However, access to L-AmB and flucytosine remains a significant challenge in low- and middle-income countries due to a combination of factors including the drugs not being included in national guidelines and countries not submitting requests to donors such as the Global Fund and PEPFAR to fund the procurement of these lifesaving medicines.
To begin addressing the challenges of accessing L-AmB and flucytosine, governments need to update national cryptococcal meningitis clinical guidance urgently, include these medicines in funding requests from major donors, and increase screening for cryptococcal meningitis among people living with HIV. Governments need to work with pharmaceutical companies and urge them to increase production and expand registration of these medicines to meet the expected increase in demand as countries start to adapt and implement the new guidelines.
Additionally, US corporation Gilead, the main supplier of quality-assured L-AmB, has failed to deliver on its promise of providing this lifesaving medicine at the access price of $16.25 per vial to treat cryptococcal meningitis (which would allow for the inclusion of L-AmB at approximately $195 per person under the new recommended treatment protocol) as promised to 116 countries in 2018. More than three years later, Gilead has still only provided L-AmB to less than half of the eligible countries at the access price. Furthermore, Gilead has done little to expand access in terms of registration of L-AmB where it is needed most – with registrations in only two countries in all of sub-Saharan Africa. In addition, despite multiple quality-assured generic manufacturers of flucytosine in the market, few have been registered and made available in low- and middle-income countries.
Dr Freddy Mangana, HIV-TB Medical Supervisor for MSF in the Democratic Republic of Congo:
“With timely and effective diagnosis and treatment, people living with HIV/AIDS can survive opportunistic infections like cryptococcal meningitis. We are optimistic that the new treatment regimen recommended in the WHO guidelines will be adopted quickly by countries, as it is much simpler to give, can be started immediately in some settings, is better tolerated and will hopefully lead to shorter hospital stays for many patients. However, the limited availability of quality-assured L-AmB and flucytosine means that treatment providers working in sub-Saharan Africa struggle to treat people with cryptococcal meningitis or risk treating them with suboptimal treatments when these medicines are not available. The good news is that this new regimen also uses less L-AmB and requires less monitoring, which could reduce the overall price for countries to implement as compared to the previous L-AmB regimen, if urgently adopted into national guidelines.”
Jessica Burry, HIV pharmacist for MSF's Access Campaign:
“We are encouraged that the WHO guidelines now include a simplified treatment regimen for people with cryptococcal meningitis, but it’s disheartening to see the persistent challenges to accessing the required medicines. This lifesaving treatment remains out of reach and unaffordable for far too many people who need it. To ensure we meet the new WHO targets for decreasing deaths from cryptococcal meningitis, Gilead needs to do everything it can to make good on its promise to provide L-AmB at their access price. In addition, there needs to be a significant effort from countries to prioritise the use of L-AmB and flucytosine, and from manufacturers to start registering and supplying these medicines.”
Liposomal amphotericin B (L-AMB)
In September 2018, Gilead announced an “access” price for 116 low- and middle-income countries of US$16.25 per vial of L-AmB, an essential medicine for treatment of fungal infections including first line treatment per WHO guidelines for management of cryptococcal meningitis in people living with HIV. However, Gilead has exclusive agreements with distributors in many countries, allowing L-AmB to be sold for prices as high as $200 per vial in South Africa and $70 per vial in India, and limiting where this access price is available. In countries outside of the territory of the access pricing, such as Brazil, L-AmB costs $373 per vial for cryptococcal meningitis in the public health system, bringing total treatment cost with L-AmB alone to approximately $5000. More than three years later, Gilead has still only provided L-AmB to less than half of the eligible countries at the access price.
While L-AmB has been off patent since 2016, generic manufacturers have been working for years to develop this product, hindered by the fact that Gilead maintains trade secrets and has not been willing to facilitate technology transfer. This allows Gilead to maintain its monopoly and high price on this drug. At the end of 2019, Gilead finally got USFDA approval for a new manufacturing site in California, US, so an end to the usual 4-6 months lead time for orders was anticipated in June 2020. However, this was further delayed until the end of the 2021 as this new facility is also used to produce remdesivir, a treatment for COVID-19, effectively displacing production of L-AmB and causing continued delays. The first generic formulation of L-AmB was approved by the USFDA in December 2021, which could potentially alleviate supply constraints if they register and supply in high-burden countries.
Finally, Gilead has done little to expand access in terms of registration of L-AmB where it is needed most. In the 63 countries where they have registered the drug, only 2 are in sub-Saharan Africa (Ethiopia and South Africa), for example.
Flucytosine is used as part of the first-line WHO-recommended treatment regimen of cryptococcal meningitis, in combination with L-AmB and fluconazole. Despite being an old drug and off patent for many years, the lack of demand meant that there was little interest by generic manufacturers to produce it, with only a few quality-assured sources available that were primarily selling the drug at very high prices in some high-income countries, and neglecting low- and middle-income markets, where demand was lower. As more countries start to update and implement cryptococcal meningitis guidelines and treat more patients, the market demand will increase further. In the past couple of years, 2 new quality-assured generic sources have started to supply the sub-Saharan Africa region, reducing the price to $65 per bottle of 100 tablets from more than $100 for many low- and middle-income countries. In addition, taking flucytosine 4 times per day is difficult for many patients, and ideally development of a sustained-release formulation would serve to improve adherence and treatment for people living with HIV/AIDS.