A hidden killer of people living with HIV

By Amy Green

In the time before HIV treatment, a cryptococcal meningitis diagnosis was a death sentence for AIDS patients. Today, with access to antiretrovirals and anti-fungal medicine, more patients are surviving – but not enough. It is still the second leading killer of people with HIV. A local screening programme is trying to plug the gap and catch the infection before it becomes deadly. But the gold-standard treatment, with the potential to save many more lives, is not registered in South Africa – or any African country.

Almost 20 years ago, Ugandan Dr Stephen Watiti ran a small clinic about 10km outside Kampala.

It was tough going. He said telling patients they had HIV when there was no access to treatment was “hell”.

“You would just end up scaring them,” he said. Watiti was also living with HIV and he too feared for his life.

He soldiered on until he was struck by a piercing pain in his head. Try as he might he could not open his eyes. It felt as if the rays of light filtering through them were spears, delivering sharp blows directly to his brain.

Doubled up and with his eyes shut tightly, he made his way to a telephone to call for help.

He was rushed to Mulago National Referral Hospital in the city, the largest public hospital in the country.

In the elevator on the way up to the sixth floor Watiti convulsed and collapsed.

“I don’t want to say it was a relief to pass out but it was in a way to get some relief from the pain,” he remembered.

Watiti woke up in a hospital bed to pain “that felt as if a train was driving through my head”.

After a lumbar puncture he was diagnosed with cryptococcal meningitis – an infection of the lining of the brain and spinal cord caused by the cryptococcus fungus.

Already suffering from the AIDS-related cancer kaposi sarcoma, and having just survived a fifth bout of tuberculosis, Watiti thought that this was finally the end for him.

But miraculously, with access to quick treatment, he survived.

“I was lucky I was near the hospital. If I had been in the rural areas with no knowledge of who to call, I’m sure I would not be here,” Watiti told Spotlight from his home near Kampala.

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 in people with weak immune systems, particularly those who have problems with certain immune cells called lymphocytes, the fungus reactivates or “wakes up”.

From the lungs, the fungus spreads to the bloodstream and, if not caught, eventually reaches the brain where “it causes a devastating meningitis”.

The severity of HIV disease is measured via CD4 cells which are a type of lymphocyte. A normal CD4 cell count ranges from 500 to 1,500. A count lower than 200 indicates a dangerously weakened immune system. In September 1999, when Watiti fell ill with cryptococcal meningitis, his CD4 count was 160.

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.

A study conducted in Uganda before access to ART or anti-fungal treatments found that, for HIV patients, cryptococcal meningitis “was universally fatal with a 100% mortality rate”.

“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.

This is even with access to ART and appropriate anti-fungal treatment in the form of amphotericin B and fluconazole.

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.

2018 WHO guidelines recommend flucytosine as the first-option treatment for cryptococcal meningitis. Last year the Southern African HIV Clinicians Society called on the Department of Health to update their outdated guidelines in line with the WHO’s recommendations. They also called on the drug manufacturer to urgently register the drug in sub-Saharan African countries.

New medicine not registered in South Africa

The South African Health Products Regulatory Authority (SAHPRA) confirmed to Spotlight 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.

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.

If there is such a pressing need for this drug, which has been shown to reduce mortality rates by a substantial 40%, why is it not registered?

According to Dr Laura Trivino-Duran, medical coordinator for Doctors Without Borders (MSF) in South Africa, it 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. Pre-qualification indicates that a medicine meets certain standards regarding quality, safety and efficacy – but WHO pre-qualification does not replace the need for registration in South Africa and is not sufficient to allow a drug to be sold or distributed here.

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.

The pharmaceutical giant has reportedly also raised concerns that it has just one manufacturing site for flucytosine, in Poland, which is unable to produce the volumes required in the region. Attempts to get comment directly from Mylan prior to publication were unsuccessful. (See the end of the article for a comment Mylan provided after we published.)

Flucytosine is available for a hefty price in countries like the United States and the United Kingdom and costs around R3,200 for a two-week course when imported under the section 21 system.

Trivino-Duran said that there is no clear reason why generic players have not entered the market in Africa considering the drug is relatively old and off patent.

In an effort to create demand and programmatic data, MSF launched a programme in November 2018 to deliver the drug to 15 hospitals, mostly in South Africa. This was facilitated through a bulk section 21 application.
The Clinton Health Access Initiative may take over the programme in the future.

Since the programme began, 372 courses have reached patients – with dramatic results.

Nel said that since the MSF programme, death rates for cryptococcal meningitis at his hospital have fallen from more than 20% to under 10%.

But the programme has only a few courses of the drug left and there is chance of facing a drug gap in which case clinicians will be forced to revert to the situation where only one in 20 patients who need flucytosine will actually receive it.

“And then avoidable mortality will presumably rise again. As a treating clinician, this is very disheartening,” said Nel.

Further bulk section 21 applications are not considered to be a sustainable solution with Trivino-Duran arguing that it is government’s responsibility to ensure access to the drug.

A life-saving screening programme

In the interim, a screening programme launched by the NICD in 2016 is trying to catch cases of cryptococcal disease in patients before it becomes meningitis, which significantly betters the chances of survival for patients.

If the fungus is identified in the blood, before it reaches the brain, and then treated the death rate plummets from 60% to around 30%, according to Govender.

Govender said it takes an average of three weeks for the fungus to spread to the brain causing meningitis, irreparable damage or death. “So we don’t have a lot of time to act,” he warned.

This is why the NICD, in collaboration with the Department of Health and the National Health Laboratory Service (NHLS), implemented a routine screening programme in October 2016.

According to national guidelines, patients who test positive for HIV in local facilities are asked to give blood so that their CD4 cell count can be determined. Under the programme, CD4 counts that fall below 100 are flagged. The NHLS then uses a simple dipstick test on the same blood sample to detect the fungus. The results of this cryptococcal antigen test are then sent back to the facility and when the patient next visits the clinic they should be immediately started on antifungal treatment if he or she tested positive.

Since the programme started over 600 000 patients’ blood samples have been screened with 34 500 testing positive for the antigen.

Many of these patients had not yet developed symptoms of meningitis and were started on treatment earlier than would have ordinarily been possible.

The true impact on lives saved is unknown, according to Govender, and this data will only be available in 2021.

While the programme is undoubtedly a good move, many more lives could be saved if it was expanded to include people with CD4 counts below 200, as recommended by the WHO (as opposed to the current cut-off of 100).

“But at this stage we’re not sure that the laboratory system can cope with doubling the volumes to 1.4-million. What needs to be done right now is a costing analysis and we also need to discuss this with the Department of Health,” said Govender.

Watiti, an HIV activist as well as clinician, said that in 2019 no one should face the same fears that he did in 1999.

“I felt so close to death. As if a blanket was coming over my head to block out my life,” he said.

The pain Watiti felt 20 years ago still haunts him and he prefers to refer his patients who are suffering with painful meningitis to his colleagues.

“It brings back the pain for me and I don’t want to scare people,” he said.

“When I see people dying of cryptococcal meningitis in this day and age it makes me very sad. We all need to make more noise about flucytosine to create demand. If we make enough noise hopefully, we will be able to prevent nonsensical deaths.”

Update: After the publication of this article Spotlight 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 Prequalification Program within the same timeframe. Additionally, we plan on filing Mylan’s generic flucytosine with the South African Health Products Regulatory Authority (SAHPRA) early next year.” (Waver here refers to the section21 mechanism described in the article.)

 

 

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