High-Dose Fluconazole Consolidation Therapy for Cryptococcal Meningitis in Sub-Saharan Africa: Much to Gain,Little to Lose

Postdischarge Mortality in Patients with Cryptococcal Meningitis Remains Very High in Sub-Saharan Africa

Two-thirds of the estimated 181,100 annual deaths from cryptococcal meningitis occur in sub-Saharan Africa, where it accounts for an estimated 25% of AIDS-associated mortality. ^{1 –3} Most deaths from cryptococcal meningitis occur early, before or during the induction phase of treatment in hospital. However, among patients in sub-Saharan Africa, there is also considerable mortality in the period after discharge, after transition to oral fluconazole, typically dosed at 400 mg/day, for consolidation antifungal therapy. In the 6 months after discharge, for example, sub-Saharan African patients with cryptococcal meningitis experience an additional 20%–30% mortality, with posthospitalization deaths peaking at 4–5 weeks after discharge, far exceeding what has been observed in North America and Europe. ^{4 –6}

Viable Cryptococcus neoformans in Cerebrospinal Fluid After Induction Therapy Contributes to High-Postdischarge Mortality

Excess posthospitalization mortality among patients with cryptococcal meningitis is likely to be, in part, related to delayed presentation to care and inadequate induction therapy contributing to residual disease at the time of discharge. ⁷ Residual disease after induction antifungal therapy is common in resource-limited settings, in part, because flucytosine—the most effective partner drug used with amphotericin B—remains unaffordable. In addition, therapeutic lumbar puncture, critical to managing elevated intracerebral pressure (ICP) and reducing fungal burden, is underutilized. ^{8 –10} Not surprisingly—at the end of amphotericin-based induction therapy—one-third to one-half of patients in resource-limited African settings still have viable Cryptococcus neoformans in cerebrospinal fluid (CSF). ^6,11 The presence of viable cryptococci after induction therapy has been shown in studies to be a major risk factor for poor outcome, including disease relapse, ongoing elevated ICP, and excess disease-specific mortality. ^5,7,9

High-Dose Fluconazole Consolidation Therapy is Linked with Improved Postdischarge Outcomes with a Low Potential for Toxicity

After induction therapy, fluconazole dosed at 400 mg/day has been the most widely used dose strategy in sub-Saharan African countries for consolidation antifungal therapy (Table 1). But this recommendation was established in clinical trials among patients who received a more optimal induction regimen consisting of amphotericin B and flucytosine—a combination associated with potent fungicidal activity and a greater likelihood of CSF sterilization. ^{12 –14} Nonetheless, the use of fluconazole 400 mg/day, a largely fungistatic regimen, as consolidation therapy has been broadly adopted by countries where induction therapy is less ideal.

A higher, fungicidal dose of fluconazole (>400 mg/day) during consolidation phase of therapy may be more effective in controlling residual infection. High-dose fluconazole in animal models was shown to markedly enhance central nervous system fungicidal responses. ¹⁵ For example, in the cryptococcal meningitis rabbit model in which low-, intermediate-, and high-dose fluconazole—100 mg, 400 mg, 1,600–2,000 mg in respective equivalent human dosing—were administered, rabbits showed a dose–response relationship with higher fluconazole dose associated with a greater reduction in quantitative titer of C. neoformans and CSF parameters of inflammation, with only the highest fluconazole dose linked with a reduction in brain edema at day 7. ¹⁵

A 2008 North American clinical trial, employing fluconazole as induction therapy, also showed a dose–response effect with higher doses of fluconazole increasing the probability of week 10 CSF sterilization, up to a dose of 1,600 mg/day. ¹⁶ In consolidation therapy, in 2009, Pappas et al. ¹⁷ found that patients who received high-dose consolidation therapy with fluconazole 800 mg/day for 8 weeks after initial amphotericin B-based induction—compared with patients who received standard-dose fluconazole consolidation (400 mg/day)—experienced a trend toward a reduction in 70-day mortality as well as higher rates of overall treatment success.

Recently, the use of high-dose fluconazole consolidation therapy was tested in a substudy of the 2015 Cryptococcal Optimal ART Timing (COAT) trial in which—after amphotericin B-based induction treatment—all patients received “enhanced” consolidation therapy with high-dose fluconazole using 800 mg/day. Participants from Uganda and South Africa at the end of standard induction therapy were given high-dose consolidation (fluconazole 800 mg/day) until CSF cultures were sterile (residually positive patients received a median of 40 days, interquartile range 22–54 days), followed by the standard consolidation using fluconazole 400 mg/day for 8 weeks. Mortality between 2 weeks and 6 months after induction therapy according to CSF culture status 14 days after amphotericin initiation was 27% [95% confidence interval (CI): 17%–37%] in the sterile CSF group and 35% (95% CI: 23%–47%) in the persistently culture positive CSF group (the group that received an additional 2 weeks of fluconazole 800 mg/day) with an adjusted hazard ratio associated with persistent culture positivity CSF of 1.21 (95% CI: 0.62–2.34). ¹¹ This suggests that with the use of this strategy, the association between residual cryptococcal culture positivity and increased mortality was no longer observed, with a fungicidal fluconazole dose potentially attenuating the impact of persistently positive cultures.

The use of high-dose fluconazole at 800 mg/day or higher for various clinical indications has been associated in trials and in cohort data with low levels of toxicity. ¹⁸ In the trial by Pappas et al., ¹⁷ the prevalence of severe or life-threatening adverse effects related to fluconazole was 4.4% in the group receiving consolidation antifungal therapy with fluconazole 800 mg/day. In long-term use, one of the largest experiences with high-dose fluconazole is among U.S. patients with coccidioidal meningitis. Mathisen et al. ¹⁹ also found low rates of serious adverse events, including hepatotoxicity, among such patients, two-thirds of whom received high-dose fluconazole (≥800 mg/day) for months to years. Common side effects noted have been nausea and dry, chapped lips and skin, usually manageable with topical agents.

High-Dose Fluconazole Consolidation Therapy as an Interim Measure in Sub-Saharan African

The use of high-dose fluconazole consolidation in cryptococcal meningitis merits examination in a randomized clinical trial to reduce posthospitalization mortality as patients await ART initiation. ¹¹ Currently the World Health Organization (WHO) ²⁰ recommends deferring the initiation of ART until 4 weeks after initiation of induction and consolidation treatment with amphotericin B-containing regimens. In the interim, consolidation therapy with 800 mg/day of fluconazole has been included as an option after a 2-week amphotericin-based induction regimen and as a recommendation after short-course induction (amphotericin for 5–7 days) in the most recent WHO HIV management guidelines. ²¹ Nonetheless, most African countries with published guidelines continue to recommend standard-dose fluconazole 400 mg/day as consolidation therapy (Table 1). To increase the evidence for a high-dose consolidation strategy, efficacy and safety data from a rigorous trial are essential. The findings of such a trial would be most applicable to settings wherein patients receive suboptimal induction therapy without combination amphotericin B plus flucytosine and in hospitals where it is challenging to obtain CSF at the end of induction therapy to demonstrate culture conversion. Fluconazole is available, through the Pfizer Diflucan Partnership, free of charge in developing countries with generalized HIV epidemics. In countries where postdischarge mortality from cryptococcal meningitis is high and flucytosine remains unavailable, the use of high-dose fluconazole consolidation therapy for 6–8 weeks—the duration that proved protective in the COAT substudy—deserves serious consideration as an interim step with little risk and the potential for considerable public health benefit (Fig. 1).

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FIG. 1.

Proposed therapeutic algorithm for managing cryptococcal meningitis when flucytosine and cryptococcal cultures are not available: 1. induction—to rapidly reduce fungal load and optimally to sterilize CSF, 2. enhanced consolidation—to kill residual cryptococci before ART initiation, 3. standard consolidation—to provide suppression in early immune recovery, and 4. maintenance—to provide suppression in late immune recovery.