Efficacious meningitis drug ‘no longer registered’ anywhere in Africa

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Despite the fact that cryptococcal meningitis is the second leading killer of people living with HIV, it mostly flies under the radar. According to the World Health Organisation (WHO), 181,100 people with HIV die annually from this form of meningitis, making it responsible for more than 15% of all Aids-related deaths. The vast majority of these deaths – 135,900 – occur in sub-Saharan Africa. “Cryptococcus is a fungus found in the environment, for example in soil with pigeon droppings and sometimes trees. Most people are exposed to the fungus at an early stage of their lives – by the time they are toddlers,” explained Professor Nelesh Govender from South Africa’s National Institute of Communicable Diseases (NICD). “The vast majority of us have antibodies and when we inhale it from the environment nothing ever happens to us,” he said.

But, says a Spotlight report, in people with weak immune systems, particularly those who have problems with certain immune cells called lymphocytes, the fungus reactivates or “wakes up”. Access to antiretroviral treatment (ART), which strengthens immune systems and increases people’s CD4 cell counts, makes HIV-infected patients much less vulnerable to developing cryptococcal meningitis. However, Govender said many South Africans are still only starting ART when they are already very ill while an “increasing number” stop taking their ART, causing their CD4 cell counts to drop again. “In routine care, in most sub-Saharan African settings including in South African hospitals, in about three months over 60% of patients with cryptococcal meningitis are dead,” said Govender.

Spotlight reports that a more effective drug called flucytosine has the potential to bring the death rate down dramatically but few people have access to it because it is not registered in South Africa, or any other African country – the region where it is most needed. “In a clinical trial setting where patients with cryptococcal meningitis were treated with combination flucytosine plus amphotericin B, the mortality was as low as 25% at 10 weeks,” said Govender. The need for the drug is massive and “is estimated to be in the hundred thousands,” across the region. According to Govender, the fact that flucytosine is not registered is a major problem and makes no sense.

Spotlight reports that the South African Health Products Regulatory Authority (SAHPRA) confirmed that flucytosine is not registered in South Africa – and no application for its registration has been submitted. It seems a flucytosine product was previously registered with the old Medicines Control Council, but its registration was not maintained.

The report says currently, the only way for patients in South Africa to get the drug is if their clinician files a section 21 application to SAHPRA. Section 21 applications are a special mechanism that allows the importation of medicines that are not registered in South Africa, providing certain conditions are met. Infectious diseases specialist at Helen Joseph Hospital in Johannesburg Dr Jeremy Nel described this process as “cumbersome and slow”. It often takes weeks making it “pointless” in many cases because patients may have already died by the time the drug arrives at the hospital.

According to Dr Laura Trivino-Duran, medical coordinator for Doctors Without Borders (MSF) in South Africa, the fact that the drug is not registered boils down to a “market failure” and procedural barriers on the part of the only WHO pre-qualified manufacturer of flucytosine, the pharmaceutical company Mylan. There are other suppliers of flucytosine, but they trail Mylan in that they do not yet have WHO pre-qualification.

The situation is compounded by a lack of awareness (including among HIV clinicians), resulting in a failure to create demand, as well as inaction on the part of government.

Mylan has indicated that it “lacked certain data”, particularly related to programmatic implementation, as its main reason for failing to register the drug locally, according to Trivino-Duran.

Spotlight reports in a follow-up that it has received the following comment from Mylan spokesperson Ritika Verma: “In August 2016, Mylan added flucytosine, ANCOTIL, to its portfolio through the Meda acquisition. It is manufactured by a third party and is available for lawful sale under waiver in South Africa and is WHO prequalified. To meet the increasing demand and ensure access to this important product, Mylan has prioritized the development of its own generic flucytosine to be manufactured by Mylan, and anticipates being able to supply countries like South Africa – under waiver – by the end of this year. We plan to file with the WHO Pre-qualification Programme within the same time-frame. Additionally, we plan on filing Mylan’s generic flucytosine with the SAHPRA early next year.”

Spotlight report

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