Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people

Background: 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. Objectives: 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), ClinicalTrials.gov, 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.