For decades cryptococcal meningitis has flown under the radar, despite its high mortality rate, but this fungal brain infection is finally getting the attention it deserves with the launch of the Ending Cryptococcal Meningitis Deaths by 2030: Strategic Framework. 

The initiative was launched by the US Centers for Disease Control and Prevention, the Clinton Health Access Initiative and UNITAID in May. 

Flucytosine is the gold-standard drug for the treatment of cryptococcal menigitis. (Photo: sigmapharm.com / Wikipedia)

Flucytosine is still not registered in South Africa despite the fact that sub-Saharan Africa accounts for more than 75% of cryptococcal meningitis deaths. This is due to market failures and a lack of generic players in the field, although the drug is more than 50 years old and off-patent. 

The initiative 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 [among] 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,” the strategic framework document noted.

“This strategic framework sets out the case for a reinvigorated 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

More and more patients are entering 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. 

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 of the National Institute for Communicable Diseases, cryptococcal meningitis “is caused by a fungus found in the environment”. 

“The fungus is found everywhere… 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 the most severe and deadly form. 

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

Dr Yogan Pillay, country director for the Clinton Health Access Initiative and former deputy director-general for HIV in the National Department of Health. (Photo: Wikipedia)

Advanced HIV disease still accounts for more than a third of new people living with HIV entering care in South Africa, said Dr Yogan Pillay, country director for the Clinton Health Access Initiative and former deputy director-general for HIV in the National Health Department. 

Access to flucytosine 

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, 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 following a 2020 merger) did, however, submit a dossier to regulatory authority in September 2020 but the latter has not had adequate time to review the drug. 

The drug had still not been registered for use at the time of publication. 

At the launch of a webinar on ending cryptococcal meningitis deaths on 12 May, Carmen Perez Casas, technical manager for UNITAID, explained that the Clinton Health Access Initiative has worked closely with drugmakers to ensure generic flucytosine is registered in countries that need it, including South Africa. 

The initiative is also working with pharmaceutical giant Gilead to improve availability and capacity when generics become available for liposomal amphotericin b — which is given in conjunction with flucytosine and also has the potential to improve survival rates. 

Before the initiative took over the flucytosine access programme, it was started by Médecins Sans Frontières (MSF) in South Africa.

To create programmatic data for the widespread use of flucytosine, MSF and the Southern African HIV Clinicians Society started a clinical access programme using a bulk Section 21 application and by August 2019, 15 hospital sites had access to the drug to treat cryptococcal meningitis. 

A Section 21 application is a special mechanism that allows the importation of medicines that are not registered in South Africa, provided certain conditions are met.

“At the end of 2019, the Department of Health requested [the Clinton Health Access Initiative] to procure flucytosine on behalf of the national department to ensure the continued optimal management of cryptococcal meningitis and to generate evidence to inform eventual national guidelines adoption, pending generic product registration with [the regulatory authority],” said Pillay.

Before this bulk Section 21 application, individual clinicians had to file applications on behalf of individual patients, a process that was often so long that the patient would have died by the time the drug arrived. 

Once the cryptococcal fungus has reached the brain “we don’t have a lot of time to act” because a patient could be dead in as little as three weeks, said Govender. 

A study in Uganda before access to antiretroviral therapy or antifungal treatments found that, for HIV patients, a diagnosis of cryptococcal meningitis was “universally fatal with a 100% mortality rate”.

According to Pillay, since 2020 the Clinton initiative has recruited more than 60 sites (including the 15 original MSF facilities) across all nine provinces and distributed more than 1,300 courses of flucytosine. 

The need for flucytosine in South Africa is estimated to be much higher — about 27,000 cases annually — according to Radha Rajasingham, an assistant professor of medicine at the University of Minnesota Medical School.

This is why the timely registration of the drug and adoption into national guidelines is so important. 

Screening programme in South Africa

To overcome the challenges and to minimise mortality from cryptococcal meningitis, the National Institute for Communicable Diseases started a screening programme for all new HIV patients with a CD4 count below 100. 

CD4 counts are a measure of immunity in people living with HIV. A count below 200 means a dangerously low immune system. 

“People get baseline CD4 tests done and we use the same blood samples to test for the cryptococcal antigen and then the doctors bring them back into the clinic only a week or so afterwards and the results are ready. Doctors can start them on antifungal treatment before the disease progresses to meningitis, greatly improving chances of survival. If there is a delay for any reason, there is a high chance the disease will progress to meningitis, and many don’t come back into care, and we assume these patients have died,” said Govender. 

He said the cryptococcal fungus has a jelly-like capsule around it that masks it from the immune system. This capsule starts to shed when it enters the bloodstream and this is what they pick up in the screening programme. 

According to Govender, South Africa is the only country with such a screening programme in place. That means in other African countries without access to flucytosine, a cryptococcal meningitis diagnosis is almost universally a death sentence because “mortality is high even with access to antifungal treatment with fluconazole and amphotericin B”. 

So far, the national institute had screened more than 800,000 blood samples over the past four years and picked up cryptococcal disease in 50,000 people. It was undertaking a study to see how many of these patients already had cryptococcal meningitis and how many of them survive.

“Someone who has a positive antigen test, it is recommended they immediately have a lumbar puncture to rule out meningitis. If they don’t have meningitis, they should be started on antifungal treatment and then survival is much better — mortality is 25% versus 70% if they already have meningitis,” said Govender. 

Access to antiretroviral therapy the ‘gold standard’

Although the screening programme has caught many cases and resulted in a “big reduction in mortality”, according to Govender, “it is not ideal”.

“We want to prevent mortality altogether. The only way to do that is making sure people never present with advanced HIV in the first place and that everyone knows their status and starts treatment with [antiretroviral therapy] as soon as possible.” 

South Africa had the “largest number of people living with HIV and an enormous number with advanced HIV disease — a quarter of a million people — and they’re all at risk for cryptococcal meningitis”.

“But we know this is not perfect and we still have thousands and thousands of cases of cryptococcal meningitis every year.” 

There is also a need to educate clinicians about the disease because if you start antiretroviral therapy first, before antifungal medicines, and the patient has cryptococcal disease there is a chance the person will develop an inflammatory response in the brain which kills — immune reconstitution inflammatory syndrome. 

“As you start [antiretroviral therapy] your immune system gets better and recognises this fungus and starts attacking it and causes a huge inflammatory response and that in itself can kill a person,” said Govender. 

In fact, the WHO now recommends that everyone with a CD4 count below 200 be screened, but public-sector labs don’t yet have the capacity to do this. 

One of the other strategies to end cryptococcal meningitis is to improve access to a cryptococcal antigen lateral flow assay — a point-of-care test that rapidly detects the cryptococcal antigen in clinical specimens and can be performed on cerebrospinal fluid or venous or finger-prick samples — like the HIV test. 

Why has generic flucytosine taken so long?

According to Dr Laura Trivino-Duran, the former medical coordinator for MSF in South Africa, generic flucytosine has taken so long to come to market because “cryptococcal meningitis doesn’t have the popularity of TB even though it’s the second-biggest killer of people with HIV behind TB”.

“There is no demand even though, in South Africa, as a country, there are many cases… cryptococcal meningitis is somehow considered a neglected disease in many programmes around the world and even in South Africa. It was not really part of the budget of the minister, that’s why we had to do the clinical access programme. It’s not that policymakers weren’t interested to do it, they knew the benefit, but they wanted to make sure that strategy was cost-effective and [that] the supplier supplies at a good price. Even if there are many patients, the volume doesn’t really correspond to the investment, and it happens with many life-threatening diseases,” she said. 

According to Pillay, the current cost of flucytosine that the Clinton Health Access Initiative pays to import the drug as part of the bulk Section 21, is R1,275 for a box of 100 tablets, excluding air freight, distribution and VAT. The number of tablets a patient needs depends on weight and other clinical factors. DM/MC

This article was commissioned and edited by Spotlight and written by Amy Green. Green is the news editor at Health-e News.