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Regulatory approval of flucytosine just a first step in treating of cryptococcal meningitis

Cryptococcal meningitis (CM) is one of the leading causes of death – second only to tuberculosis – in people living with HIV. And yet, writes Spotlight’s Catherine Tomlinson, South Africa still doesnʼt provide flucytosine as part of its standard treatment regimen.

Tomlinson writes:

CM occurs mainly in people with advanced HIV disease and low CD4 counts. It accounts for 15% to 20% of HIV-related deaths. The extremely painful and debilitating illness occurs when the fungus Cryptococcus spreads to and causes infection of the brain and spinal cord. Without treatment, all people who develop cryptococcal meningitis will die of the disease.

It is no wonder then that clinicians celebrated when flucytosine, a critical drug for the treatment of CM, was recently approved in South Africa. Yet, while an essential step forward, regulatory approval on its own is insufficient to ensure widespread access.

To understand the complexities involved, we look back at the history of CM treatment access in South Africa.

A brief history of CM in SA

In the early days of the HIV pandemic in South Africa, the only treatment available for CM here was the drug fluconazole. To demonstrate how high prices limited access to the life-saving medicine, Zackie Achmat, former head of the Treatment Action Campaign (TAC), imported generic fluconazole into SA in 2000 in defiance of pharmaceutical company Pfizerʼs patents on the drug.

Fluconazole alone improves CM survival rates from zero 20%. At the time, however, life-saving antiretroviral treatment remained largely unavailable in the country – making people living with HIV more vulnerable to CM and other life threatening opportunistic infections.

After antiretroviral treatment access began steadily increasing in South Africa from the mid-2000s onwards, treatment regimens for CM also began to improve. In 2007, the Southern African HIV Clinicians Society (SAHCS) released guidelines for management of CM recommending a treatment regimen combining both oral fluconazole and intravenous (IV) amphotericin B deoxycholate. Survival rates at one year for CM patients treated with fluconazole and amphotericin B are around 40%.

Following the SAHCS recommendations, the National Essential Medicine List Committee (NEMLC) eventually added amphotericin B to its essential medicine list and included it, with fluconazole, in South Africaʼs standard treatment guidelines for CM.

Flucytosine and the landmark ACTA trial

Yet despite these advances, an important drug required to further reduce CM deaths remains inaccessible in SA. The drug, flucytosine, is an old, off-patent medicine developed in the 1950s. It should be given orally to patients with CM for one to two weeks as part of their treatment regimen.

“For many years, the expert opinion was that flucytosine was a key component [of CM treatment] because it improved outcomes and saved lives. But the ACTA trial… was the definitive evidence that if you add flucytosine to treatment it significantly reduces mortality,” said Professor Graeme Meintjes, infectious disease expert at the University of Cape Town.

Results from the ACTA trial, published in March 2018, showed that the addition of flucytosine to CM treatment regimens improves CM survival at one year to over 70%. In other words, adding flucytosine to treatment regimens for CM cuts deaths by almost half. This is an astounding survival benefit from the simple addition of an old, oral medicine to an existing package of care.

Based on evidence from the ACTA trial, both the World Health Organization (WHO) and the SAHCS updated their treatment guidelines, in 2018 and 2019 respectively, to recommend flucytosine as part of preferred treatment regimens for cryptococcal meningitis.

The preferred treatment regimen recommended by the WHO and SAHCS involves one week of intravenous amphotericin B deoxycholate and oral flucytosine treatment, followed by one week of high-dose oral fluconazole, and then at least a year of lower dose fluconazole maintenance treatment.

Slow progress

Somehow, four years since publication of the ACTA trial results, South Africa – the country with the highest absolute number of people living with HIV – still does not provide flucytosine as part of standard treatment regimens for CM.

Multiple factors are to blame.

Yet many of these impediments have now been overcome and the National Department of Health (NDoH) is positioning itself to begin rolling out flucytosine nationally – albeit concerningly slowly.

Amir Shroufi, Médecins Sans Frontières (MSF) Southern Africa board member, highlights the urgency of ensuring universal access to flucytosine for all CM patients.

“Doctors are not being given the tools they need to treat [CM],” he says. “The first tool they have to have is flucytosine and they still donʼt have flucytosine. So, thatʼs the thing that needs to happen urgently, you know, tomorrow! Everyone with cryptococcal meningitis must get access to flucytosine.”

So why then is it taking so long to rollout flucytosine in SA? There are at least five factors involved.

1. Market failure and manufacturing challenges
To provide flucytosine to CM patients, it needs to be manufactured and available for procurement. For many years, it simply was not.

“Thereʼs been market failure in terms of the medicines,” said Shroufi. “For many years nobody wanted to produce flucytosine. They didnʼt think there was a market… a lot of us have been involved for many years in advocacy, just to get Mylan and others to produce flucytosine.”

Mylan (a pharmaceutical company now part of Viatris) received WHO prequalification for its 500mg flucytosine tablets in March 2018 – meaning that its products meet international safety, efficacy, and quality standards. Its 250mg tablets have also subsequently received WHO prequalification.

2. Medicine registration
Once Mylanʼs product became available globally, the next challenge was getting the company to file an application for registration of flucytosine in South Africa.

Professor Nelesh Govender from the National Institute for Communicable Diseases (NICD) said the registration is prompted by the manufacturer and that Mylan submitted a dossier to the South African Health Products Regulatory Authority (SAHPRA) in December 2019.

“We followed up from the HIV Clinicians Society regularly with SAHPRA, to
make sure … this registration process was fast tracked… we wrote to SAHPRA several times. And I think that helped… [but] it did take two years,” he says.

Yuven Gounden communications manager for SAHPRA, confirmed to Spotlight that 250mg and 500mg flucytosine tablets from Mylan were registered in December 2021.

While Govender welcomes the registration of Mylanʼs flucytosine, he notes the ongoing need for other manufacturers to submit registration applications to SAHPRA to improve flucytosine supply security in the country.

3. Medicine affordability
Another potential obstacle is cost. This is an issue Dr Jacqui Miot, Division director of the Wits University Health Economics and Epidemiology Research Office, has been looking at since 2015 after a request from the Essential Medicines Committee. She says her work on the cost effectiveness of flucytosine went through various iterations, “but really it was the ACTA trial that triggered the updated review because it showed there was definitely a mortality benefit with flucytosine”.

Miotʼs analysis, shared with Spotlight by the NDoH, concluded that “flucytosine [should] be considered for inclusion to the EML, pending SAHPRA registration with a reduction in price”.

The analysis found that if the price of a 100-tablet pack of 500mg flucytosine is reduced to R1,500, then the rollout of this medicine nationally would have a “cost-neutral” impact on the budget. In 2019 the Western Cape Department of Health paid R3,756 to procure and import a hundred 500mg unregistered flucytosine tablets under Section 21 authorisation.

The NDoH has subsequently referred to R1,500 as the “threshold price” that must be met to roll out flucytosine nationally. Khadija Jamaloodien, director of Affordable Medicines at the NDoH, told Spotlight that in evaluating flucytosine for inclusion on the essential medicines list “affordability of flucytosine also needs to be considered and that the supplier can meet the threshold price”.

While the NDoH must still negotiate a price with Mylan, it is anticipated the threshold price will be met, as Mylan currently supplies flucytosine to the Clinton Health Access Initiative (CHAI) for use in South Africaʼs flucytosine access programme at a cost of R1,470 per pack. Each pack contains a hundred 500mg scored tablets.

While the dosage and therefore the total number of tablets needed to treat a patient depends on the patientʼs weight, Shroufi says one pack “is about enough to treat one person”.

4. Inclusion on the standard treatment guidelines and essential medicines list
Now that flucytosine is registered and is likely to be available to the NDoH at its required “threshold price”, it must be included on the essential medicines list and in CM treatment guidelines before it can be rolled out nationally.

The guidelines for treatment of cryptococcal meningitis in South Africa are contained in the Adult Hospital Level Standard Treatment Guidelines (STGs) and Essential Medicines List (EML). Inclusion of a medicine in the Hospital STGs and EML automatically means it must also be available at tertiary and quaternary levels of care.

While tertiary and quaternary guidelines are updated on an ongoing basis, the Hospital STGs and EML is typically only updated every three years. The process of updating the Hospital STGs and EML is currently under way and a draft document has been circulated to stakeholders for comment.

The draft Hospital STGs and EML seen by Spotlight recommends the inclusion of flucytosine in treatment guidelines for CM, aligning its recommendations with those of the WHO and the SAHCS.

Jamaloodien notes that the updated Hospital STGs and EML will only be published in 2023, but adds that “if the HIV chapter [which contains treatment guidelines for CM] is ratified earlier by the NEMLC, the HIV chapter may be published on the Knowledge Hub platform before the complete review of the Adult Hospital STGs and EML are finalised”.

Meintjes says clinicians will probably motivate for release and implementation of the CM guidelines before finalisation and publication of the full Adult Hospital STGs and EML. “Weʼve been waiting a very long time for it. And now [with a medicine registered] weʼre at this point where it can now be implemented… One would hope that thereʼre not further delays.”

5. Getting the medicine on tender
Finally, before flucytosine can be rolled out nationally, the NDoH will need to award a tender to a supplier (most likely Mylan [Viatris], as the only company with a registered product). Jamaloodien told Spotlight that “once the NEMLC approves the inclusion of medicines on the EML, it is included in the tender process. The NEMLC has recommended that flucytosine be advertised in the next tender, which will only start on 1 October 2023. In the interim, provinces are able to procure this item on quotation.”

According to Meintjes, the Western Cape has been procuring flucytosine at a provincial level since May 2021 and it is now available in all facilities treating CM in the province.

Meanwhile, a flucytosine access programme saves lives, but reaches few

While flucytosine remains unavailable to everyone who need it nationally, some patients can access it through CHAIʼs access programme. The South African flucytosine access programme was started by MSF in 2018 and transferred to CHAI in 2019. While flucytosine was unregistered in the country at the time, MSF and subsequently CHAI were able to import flucytosine for use in the access programme through Section 21 authorisation, which allows for the importation and use of unregistered medicines into the country.

“CHAI accepted the invitation of the South African NDoH in 2019 to provide support with provision of flucytosine to target facilities until registration of this commodity with SAHPRA,” CHAIʼs Desmond Munemo told Spotlight. “This work entailed building off from a previously established programme by MSF, seeking permission to venture into new provinces and identifying and recruiting new flucytosine facilities …To date, over 80 sites across provinces benefit from access to this critical commodity.”

‘Substantial reduction in mortalityʼ

Govender notes that the access programme has shown comparable survival benefits from flucytosine when provided in routine care as those shown in the ACTA trial.

“Weʼve got data from the access programme showing a substantial reduction in mortality…when we looked at the data between 2018 and 2020, among about 1,500 patients, we found that those treated with flucytosine had about a 50% reduction in mortality.”

However, he says only a small minority of patients can get flucytosine through the access programme. “Fewer than 10% of all cases of crypto meningitis across the country have access to flucytosine. So obviously, thatʼs a problem,” he says.

“Every day, week, month that flucytosine isnʼt on the national essential medicines list, isnʼt in national guidelines, [and] isnʼt given to the vast majority of patients…it is resulting in deaths that could be avoided,” says Shroufi.

Note: Spotlight understands that the WHO will soon update its guidelines for the treatment of CM. The new guidelines are anticipated to recommend the use of liposomal amphotericin B, in addition to flucytosine and fluconazole, as part of preferred treatment regimens for CM.



Spotlight article – In-depth: What the approval of flucytosine means for the treatment of cryptococcal meningitis in SA (Republished under Creative Commons Licence)


See more from MedicalBrief archives:


MSF takes SAHPRA to task for delay in meningitis drug approval


Improved access to antifungal flucytosine is critical


Regimen change may halve cryptococcal meningitis deaths


Efficacious meningitis drug 'no longer registered' anywhere in Africa




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