Cryptococcal meningitis is the second biggest killer of people living with HIV after tuberculosis (TB). For decades it has flown under the radar – despite its high mortality rate – but it is finally getting the attention it deserves with the launch of a new global initiative to end deaths due to this fungal brain infection by 2030.

The initiative, launched by the United States Centre for Disease Control, Clinton Health Access Initiative (CHAI) and UNITAID last month, aims to get the gold standard drug to treat cryptococcal meningitis – flucytosine – registered in countries that need it. Flucytosine is still not registered in South Africa although sub-Saharan Africa accounts for over 75% of cryptococcal meningitis deaths. That it remains unregistered is due to a combination of market failures and a lack of generic players in the field although the drug is over 50 years old and off-patent.

The Ending Cryptococcal Meningitis Deaths by 2030 Strategic Framework aims to create a strategy for all roleplayers to create targets for, and facilitate access to, the treatment of the disease – mimicking the broader end HIV and end TB goals already in place.

“Cryptococcal meningitis is one of the main causes of death of people living with HIV. While diagnostic tests and medicines for prevention and treatment exist, access in resource-limited settings is extremely limited. Treatment with fluconazole alone, most commonly used in low-income settings, results in around 20% survival,” noted the document.

“This Strategic Framework sets out the case for a re-invigorated global drive to end cryptococcal meningitis deaths by 2030, as part of a broader drive to end all HIV-related deaths. [W]e now call for high-level targets and lay out strategic building blocks to help countries develop their own strategies to minimise deaths from cryptococcal meningitis. Earlier diagnosis and optimised treatment with flucytosine and amphotericin B, as recommended by the World Health Organization (WHO), could improve survival to around 70%.”

Advanced HIV disease and cryptococcal meningitis

More and more patients are coming into care with advanced HIV disease – formerly known as AIDS – and at risk of developing a deadly infection with cryptococcal meningitis. This is according to Professor Yunus Moosa head of infectious diseases at the University of KwaZulu-Natal, who works at King Edward VIII Hospital in Durban, KwaZulu-Natal.

He said treating patients with cryptococcal meningitis, considering its high mortality rate, “is a tragedy” and many of his patients die despite his best efforts because they simply present to care too late.

According to Professor Nelesh Govender from the National Institute for Communicable Diseases (NICD) cryptococcal meningitis “is caused by a fungus found in the environment”.

“The fungus is found everywhere in the environment, including in the soil, bird droppings and in trees. Most of us are exposed to the fungus on a daily basis. From the time we are young, we inhale it into the lungs and, if you have a normal healthy immune system, there are no further consequences, you develop antibodies and you don’t get sick. But in people with a weakened immune system – like if you have advanced HIV disease – the fungus ‘wakes up’ and spreads from wherever it is in the body to the bloodstream,” said Govender.

From the bloodstream, if not caught, it can spread to the brain where it causes “a devastating – and deadly – meningitis”.

Cryptococcal disease exists on a spectrum with meningitis being the most severe and deadly form.

Over 95% of people with cryptococcal disease in South Africa have advanced HIV disease, according to Govender.

Advanced HIV disease still accounts for over a third of new people living with HIV entering care in South Africa according to Dr Yogan Pillay, country director for the CHAI and former deputy director-general for HIV in the National Department of Health.

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Access to flucytosine for cryptococcal meningitis

In August 2019, Spotlight published an article on access to flucytosine in South Africa. At that time no registration dossier had been submitted to the South African Health Products Regulatory Authority (SAHPRA) despite the life-saving potential of the drug and the heightened need for it in the country considering the extent of its advanced HIV epidemic.

The owner of the drug, Mylan, (now part of Viatris Inc. following a 2020 merger) did however submit a dossier to SAHPRA in September 2020 but the regulating authority has not had adequate time to review the drug and it still has not been registered for use at the time of publication of this story.

At the launch of the end cryptococcal meningitis deaths webinar on 12 May, Carmen Perez Casas, Technical Manager for UNITAID explained that CHAI has worked closely with the drug manufacturers to ensure generic flucytosine is registered in countries that need it, including in South Africa.

Flucytosine has the potential to dramatically improve survival rates of patients with cryptococcal meningitis. (Photo: OpturaDesign)