New treatment for deadly HIV-linked meningitis enters phase II trial.

There is hope in the fight against cryptococcal meningitis, the second leading cause of death in patients with advanced HIV (previously called AIDS), as scientists work around the clock to release new medicine to treat the disease.

This comes amid a cut of donor funding with the signing of stop-work order by U.S. President Donald Trump, a move likely to increase cases of cryptococcal meningitis leading to deaths.

Scientists from the Drugs for Neglected Diseases Initiative (DNDI) and partners have launched a Phase II trial in Malawi and Tanzania to develop a simpler, patient-friendly treatment for cryptococcal meningitis.

“When people with HIV can’t access effective treatment, they risk developing advanced HIV disease—and that opens the door to deadly infections like cryptococcal meningitis,’ said Dr Justine Odionyi, Head of HIV Disease at DNDI.

Additionally, she said many patients arrive at the hospital already in a coma, forcing healthcare staff to crush the tablets and administer them via nasogastric tube, a method not formally approved but often the only available option.

‘We were already struggling with limited supplies of flucytosine across many countries. Now, with the HIV funding cuts, the situation is becoming worse. Widespread stockouts are just around the corner.

Without this life-saving drug, preventable deaths are inevitable,’ added Dr Odionyi.

The easier-to-administer and patient-friendly sustained-release formulation of flucytosine is the one under development.

Flucytosine, an effective and key component of the World Health Organisation (WHO) first-line treatment regimen for cryptococcal meningitis, is difficult to administer in overburdened, resource-limited settings.

The current formulation must be taken every six hours, which can lead to missed doses.

The open-label, randomised Phase II study for the new sustained-release flucytosine formulation will include 72 adult participants in Tanzania and Malawi.

It simplifies dosing from four times to twice daily. It also comes in pellet form, making it easier to take with water or through a nasogastric tube, and is suitable for outpatient self-administration.

Participants have been divided into two groups: one will receive the current regimen of flucytosine every six hours for 14 days, while the other will receive the new sustained-release version—6000 mg taken twice every day.

After completion of the study, the results will be submitted to the WHO for review, and the drug will be distributed to respective countries to help in the treatment of cryptococcal meningitis, a leading cause of death in people with advanced HIV disease, after Tuberculosis (TB).

In Kenya, at least 1.4 million people are living with HIV, with at least 20,000 deaths reported annually.

“The need for faster diagnostic testing and simpler, more practical treatment options has never been more urgent,’ said Dr Cecilia Kanyama, Principal Investigator for the study at the University of North Carolina Project in Malawi.

‘The current flucytosine formulation is difficult to administer, which has impacted treatment outcomes for years. We’re hopeful this new formulation will be easier to use and lead to better outcomes for our patients.’

DNDI is developing the sustained-release flucytosine formulation in partnership with Mylan Laboratories Limited, India (a Viatris Company), the National Institute for Medical Research, Tanzania; the University of North Carolina Project, Lilongwe, Malawi; the Luxembourg Institute of Health; St George’s, University of London; and FARMOVS.

“As HIV funding cuts threaten to undo decades of progress in Africa, treatment interruptions are already threatening to push thousands into advanced HIV disease (AHD),” Dr Luis Pizarro, Executive Director of DNDI, said in a statement.

Pizarro said essential AHD services have been disrupted, and stockouts of life-saving medicines like flucytosine are looming.

“Amidst this unprecedented crisis in multilateral cooperation, we must continue developing new treatment options for people living with HIV/AIDS and urgently strengthen international scientific collaborations,” added the researcher.

Cryptococcal meningitis is caused by the fungus Cryptococcus neoformans, found in soil and bird droppings, and is a major health threat to people with weakened immune systems.

Those with advanced HIV are particularly at risk.

The disease presents with severe headaches, fever, nausea, and vomiting, progressing to neck stiffness, confusion, and, in late stages, coma due to inflammation of the brain and spinal cord.

In Africa, where access to timely treatment is limited, the disease kills up to 70 per cent of those who get it.

In 2023 alone, AIDS-related illnesses killed 390,000 people in Africa, with Kenya recording 20,000 deaths.

Cryptococcal meningitis claimed 130,000 of those lives, deaths driven by treatment gaps.

Scientists worry that with funding cuts, more people will be left without care, with multiple deaths.

Lack of access to timely diagnosis and treatment is a major reason why cryptococcal meningitis remains so deadly.

Across many countries, point-of-care CD4 testing—important for identifying people with advanced HIV—is in short supply.

There are also growing shortages of cryptococcal antigen lateral flow assay (CrAg LFA) tests, which are recommended for routine screening in people living with HIV with low CD4 count.

With fewer diagnostic tools available and a shrinking health workforce, linking patients to life-saving AHD care will become harder by the day.

Unless urgent action is taken, continued disruptions to the AHD care package will result in hundreds of thousands of preventable deaths.

“We’ve been telling people HIV is no longer a death sentence—if you can access and stay on treatment,’ said Prof Sayoki Mfinanga, Global Coordinating Investigator at the National Institute for Medical Research (NIMR) in Tanzania.

“But with supply chains under threat, that progress is at risk. We urgently need innovative, simpler treatments to protect those with advanced HIV and stop unnecessary loss of life.’

This clinical trial is financially supported by the second European and Developing Countries Clinical Trials Partnership (EDCTP2) programme supported by the European Union (grant RIA2018CO-2516), with additional funding from the UK National Institute for Health and Care Research (Department of Health and Social Care).

The trial is also supported by the Swiss Agency for Development and Cooperation (SDC), Switzerland; Médecins Sans Frontières International, and other private foundations and individuals.