Cryptococcus
Cryptococcus is the organism that can cause crytococcal meningitis, a particular threat to people with HIV in South East Asia and sub-Saharan Africa.

Image credit: Dr Justin Beardsley

The definition of success

Tom Calver

Oxford University scientists carry out clinical trials for a range of medical conditions every year. The hope with each one is that it could lead to a viable treatment to cure or alleviate that condition. It is easy, therefore, to think that a successful trial is one that produces such a treatment, while any other result is a failure. Not so, as a recent study from Oxford's researchers in South East Asia shows.

Cryptococcal meningitis is a fungal infection of the brain, which primarily affects people living with HIV. The disease is estimated to cause over 600,000 deaths each year, with the majority of cases occurring in sub-Saharan Africa and Asia.

Dexamethasone is already being used by some doctors as a treatment for cryptococcal meningitis. They are doing that with the best of intentions, believing it will benefit their patients. However, our trial has shown that that is in fact worse than standard treatment.

Dr Justin Beardsley, Oxford University Clinical Research Unit 

Recent research has shown the best way to use the available anti-fungal therapies, but even with optimal treatment, between 3 and 7 out of every ten people affected will die in areas where the disease is most prevalent. The Oxford team therefore studied what happened when an extra drug was given alongside anti-fungal treatments.

Dr Justin Beardsley led the study. He explains: 'Given the relatively poor success rate for existing anti-fungals and the fact that there are no new anti-fungal drugs in the pipeline we decided to trial an adjunctive treatment to reduce HIV-associated cryptococcal meningitis' unacceptably high rates of death and disability. An adjunctive treatment is something given to patients to improve the effectiveness of their primary treatment – in this case, the anti-fungal drugs.'

The team selected a steroid called dexamethasone as the adjunctive agent. It had shown promise in observational studies and lab-based animal models and has proven efficacy in some other forms of meningitis. It is also a well-understood drug which hadn't been associated with adverse events when used to treat infectious diseases. Furthermore, despite a lack of evidence, it is already frequently used to treat cryptococcal meningitis.

For the trial, volunteers with cryptococcal meningitis were given either dexamethasone or placebo alongside the standard antifungal therapy. The volunteer patients were in Vietnam, Thailand, Indonesia, Laos, Uganda and Malawi. Each was carefully monitored to see the microbiological and clinical responses to treatment.

The trial was stopped, because the team recognised that outcomes were worse for patients receiving dexamethasone: while they were no more likely to die than those receiving placebo, their infection cleared more slowly, they had more treatment complications and they were less likely to recover without disability.

So is this a failure?

The clinical trial has ended but our work is ongoing. 

Dr Justin Beardsley, Oxford University Clinical Research Unit 

Dr Beardsley explains that success in a clinical trial is a definitive result. A definite 'yes' is wonderful but a definite 'no' means you can stop researching a treatment that will be ineffective and focus efforts elsewhere. In this case, there is an added and immediate benefit for current patients:

'Dexamethasone is already being used by some doctors as a treatment for cryptococcal meningitis. They are doing that with the best of intentions, believing it will benefit their patients. However, our trial has shown that that is in fact worse than standard treatment. Our evidence will inform those doctors so they know to stop using a potentially harmful treatment.

'It is also important to note that we don't simply record whether something works or not. Samples from patients are analysed and studied, offering huge amounts of data. The clinical trial has ended but our work is ongoing. It should reveal more details about how the immune system responds to cryptococcal meningitis. In turn, those insights may deliver future breakthroughs in the treatment of this deadly and neglected condition.'

It’s worth remembering: Even apparently negative results contribute to positive improvements in healthcare.

The paper, Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis, is published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1509024).