Access to medicines for treating people with cryptococcal meningitis

Publication summary

Cryptococcal meningitis is a fungal infection that, despite global advances in improving HIV/AIDS care and prevention, causes about 20% of AIDS-related deaths around the world. In 2020, about 152,000 cases of cryptococcal meningitis and 112,000 deaths occurred globally. In 2022, the World Health Organization (WHO) published treatment guidelines for cryptococcal meningitis in people living with HIV, advocating a regimen that includes a single high dose (10 mg/kg) of liposomal amphotericin B and 14 days of flucytosine and fluconazole. Although the WHO guidelines provide options for alternative regimens if the recommended antifungals are unavailable, the rationale behind including one high dose of liposomal amphotericin B was premised on the lower risk of toxicity, the lower probability that the regimen will cause anemia or hypokalemia, and the ease of the dose’s preparation and administration. In this paper, the authors describe problems associated with access and affordability of the recommended antifungal treatment regimen for cryptococcal meningitis, despite global guidelines that posit it as preferred first-line therapy.

Who this is for

• Researchers and clinicians who work on access to medicines
• HIV/AIDS and fungal diseases specialists
• Policymakers with an interest in the pharmaceutical industry and affordable medicines

Key findings

• Liposomal amphotericin B was approved in 1997. The brand antifungal is made by Gilead, though it went off-patent in 2016 in the US. It is largely unavailable and unaffordable in most low-income countries and many middle-income countries, and it has limited availability in many public healthcare systems. Liposomal amphotericin B also plays a role in treating disseminated histoplasmosis and visceral leishmaniasis in people living with HIV.
• In 2018 Gilead worked with Geneva-based global health agency Unitaid to offer a preferential price of $16.25 USD per vial of liposomal amphotericin B to 116 countries, although procurement problems have plagued access to the antifungal. Less than half of countries eligible for the preferential price have been able to procure the drug at that price, and countries that have been able to affordably obtain the drug have found their efforts frustrated by shortages and delays. Despite these challenges with access, Gilead intends to raise the preferential procurement price to about $19 or $20 USD per vial in 2023.
• Generic versions of liposomal amphotericin B are in development, with one having received US Food and Drug Administration approval in 2021, though manufacturers of generic antifungals have very little financial incentive to increase access in low- and middle-income countries. Liposomal amphotericin B is not registered for use in many low- and middle-income countries, and it’s registered in only two sub-Saharan African countries, creating additional barriers to procurement. The authors recommend policies that incentivize generics manufacturers to devote some manufacturing capacity to affordably supplying antifungals to low- and middle-income countries.
• The authors provide examples from South Africa, India, and Brazil to illustrate the problems in procuring liposomal amphotericin B in low- and middle-income countries. In South Africa, liposomal amphotericin B is not available through public healthcare providers and is priced at $205 USD per vial for private systems. Similarly in India, the antifungal is only available privately through a Gilead distributor for $69 USD per vial. In Brazil, preferential pricing for liposomal amphotericin B is only available for leishmaniasis, and pricing for cryptococcal meningitis is around $373 per vial.
• Flucytosine, also recommended as part of first-line therapy for cryptococcal meningitis in people living with HIV, is also not available in many low- and middle-income countries. Five generic versions of the drug have been approved, but there are currently no plans to improve access to the antifungal for low- and middle-income countries, and two manufacturers of the generic version have registered only in the US.
• The authors note that demand for liposomal amphotericin B and flucytosine may increase as the new WHO guidelines are adopted by countries, perhaps resulting in greater incentives for companies to make the antifungals accessible across poorer economies. However, a pervasive lack of diagnostic testing capability for cryptococcal meningitis and inconsistent national guidelines for treating the infection in people living with HIV remain barriers for manufacturers to provide greater access to the two drugs.