A new sustained-release formulation of flucytosine, a critical medicine for treating cryptococcal meningitis, has entered Phase II clinical trials in Malawi and Tanzania. Developed by the Drugs for Neglected Diseases initiative (DNDi) and partners, this innovative formulation aims to address significant treatment challenges in resource-limited settings.
The open-label, randomized study will include 72 adult participants across both countries, comparing the current regimen requiring administration every six hours with the new sustained-release version that needs to be taken just twice daily. The new formulation also comes in pellet form, making it easier to administer with water or through a nasogastric tube for patients who arrive at hospitals in advanced stages of illness.
"The current flucytosine formulation is difficult to administer, which has impacted treatment outcomes for years," said Dr. Cecilia Kanyama, Principal Investigator at the University of North Carolina Project in Malawi. "We're hopeful this new formulation will be easier to use and lead to better outcomes for our patients."
The Deadly Impact of Cryptococcal Meningitis
Cryptococcal meningitis, caused by the fungus Cryptococcus neoformans found in soil and bird droppings, is the second leading cause of death in patients with advanced HIV after tuberculosis. The disease typically begins with severe headaches, fever, nausea, and vomiting, progressing to neck stiffness, confusion, and potentially coma due to inflammation of the brain and spinal cord.
In Africa, where access to timely diagnosis and treatment remains limited, the mortality rate reaches up to 70% of those infected. In 2023 alone, AIDS-related illnesses killed approximately 390,000 people in Africa, with cryptococcal meningitis accounting for 130,000 of these deaths.
Dr. Justine Odionyi, Head of HIV Disease at DNDi, explained the connection between HIV treatment access and opportunistic infections: "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."
Treatment Challenges and Innovations
Flucytosine is a key component of the World Health Organization's first-line treatment regimen for cryptococcal meningitis. However, its current formulation presents significant challenges in resource-limited healthcare settings:
- It requires administration every six hours, leading to missed doses
- Many patients arrive at hospitals already in coma, requiring healthcare workers to crush tablets for nasogastric tube administration
- Supply shortages are common across many countries
The new sustained-release formulation addresses these challenges by:
- Reducing dosing frequency from four times to twice daily (6000 mg taken twice daily)
- Providing a pellet form that's easier to administer orally or through nasogastric tubes
- Being suitable for outpatient self-administration
Funding Crisis Threatens Progress
The clinical advancement comes at a critical time when HIV funding cuts threaten to reverse decades of progress in Africa. Healthcare systems are already experiencing disruptions to essential advanced HIV disease services, with experts warning of looming stockouts of life-saving medicines like flucytosine.
"As HIV funding cuts threaten to undo decades of progress in Africa, treatment interruptions are already threatening to push thousands into advanced HIV disease," warned Dr. Luis Pizarro, Executive Director of DNDi. "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."
The situation is further complicated by shortages of diagnostic tools. Point-of-care CD4 testing—crucial for identifying people with advanced HIV—is in short supply across many countries. Similarly, cryptococcal antigen lateral flow assay (CrAg LFA) tests, recommended for routine screening in people living with HIV with low CD4 counts, are becoming increasingly scarce.
Prof. Sayoki Mfinanga, Global Coordinating Investigator at the National Institute for Medical Research in Tanzania, emphasized the stakes: "We've been telling people HIV is no longer a death sentence—if you can access and stay on treatment. 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."
International Collaboration
The development of the sustained-release flucytosine formulation represents a significant international collaborative effort. DNDi is working with multiple partners including Mylan Laboratories Limited, India (a Viatris Company), the National Institute for Medical Research in Tanzania, University of North Carolina Project in Malawi, Luxembourg Institute of Health, St George's University of London, and FARMOVS.
The clinical trial receives financial support from the European and Developing Countries Clinical Trials Partnership Association programme supported by the European Union, with additional funding from the UK National Institute for Health and Care Research, the Swiss Agency for Development and Cooperation, Médecins Sans Frontières International, and other private foundations and individuals.
If successful, the results will be submitted to the WHO for review, potentially leading to wider distribution of this improved treatment option for cryptococcal meningitis across affected countries.
