Fighting cryptococcal meningitis on many fronts

In summary

Cryptococcal meningitis causes around 180,000 deaths annually, mostly in Africa among people with advanced HIV.

Despite improved HIV treatments, meningitis cases remain high. Professor Tom Harrison’s team has led clinical trials to find safer, more effective, and affordable treatment regimens.

Their work has influenced WHO guidelines and saved lives, but challenges remain in ensuring global access to these therapies and diagnostics.

What did we explore and how?

City St George’s researchers, led by Professor Harrison, conducted multiple clinical trials over 15 years to improve cryptococcal meningitis treatment. Early phase 2 trials identified promising drug combinations, leading to the large ACTA trial comparing these to the WHO-recommended two-week treatment.

They found that a one-week course of amphotericin B plus flucytosine was more effective and cheaper, cutting mortality from 38% to 24%, while a fluconazole and flucytosine combination was equally effective but less costly.

Building on this, the AMBITION-CM phase 3 trial showed a single high dose of liposomal amphotericin B was safer and easier to administer, further reducing side effects.

Their team also developed the Early Fungicidal Activity endpoint, a novel way to quickly assess drug effectiveness in clinical trials, now widely adopted.

Benefits and influence of this research

The trials have directly influenced WHO treatment guidelines, with the ACTA regimen now preferred globally and the AMBITION single-dose regimen recommended where available.

In South Africa, the introduction of these treatments reduced hospital death rates by 30%, from 36% to 24%.

The team also leads advocacy for better access to drugs and a WHO-recommended cryptococcal screening test to identify at-risk patients before symptoms develop.

Their advocacy helped launch a US$20 million UNITAID programme to reduce HIV deaths with these interventions.

Since then, costs for flucytosine have nearly halved, thanks to commitments from four generic manufacturers.

We have always worked closely with the WHO and other global health organisations to make sure that our research can change guidelines as soon as possible.

Following ACTA, they changed their guidance to recommend 1-week of amphotericin B with flucytosine as the preferred treatment.

We are beginning to see that the ACTA regimens can bring mortality down to 25-35%, potentially halving deaths and saving tens of thousands of lives each year.

The single dose AMBITION regimen is even safer and easier to administer for overstretched hospitals.

But recommendations would not change the situation without an improvement in access to therapies and diagnostics.

Reaching people before the infection is advanced is crucial. This screening is now routine in South Africa, Botswana and parts of Tanzania and recommended by more than 20 Sub-Saharan African countries.

It is my hope that with broader access to these treatments, we will see the results that are emerging in South Africa widely replicated.