Cryptococcal meningitis remains a leading killer of people living with HIV

Despite increases in access to antiretroviral treatment (ART), HIV-related cryptococcal meningitis accounts for 15% of AIDS deaths globally, falling behind only tuberculosis (TB) as a leading killer of people living with HIV.

In a new Lancet Infectious Diseases report – the first in eight years to look at the global burden of cryptococcal disease – 181,100 people died from cryptococcal meningitis in 2014, with 135,900 (75%) deaths in sub-Saharan Africa alone. The authors estimate that around 6% of all people living with HIV with CD4 counts below 100 cells/mm3 had the cryptococcal antigen, a major predictor of cryptococcal meningitis.

Health outcomes for people with cryptococcal meningitis are generally very poor, and without treatment it is mostly fatal. Depending on the types of treatment available, outcomes vary considerably geographically, with many countries reporting anywhere between 20% to 50% mortality rates in the first year after diagnosis.

Cryptococcal meningitis is an AIDS-defining illness caused by the fungus, cryptococcus neoformans. For people who have been exposed, the fungus remains largely latent in the body and most will never fall ill. But for those living with a compromised immune system, infection can spread from the lungs to the brain and spinal cord, causing meningitis.

Cryptococcal meningitis is particularly difficult to treat, so prevention is crucial through effective ART which keeps the immune system healthy.
    
Of treatment options available, the first-line antifungal agent used, amphotericin B, is old, ill-tolerated and requires expensive hospital monitoring. In high-income countries, the use of amphotericin B in combination with a more expensive drug, flucytosine, is most effective; but access to fluctyosine is severely limited in middle and low-income countries.
    
In the new analysis, the researchers compiled data relating to immunological risk for cryptococcus – including CD4 count below 100 cells/mm3, virological failure and losses to follow-up. They combined this with data relating to biological risk, the presence of the cryptococcal antigen, as well as health outcome data after diagnosis.

While absolute numbers of people with cryptococcal meningitis have fallen during the pre-ART era, the proportion of AIDS-related deaths remains largely unchanged, indicating that prevention based solely on increased antiretroviral treatment uptake may be insufficient.

A study from Botswana, a country often hailed for being on the cusp of reaching the Fast-Track 90-90-90 targets (90% of people living with HIV tested, 90% of those people on treatment, and 90% of people on treatment virally suppressed), shows rates of cryptococcal meningitis have failed to change in recent years.  

An estimated 20% to 25% of people living with HIV still present late to care and with CD4 counts below 100 cells/mm3. The authors state, “in 2016, no person with HIV should develop cryptococcal disease, yet due to challenges with late diagnosis, linkage to care, ART access, retention in care and virological failure on ART, the often final event in a failed cascade of HIV care is the development of cryptococcal meningitis.”

Cryptococcal antigenaemia screening has the potential to reduce costs and mortality relating to cryptococcal meningitis. While treatment for cryptococcal meningitis is costly and laborious on the health system, implementing screening programmes to identify those at risk, and providing them with a pre-emptive and low-cost therapy (fluconazole), and an antiretroviral adherence support programme, is a strategy to curb cryptococcus prevalence.

One study from Uganda, and noted in the research discussion, found that this type of programme would reduce the cost of meningitis treatment by 15% and yield a 40% improvement on long-term survival.  

There also remain questions beyond behavioural factors relating to the persistence of cryptococcal meningitis.

In an accompanying editorial in the journal, Peter R Williamson commented that the HIV reservoir in patients on ART may be important: “Survival and growth of latent fungal organisms within the brain meningeal immune cells might be facilitated by the presence of a latent HIV viral infection, stubbornly persistent within macrophages and the CNS [central nervous system].”

“This persistent HIV reservoir, which is postulated to contribute to neurocognitive decline in patients on ART, might thus also have a role in the development of cryptococcal meningitis in patients on ART because fungal macrophage residence is key to survival and virulence of the pathogen.”

Williamson called the Lancet research “a seminal contribution to the quantification of the global burden of cryptococcal disease in patients infected with HIV.”