This article is part of a series of research impact stories related to our REF 2021 submission.
Meningitis caused by the cryptococcus fungus is responsible for around 180,000 deaths per year, mainly in people in Africa with advanced HIV. It accounts for 15-20% of HIV-related deaths. St George’s researchers have been pioneering research to make treating cryptococcal meningitis more effective, lower cost and accessible.
Professor Tom Harrison of the Institute for Infection and Immunity has been at the forefront of research into cryptococcal meningitis for the past 20 years, finding the most effective combinations of drugs as well as improving access to treatment and developing diagnostics.
Cryptococcal meningitis is an infection of the membranes covering the brain and spinal cord. It affects people with weakened immune systems, like those with advanced HIV. Although access to antiretroviral drugs for HIV is improving, cases of cryptococcal meningitis have not fallen significantly in many countries.
Until a few years ago, the WHO recommended a two-week course of therapy for cryptococcal meningitis: a combination of two antifungals, amphotericin B and flucytosine; but the drugs were not widely available in Africa and most patients in Africa were treated with much less effective fluconazole. Even with treatment, the mortality rate was 50-70%, and the side effects of amphotericin B, when available, could be life-threatening.
Professor Harrison and his colleagues have coordinated a number of clinical trials over the past 15 years to find better treatment options, and early indications are that, if rolled out, these could halve deaths.
Between 2007 and 2012 they ran a series of phase 2 trials and identified two new promising regimens.
The team then went on to run a large multicentre trial (known as ACTA) in cryptococcal meningitis. The trial enrolled hundreds of people to compare their new treatment options with the WHO-recommended two-week course.
They found that just one week of amphotericin B plus flucytosine was more effective and cheaper than the two-week course, cutting deaths from 38% to 24% and saving US$424 per patient. A combination of fluconazole with flucytosine was just as effective as the recommended course but cost much less: a saving of US$843 per patient.
Building on the ACTA results, and a further supportive phase 2 study, the team, with key collaborators at the London and Liverpool Schools of Tropical Medicine, have just completed a second large phase 3 trial (AMBITION-CM). The trial demonstrated that the amphotericin B component can be given as just one high dose on the first day of the course, in a form where the drug is encased in lipids, further reducing side effects.
The clinical trials work has been accelerated by the St George’s team’s development of a new way of assessing drug effectiveness during clinical trials. The Early Fungicidal Activity endpoint is a method that tests the cerebrospinal fluid of trial participants to determine if a drug is working, and has now been widely adopted in the field.
But there are challenges to rolling out new therapies. “We’ve always worked closely with the WHO and other global health organisations to make sure that our research can change guidelines as soon as possible,” says Professor Harrison.
“We were able to share the ACTA and AMBITION trial results with the WHO quickly. In 2018, after ACTA, they changed their guidance to recommend 1-week of amphotericin B with flucytosine as the preferred treatment, followed by the oral combination where amphotericin B isn’t available.”
Following publication of the AMBITION-CM results in March this year, they have issued an update to prioritise the single high dose liposomal amphotericin-based regimen where this formulation is available.
Professor Harrison and his team are beginning to see the impact of their work. In South Africa, for example, the rate of people dying in hospital has reduced by 30% from 36% to 24% using the ACTA one-week treatment.
“We’re beginning to see that the ACTA regimens can bring mortality down to 25-35%, potentially halving deaths from cryptococcal meningitis and savings tens of thousands of lives each year."
"The single dose AMBITION regimen is even safer and easier to administer for overstretched hospitals,” says Professor Harrison.
“But recommendations won’t change the situation without an improvement in access to therapies and diagnostics,” he adds. His team have been leading advocacy efforts to boost access to the drugs and also to the screening test that they have helped to develop to identify and pre-emptively treat people infected with cryptococcus who are yet to show symptoms, which is now also WHO recommended.
“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,” he says.
Their advocacy work has helped lead to a US$20 million UNITAID programme aiming to reduce HIV deaths in patients with advanced disease with interventions like those developed by Harrison’s team.
Since then four generic pharmaceutical manufacturers have committed to supply flucytosine, and the costs have almost halved from US$1.2 to around US$0.7 per tablet.
“It’s my hope that with broader access to these treatments, we’ll see the results that are emerging in South Africa widely replicated,”
says Harrison.
You can find out more about St George’s research into tackling a broad range of infectious diseases on the Institute for Infection and Immunity webpages.