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)
CHAI is also working with pharmaceutical giant Gilead to improve availability and capacity when generics become available for liposomal amphotericin b – another drug that is given in conjunction with flucytosine and also has the potential to improve survival rates.
Before CHAI took over the flucytosine access programme, it was started by Medicines Sans Frontiers (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 in August 2019, 15 hospital sites had access to the drug to treat cryptococcal meningitis.
Section 21 applications are 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 National Department of Health requested CHAI 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 SAHPRA,” said Pillay.
Before this bulk section 21 application, individual clinicians had to file section 21 applications on behalf of individual patients and the process would often take so long that the patient would have died by the time the drug had 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 conducted in Uganda before access to antiretroviral therapy or anti-fungal treatments found that, for HIV patients, a diagnosis with cryptococcal meningitis was “universally fatal with a 100% mortality rate”.
According to Pillay, since 2020, CHAI has recruited over 60 sites (including the 15 original MSF facilities) across all nine provinces and has distributed over 1 300 courses of flucytosine.
The actual need for flucytosine in South Africa is estimated to be much higher with approximately 27 000 cases occurring annually in the country, according to Professor Radha Rajasingham, an Assistant Professor of Medicine at the University of Minnesota Medical School.
This is why the timely registration of the drug with SAHPRA 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 NICD started a screening programme for all new HIV patients with a CD4 count of below 100.
CD4 counts are a measure of immunity in people living with HIV and a CD4 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 anti-fungal 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.
Govender 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 diagnosis with cryptococcal meningitis is almost universally a death sentence because “mortality is high even with access to antifungal treatment with fluconazole and amphotericin B”.
According to Govender, so far, the NICD has screened over 800 000 blood samples over the last four years and picked up cryptococcal disease in 50 000 people. The NICD is currently undertaking a study to see how many of these patients already have cryptococcal meningitis and how many of these people 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,” he said.
Access to ART the ‘golden 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 ART as soon as possible,” he said.
According to him, South Africa has the “largest number of people living with HIV and an enormous number of people 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,” he said.
There is also a need to educate clinicians about the disease because if you start ART first, before antifungal medicines and that person has cryptococcal disease there is a chance the patient will develop an inflammatory response in the brain which kills called iris immune reconstitution inflammatory syndrome.
“As you start ART 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 is 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 cryptococcal antigen in clinical specimens and can be performed on cerebrospinal fluid, venous or finger prick samples – like the HIV test.
Role-players want access to a rapid point of care test to detect disease before it becomes cryptococcal meningitis similar to the HIV finger prick test featured here. (Photo: UNICEF Ethiopia)
According to Dr Laura Trivino-Duran, who is 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 but 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 that strategy was cost-effective and to make sure 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 CHAI pays to import the drug as part of the bulk section 21 is R1 275 for a box of 100 tablets, excluding the cost of air freight, distribution and VAT. Administration, the number of tablets a patient needs, is weight dependent among other clinic factors.