In a clinical trial of adults with HIV-related cryptococcal disease, those treated with a two-drug combination had a 21% lower risk of dying than those treated with just one drug. This is according to City St George’s research being presented today at the International AIDS Conference 2026 in Brazil.
Meningitis caused by the Cryptococcus fungus is an infection of the membranes covering the brain and spinal cord, as well as the brain itself. The destructive condition is responsible for around 110,000 deaths globally every year and accounts for almost 20% of HIV-related deaths. People with this type of meningitis often only have a short window left to live, with between a third to a half dying within 10 weeks even with treatment - a death rate similar to the Bundibugyo strain of Ebola virus disease.
Catching the disease early
Screening for traces of the fungus in the blood can identify cryptococcal disease at a much earlier stage. Catching it early and treating with antifungal medication can prevent meningitis from happening at all. The usual approach is with one antifungal drug, but even so, some patients still go on to develop meningitis and die.
The research team explored a two-drug oral combination already known to be powerful at treating full-blown cryptococcal meningitis. Their new approach looked to see if this combination could prevent more deaths than the standard single-drug approach when used earlier, before meningitis sets in.
They recruited 604 people to the EFFECT trial in 11 different sites across South Africa and Tanzania who were living with HIV and had the cryptococcal antigen in their blood – a red flag that shows they have the Cryptococcus fungus – but had no meningitis symptoms. Almost all people entering the trial agreed to have a spinal tap beforehand to check the cerebrospinal fluid that they did not already have a silent meningitis.
Participants were randomised to receive either a combination therapy of fluconazole and flucytosine or the standard treatment of fluconazole alone for two weeks. Fluconazole was given once a day and flucytosine four times a day. All participants were then given a lower dose of once-daily fluconazole for eight weeks, and a further reduced dose thereafter, as per current guidelines.
The team contacted all participants over the first two weeks to ensure they were adhering to the medication and followed up again at one, two and a half, and six months.
The combination therapy group had a 21% lower risk of death due to any reason after six months – a 13% death rate (40 deaths out of 304 people), compared to a 17% death rate (50 out of 300) in the control group.
Among those who took their medications consistently during the entire treatment course, the risk of death at six months was 29% lower in the combination treatment group - a 13% death rate (30 deaths out of 239 people), compared to a 18% death rate (46 out of 260) in the control group.
In a subgroup of 134 people with higher levels of the cryptococcal antigen in their blood, the risk of death was 47% lower in the group who had the combination therapy.
More research is needed
An important caveat is that the study was not able to demonstrate a statistically significant difference in survival between the treatment groups. While death rates were consistently lower among people receiving the two-drug combination, a larger study would be needed to determine with greater certainty whether the treatment itself was responsible for the observed benefit.
However, there was clearly no difference in the number of serious adverse events leading to hospitalisation or death between the treatment groups, confirming that the combination therapy is safe for patients.
Dr Síle Molloy, co-Chief Investigator from the School of Health & Medical Sciences, said:
"The two-drug therapy was safe and was associated with lower death rates, providing encouraging evidence to support further research and implementation studies in real-world settings.”
Professor Nelesh Govender, co-Chief Investigator from the University of the Witwatersrand in Johannesburg and Visiting Professor at City St George’s, said:
"We need to conduct implementation studies in the real world to understand if the oral combination treatment will work better in the many low-resource settings where routine spinal taps for people with fungal antigen are not feasible or implemented, and those with a silent meningitis are under-treated with just one drug.”
The trial was funded by a £5.1m grant from the Department of Health and Social Care (DHSC), the Foreign, Commonwealth & Development Office (FCDO), the Medical Research Council (MRC) and Wellcome. This UK funded award was part of the EDCTP2 programme supported by the European Union.