Rif Ultra assay and metagenomic next generation sequencing) and three point of care tests (Alere TB-LAM, FujiLAM and lactate). They found that the Xpert Ultra approach is the best CSF test for TB meningitis, although it misses about 1:4 cases, so whilst it should be the first test used, it cannot rule out TB meningitis and should not be the last test in patients with a high index of suspicion. On the other hand, the next generation sequencing approach, performed less well than the Xpert Ultra but yielded lots of interesting insights into the other pathogens causing meningitis in this population (including measles and varicella zoster virus, and toxoplasma gondii) and a host CSF ribonucleic acid (RNA) signature is predictive of TB meningitis. In terms of bedside diagnostic tests, the FujiLAM assay was sensitive and specific enough on CSF to have diagnostic value and a high CSF lactate (>5.5 IU) is also highly suggestive of TB meningitis. Unfortunately, Alere TB-LAM which is the most available point of care test locally performs very poorly on CSF.

The team also conducted a phase II clinical trial of high dose oral and intravenous rifampicin for TB meningitis as standard dose rifampicin penetrates poorly into CSF. They found that it was safe to give considerably higher doses of rifampicin (3.5-fold dose increase) in adults with advanced HIV infection. The higher doses also gave significantly better rifampicin pharmacokinetic exposures in the blood and CSF. Along with colleagues in Indonesia and South Africa they are now conducting a bigger study, including 500 people, to see whether high dose rifampicin can reduce death and disability from TB meningitis. ‘I look forward to sharing the results in 2024.’added Dr. Cresswell.

Over the last 3 years Fiona Cresswell and the meningitis research team have engaged with the community, research participants, their families, and other key stakeholders about HIV-associated meningitis. They wanted to dispel myths that meningitis is a form of witchcraft and that lumbar puncture (a needle is inserted between two bones in the spine (vertebrae) to remove a sample of cerebrospinal fluid) is a dangerous procedure, both of which result in people presenting to hospital very late, when the research interventions may be ineffective. The team gave research participants an opportunity to share their experiences of surviving meningitis and participating in clinical research through TV and radio in Uganda. The team also interacted and exchanged knowledge with the healthcare worker community in over 30 district hospitals and clinics to understand and overcome barriers in the management of meningitis.

Conducting her PhD research in Uganda, Dr. Cresswell says it has been a hugely important period of both her personal and professional growth. She has loved working with colleagues of many nationalities with diverse skill sets. ‘I now realise what an enormous collective effort goes into a single study, from acquiring funding, study design, navigating regulatory processes, initial lift off, completing the study to a high standard, data management and analysis, through to publication’ she noted. It is therefore absolutely crucial to maximise the research outputs of every individual study though nested sub-studies and storage of samples for future research. Dr. Cresswell is keen to continue her academic journey and hopes that the lessons learned during her PhD, and the trainings she received through MUII, will stand her in good stead to continue working internationally in the field of HIV/AIDS, brain infections and global health.