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- Cryptococcal meningitis (CM) kills many HIV patients in South Africa.
- L-AmB, a new drug, is less toxic than amphotericin B deoxycholate, which is currently used to combat CM.
- Manufacturer, Gilead, has, however, not dropped the price of L-AmB as promised, putting the drug out of reach of most South Africans.
Cryptococcal meningitis (CM) is the second leading killer of people living with HIV in South Africa, behind only tuberculosis. Without treatment, the condition, which mainly affects people with advanced HIV disease, is 100% fatal.
CM is ideally treated with a regimen of three different drugs – fluconazole, flucytosine, and liposomal amphotericin B (L-AmB). A previous Spotlight article focused on access to flucytosine. In this article, we focus on L-AmB.
Price limits access in SA
In 2018 the pharmaceutical company Gilead committed to selling L-AmB, marketed under the brand name AmBisome, to public health sectors in low-and middle-income countries (LMICs) at an “access price” of R240 ($16.25) per 50 mg vial.
Yet the company has done little to deliver on this promise to date. According to Médecins Sans Frontières (MSF), Gilead has only registered L-AmB in two Sub-Saharan African countries, and in South Africa where the medicine is registered, it is sold at more than ten times the committed access price.
L-AmB is marketed in South Africa by Key Oncologics, which has an exclusive distributor arrangement with Gilead for the medicine. Key Oncologics sells L-AmB in South Africa’s private sector at R 2 880 ($ 195) per 50 mg vial. According to data compiled by MSF, this price is more than double what is charged for the medicine in the high-income countries Spain and Luxembourg, where it is sold at R1 280 ($87) and R1 427 ($97), respectively.
Because of its high price, L-AmB is not procured by the National Department of Health (NDoH) for use in the public sector, where the vast majority of cryptococcal meningitis patients receive care. Instead, the NDoH has continued to use an older, more toxic formulation of amphotericin B called amphotericin B deoxycholate.
Meanwhile, L-AmB is being used to treat fungal infections in private-sector cancer patients in South Africa. It is for this private sector market that the drug appears to have been priced.
New WHO guidance changes the picture
However, calculations regarding the affordability of L-AmB have changed dramatically with the release of new World Health Organization (WHO) guidelines for the treatment of CM last week.
The updated WHO guidelines replace one week of intravenous amphotericin B plus flucytosine, followed by one week of high dose fluconazole, with a simpler regimen of a single day of intravenous, high-dose L-AmB, followed by two weeks of flucytosine and fluconazole, as the preferred treatment regimen for CM.
There is compelling evidence in support of this change.
Recently published results from the AMBITION-cm trial – the largest ever trial of CM treatment – showed that a single dose of L-AmB infused over a couple of hours and followed with two weeks of flucytosine and fluconazole is as effective as the WHO’s previously recommended standard of care: one week of amphotericin B deoxycholate plus flucytosine, followed by one week of high dose fluconazole. The AMBITION-cm trial was conducted in eight hospitals across Africa, including the Khayelitsha and Mitchells Plain Hospitals in Cape Town.
Prior to findings from the AMBITION-cm trial, L-AmB was widely viewed as a superior drug to amphotericin B deoxycholate for cryptococcal meningitis treatment, which caused far fewer serious side effects, but was priced too high for widespread use in LMICs. The AMBITION-cm trial changed those perceptions by showing that effectiveness was maintained when L-AmB was only given as a single high dose infusion.
What would replacing amphotericin deoxycholate B with L-AmB cost?
Under the WHO’s new guidelines, patients should be given a single high dose of L-AmB on the first day of their treatment, followed by 14 days of oral flucytosine and fluconazole pills.
The recommended L-AmB dosage is 10 mg per kg, which equates to twelve 50 mg vials for an individual weighing 60 kilograms. The cost of 12 vials at Gilead’s promised, but not delivered, access price would be R2 880. At the price currently charged by Key Oncologics, however, 12 vials would cost R34 560.
In South Africa, amphotericin B deoxycholate is still typically given for two weeks at 1 mg per kilogram per day in combination with fluconazole, as flucytosine is not yet universally available to CM patients (read about what must be done to ensure universal access to flucytosine here). Someone who weighs 60 kilograms would therefore require seventeen 50 mg vials as part of their two-week treatment course (assuming no wastage), which, at a cost of R150 per vial, would total R2 550.
While understanding the actual cost of replacing amphotericin B deoxycholate with L-AmB is more complex – and must also account for the introduction of flucytosine for two weeks, as well as savings arising from reduced treatment-related complications and potentially shortened periods of hospitalisation – our back of the envelope calculations suggest that if access prices are met, then universal provision of L-AmB to all CM patients in the country may be feasible.
In response to queries about the feasibility and affordability of providing L-AmB for CM treatment in South Africa’s public sector, Khadija Jamaloodien, director of Affordable Medicines at the NDoH, told Spotlight “An HTA [Health Technology Assessment] is required for this treatment protocol”, adding “there are concerns regarding pricing [including access prices from the manufacturer] and the lack of generic formulations in the market to stimulate competition”.
What the companies say
Spotlight contacted both Gilead and Key Oncologics to query why the promised access prices have not been delivered in South Africa.
Craig Atherfold from the PR firm Corporate Image responded to Spotlight on behalf of Gilead, writing that “Key Oncologics is the marketing authorisation holder for AmBisome in South Africa. Any questions relating to the current arrangements for supply of AmBisome for patients in South Africa should be directed to Key Oncologics as the marketing authorisation holder.”
Magriet de Wet, the CEO of Key Oncologics told Spotlight, “Key Oncologics (Pty) Ltd is the Marketing Authorization Holder (MAH) for AmBisome in South Africa. We work closely with Gilead as we are their exclusive distributor for AmBisome in South Africa.” She noted, however, that regarding the public sector where Key Oncologics is not selling L-AmB, “Gilead has made an obligation to governments and public sectors of LMICs – we are committed to working with Gilead to support this initiative.”
In addition to Gilead’s AmBisome, there are several other companies selling L-AmB products on the global market – although few of these products have been registered by a stringent regulatory authority.
Spotlight contacted Sun Pharma which recently announced that their L-AmB product has been registered with the United States Food and Drug Administration – a regulatory authority with which South Africa’s own regulatory authority has reliance mechanisms in place that can be used to fast track the registration of new products – to ask whether they had submitted or planned to submit an application for registration of their L-AmB product in South Africa. Sun Pharma did not respond by the time of publication.
The benefits of replacing 'ampho-terrible' with L-AmB
“Amphotericin B [deoxycholate] is a drug that doctors and nurses used to call ampho-terrible,” says Amir Shroufi, MSF Southern Africa board member. He says “it's a really nasty drug. Doctors and nurses don't like it because it can cause severe anaemia. It's toxic to the kidneys, so it can cause kidney damage and even kidney failure… and the infusion line used for the drug can often become infected and it can cause inflammation of the veins where it's going into the body.”
He describes L-AmB as a “much better drug” and stresses the benefits of giving it for one day as opposed to a week or two.
Professor Graeme Meintjes, an infectious disease expert at the University of Cape Town, explains that adopting the WHO’s new recommendations for a single high dose of L-AmB followed by two weeks of flucytosine and fluconazole “would make the management algorithms more simple to implement because it's just a single infusion, would reduce the complications for patients, and would reduce the complexity for the health system of treating cryptococcal meningitis”.
Dr Jacqui Miot, division director of the Wits Health Economics and Epidemiology Research office, explains that given the seriousness of CM, its treatment is likely to continue to require hospitalisation, but updating treatment regimens in line with the WHO’s new recommendations means that patients won’t be tethered to a drip for two weeks and may be able to go home earlier – something she points out has quality of life implications for patients.
'You have to have flucytosine'
There are other benefits, Jessica Burry, a pharmacist with the MSF Access Campaign, says that because L-AmB has far fewer side effects than amphotericin B deoxycholate, there’s less monitoring and lab work required, which could provide cost savings.
Shroufi adds that due to the suboptimal capacity for monitoring side effects related to amphotericin B in many hospitals in Africa, the introduction of a simpler regimen containing a single day of L-AmB that requires less intensive monitoring will likely prevent treatment-related deaths among cryptococcal meningitis patients. However, he stresses that “whatever you're doing, you have to have flucytosine. That's your baseline, even if you're giving liposomal amphotericin B, you have to have the flucytosine.”
For now, though, it remains unclear when the WHO’s new recommended CM treatment regimen containing both L-AmB and flucytosine will become widely available in South Africa.
“In this day and age, we shouldn't be having people dying because they cannot access improved medical interventions… if we don’t have access because of cost, that’s really sad,” says Makhosazana Mkhatshwa, research officer at the Treatment Action Campaign. “People are still dying in numbers. I mean, crypto is the second killer of people living with HIV, after TB.”
Note: A representative of the TAC is quoted in this article. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
*This article was published by Spotlight - health journalism in the public interest.
