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Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention

Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention
Authors:
Gary M Cox, MD
John R Perfect, MD
Section Editor:
John A Bartlett, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Literature review current through: Nov 2022. | This topic last updated: Oct 11, 2022.

INTRODUCTION — Cryptococcus neoformans meningoencephalitis is one of the leading opportunistic infections seen in patients with untreated AIDS [1]. Management of these severely immunocompromised patients includes antifungal therapy combined with antiretroviral therapy (ART), with careful monitoring for complications related to the invasive fungal infection and the inflammatory syndrome that can develop secondary to immune recovery [2].

This topic will review the treatment of C. neoformans meningoencephalitis in patients with human immunodeficiency virus (HIV) infection. Other topic reviews that discuss cryptococcal infections (C. neoformans and Cryptococcus gattii) include:

(See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

(See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

(See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

(See "Cryptococcus neoformans infection outside the central nervous system".)

(See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)

(See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

(See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis".)

(See "Cryptococcus gattii infection: Clinical features and diagnosis".)

(See "Cryptococcus gattii infection: Treatment".)

TREATMENT

Overview — Patients with HIV and advanced immunosuppression (eg, CD4 cell count <50 cells/microL) are at risk for severe cryptococcal meningoencephalitis, which is uniformly fatal within approximately two weeks if untreated [3]. Common presenting symptoms include fever, headache, photophobia, nausea, and vomiting; patients with fulminant disease may present with coma. Predictors of poor outcome include high cerebrospinal fluid (CSF) cryptococcal antigen levels (titer >1:1024 by latex; >1:4000 by lateral flow assay), low body weight, poor CSF inflammatory response (<20 cells/microL of CSF), and altered mental status on presentation [4]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

Management of cryptococcal meningoencephalitis includes all of the following:

Antifungal therapy. (See 'Antifungal therapy' below.)

Control of intracranial pressure, which can lead to blindness, herniation, persistent headaches, and/or neuropathies if left untreated. (See 'Management of increased intracranial pressure' below.)

Immune recovery with potent antiretroviral medications. However, to reduce the risk of developing an immune reconstitution inflammatory syndrome (IRIS), antiretroviral therapy (ART) should be started between 2 and 10 weeks after antifungal therapy has been initiated. In resource-limited areas, the timing of ART is commonly between four and six weeks, but in resource-rich health care systems, ART initiation can be delayed up to 10 weeks. (See 'When to initiate antiretroviral therapy' below.)

There is no role for empiric glucocorticoids during induction therapy. This is in contrast to other conditions (eg, tuberculous meningitis) in which glucocorticoids are routinely administered as part of initial therapy. The use of glucocorticoids for patients with cryptococcal meningitis was evaluated in a randomized trial that included 451 patients from Asia and Africa [5]. Patients received amphotericin B plus fluconazole with or without dexamethasone (starting at 0.3 mg/kg per day and then tapered over six weeks). The trial was stopped early after an interim analysis found no difference in mortality or the rate of IRIS between the two groups at 10 weeks; in addition, patients who received adjunctive glucocorticoids were less likely to have a good neurologic outcome (13 versus 25 percent; odds ratio 0.42, 95% CI 0.25-0.69). Patients who received dexamethasone also had significantly slower rates of fungal CSF clearance after approximately two weeks and were significantly more likely to develop an adverse event (eg, infection, renal or cardiac event) by six months (667 versus 494 adverse events).

Antifungal therapy — The optimal approach to antifungal therapy involves three phases: induction therapy for approximately two weeks, followed by consolidative therapy for eight weeks [2,6], and then maintenance (ie, suppressive) therapy for at least one year to decrease the risk of relapse (table 1). (See 'Induction therapy' below and 'Consolidation regimen' below.)

The primary antifungal agents used for the treatment of cryptococcal meningoencephalitis include intravenous (IV) amphotericin B, oral flucytosine, and oral fluconazole. Use of intrathecal or intraventricular amphotericin B is not advised except in extreme circumstances, since systemic administration demonstrates good efficacy and these other direct routes can be associated with arachnoiditis [7]. In addition, echinocandin antifungals should not be used to treat this infection, since echinocandins do not have significant activity against C. neoformans.

The approach to treatment below describes treatment in nonpregnant adults. Treatment of pregnant persons should be managed in conjunction with an infectious diseases specialist since flucytosine and fluconazole may be teratogenic during pregnancy, particularly in the first trimester.

Induction therapy

Preferred regimens — This section will review our preferred approach to regimen selection. Discussions of alternative regimens and the data evaluating these regimens are found below. (See 'Efficacy of induction regimens' below and 'Alternative regimens' below.)

When resources are available – When resources allow, we suggest induction therapy with liposomal amphotericin B (3 to 4 mg/kg IV daily) plus flucytosine (100 mg/kg per day orally in four divided doses) for two weeks (table 1). The use of combination therapy with amphotericin B plus flucytosine has been supported in several randomized trials, and this specific regimen was found to have a survival benefit when compared with amphotericin alone [8]. This two-week regimen also allows appropriate monitoring of patients to minimize the risk of toxicity and is well established in clinical practice.

For patients with reduced kidney function, the dose of flucytosine must be reduced. Dose modifications are discussed in the Lexicomp drug information topic within UpToDate and within a separate topic review. (See "Pharmacology of flucytosine (5-FC)", section on 'Renal dysfunction'.)

If liposomal amphotericin B is not available, amphotericin B lipid complex (5 mg/kg IV daily) can be used [2]. Amphotericin B deoxycholate (0.7 mg/kg IV daily) can also be used for the two-week induction regimen if a lipid formulation is not available (eg, because of cost) and/or the patient is not at risk for developing nephrotoxicity. Although some guideline panels use higher doses of amphotericin B deoxycholate (eg, 1 mg/kg/day) [9], a comparison of 0.7 mg/kg/day with 1 mg/kg/day of amphotericin B demonstrated no difference in mortality at 10 weeks in a small trial of 64 patients with HIV and cryptococcal meningoencephalitis [10], and we favor the lower amphotericin B daily dose to reduce nephrotoxicity.

Induction regimens with a shortened duration of polyene therapy (a single dose of high-dose liposomal amphotericin B plus fluconazole/flucytosine for 14 days) (table 1) may be considered on rare occasion (eg, a patient who adamantly refuses hospitalization). However, this regimen should only be considered on a case-by-case basis. Although data in resource-limited settings suggest that short courses of amphotericin B deoxycholate or liposomal amphotericin B are effective for treatment of cryptococcal meningitis, and may limit some treatment-related toxicity [11,12], patients still require close monitoring in the hospital for the two-week induction course since serious complications such as increased intracranial pressure and/or seizures can occur acutely during this time.

When resources are limited – In certain settings, administering liposomal amphotericin plus flucytosine for two weeks may not be feasible due to cost and/or limited access, as well as the inability to monitor and manage potential toxicities. This is particularly relevant to resource-limited settings.

In this setting, we suggest a regimen that uses a shortened duration of polyene therapy. The World Health Organization (WHO)-preferred regimen uses a single 10 mg/kg dose of liposomal amphotericin B with 14 days of oral flucytosine and fluconazole (1200 mg/day) [9]; if liposomal amphotericin B is not available, a regimen that includes one week of therapy with amphotericin B deoxycholate plus flucytosine, followed by a week of high dose fluconazole would be acceptable (table 1). In resource-limited settings, data support the 1 mg/kg/day dose of amphotericin B deoxycholate.

Alternative regimens when amphotericin B and/or flucytosine are not available are discussed below. (See 'Alternative regimens' below.)

Alternative regimens — Several alternative regimens are available for treatment of cryptococcal meningitis (table 1). The choice of regimen depends upon why the preferred regimen cannot be used.

When amphotericin B cannot be used – When IV therapy is not possible or if a patient is unable to tolerate amphotericin B, a two-week oral induction regimen using fluconazole (1200 mg daily) plus flucytosine (100 mg/kg/day, divided into four doses per day) is a reasonable alternative.

Studies evaluating the use of fluconazole plus flucytosine as an alternative regimen include early open-label studies, in which the combination did better than fluconazole monotherapy [13,14]. These studies used fluconazole doses that were in the 200 to 400 mg range. A subsequent study using high doses of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) suggests that a combination oral regimen is comparable to a polyene-containing regimen [11]. In this trial, the oral combination regimen had a 10-week mortality of approximately 35 percent, which was similar to the mortality reported when induction therapy with certain amphotericin B-containing regimens were used.

If flucytosine cannot be used – If flucytosine is not available or cannot be tolerated, two weeks of amphotericin B plus fluconazole (800 to 1200 mg daily) can be used [15]. The 1200 mg per day dosing of fluconazole in this combination regimen has been best studied in resource-limited settings [11].

In some settings, it is not feasible to administer the combination of amphotericin B plus fluconazole (1200 mg daily) for two weeks. When this occurs, amphotericin B can be given for one week with fluconazole (1200 mg daily), followed by one week of fluconazole (1200 mg daily) alone.

It is important that patients receiving amphotericin B plus fluconazole are monitored closely for evidence of treatment failure since CSF sterilization may be suboptimal [2,8,14]. (See 'Efficacy of induction regimens' below and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Evaluation for treatment failure'.)

If only fluconazole can be used – On occasion, if neither amphotericin B nor flucytosine are available or can be tolerated, oral fluconazole alone (1200 mg daily) can be used [6]. However, this regimen is not as effective as amphotericin B monotherapy or combination therapy [16,17], and patients receiving this regimen should be monitored closely for evidence of treatment failure.

Fluconazole alone is only fungistatic (ie, inhibits without killing). The importance of fungicidal (eg, amphotericin B) versus fungistatic therapy (eg, fluconazole) for induction therapy was illustrated in a trial of 194 patients who were randomly assigned in a 2:1 ratio to either fluconazole (200 mg/day) or amphotericin B (0.5 mg/kg per day) [17]. In this trial, the mortality was higher within the first two weeks among patients assigned to the fluconazole arm compared with the amphotericin B arm (15 versus 8 percent). In addition, compared with fluconazole, treatment with amphotericin B resulted in more rapid CSF sterilization (42 versus 64 days) [2,9,10].

Efficacy of induction regimens — Data supporting this approach to induction therapy include:

Efficacy of combination therapy – Rapid sterilization of the CSF is linked to better survival rates and decreased rates of relapse among symptomatic patients with cryptococcal meningoencephalitis [8,18-20]. However, many patients with HIV and cryptococcal meningoencephalitis have a high burden of infection in the central nervous system (CNS), with yeast concentrations that can reach a million yeasts/mL of CSF. This high burden of infection requires a combination treatment regimen with fungicidal activity, such as IV amphotericin B with flucytosine, to rapidly sterilize the CSF during induction therapy [8,18].

The use of combination therapy with amphotericin B plus flucytosine was supported in a landmark multicenter, double-blind trial in 381 patients with HIV and cryptococcal meningoencephalitis, which evaluated the effectiveness of two weeks of induction therapy with amphotericin B (dosed at 0.7 mg/kg per day), with or without the flucytosine (100 mg/kg per day) [19]. Induction therapy was followed by eight weeks of consolidation therapy with an azole. This trial demonstrated that CSF sterilization at two weeks occurred more frequently among patients receiving combination therapy compared with amphotericin B alone (60 versus 51 percent) without increased toxicity. A multivariate analysis demonstrated that the likelihood of CSF sterilization at the end of 10 weeks was highest among those patients who were assigned combination therapy followed by fluconazole. In this trial, there was no mortality benefit noted among those who received combination therapy. Other trials have confirmed faster rates of CSF sterilization and lower rates of relapse with amphotericin B plus flucytosine than with amphotericin B alone [21-24].

A subsequent randomized, open-label trial found a survival benefit when amphotericin B plus flucytosine was compared with amphotericin B monotherapy or a different combination regimen [8]. In this trial, 299 HIV-positive patients with cryptococcal meningitis in Vietnam were randomly assigned to monotherapy with amphotericin B deoxycholate 1 mg/kg daily for four weeks, combination therapy with amphotericin B deoxycholate 1 mg/kg daily plus flucytosine 100 mg/kg per day in three or four divided doses for two weeks, or amphotericin B deoxycholate 1 mg/kg daily plus fluconazole 400 mg twice daily for two weeks. In addition to demonstrate increased rates of yeast clearance in the CSF, this trial found that fewer deaths occurred by days 14 and 70 in patients who received amphotericin B plus flucytosine compared with patients who received amphotericin B monotherapy (15 versus 25 deaths by day 14, hazard ratio [HR] 0.57, 95% CI 0.30-1.08; 30 versus 44 deaths by day 70, HR 0.61, 95% CI 0.39-0.97). The mortality reduction was statistically significant at 70 days but not at 14 days. Similar survival rates were observed in patients who received combination therapy with amphotericin B plus fluconazole and amphotericin B monotherapy. Rates of adverse events were similar in all groups, although neutropenia was more common in patients receiving combination therapy versus amphotericin B monotherapy (approximately 32 percent versus 19 percent).

Combination therapy with shortened polyene or oral regimens – The use of shortened polyene therapy and oral regimens for induction therapy were supported in a randomized trial of 721 patients with HIV and cryptococcal meningitis in Africa (the ACTA trial) [11]. This trial compared a two-week amphotericin-based regimen (amphotericin B in combination with fluconazole or flucytosine) with a shortened amphotericin-based regimen (one week of amphotericin B in combination with flucytosine or fluconazole, followed by fluconazole for one week) and a two-week oral regimen (fluconazole plus flucytosine). The antifungal doses used for induction therapy in this trial were 1 mg/kg/day for amphotericin B, 1200 mg/day for fluconazole, and 100 mg/kg/day (in four divided doses) for flucytosine. These induction regimens were followed by consolidation therapy (800 mg/day of fluconazole until ART was started and then 400 mg/day of fluconazole until week 10). Maintenance therapy with fluconazole (200 mg/day) was continued thereafter.

This trial supported the mortality benefit of amphotericin B plus flucytosine. The one-week regimen that included amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2 percent); this was significantly lower than any other amphotericin B group (unadjusted HR, 0.56 [95% CI, 0.35-0.91]). The lower mortality of the one- versus two-week IV regimen may be due in part to reduced toxicity. The mortality at 10 weeks was comparable between the oral regimen and the amphotericin-based regimens.

These findings were supported in a subsequent network meta-analysis that included 13 studies from primarily resource-limited settings, in which the use of an induction regimen consisting of one week of amphotericin B deoxycholate plus flucytosine followed by fluconazole for one week was associated with the lowest mortality at 10 weeks [25]. A two-week course of fluconazole and flucytosine appeared to have similar efficacy to amphotericin-containing regimens. In this analysis, the combination of amphotericin B deoxycholate plus fluconazole was not associated with a mortality benefit compared with amphotericin B alone. However, other studies have found that this combination therapy is associated with improved CSF sterilization [22].

Clinical trials have examined whether there may be a role for triple combination therapy with amphotericin B/flucytosine/fluconazole compared with dual therapy. Although no additional benefit was observed in one study [22], subsequent trials have supported the use of this combination [12,26], as demonstrated in the Ambition trial that successfully utilized single high-dose on a flucytosine/fluconazole base [12].

The Ambition trial is a randomized, open-label trial of 844 patients with cryptococcal meningitis in Africa that compared a single dose of liposomal amphotericin (10 mg/kg) in combination with flucytosine (100 mg/kg/day) and fluconazole (1200 mg/day) for 14 days with the preferred WHO regimen (amphotericin B deoxycholate [1 mg/kg per day] plus flucytosine [100 mg/kg per day] for seven days, followed by fluconazole [1200 mg/day] alone for seven days) [12]. In this trial, there was a similar rate of all-cause mortality at 10 weeks (24.8 versus 28.7 percent) in those who received the single-dose liposomal regimen versus the standard regimen, respectively. There was also a similar rate of CSF clearance over the 14 days of induction therapy in the two groups. However, there were fewer serious adverse events in the group that received the single dose of liposomal amphotericin B (50 versus 62.3 percent).

Amphotericin B formulation – We suggest that lipid formulations of amphotericin B be administered rather than amphotericin B deoxycholate. The use of lipid formulations is particularly important in patients with or at risk for renal failure (eg, those with diabetes or uncontrolled hypertension, patients taking other nephrotoxic drugs, or patients with suspected HIV nephropathy) [27-30]. Lipid formulations reduce toxicity (eg, nephrotoxicity, infusion reactions, anemia) and, therefore, are able to improve the ability to give an uninterrupted induction period of treatment, which is critical for the successful management of cryptococcal meningoencephalitis [31].

Although most of the clinical trials have evaluated the deoxycholate formulation of amphotericin B in combination with flucytosine, lipid formulations appear effective for the treatment of cryptococcal meningitis [27,30]. The efficacy of conventional amphotericin B (0.7 mg/kg/day) was compared with two dosing regimens of liposomal amphotericin B (3 mg/kg/day in the second arm; 6 mg/kg/day in a third arm) among 267 patients with HIV and cryptococcal meningoencephalitis [27]. The mean serum creatinine among the trial participants was approximately 1.1 mg/dL; those with a serum creatinine greater than twice the normal range were excluded. Efficacy was similar in all arms, although there was less nephrotoxicity among patients in the 3 mg/kg/day liposomal amphotericin B arm. Infusion reactions were less frequent in both liposomal treatment groups compared with the standard amphotericin B group.

Alternative to flucytosineFluconazole should be used as part of a combination regimen if flucytosine cannot be used. When measuring rates of CSF sterilization, the combination of amphotericin B plus fluconazole appears to be more effective than amphotericin B monotherapy [22]. However, flucytosine in combination with amphotericin B is superior to amphotericin B plus fluconazole [8,11,22]. In the randomized trial from Vietnam (described above), the combination of amphotericin B plus fluconazole had no significant effect on survival compared with amphotericin B monotherapy; by contrast, there was a survival benefit if amphotericin B plus flucytosine was used [8].

If fluconazole is administered as part of a combination regimen, clinical trial data suggest that high doses of fluconazole should be used [15,32]. In an open-label study, 143 individuals with HIV in the United States or Thailand diagnosed with cryptococcal meningitis were randomly assigned to induction therapy with amphotericin B deoxycholate (0.7 mg/kg/day) alone, or amphotericin B deoxycholate (0.7 mg/kg/day) plus fluconazole (400 mg/day), or amphotericin B deoxycholate (0.7 mg/kg/day) plus fluconazole (800 mg/day) [15]. Following the induction phase of therapy, patients who initially received amphotericin B monotherapy were switched to fluconazole (400 mg/day) for eight weeks, whereas those who initially received amphotericin B plus fluconazole were switched to consolidation therapy with fluconazole at the same dose to which they were randomly assigned (400 or 800 mg per day) for eight weeks. Although this study was not powered to demonstrate statistically significant differences in efficacy among the treatment arms, the arm that received high-dose fluconazole (800 mg per day) showed a trend toward better outcomes, and the regimen was well tolerated.

Consolidation therapy

Evaluation prior to switching to consolidation therapy — Induction therapy should be administered for a minimum of two weeks. The duration of induction therapy should be extended if clinical improvement is not observed and/or if CSF sterilization has not yet been achieved [2]. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Sterilization of cerebrospinal fluid'.)

To assess CSF sterilization, our approach depends upon the regimen.

For those who received two weeks of amphotericin B plus flucytosine, a repeat lumbar puncture (LP) for fungal culture should be performed at the end of the two-week course of induction therapy. The opening pressure should also be measured at that time. We suggest the two-week LP be performed in all patients, even among patients who have clinically improved, which is consistent with the Infectious Diseases Society of America (IDSA) guidelines [2].

However, in resource-limited settings, it may be difficult to obtain a repeat LP. The WHO states that in low- and middle-income countries a routine follow-up lumbar puncture to assess for CSF sterilization after completing induction therapy is not indicated if the patient has had a clear clinical response to treatment.

For those receiving a regimen that uses a shortened duration of amphotericin B, we suggest an LP be done to assess the response sometime between 7 and 14 days after the last dose of polyene therapy. For those who have a positive culture, we would repeat induction therapy with the standard two-week regimen of amphotericin B plus flucytosine (table 1).

Although short courses of amphotericin B have been found to be effective in treatment cryptococcal meningitis, as described above, the mortality rate at 10 weeks is still about 25 percent, which is higher than the approximately 10 percent mortality noted in earlier studies that were conducted in resource-available areas with longer-course polyene induction therapy [19]. Thus, pending more experience with these regimens, we prefer to do earlier monitoring so we can better identify those at risk for treatment failure. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Evaluation for treatment failure' and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Management of persistent or relapsing infection'.)

Consolidation regimen — After completing induction therapy, patients should receive consolidation therapy with fluconazole for a minimum of eight weeks (table 1). We typically extend the duration of consolidation therapy in patients who have had a slow clinical response to therapy or who do not have sterile CSF at two weeks and in patients whose ART is delayed for more than 10 weeks after diagnosis. (See 'When to initiate antiretroviral therapy' below.)

The dose of fluconazole for consolidation therapy ranges between 400 mg to 800 mg/day; guidelines have recommended this range as this gives flexibility to clinicians [6]. We generally initiate consolidation therapy with the 800 mg/day dosing of fluconazole with adjustment for renal function.

In resource-available settings, the dose can then be reduced to 400 mg/day to complete the eight-week consolidation phase if all of the following criteria are met:

The patient received induction therapy with amphotericin B plus flucytosine for two weeks. (See 'Preferred regimens' above.)

CSF cultures obtained after two weeks of induction therapy are negative. (See 'Evaluation prior to switching to consolidation therapy' above.)

ART has been started. (See 'When to initiate antiretroviral therapy' below.)

The lower dose (400 mg/day) was supported in early studies [19], but the 800 mg/day dose has been favored more recently in resource-limited settings with high CSF burden of yeasts [11,12].

Itraconazole (200 mg twice daily) is an alternative to fluconazole. However, fluconazole is preferred over itraconazole because it achieves more reliable drug levels and has fewer drug interactions and less gastrointestinal toxicity. The use of fluconazole versus that of itraconazole for consolidation therapy was evaluated in a trial of 381 patients (also discussed above), in which investigators compared eight weeks of fluconazole (400 mg daily) or itraconazole (400 mg daily) as consolidation therapy [19]. Among the patients who underwent a repeat LP at the end of the consolidation phase, the CSF culture was negative in 97 percent of patients on the fluconazole arm (139 of 151) compared with 92 percent in the itraconazole group (93 of 101 patients). The data from this trial were somewhat limited since a significant percentage of patients assigned to the itraconazole and fluconazole arms did not undergo a repeat LP (35 and 26 percent, respectively). Clinical outcomes were similar between the two arms.

Maintenance therapy

Choice of agent – After completing induction and consolidation therapy, maintenance therapy with a lower dose of fluconazole (200 mg daily) should be continued for long-term suppression.

Early in the AIDS epidemic, primary therapy for cryptococcal meningoencephalitis was followed by frequent relapse after treatment discontinuation [33]. In one study of 84 patients with AIDS and a history of cryptococcal meningoencephalitis, those who were randomly assigned to 200 mg of daily fluconazole (after primary induction and consolidative therapy) had a much lower incidence of relapse than those who were assigned to placebo (none versus 15 percent) [33]. Subsequent trials comparing fluconazole with either weekly IV amphotericin B or oral itraconazole for cryptococcal meningoencephalitis demonstrated that fluconazole was the most efficacious antifungal agent for maintenance therapy [21,34]. As an example, in one clinical trial of 108 patients with HIV, the relapse rate among those treated with itraconazole was 23 percent compared with 4 percent of those taking fluconazole [21].

Duration and monitoring – Patients should receive maintenance therapy for at least one year after initiating antifungal therapy. Maintenance therapy can be discontinued after a year in patients receiving ART if the CD4 count is ≥100 cells/microL and the viral load is undetectable for more than three months [2,6]. If viral load testing is not available (eg, in resource-limited settings), maintenance therapy should be continued until the CD4 count is ≥200 cells/microL [9].

After discontinuation of azole maintenance therapy, the clinician must continue to follow patients closely. Reinitiation of maintenance therapy is indicated if the patient's CD4 cell count declines to less than 100 cells/microL and/or there is a significant rise in serum cryptococcal antigen titers. The role of serum cryptococcal antigen monitoring in a patient who discontinues treatment is discussed elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring of serum cryptococcal antigen'.)

Small trials and observational studies suggest that maintenance therapy for C. neoformans can be safely discontinued in the majority of patients who have a CD4 cell count >100 cells/microL on effective ART. As an example, in an observational study, 4 of 100 patients who discontinued maintenance therapy had a clinical relapse of cryptococcal infection after approximately two years (incidence, 1.53 events per 100 person-years; 95% CI, 0.42-3.92) [35-37].

Adverse events — Adverse reactions to the commonly used antifungal agents are summarized here and discussed in detail in separate topic reviews.

AmphotericinAmphotericin B deoxycholate is frequently associated with electrolyte disturbances, anemia, renal insufficiency, and infusion site reaction, such as drug fever and rigors.

These adverse events are reduced when liposomal preparations are used [27]. The symptoms of an infusion reaction can be minimized or prevented by premedication with acetaminophen (usual adult dose, 650 to 1000 mg orally) and/or diphenhydramine (usual adult dose, 25 to 50 mg orally or IV). The risk of renal dysfunction associated with amphotericin B may be reduced with infusion of normal saline before and during therapy.

Additional information on the management of adverse events related to amphotericin B can be found in separate topic reviews. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring for drug toxicity' and "Pharmacology of amphotericin B", section on 'Infusion-related reactions' and "Amphotericin B nephrotoxicity".)

Flucytosine – Flucytosine is mainly associated with gastrointestinal intolerance. However, laboratory abnormalities that include elevations in aminotransferases, anemia, leukopenia, and thrombocytopenia can also be seen. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring for drug toxicity'.)

For those with an adverse reaction to flucytosine, serum levels may be helpful to assess if a dose adjustment is required. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring for drug toxicity' and "Pharmacology of flucytosine (5-FC)", section on 'Management of toxicities'.)

AzolesFluconazole is generally well tolerated [15]; patients occasionally may develop rash or abnormal aminotransferases. By contrast, itraconazole is associated with significant gastrointestinal intolerance and pedal edema and requires drug monitoring due to significant differences in bioavailability from person to person. (See "Pharmacology of azoles".)

Patient and laboratory monitoring during induction/consolidation and maintenance therapy are discussed elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

Management of increased intracranial pressure — The intracranial pressure (ICP) should be measured at the time of the initial LP. Patients suspected of having increased ICP and/or CNS mass lesions should first have neuroimaging (eg, computed tomography [CT] scan or magnetic resonance imaging [MRI]) to rule out the presence of a concomitant space-occupying lesion. The use of neuroimaging and LP for initial diagnosis and assessment of ICP in patients with suspected cryptococcal meningoencephalitis, including those in resource-limited settings, is discussed in greater detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Diagnosis' and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Special considerations in resource-limited settings'.)

Increased ICP in patients with cryptococcal meningoencephalitis should be managed aggressively to decrease mortality [38,39]:

LP should be performed to reduce the opening pressure to <20 cm CSF; in symptomatic patients with extremely high CSF pressures (eg, ≥50 cm CSF), the goal is to reduce the ICP by 50 percent of the initial value. We perform daily LPs until the patient is asymptomatic and the CSF pressure has been documented to be normal and/or stable.

Lumbar or ventricular drains may be preferred in patients who require frequent LPs, and they can be lifesaving. Theoretical concerns about placing drains into infected spinal fluid should not preclude their use as long as effective antifungal therapy has been started.

The further management of patients who have a continued increase in ICP despite antifungal therapy is discussed elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Management'.)

There is no role for acetazolamide, mannitol, or corticosteroids to reduce increased ICP in this acute setting [6,40]. In addition, routine use of dexamethasone at the start of induction therapy (similar to tuberculous meningitis) is not effective and should not be used, as it can reduce the fungicidal activity of drugs and increase morbidity [5]. However, corticosteroids should be administered to manage CNS IRISs. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Management of IRIS'.)

The LP, which leads to transient improvement in ICP, can be lifesaving. As an example, in a study of 248 individuals with HIV and cryptococcal meningitis from Uganda and South Africa, the 75 patients who had at least one therapeutic LP in the first week were more likely to survive compared with the 173 patients who did not have a therapeutic LP (adjusted relative risk of mortality 0.31; 95% CI 0.12-0.82) [39]. Whether reduction of ICP has a beneficial effect on other outcomes, such as visual or auditory acuity, is uncertain [2,41,42].

When to initiate antiretroviral therapy — For patients with cryptococcal meningoencephalitis, we suggest antiretroviral therapy (ART) be started between 2 and 10 weeks after antifungal therapy has been initiated. The timing of ART initiation must weigh the potential advantage of early immune recovery against the risk of developing IRIS. Although immune recovery is an important part of the successful treatment of cryptococcal meningoencephalitis, trials comparing early versus delayed initiation of ART in patients undergoing treatment for cryptococcal meningoencephalitis consistently show improved survival with delayed initiation [43-45]. This is in contrast to other opportunistic infections, such as Pneumocystis pneumonia, for which early ART initiation has been found to be clinically beneficial [46]. Discussions of ART selection are found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings".)

Deciding when to initiate ART within the 2- to 10-week window is less clear. For individuals in resource-limited health care systems, ART should generally be started between four to six weeks after initiating antifungal therapy since the benefits of a more rapid immune recovery usually outweigh the risks of IRIS [9]. Some experts also initiate ART during this time period in resource-available settings [6,47]; however, others may delay ART by up to 10 weeks (ie, after induction and consolidation antifungal therapy) in patients who have close follow-up and access to treatment that can prevent further opportunistic infections. This approach minimizes the risk of IRIS and avoids drug interactions associated with high-dose antifungal therapy. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Immune reconstitution inflammatory syndrome'.)

The benefit of delayed ART was best illustrated in a trial of 177 patients with HIV from Uganda and South Africa who were randomly assigned to receive either early ART (within one to two weeks after initiating antifungal therapy) or delayed ART (four to six weeks after initiating antifungal therapy) [44]. Antifungal therapy in these resource-limited settings included two weeks of induction therapy with amphotericin and fluconazole, followed by 12 weeks of consolidation therapy with fluconazole alone. The mortality at 26 weeks was significantly higher in patients who received early compared with delayed ART (45 versus 30 percent; HR 1.73; 95% CI 1.06-2.82). Most excess deaths associated with early ART initiation occurred two to five weeks after initiating antifungal therapy and among patients who had fewer than five white blood cells/microL in their initial CSF sample (a marker of more severe immunosuppression and a risk factor for paradoxical IRIS).

Patient monitoring — During the two-week induction therapy regimen, clinical response should be assessed daily (in a hospital setting if possible) since multiple complications related to adverse drug reactions can occur.

In addition, patients with severe cryptococcal meningoencephalitis may have persistent increased ICP, which can lead to significant morbidity and mortality and needs acute treatment. Some patients who initiate ART can also develop an inflammatory CSF profile with symptomatic increased ICP that is related to immune recovery.

A full discussion of the symptoms, signs, and management of these complications, as well as the approach to treatment failure, is found elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

PREVENTING SYMPTOMATIC DISEASE — The best way to prevent cryptococcal disease in individuals with HIV is through early initiation of antiretroviral therapy (ART) even at high CD4 counts. ART reduces mortality, as well as serious AIDS- and non-AIDS-related complications, and should be initiated regardless of the CD4 count. (See "When to initiate antiretroviral therapy in persons with HIV".)

However, in patients with a low CD4 count, a strategy involving serum or plasma cryptococcal antigen (CrAg) screening and antifungal therapy in addition to ART may further reduce the risk of developing cryptococcal meningitis in high endemic areas [48-52]. CrAg is detectable in serum at least three weeks prior to the onset of neurologic symptoms. (See 'Screening and treatment of early infection' below.)

If CrAg screening is not available, primary prophylaxis with antifungal therapy may be warranted in specific high-risk settings. (See 'If screening is not available' below.)

The approach to antifungal therapy below is for nonpregnant adults. Pregnant women should be managed in conjunction with an infectious diseases specialist since fluconazole may be teratogenic during pregnancy, particularly in the first trimester.

Screening and treatment of early infection

Who should be screened — We suggest serum CrAg screening for asymptomatic patients with a CD4 count ≤100 who are not receiving effective ART. There may also be a benefit to screening at a higher CD4 count threshold (eg, <200 cells/microL) in certain areas of high prevalence for cryptococcal disease, such as resource-limited settings where the accuracy of CD4 counts may be reduced [52,53]; at least 28 countries have adopted screening at this threshold. In one report, screening patients with a CD4 count between 100 and 200 cells/microL more than doubled the number of CrAg-positive individuals identified; however, the clinical significance of these findings remains unclear [54].

This approach to screening is in agreement with recommendations from the World Health Organization (WHO) [9]. In the United States, guidelines also support screening asymptomatic patients with a CD4 count <100 cells/microL [6,47,55]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

Approach to pre-emptive therapy — Patients who test negative for serum CrAg do not require antifungal therapy and should initiate ART. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings".)

Patients who test positive for serum CrAg should undergo a careful history and exam to elicit signs and symptoms of cryptococcal meningitis, as well as a lumbar puncture (LP; regardless of signs and symptoms) to evaluate for the presence of cerebrospinal fluid (CSF) CrAg or positive CSF cryptococcal cultures. In one study that evaluated the CSF in 90 CrAg-positive patients who were asymptomatic, approximately one-third had evidence of cryptococcal meningitis [56]. Meningitis is particularly associated with a serum CrAg lateral flow assay (LFA) titer ≥1:160 [16,56].

ART should be held pending return of the CSF studies. Antifungal therapy with fluconazole 400 mg daily can be started in asymptomatic patients with CrAg LFA titers <1:160. By contrast, in patients with symptoms or CrAg LFA titers >1:160, it is reasonable to initiate induction amphotericin B therapy pending the CSF results.

Once the CSF studies return, our approach is as follows:

If the LP is negative (ie, negative CSF CrAg and culture), antifungal therapy with fluconazole (400 mg daily) is warranted, and ART can be started. We discontinue pre-emptive fluconazole therapy in those patients receiving ART if they achieve a CD4 cell count >100 cells/microL for at least three months.

If there is evidence of central nervous system (CNS) involvement (ie, positive CSF CrAg or culture), patients should be treated for cryptococcal meningoencephalitis, and ART should be initiated 2 to 10 weeks after induction treatment, as discussed above. (See 'Induction therapy' above and 'When to initiate antiretroviral therapy' above.)

In certain resource-limited settings, it may not be possible to perform an LP on all asymptomatic patients, and the choice of antifungal therapy is based only on the serum titer and the absence of clinical disease. For such patients with a CrAg <1:160, we would initiate ART two weeks after pre-emptive therapy with fluconazole has been started. For those with a CrAg >1:160, we would encourage LP and, if no LP, then initiate ART two to four weeks after induction therapy. (See 'When to initiate antiretroviral therapy' above.)

Several studies in resource-limited settings with a high prevalence of disease have suggested a benefit of using a strategy of screening and pre-emptive antifungal therapy to prevent the development of cryptococcal meningitis [48-52,57-59]. As examples:

In a study of 295 ART-naïve patients in Uganda starting HIV therapy, 26 patients with a CD4 cell count ≤100 cells/microL had a positive serum CrAg. All of the patients with a positive serum CrAg were started on ART [49]. In addition, 21 were treated with fluconazole (200 to 400 mg/day) for two to four weeks, whereas five were treated with ART alone. Clinical cryptococcal meningitis developed in three of the fluconazole-treated persons, and the 30-month survival was 71 percent (95% CI 48-89). Of the five CrAg-positive persons who were not treated with fluconazole, all died within two months of ART initiation.

In another trial that evaluated approximately 2000 patients in Tanzania and Zambia with a CD4 count <200 cells/microL, an intervention that included ART, community adherence support, and CrAg testing with pre-emptive fluconazole was compared with standard of care (ART plus clinic-based visits) [52]. Patients who received the intervention had a significant reduction in mortality at 12 months compared with those who received standard of care (13 versus 18 percent). It is unclear if the mortality benefit was attributable to CrAg screening or enhanced community support. However, CrAg-positive persons who were pre-emptively treated had a 70 percent one-year survival.

In a prospective study of 645 ART-naïve patients with a CD4 count ≤100 cells/microL from South Africa, 28 patients tested positive for serum CrAg using the LFA, and 21 received antifungal therapy [51]. Ten patients agreed to LP and four tested positive for CrAg in the CSF and received amphotericin B. Of the remaining 17, all received fluconazole and none developed cryptococcal meningitis B. These findings were compared with a historical control in which 7 of 25 serum CrAg-positive patients (28 percent) who did not receive pre-emptive antifungal therapy went on to develop cryptococcal meningoencephalitis, and only half were alive in care after six months [60].

Studies evaluating cost-effectiveness have also suggested that this screen-and-treat strategy can be cost effective in resource-limited areas where the prevalence of cryptococcal antigenemia is >3 percent (based on the CrAg latex agglutination test) [49,50,61,62]. These findings were derived from reductions in mortality found in some of the studies above [49,50]. Although the low quality of the evidence results in substantial uncertainty as to the true effect of this approach on mortality, when assessing the cost of the CrAg LFA and the avoided cost of hospitalizations, CrAg screening is likely cost-saving to the health care system [63].

Despite these potential benefits of screening and pre-emptive treatment, the mortality due to cryptococcal disease remains substantial. In one study of 67 CrAg-positive and 134 CrAg-negative patients, the mortality was 25 and 9 percent, respectively, and cryptococcal disease was an immediate or contributing cause of death in 71 percent of those who were CrAg positive, even with screening and fluconazole therapy [64]. A more potent antifungal pre-emptive strategy may be necessary to further reduce mortality and studies have been initiated with other pre-emptive regimens. In addition, more consistent, high-quality data are needed to demonstrate the precise efficacy of this approach in all high-risk regions of the world.

If screening is not available — If screening is not available, we suggest not using routine antifungal prophylaxis for primary prevention of cryptococcal infection in resource-available countries where the incidence of cryptococcal infection is low (eg, the United States). This approach is supported by major guideline panels because of the lack of overall survival benefit and the increased risk of drug interactions, adverse effects, potential antifungal drug resistance, and cost [2,6]. However, in resource-limited areas, where the incidence of disease is high, the WHO recommends fluconazole prophylaxis in adults with HIV and CD4 counts <100 cells/microL [9].

A 2005 Cochrane systematic review identified five randomized controlled trials using antifungal interventions for primary prevention of cryptococcal disease in a total of 1316 patients with HIV [65]. Although the incidence of cryptococcal disease decreased significantly in patients taking either fluconazole or itraconazole, there was no significant effect on overall mortality. However, a subsequent meta-analysis that was described in the 2018 WHO guidelines appears to favor primary prophylaxis in resource-limited settings if there is no pre-emptive CrAg screening and the patient has a CD4 count <100 cells/microL [9,66].

PREGNANT PERSONS — Pregnant persons should be managed in conjunction with an infectious diseases specialist, since flucytosine and fluconazole may be teratogenic during pregnancy, particularly in the first trimester. In such patients, the duration of amphotericin may need to be extended. As an example, for pregnant persons diagnosed with cryptococcal meningitis in the first trimester, a reasonable approach would be daily amphotericin B alone for induction therapy, weekly amphotericin B for consolidation therapy, and then maintenance therapy with fluconazole during the second and third trimesters [6].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis" and "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)

SUMMARY AND RECOMMENDATIONS

Overview of treatment – Patients with HIV and advanced immunosuppression (eg, CD4 cell count <50 cells/microL) are at risk for cryptococcal meningoencephalitis, which is uniformly fatal within approximately two weeks if untreated. (See 'Overview' above.)

Treatment of cryptococcal meningoencephalitis includes antifungal therapy (induction, consolidation, and maintenance therapy) (table 1), control of intracranial pressure (ICP), and immune recovery with HIV therapy.

Preferred induction therapy regimens – For most patients with cryptococcal meningoencephalitis, we recommend a combination therapy regimen that includes intravenous (IV) amphotericin B and flucytosine (Grade 1B). (See 'Induction therapy' above.)

When resources allow, we suggest induction therapy with amphotericin B and flucytosine for at least two weeks (table 1) (Grade 2C). (See 'Preferred regimens' above.)

We prefer liposomal amphotericin B rather than amphotericin B deoxycholate, particularly in patients with or at risk for reduced kidney function. Liposomal amphotericin is associated with fewer toxicities compared with amphotericin B deoxycholate, and therefore therapy is less likely to be interrupted. However, for patients with normal kidney function, amphotericin B deoxycholate is a suitable alternative if liposomal amphotericin is not available.

When resources are limited (eg, prolonged monitoring for medication toxicity is unfeasible), we suggest induction therapy with a regimen that uses a shortened duration of amphotericin B treatment (Grade 2B). This includes a regimen that uses a single 10 mg/kg dose of liposomal amphotericin B with 14 days of oral flucytosine and fluconazole, or, if liposomal amphotericin is not available, a regimen that includes one week of therapy with amphotericin B deoxycholate plus flucytosine, followed by a week of high dose fluconazole (table 1). (See 'Preferred regimens' above.)

Alternative induction therapy regimens – Several alternative regimens are available when one of the preferred regimens cannot be used (table 1). The choice of regimen depends upon why the preferred regimen cannot be used (lack of availability, toxicity). (See 'Alternative regimens' above.)

Evaluation prior to consolidation therapy – The duration of induction therapy should be extended if clinical improvement is not observed and/or if cerebrospinal fluid (CSF) sterilization has not yet been achieved.

To assess CSF sterilization in patients receiving a regimen that includes two weeks of amphotericin B plus flucytosine, a repeat a lumbar puncture (LP) for fungal culture should be performed after two weeks of induction therapy, even among patients who have clinically improved.

For patients receiving a regimen with a shortened duration of amphotericin B, we suggest an LP 7 to 14 days after completion of polyene therapy, followed by a repeat course of induction therapy in those who have a positive culture (Grade 2C). In this setting, we would use an induction regimen that includes two weeks of amphotericin B plus flucytosine. (See 'Evaluation prior to switching to consolidation therapy' above.)

Consolidation regimen – When patients transition to consolidation therapy, we suggest fluconazole rather than itraconazole (Grade 2C). Fluconazole is generally preferred over itraconazole due to better bioavailability and a reduced risk of drug interactions and gastrointestinal symptoms.

Patients should receive consolidation therapy for a minimum of eight weeks. We generally initiate consolidation therapy with fluconazole 800 mg/day (table 1). In resource-available countries, the dose can be reduced to 400 mg/day to complete the consolidation phase if the patient received induction therapy with amphotericin B plus flucytosine for two weeks, CSF cultures obtained after two weeks of induction therapy are negative, and antiretroviral therapy (ART) has been started. (See 'Consolidation regimen' above.)

Maintenance regimen – For patients who complete the induction and consolidation phases of therapy, we recommend fluconazole (200 mg daily) for maintenance treatment compared with no therapy or itraconazole (Grade 1B). In early studies, patients who received maintenance therapy had a much lower incidence of relapse.

The minimum duration of maintenance therapy is at least one year. After that, maintenance therapy can be discontinued in individuals receiving ART who have a CD4 cell count greater than 100 cells/microL and have achieved an undetectable viral load on ART for more than three months. (See 'Maintenance therapy' above.)

Managing increased ICP – Patients with increased intracranial pressure (ICP) should be managed aggressively to reduce the risk of mortality associated with cryptococcal meningoencephalitis. In general, repeat LPs should be performed to reduce the opening pressure to <20 cm CSF; however, in symptomatic patients with extremely high CSF pressures, the goal is to reduce the ICP by 50 percent of the initial value.

We perform daily LPs until the patient is asymptomatic and the CSF pressure has been documented to be normal and/or stable. Lumbar or ventricular drains may be preferred in patients who require frequent LPs. (See 'Management of increased intracranial pressure' above.)

When to initiate ART – For patients with cryptococcal meningoencephalitis who are not receiving ART, we suggest initiation of ART be delayed at least two weeks after antifungal induction therapy has been started (Grade 2B). For patients with access to close medical follow-up and preventative therapy, we often start ART 10 weeks after the initiation of antifungal therapy to minimize the risk of drug interactions and development of an immune reconstitution inflammatory syndrome (IRIS). However, for individuals without these resources, we typically start ART four to six weeks after induction therapy has been initiated. (See 'When to initiate antiretroviral therapy' above.)

Prevention – The best way to prevent cryptococcal disease in individuals with HIV is through early initiation of ART at high CD4 counts. However, in patients with a low CD4 count, a strategy involving serum cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy in addition to ART may further reduce the risk of developing cryptococcal meningitis.

For asymptomatic patients with a CD4 count <100 cells/microL who are not receiving ART, we test for cryptococcal antigen prior to initiation of ART. There may also be a benefit to screening at a higher CD4 count threshold (eg, <200 cells/microL) in certain areas of high prevalence for cryptococcal disease, such as resource-limited settings where the accuracy of CD4 counts may be reduced. The management of patients who screen positive for cryptococcal antigen is discussed above. (See 'Preventing symptomatic disease' above.)

If screening is not available, we do not routinely administer antifungal prophylaxis for prevention of cryptococcal disease in resource-available countries where the incidence of cryptococcal infection is low. However, in certain resource-limited areas with a high prevalence of disease, it is reasonable to initiate primary prophylaxis with fluconazole in asymptomatic adults with CD4 counts <100 cells/microL. (See 'If screening is not available' above.)

Considerations during pregnancy – Pregnant persons should be managed in conjunction with an infectious diseases specialist, since flucytosine and fluconazole may be teratogenic during pregnancy, particularly in the first trimester. (See 'Pregnant persons' above.)

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Topic 83651 Version 26.0

References