Fluconazole plus flucytosine vs fluconazole alone for cryptococcal antigen-positive patients identified through screening: A randomised trial

Background - burden of cryptococcal disease

Despite ART roll-out in Africa, about one-third of HIV-infected individuals still present for care with very low CD4 counts, and the incidence of opportunistic co-infections such as cryptococcal meningitis (CM) in this group is high. Furthermore, each year a number of patients drop out of HIV care, later re-presenting with advanced HIV disease and complications such as CM.

Consequently, CM rates are not decreasing in most of Africa. CM is the commonest form of meningitis in sub-Saharan Africa (SSA) and is a key driver of global HIV mortality resulting in ~180,000 deaths/year globally with over 75% in SSA, and accounting for 15-20% of all HIV-related deaths. Targeting cryptococcal disease, prior to the development of life-threatening meningitis, can reduce this persistently high HIV-related mortality: an urgent goal of WHO's 2017 guideline on advanced HIV disease management and in order to achieve the 2030 WHO Sustainable Development Goals.

Cryptococcal antigen (CrAg) screening and pre-emptive treatment

Over half the patients diagnosed with CM die within 10 weeks, a death rate similar to Ebola virus disease. Fortunately, the infection can be detected early, before the development of meningitis, using a simple point-of-care blood test for cryptococcal antigen (CrAg). Studies suggest that 70% of people testing positive for CrAg would progress to develop CM or die without diagnosis and data shows that routine CrAg screening of patients presenting to HIV centres, combined with pre-emptive fluconazole treatment, can cost effectively reduce the risk of developing CM and reduce mortality.

CrAg screening has now been incorporated into 28 National Guidelines and screening programs are being rolled out across SSA. The problem: Need for a more potent antifungal treatment

There is now a considerable body of evidence revealing that CrAg-positive patients treated pre-emptively with fluconazole alone have substantially higher mortality compared to CrAg-negative patients despite this pre-emptive treatment (25-33% mortality vs 9-15% in different studies). In the REMSTART trial, conducted in Tanzania and Zambia, there was 3-fold excess mortality in CrAg-positive asymptomatic patients, compared to CrAg-negative patients with a similar risk of death observed from a recent study in South Africa (SA).

This, and other evidence, suggests that more effective antifungal treatment may be needed to reduce these excess deaths and realize the full benefits of screening programmes. Combined therapy of fluconazole plus flucytosine

The EFFECT trial aims to compare the efficacy of an oral combination of fluconazole plus flucytosine with fluconazole alone (the current recommended treatment) in reducing all-cause mortality in advanced HIV patients in Tanzania and SA. There is now compelling evidence from the recently completed ACTA trial showing that combined treatment of fluconazole plus flucytosine for 2 weeks is well-tolerated and as effective as the standard of 2 weeks intravenous amphotericin B plus flucytosine for in-patients with symptomatic CM.

Mortality was almost halved compared to historic cohorts treated with fluconazole alone. Although the ACTA trial results cannot be directly generalised to CrAg-positive patients without symptomatic meningitis, flucytosine plus fluconazole could also be effective in reducing mortality associated with asymptomatic CrAg-positive patients. And importantly, this oral combination could be given to outpatients without any need for hospitalisation.

Impact

The impact of a combined treatment for CrAg-positive patients identified through screening has not yet been tested and robust clinical trial data are urgently needed to inform policy. Demonstrating the effectiveness of the addition of flucytosine to the fluconazole treatment currently in use could have an important global impact on the reduction of late-stage HIV mortality as has been seen for CM inpatients