Renewed hope for crypto, a deadly AIDS-defining fungal opportunistic infection

This is a plate culture of the fungus Cryptococcus neoformans. Credit: publicdomainfiles.com

By A/Professor Nelesh Govender, National Institute for Communicable Diseases, Johannesburg

Cryptococcosis (“crypto”) is a common AIDS-defining fungal opportunistic infection worldwide. It has been neglected for many years. This is about to change; two exciting new developments in the fight against crypto will directly contribute to the UNAIDS goal of substantially reducing global AIDS deaths:

1. A simple screening programme to detect and treat crypto earlier (“crypto screen-and-treat”) was implemented across South Africa in October 2016. Recommendations to screen-and-treat for crypto have now been included in the national HIV guidelines of at least 24 countries.
2. Shorter, simpler and less toxic antifungal treatment regimens for crypto meningitis (the most severe and deadly form of the disease), which are suitable for resource-limited settings, were proven to be equivalent to the gold standard in the ACTA (Advancing Cryptococcal meningitis Care in Africa) trial, recently reported on at the 2017 International AIDS Society conference in Paris.

Nevertheless, the following barriers need to be overcome before we see a reduction in deaths:

1. We need to focus on differentiated care for patients with advanced HIV disease who have been “left behind” in HIV programmes and are at high risk for opportunistic infections such as crypto
2. We need the crypto screen-and-treat policy to be actively implemented in resource-limited countries with a high crypto burden
3. We need improved access to affordable antifungal medicines, including quality-assured flucytosine. Flucytosine is an off-patent medicine which isn’t registered or available in any sub-Saharan African country

What is the scope of the problem?

Over a million people died from AIDS-related illnesses in 2015. Globally, crypto affects hundreds of thousands of the sickest patients with HIV each year and accounts for 15% to 20% of all AIDS deaths, second only to tuberculosis. Crypto is the commonest cause of meningitis in sub-Saharan Africa and South East Asia and disproportionately affects people in low and middle income countries. Without treatment, crypto meningitis is universally fatal. Even with treatment, between 20% and 60% of patients will die. Patients may be disabled by severe headaches which occur weeks before diagnosis or complications such as blindness and deafness which may occur after the severe brain infection. Crypto is a substantial economic burden on patients and their families.

The current gold standard treatment (amphotericin B and flucytosine for 2 weeks followed by fluconazole for many months) is intensive, costly and requires hospital admission for intravenous amphotericin B and laboratory monitoring for toxicities related to this medicine. In addition, flucytosine is neither registered nor available in any sub-Saharan African country.

Diagnostic/ screening tests for crypto, in particular the accurate, quick, simple and cheap antigen detection tests, are unfortunately not available in all countries with a high crypto burden.

We need differentiated care for patients with advanced HIV disease

The World Health Organization (WHO) has recently issued a guideline that strongly recommends that all patients with advanced HIV disease (CD4 <200 or WHO clinical stage 3/4) be offered a package of interventions including opportunistic infection screening, treatment or prophylaxis. It is essential that CD4 testing be offered before or at the time of ART initiation so that patients with advanced disease can be identified. For crypto, the focus is on screening and treatment of patients with CD4 <100 for early crypto. Governments and donor agencies should implement this recommendation.

We need the crypto screen-and-treat policy to be actively implemented by countries

Following South Africa’s lead in rolling out a national crypto screen-and-treat programme (approximately 250 000 people will be screened per year), other resource-limited countries with a high crypto burden should make similar efforts. This may depend on donor-funded access to crypto antigen tests and antifungal medicines. A challenge in many countries is that laboratory screening for early crypto may not be possible with limited laboratory infrastructure.

We need access to quality-assured and affordable antifungal medicines for crypto including flucytosine

The ACTA trial aimed to define antifungal regimens for crypto meningitis that could be more feasibly implemented than the accepted gold standard of 2 weeks of amphotericin B and flucytosine. The trial compared an oral combination of fluconazole and flucytosine for 2 weeks OR short-course (1 week) amphotericin B with either fluconazole or flucytosine to the gold standard. Both oral and 1-week regimens were equivalent to the gold standard based on deaths at 2 weeks. The best performing arm was 1 week of amphotericin B with flucytosine in terms of deaths at 10 weeks. Notably, all the best-performing arms in the trial contained flucytosine which was associated with better clearance of the fungus from patients’ cerebrospinal fluid.

Urgent efforts are required to ensure that affordable and quality-assured antifungal medicines, including flucytosine are made widely available for the treatment of crypto meningitis. Once flucytosine is available, the 1-week amphotericin B regimen with flucytosine should be used preferentially

Future research

The CAST-NET implementation science study will evaluate the effectiveness of South Africa’s national crypto screen-and-treat programme to reduce crypto deaths over the next 4 years. The planned AMBITION trial will explore the efficacy of single high-dose liposomal amphotericin B with oral flucytosine versus the gold standard for the initial treatment of crypto meningitis. Study results are expected in a few years’ time. Liposomal amphotericin B may allow shorter hospital admissions and fewer toxic side effects compared to conventional amphotericin B. Several other planned trials, including REFINE, have been designed to simplify the “treat” arm of the crypto screen-and-treat intervention by defining more efficacious and potentially shorter antifungal regimens for patients with early crypto.