Off the radar: Cryptococcal meningitis
Cryptococcal meningitis (crypto) may not be the first thing that comes to mind when talking about HIV – but this common opportunistic infection and AIDS-defining illness is one of the leading killers of people living with HIV globally.
With a million cases of crypto each year and 625,000 deaths, this deadly fungal infection is particularly prevalent in sub-Saharan Africa, where it is the leading cause of meningitis in the region and accounts for around 15% to 20% of all AIDS-related deaths. 1
Given the numbers, the global profile of cryptococcal meningitis is low, as Patrick Adams writes in a recent World Report for The Lancet.
Despite being dubbed the ‘blind spot in curbing AIDS’, and the infection that is ‘forgotten but not gone,’ crypto is not considered a ‘neglected disease’ by the World Health Organisation (WHO). 2 3 The treatment options are old, expensive and ill-tolerated and there seems to be little appetite to address this major health challenge.
So what is cryptococcal meningitis? Cryptococcal meningitis is caused by cryptococcus neoformans, a fungus found in soil around the world. Harmless to most, the fungus can be deadly for people living with an autoimmune disorder such as HIV, spreading from the lungs to the brain and spinal cord, causing meningitis.
Symptoms can be severe and include debilitating headaches, coma, fever, vomiting, among other things. If left untreated, it can lead to death. Rose Sabina, a survivor from Uganda, told Newsweek: “You cannot eat, you cannot talk, you do not know where you are, the head wants to burst. The pain is too much.”
Onset of cryptococcal meningitis is most likely among people living with HIV with CD4 counts of 100 cells/mm3 or below.
In high-income countries, increased access to effective treatment has prevented people reaching the severely immunocompromised state that makes them vulnerable to cryptococcus infection. But in sub-Saharan Africa, poor healthcare systems, delays in presenting to care, poor linkages to treatment and inadequate treatment options for crypto, mean that mortality is high.
Tom Harrison, a professor of medicine at St George's, University of London, told Adams, “Some [scientists] say we've solved HIV and that crypto will soon go away. And then there are those on the medical wards in Africa, still seeing cases, who say, ‘No, we haven't. We have to do more.'”
Many people present to care at an already late stage of infection and once they have fallen ill. Those that do present to care are often ‘lost to follow up’, meaning they do not return to care after their initial HIV diagnosis.
Angela Loyse, chair of the Cryptococcal Meningitis Action Group (CryptoMAG), a self-funded group led by scientists from the Centers for Disease Control (CDC), the The World Health Organization (WHO) and Medicines san Frontier (MSF), among others, told Adams: “You're talking about a mortality rate as high as 70% in routine care settings. That's linked to delays in diagnosis and treatment—and to the fact that access to current drugs is limited, and that those drugs have significant drawbacks.”
When people do present to care, treatment is not simple. The antifungal treatment used to treat crypto are dated, poorly tolerated, expensive and largely unavailable where they are needed most. Deaths arising from infection in clinical trial settings can be between 30% and 50%.4
The drug amphotericin B, recommended for use in first-line therapy, is over 60 years old and requires hospitalisation and close monitoring of side-effects. The cost of hospitalisation on top of the already high price of the drug puts significant strains on already weak health systems
Flucytosine, also recommended for use in first-line therapy, is another old drug that is unavailable in most low and middle-income countries. Lack of demand and supply mean that the drug is prohibitively expensive to obtain. It is currently not registered in any African country. 5
In lieu of these two drugs, fluconazole monotherapy is often used, a drug that is offered for free in many parts of Africa – although reports suggests that it is in low supply.6 However, as a treatment regimen, it is sub-optimal and associated with higher rates of mortality.
The development of new and effective treatments for crypto has been seriously lacking. There have been no new recent clinical trials that look at new antifungal treatment for crypto – only trials that look at new combinations of older treatment regimens.7
While the need to develop new and effective treatment regimens is clear, as well as strategies to ensure that they are affordable and available in countries where they are needed most – it’s just not happening.
A 2009 study in AIDS Journal attempted to understand the global burden of crypto, they state: “The worldwide number of infections and deaths due to crypto appear similar to those for diseases that have received greater public health attention. In sub-Saharan Africa, deaths due to crypto (530,000) may be more frequent than tuberculosis (350,000).”8
The fact that crypto is not labelled as a ‘neglected disease’ by the WHO is important. This status takes it off the radar, with no incentives to channel philanthropic funding for research and development. Adams states: “When it comes to cryptococcal meningitis… donors have largely looked the other way, and the result is a barren drug pipeline.”
Yet the news isn’t all bad – a study in Tanzania showed that a simple and cost-effective package of screening for crypto, plus community support for ART adherence, reduced deaths by 30% among people starting treatment at a CD4 count below 100 cells/mm3.9
The screening tests for the cryptococcal antigen – an important marker for the onset of crypto. If people test positive for the antigen, they can be put on a pre-emptive treatment of fluconazole, which helps the body fight off infection before symptoms occur.
But uptake of crypto screening programmes have not been universally implemented, despite being advocated by WHO and the CDC. Until crypto gains more attention on the global health forum, it will continue to affect progress in responding to the epidemic.
WHO now recommends HIV treatment for all, regardless of CD4 count. But until low- and middle-income countries are able to increase access to ART, cryptococcal meningitis will remain a significant cause of mortality and morbidity for them.
- 1. Park, Benjamin et.al. (2009) ‘Estimation of the current global burden of crypto among persons living with HIV/AIDS’ AIDS Journal
- 2. Adams, P. (2016) ‘Cryptococcal meningitis: a blind spot in curbing AIDS’ The Lancet
- 3. Jarvisemail, Joseph & Harrison, Thomas (2016) “Forgotten but not gone: HIV-associated cryptococcal meningitis” The Lancet Infectious Diseases
- 4. Jarvisemail, Joseph & Harrison, Thomas (2016) “Forgotten but not gone: HIV-associated cryptococcal meningitis” The Lancet Infectious Diseases
- 5. Loyse, A. et.al. (2013) ‘Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries’ The Lancet
- 6. CDC (2014) ‘Preventing Deaths Due to Cryptococcus with Targeted Screening’
- 7. Rhein, J. et.al (2016) ‘Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study’ The Lancet Infectious Diseases
- 8. Park, Benjamin et.al. (2009) ‘Estimation of the current global burden of crypto among persons living with HIV/AIDS’ AIDS Journal
- 9. >Mfinanga, S. et.al. (2015) ‘Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial’ The Lancet