Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people: Cochrane systematic review



Cryptococcal disease remains one of the main causes of death in HIV-positive people who have low cluster of differentiation 4 (CD4) cell counts. Currently, the World Health Organization (WHO) recommends screening HIV-positive people with low CD4 counts for cryptococcal antigenaemia (CrAg), and treating those who are CrAg-positive. This Cochrane Review examined the effects of an approach where those with low CD4 counts received regular prophylactic antifungals, such as fluconazole.


To assess the efficacy and safety of antifungal drugs for the primary prevention of cryptococcal disease in adults and children who are HIV-positive.

Search methods

We searched the CENTRAL, MEDLINE PubMed, Embase OVID, CINAHL EBSCOHost, WHO International Clinical Trials Registry Platform (WHO ICTRP),, conference proceedings for the International AIDS Society (IAS) and Conference on Retroviruses and Opportunistic Infections (CROI), and reference lists of relevant articles up to 31 August 2017.

Selection criteria

Randomized controlled trials of adults and children, who are HIV-positive with low CD4 counts, without a current or prior diagnosis of cryptococcal disease that compared any antifungal drug taken as primary prophylaxis to placebo or standard care.

Data collection and analysis

Two review authors independently assessed eligibility and risk of bias, and extracted and analysed data. The primary outcome was all-cause mortality. We summarized all outcomes using risk ratios (RR) with 95% confidence intervals (CI). Where appropriate, we pooled data in meta-analyses. We assessed the certainty of the evidence using the GRADE approach.

Main results

Nine trials, enrolling 5426 participants, met the inclusion criteria of this review. Six trials administered fluconazole, while three trials administered itraconazole.

Antifungal prophylaxis may make little or no difference to all-cause mortality (RR 1.07, 95% CI 0.80 to 1.43; 6 trials, 3220 participants; low-certainty evidence). For cryptococcal specific outcomes, prophylaxis probably reduces the risk of developing cryptococcal disease (RR 0.29, 95% CI 0.17 to 0.49; 7 trials, 5000 participants; moderate-certainty evidence), and probably reduces deaths due to cryptococcal disease (RR 0.29, 95% CI 0.11 to 0.72; 5 trials, 3813 participants; moderate-certainty evidence). Fluconazole prophylaxis may make no clear difference to the risk of developing clinically resistant Candida disease (RR 0.93, 95% CI 0.56 to 1.56; 3 trials, 1198 participants; low-certainty evidence); however, there may be an increased detection of fluconazole-resistant Candida isolates from surveillance cultures (RR 1.25, 95% CI 1.00 to 1.55; 3 trials, 539 participants; low-certainty evidence). Antifungal prophylaxis was generally well-tolerated with probably no clear difference in the risk of discontinuation of antifungal prophylaxis compared with placebo (RR 1.01, 95% CI 0.91 to 1.13; 4 trials, 2317 participants; moderate-certainty evidence). Antifungal prophylaxis may also make no difference to the risk of having any adverse event (RR 1.07, 95% CI 0.88 to 1.30; 4 trials, 2317 participants; low-certainty evidence), or a serious adverse event (RR 1.08, 95% CI 0.83 to 1.41; 4 trials, 888 participants; low-certainty evidence) when compared to placebo or standard care.

Authors' conclusions

Antifungal prophylaxis reduced the risk of developing and dying from cryptococcal disease. Therefore, where CrAG screening is not available, antifungal prophylaxis may be used in patients with low CD4 counts at diagnosis and who are at risk of developing cryptococcal disease.


Awotiwon Ajibola A, Johnson Samuel, Rutherford George W, Meintjes Graeme, Eshun-Wilson Ingrid


Preventing cryptococcal disease in HIV-positive people

What is the aim of this review?

The aim of this Cochrane Review was to find out if taking an antifungal drug regularly, such as fluconazole, prevented HIV-positive people who have low cluster of differentiation 4 (CD4) cell counts, from getting cryptococcal disease, and what the potential complications were. Cochrane researchers collected and analysed all relevant studies to answer this question, and found nine trials that looked at this question.

Key messages

We found that regularly taking antifungal medication prevented HIV-positive people who had low CD4 counts from developing cryptococcal disease. We also found that primary prophylaxis probably reduced the number of people dying specifically from cryptococcal disease. However it probably did not reduce the number of people dying overall.

What was studied in the review?

Cryptococcal disease is one of the leading causes of death for HIV-positive people who have low CD4 counts. The current recommended strategy in most countries to prevent people from developing cryptococcal disease, is to screen eligible patients with a blood test that picks up early signs of disease. We looked at trials that studied whether taking antifungal prophylaxis stopped people from dying or developing cryptococcal disease. We also looked at the side effects of the antifungal drug and whether it caused resistance to antifungal drugs in other fungal infections, such as thrush.

What are the main results of the review?

We found nine trials that included 5426 participants. These trials were conducted in Australia, Canada, South Africa, the UK, the USA,Thailand, and sub-Saharan Africa. Seven trials were conducted before the availability of modern antiretroviral therapy. The participants in two large trials received modern HIV treatment regimens.

We found that antifungal prophylaxis may have no effect on death overall, although it reduced the risk of those with low CD4 counts developing cryptococcal disease by 71%. Prophylaxis with an antifungal probably also reduced deaths specifically from cryptococcal disease. There may be an increased risk of the vaginal tract becoming colonized with fluconazole-resistant Candida organisms if someone takes prophylaxis, however, this may not necessarily result in an increased risk of clinical disease that doesn't respond to treatment. Generally, there were few side effects of taking antifungal prophylaxis, and it was well-tolerated when compared to placebo.

How up to date is this review?

The review authors searched for studies that had been published up to 31 August 2017.

Reviewer's Conclusions

Implications for practice

Primary prophylaxis with either fluconazole or itraconazole probably reduces the risk of developing cryptococcal disease. Prophylaxis also probably reduces the risk of death due to cryptococcal disease, however, this may not have translated to a reduction in all-cause mortality in the trials identified. Clinicians and policy makers will have to consider the benefit of providing antifungal prophylaxis in the context of cryptococcal disease prevalence, cost, consistent drug supply, and the availability of cryptococcal antigen (CrAg) screening in their setting. Antifungal primary prophylaxis could be considered a part of differentiated packages of care for those who are diagnosed late with low cluster of differentiation 4 (CD4) cell counts, and those at risk of cryptococcal disease, particularly where CrAg screening is unavailable.

Implications for research

The authors do not believe that further research is required to show the efficacy of primary antifungal prophylaxis in reducing the occurrence of cryptococcal disease, particularly among patients where CrAg status is unknown. The cost-benefit of providing antifungal prophylaxis to CrAg-negative patients remains an area of debate, due to the low occurrence of cryptococcal disease in this group. Further analyses of the cost effectiveness and feasibility of implementing this intervention in different settings are needed, as well as comparisons between the primary prophylaxis strategy and the strategy of CrAg screening plus pre-emptive antifungal therapy for those who screened positive.

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