Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients Authors Gary M Cox, MD John R Perfect, MD Section Editor John G Bartlett, MD Deputy Editor Jennifer Mitty, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2016. | This topic last updated: Jan 04, 2016.

INTRODUCTION — Disseminated Cryptococcus neoformans infection is a serious opportunistic

infection that occurs in patients with untreated AIDS [1]. Although cryptococcal infection begins in the

lungs, meningitis is the most frequently encountered manifestation of cryptococcosis among those with

advanced immunosuppression. However, the infection is more properly characterized as

"meningoencephalitis" rather than meningitis since the brain parenchyma is almost always involved on

histologic examination [2,3].

The clinical manifestations and diagnosis of C. neoformans meningoencephalitis in AIDS patients will

be reviewed here. Treatment and monitoring of AIDS patients with cryptococcal meningoencephal itis is

found elsewhere. The microbiology, clinical manifestations, and treatment of this infection in other

patient populations, such as transplant patients, are discussed elsewhere. C. gattii infection is also

presented separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-

infected patients" and "Clinical management and monitoring during antifungal therapy of the HIV-

infected patient with cryptococcal meningoencephalitis" and "Microbiology and epidemiology of

Cryptococcus neoformans infection" and "Clinical manifestations and diagnosis of Cryptococcus

neoformans meningoencephalitis in HIV-seronegative patients" and "Treatment of Cryptococcus

neoformans meningoencephalitis and disseminated infection in HIV seronegative

patients" and "Cryptococcus neoformans infection outside the central nervous

system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and

pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus

gattii infection: Treatment".)

EPIDEMIOLOGY — Globally, it has been estimated that approximately 957,900 cases of cryptococcal

meningoencephalitis occur each year, resulting in more than 600,000 deaths [4,5]. The vast majority of

cases occur among patients with AIDS and a CD4 count <100 cells/microL. The region with the

highest number of estimated cases in 2006 was sub-Saharan Africa (720,000 cases; range, 144,000 to

1.3 million), followed by South and Southeast Asia (120,000 cases; range, 24,000 to 216,000) [4].

Although the incidence of cryptococcal meningoencephalitis has declined in patients who have access

to antiretroviral therapy (ART) [6], cryptococcal disease remains a leading cause of mortality in the

developing world where access to ART is limited and HIV prevalence remains high [7].

Early diagnosis and treatment may help reduce cryptococcal meningitis-related mortality [8]. One way

to diagnose cryptococcal infection early in the course disease is through the detection of serum

cryptococcal antigen (CrAg), which can be detected at least three weeks prior to the onset of

neurologic symptoms. The prevalence of antigenemia has been found to vary depending upon the

geographical area. As an example, in the United States, the prevalence of cryptococcal antigenemia

among patients with a CD4 count <100 cells/microL was reported to be approximately 3 percent,

whereas in Uganda the prevalence among such patients was 13.5 percent [9,10]. A discussion on the

use of screening and early therapy to prevent meningoencephalitis is found elsewhere.

(See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section

on 'Screening and treatment of early infection'.)

CLINICAL MANIFESTATIONS

Symptoms — Symptoms of cryptococcal meningoencephalitis typically begin indolently over a period

of one to two weeks. The most common symptoms are fever, malaise, and headache [2]. Stiff neck,

photophobia, and vomiting are seen in one-fourth to one-third of patients. Patients rarely present with

coma and fulminant death in days.

Other symptoms suggesting disseminated disease include cough, dyspnea, and skin rash [11]. Visual

and hearing loss has also been reported [12,13].

Physical examination — The initial physical examination may be notable for lethargy or confusion in

association with fever. In one report, 24 percent of patients had altered mentation on presentation, and

6 percent presented with focal neurologic deficits [2]. Other manifestations of disseminated disease

may be evident, including tachypnea and skin lesions resembling molluscum contagiosum (picture 1)

[11]. Increased diastolic hypertension may be reflective of increased intracranial pressure.

Laboratories — General laboratory studies are nonspecific. Patients with advanced

immunosuppression may have leukopenia, anemia, hypoalbuminemia, and an increased gamma

globulin antibody fraction.

DIAGNOSIS — We have a high index of suspicion for cryptococcal meningitis in patients with

advanced HIV infection (CD4 cell count <100 cells/microL) who have isolated fever and headache.

Initial evaluation includes a careful history, neurologic exam, and serum cryptococcal antigen.

Evaluation should also include a lumbar puncture to assess for increased intracranial pressure and

culture of cerebrospinal fluid (CSF) to confirm the diagnosis in those with symptoms and/or a positive

serum cryptococcal antigen (CrAg).

A more detailed discussion on the diagnosis of cryptococcal meningitis in resource limited settings is

found below. (See 'Resource limited settings' below.)

Importance of neuroimaging — Prior to a lumbar puncture (LP), patients suspected of having

increased intracranial pressure and/or CNS mass lesions must have neuroimaging (eg, computed

tomography [CT] scan or magnetic resonance imaging [MRI]). A detailed discussion on when to

perform neuroimaging prior to LP is found elsewhere. (See "Lumbar puncture: Technique, indications,

contraindications, and complications in adults", section on 'Cerebral herniation'.)

Imaging can detect the presence of mass lesions, increased intracranial

pressure, and/or hydrocephalus, all of which impact treatment decisions.

●Imaging may suggest possible increased ICP with or without mass/space occupying lesions in

patients with cryptococcal meningitis. While LP and removal of CSF may be beneficial for both

diagnostic and therapeutic purposes, the risks and benefits of the procedure must be discussed

with the patient and/or health care proxy given the very small, but possible chance of cerebral

herniation in the setting of raised intracranial pressure. Consultation with

neurology and/or neurosurgery can be obtained to help guide this discussion. A more detailed

discussion on the risks of lumbar punctures is found elsewhere. (See "Lumbar puncture:

Technique, indications, contraindications, and complications in adults", section on 'Cerebral

herniation'.)

●If mass lesions are identified we consider alternative diagnosis (eg toxoplasmosis, lymphoma,

tuberculosis) since mass lesions due to C. neoformans are rarely seen in patients with HIV

infection [14,15]. The diagnostic approach to HIV-infected patients with mass lesions is discussed

elsewhere. (See "Approach to HIV-infected patients with central nervous system lesions".)

●If imaging is consistent with cryptococcal-associated hydrocephalus, placement of a ventricular

shunt may be required. (See "Clinical management and monitoring during antifungal therapy of

the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Monitoring of

intracranial pressure'.)

Lumbar puncture — A lumbar puncture is required to obtain CSF for confirmatory testing to make the

diagnosis of cryptococcal meningitis. The cerebrospinal fluid (CSF) profile classically demonstrates a

low white blood cell count in the CSF (eg, <50 cells/microL) with a mononuclear predominance [16].

The CSF protein may be slightly elevated, while the glucose concentrations are commonly low [13].

Approximately 25 to 30 percent of patients with culture-proven cryptococcal meningoencephalitis have

a normal CSF profile [17,18].

A lumbar puncture is also important for determining the patient’s intracranial pressure (ICP), which can

be associated with significant morbidity and mortality [2,13]. The management of increased ICP is

discussed elsewhere. (See "Clinical management and monitoring during antifungal therapy of the HIV-

infected patient with cryptococcal meningoencephalitis", section on 'Monitoring of intracranial

pressure'.)

Cryptococal culture — CSF should be sent for cryptococcal culture; cream-colored mucoid colonies

are seen on agar plates generally within three to seven days.

India ink staining — Since the burden of organisms is usually high in AIDS patients, an India ink

preparation of the CSF will usually demonstrate typical round encapsulated yeast organisms

consistent with cryptococcus in 60 to 80 percent of patients [19]. The advantage of the India ink

preparation is that a diagnosis of cryptococcal infection can be made rapidly while confirmatory testing

is being performed (eg, CSF culture or antigen). India ink stains should be reviewed by a

microbiologist who is familiar with the physical characteristics of the organism.

Regardless of India ink results, a CrAg test should also be performed to confirm the diagnosis. The

antigen titer measurement can also provide an estimate of fungal burden and prognosis.

(See 'Prognostic factors' below.)

Cryptococcal antigen (CrAg) — CrAg can be detected in serum and CSF through immunodiagnostic

techniques, such as latex agglutination or sandwich enzyme-linked immunosorbent assay (ELISA).

The lateral flow assay (LFA) is an alternative approach to detecting cryptococcal antigen. It is a simple

dipstick test that is inexpensive to perform and can be used on urine, blood, serum, CSF, or plasma

samples. The LFA compares favorably with the latex agglutination and ELISA, and is used in both

resource-limited and resource-available areas [20,21]. In resource-limited settings, the LFA has the

potential to improve access to diagnostic testing since centralized laboratory facilities are often

unavailable.

Spinal fluid — A positive CrAg in the CSF strongly supports the diagnosis of cryptococcal meningitis

and is sufficient evidence to initiate treatment in patients with symptoms and/or risk factors that are

consistent with infection. Results of the antigen test can be obtained immediately after the lumbar

puncture is performed. A positive antigen test can suggest the presence of infection well before the

cultures become positive.

The CrAg is very sensitive and specific in the CSF and is commonly detected by latex agglutination. In

a study of four latex agglutination assays and one enzyme linked immunoassay, all performed well

with sensitivities ranging from 93 to 100 percent and specificities from 93 to 98 percent [22]. With latex

agglutination, diagnostic false positive tests can result from infection due to the fungus Trichosporon

asahii (formerly T. beigelii) or bacteria of the Stomatococcus and Capnocytophaga genera [23-25].

These positive results are usually present with low titers. False positive CSF cryptococcal antigen

results have been reported rarely following exposure of samples to disinfectants or soap, or after

samples were placed into an anaerobic transport vial [26-28]. (See "Infections due to Trichosporon

species and Blastoschizomyces capitatus".)

The lateral flow assay (LFA) is an alternative approach to detecting cryptococcal antigen, and is easier

to use and less expensive compared with latex agglutination. In addition, it appears to perform equally

as well as other tests. As an example, in a study of 832 HIV-infected individuals from sub-Saharan

Africa, LFA was shown to have >99 percent sensitivity and specificity among persons with suspected

meningitis [21]. In this study, LFA had the best test performance when compared with latex

agglutination, culture, and India ink microscopy.

Serum — In AIDS patients with suspected cryptococcal meningoencephalitis, the sensitivity of serum

antigen testing is comparable to CSF testing and is a useful diagnostic modality in patients who cannot

undergo lumbar puncture [29].

Screening with serum cryptococcal antigen may also be of high clinical utility in areas where

cryptococcal infection is endemic. In Cambodia, for example, cryptococcal antigen screening among

327 HIV-infected patients with advanced immunosuppression demonstrated a prevalence of 18

percent [30]. Of the 59 patients diagnosed with cryptococcal infection, more than one-fourth did not

have symptoms suggestive of cryptococcal meningitis. These data suggest that screening may be

beneficial in identifying earlier disease in patients with advanced immunosuppression who live in

endemic areas.

CrAg titers generally correlate with organism burden and prognosis. However, following titers are not

helpful in management of acute disease in HIV-infected patients since changes in titer do not precisely

correlate with clinical response [31]. Also, the slope of decline is not helpful in predicting those patients

who may relapse [32]. (See"Clinical management and monitoring during antifungal therapy of the HIV-

infected patient with cryptococcal meningoencephalitis", section on 'Laboratory monitoring for fungal

infection'.)

Extraneural cultures — The diagnosis of cryptococcal disease is occasionally made only after C.

neoformans is recovered from another body site, such as blood, urine, or sputum. Routine blood

cultures may be positive for cryptococci in approximately two-thirds of AIDS-associated cases of

meningoencephalitis [2]. If cryptococcemia is suspected, fungal isolator tubes can be ordered for

improved sensitivity.

The prostate gland is recognized as an extraneural site from which cryptococci can reside, leading to

relapse with systemic dissemination after discontinuation of treatment. Detection of cryptococcus on

urine culture can be improved with prostatic massage. Prior to the era of potent antiretroviral therapy

(ART), persistent prostatic sequestration of cryptococcus was described in patients who were treated

for six weeks with amphotericin with or without flucytosine, with subsequent relapse after treatment

discontinuation [33].

Resource limited settings — In resource-limited settings, especially in areas where the prevalence of

cryptococcal disease is high, the diagnostic approach may be modified. Prompt lumbar puncture with

measurement of CSF opening pressure and rapid CSF CrAg assays remains the preferred diagnostic

approach. However, obtaining a diagnosis can be challenging in some settings because of limited

access to lumbar puncture (LP) and/or neuroimaging. In this setting, the risks and benefits may favor a

lower threshold for performing LP without prior neuroimaging than in resource-available settings where

the prevalence of cryptococcal meningitis is also lower.

Patients who have symptoms consistent with cryptococcal meningoencephalitis should be managed in

a medical facility that has access to lumbar punctures. If an individual does not have immediate access

to LP, or if an LP is clinically contraindicated, the patient should be transferred to a facility where they

can undergo further diagnostic evaluation. For these patients, we support the recommendations of the

World Health Organization (WHO) that recommend serum or plasma CrAg testing be performed if the

results can be delivered in <24 hours [8]. The results of serum/plasma CrAg testing can be used to

determine if antifungal treatment should be administered pending further work-up.

●If testing for CrAg is positive, treatment with antifungal therapy should be initiated.

(See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients",

section on 'Approach to antifungal treatment'.)

●If rapid serum or plasma CrAg is negative or not available, empiric therapy should

generally not be administered. Instead, the patient should undergo further diagnostic evaluation,

in an appropriate setting, as soon as possible.

A strategy involving serum cryptococcal antigen screening and antifungal therapy may reduce the risk

of developing cryptococcal meningitis in asymptomatic patients who are at high risk for developing

disease. A detailed discussion on the prevention of cryptococcal disease is found elsewhere.

(See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section

on 'Screening and treatment of early infection'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis in the advanced AIDS patient with fever

and headache includes toxoplasmosis, tuberculosis meningitis, lymphoma, syphilis, and progressive

multifocal leukoencephalopathy. Patients with toxoplasmosis may also have focal findings, such as

specific hand weakness, while patients with cryptococcal meningoencephalitis usually have cranial

neuropathies. Patients with tuberculosis meningitis may also have other clues to the diagnosis, such

as cough, hemoptysis, and an abnormal chest x-ray. Patients with secondary syphilis with aseptic

meningitis usually have normal mentation and a disseminated maculopapular rash. Those with central

nervous system (CNS) lymphoma may have focal neurologic deficits with abnormal neuroimaging

reflecting an intracranial tumor. (See "Toxoplasmosis in HIV-infected patients" and "Progressive

multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis" and "Syphilis:

Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients", section on

'Clinical manifestations'.)

PROGNOSTIC FACTORS — The prognosis for patients with AIDS-associated central nervous system

(CNS) cryptococcosis has improved dramatically with antifungal treatment coupled with potent

antiretroviral therapy (ART), which leads to effective viral suppression and immunologic recovery

[34,35]. Treatment of cryptococcal meningitis and the timing of ART are discussed elsewhere.

(See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected

patients" and "Clinical management and monitoring during antifungal therapy of the HIV-infected

patient with cryptococcal meningoencephalitis".)

Acute mortality from cryptococcal meningoencephalitis with underlying HIV infection ranges from 6 to

16 percent in resource-available environments [16,34,36-38]. The significant clinical and laboratory

predictors of death during the initial few weeks of treatment include [36]:

●Abnormal mental status

●Cerebrospinal fluid (CSF) antigen titer >1:1024

●CSF white blood cell count <20/microL

Abnormal mental status on baseline examination or a deterioration of mental status can reflect

increased intracranial pressure (ICP). Raised ICP should be considered an urgent medical issue

requiring prompt intervention. (See "Clinical management and monitoring during antifungal therapy of

the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Monitoring of intracranial

pressure'.)

SUMMARY AND RECOMMENDATIONS

●Cryptococcosis is an invasive fungal infection, most commonly caused by Cryptococcus

neoformans. Infection begins in the lungs; meningoencephalitis is the most frequently

encountered manifestation of cryptococcosis in HIV-infected patients. (See 'Introduction' above.)

●The incidence of cryptococcal meningoencephalitis has declined in patients who have access to

antiretroviral therapy (ART). However, cryptococcal disease remains a leading cause of mortality

in the developing world. (See 'Epidemiology' above.)

●Symptoms typically begin indolently over a period of one to two weeks. The most common

symptoms are fever, malaise, and headache. Other symptoms, suggesting disseminated disease,

may be present including cough, dyspnea, and skin rash. (See 'Clinical manifestations' above.)

●The definitive diagnosis of cryptococcal meningoencephalitis is made by culture of the organism

from the cerebrospinal fluid (CSF). A positive cryptococcal polysaccharide antigen in the CSF or

serum strongly suggests the presence of infection well before the cultures become positive.

(See 'Diagnosis' above.)

●Radiographic imaging of the brain must be performed prior to lumbar puncture if there is a

concern for increased intracranial pressure (ICP) and/or other space-occupying lesions.

(See 'Importance of neuroimaging' above.)

●The significant clinical and laboratory predictors of death during initial therapy include an

abnormal mental status, a CSF antigen titer of 1:1024, and a pleocytosis of <20 cells/microL.

(See 'Prognostic factors' above.)

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16. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363:1764.

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Topic 3757 Version 13.0

GRAPHICS

Disseminated cryptococcosis

Multiple umbilicated papules are present on the face of this patient with cryptococcosis. The

lesions resemble molluscum contagiosum.

Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients Authors Gary M Cox, MD John R Perfect, MD Section Editor John G Bartlett, MD Deputy Editor Jennifer Mitty, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2016. | This topic last updated: Feb 26, 2016.

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

syndromes secondary to immune recovery [2].

This topic is devoted to the treatment of the HIV-infected host with C. neoformans meningitis. The

epidemiology, clinical manifestations, diagnosis, treatment and management of complications of

disease are discussed elsewhere. C. neoformans infection outside the central nervous system, C.

neoformans infection in HIV seronegative patients, and Cryptococcus gattii infection are also

discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus

neoformans meningoencephalitis in HIV-infected patients" and "Microbiology and epidemiology of

Cryptococcus neoformans infection" and "Immune reconstitution inflammatory syndrome" and "Clinical

management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis" and"Cryptococcus neoformans infection outside the central nervous

system" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis

in HIV-seronegative patients" and "Treatment of Cryptococcus neoformans meningoencephalitis and

disseminated infection in HIV seronegative patients" and "Cryptococcus gattii infection: Microbiology,

epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and

diagnosis" and "Cryptococcus gattii infection: Treatment".)

ANTIFUNGAL AGENTS — The primary antifungal agents used for the treatment of cryptococcal

meningoencephalitis include intravenous amphotericin B deoxycholate or its lipid formulations,

oral flucytosine, and oral fluconazole. For most patients, liposomal preparations of amphotericin B are

preferred to minimize the risk of toxicity and improve the ability to give an uninterrupted induction

period of treatment. Echinocandin antifungals do not have significant activity against C.

neoformans and should not be used to treat this infection [3]. (See "Pharmacology of

azoles" and "Pharmacology of amphotericin B".)

Combination therapy with amphotericin B and flucytosine is fungicidal (inhibition leads to cell death),

while fluconazole alone is only fungistatic (ie, inhibits without killing). Importantly, the use of a

fungicidal regimen during the initial phase of therapy has been associated with better clinical outcomes

[4]. (See 'Induction and consolidation therapy' below.)

GENERAL PRINCIPLES — The HIV-infected patient with advanced immunosuppression (CD4 cell

count <50 cells/microL) is at risk for severe cryptococcal meningoencephalitis, which is uniformly fatal

within approximately two weeks if untreated [5]. 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), low body weight, poor CSF inflammatory response (<20 cells/ul of CSF), and altered

mental status on presentation [6]. (See "Epidemiology, clinical manifestations, and diagnosis of

Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section on 'Clinical

manifestations'.)

Clinical trial data demonstrate that the optimal approach to treatment involves three phases: induction

therapy for approximately two weeks followed by consolidative therapy for approximately eight weeks

[2,7]. Many HIV-infected patients with cryptococcal meningoencephalitis have a high burden of

infection in the central nervous system (CNS) with yeast concentrations in the range of a

million yeasts/mL of CSF. This high burden of infection requires a combination treatment regimen with

fungicidal activity such as amphotericin B with flucytosine to rapidly sterilize the cerebrospinal fluid

during induction therapy [4,8]. Long-term maintenance (ie, suppressive) therapy is required to

decrease the risk of relapse. (See "Pharmacology of amphotericin B" and "Pharmacology of flucytosine

(5-FC)" and "Pharmacology of azoles".)

An important component of treatment of cryptococcal meningoencephalitis includes immune

reconstitution with potent antiretroviral medications. However, the initiation of antiretroviral therapy

(ART) can also lead to complications such as immune reconstitution inflammatory syndrome (IRIS).

(See "Clinical management and monitoring during antifungal therapy of the HIV-infected patient with

cryptococcal meningoencephalitis", section on 'Immune reconstitution inflammatory syndrome'.)

Effective patient management also requires careful evaluation for complications directly related to

cryptococcal brain infections, such as increased intracranial pressure, which can lead to blindness,

herniation, persistent headaches, and/or neuropathies, if untreated. (See "Clinical management and

monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis", section on 'Monitoring of intracranial pressure'.)

CLINICAL TRIAL DATA — The following section illustrates a few of the major trials that have guided

the approach to therapeutic management of the HIV-infected patient with cryptococcal

meningoencephalitis and form the foundation for the 2010 Infectious Diseases Society of America

(IDSA) guidelines [2], as well as recent updates [7].

Induction and consolidation therapy — Rapid sterilization of the cerebrospinal fluid (CSF) is linked

to better survival rates and decreased rates of relapse among symptomatic patients with cryptococcal

meningoencephalitis [4,8-10]. Rapid sterilization also allows conversion from potentially toxic

intravenous amphotericin B to better tolerated oral agents. It is critically important to complete this two-

week induction fungicidal regimen to optimize clinical outcomes. Thus, lipid formulations of

amphotericin B are typically used for initial induction therapy to minimize the risk of toxicity. In addition,

adverse events related to amphotericin B or flucytosine should be actively managed, rather than

switching to a less potent combination of drugs. (See 'Adverse events' below and 'Approach to

antifungal treatment' below and 'Patients who are intolerant of amphotericin B and/or

flucytosine' below.)

The period of induction therapy should be extended longer than two weeks if the CSF cultures remain

positive after two weeks of treatment and/or the patient has not demonstrated significant clinical

improvement. Treatment can also be extended if the CSF cultures are anticipated to remain positive at

the end of two weeks of treatment (eg, a severely immunosuppressed patient with a CSF culture that

is positive after a week of treatment) [2]. Although persistence of positive cultures may suggest the

development of direct drug resistance, this is an extremely uncommon occurrence. (See "Clinical

management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis", section on 'Drug resistance testing'.)

The importance of fungicidal therapy (eg, amphotericin B) versus fungistatic therapy (eg, fluconazole)

for induction therapy was illustrated by 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) [11]. Two important

findings emerged from this trial:

●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).

●Compared with fluconazole, treatment with amphotericin B resulted in more rapid CSF

sterilization (42 days versus 64 days).

A multicenter, double-blind trial evaluated the effectiveness of two weeks of amphotericin B (dosed

higher at 0.7 mg/kg per day), with or without the flucytosine (100 mg/kgper day), as induction therapy

in 381 HIV-infected patients with cryptococcal meningoencephalitis [9]. In addition, the investigators

compared eight weeks of fluconazole(400 mg daily) or itraconazole (400 mg daily) as consolidation

therapy. 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.

●Among the patients who underwent a repeat lumbar puncture at the end of the consolidation

phase, the CSF culture was negative in 97 percent of patients on thefluconazole arm (139 of 151)

compared with 92 percent in the itraconazole group (93 of 101 patients). However, the data are

somewhat limited since a significant percentage of patients assigned to the itraconazole and

fluconazole arms did not undergo repeat lumbar puncture (35 and 26 percent, respectively).

Clinical outcomes were similar between the two arms.

●Overall mortality was 5.5 percent within the first two weeks and 3.9 percent in the next eight

weeks, with no significant difference between groups.

●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 contrast to the trial described above [9], a subsequent randomized open-label trial that compared

the efficacy of three different induction therapy regimens showed a mortality benefit with amphotericin

B plus flucytosine [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

100mg/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. The following findings were

observed:

●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.

●Combination therapy with amphotericin B plus flucytosine was associated with significantly

increased rates of yeast clearance from the CSF (-0.42 log10 colony-forming units [CFU]/mL per

day compared with -0.31 log10 CFU/mL per day with amphotericin B monotherapy and -0.32

log10 CFU/mL per day with combination therapy with amphotericin B plus fluconazole).

●Rates of adverse events were similar in all groups, although neutropenia was more common in

patients receiving combination therapy with either amphotericin B plusflucytosine (34 percent) or

amphotericin B plus fluconazole (32 percent) compared with amphotericin B monotherapy (19

percent).

The superiority of combination therapy with amphotericin B plus flucytosine observed in this trial with

respect to both mortality and rates of yeast clearance from the CSF strongly supports the

recommendation to use this regimen for induction therapy of cryptococcal meningitis [12].

(See 'Induction and consolidation' below.)

Other trials have confirmed faster rates of CSF sterilization and lower rates of relapse with

amphotericin B plus flucytosine than amphotericin B alone [13-16], and it is the combination of choice

for the induction phase of therapy for cryptococcal meningitis. However since flucytosine is not

available in some resource-limited settings, an important question is whether combination therapy with

amphotericin B plus an azole results in comparable outcomes as amphotericin B plus flucytosine. This

was addressed in a trial of 80 HIV-positive antiretroviral therapy (ART)-naïve patients in South Africa

who presented with cryptococcal meningitis [17]. Patients were randomly assigned to four treatment

arms for a two-week period of induction therapy: amphotericin B deoxycholate (0.7 to

1 mg/kg/day) plus flucytosine (25 mg/kg orally four times daily), amphotericin B deoxycholate (0.7 to

1 mg/kg IV daily) plus fluconazole (800 mg orally daily), amphotericin B deoxycholate (0.7 to

1 mg/kg/day) plus fluconazole (600 mg orally daily), or amphotericin B deoxycholate (0.7 to

1 mg/kg/day) plus voriconazole (300 mg orally twice daily). There were no statistically significant

differences in the rate of clearance of cryptococcal CFU in CSF samples among the four treatment

groups. Overall mortality was 12 percent at 2 weeks and 29 percent at 10 weeks, with no statistically

significant differences among the groups.

In an open-label study, 143 HIV-infected individuals 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) [18]. 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 towards better outcomes and the regimen was well tolerated.

Trials examined whether there may be a role for triple combination therapy with

amphotericin B/flucytosine/fluconazole compared with dual therapy. No additional benefit was

observed in one study [14], but triple combination therapy appeared to have a more favorable outcome

in another study [19].

The optimal induction dose of amphotericin B is imprecise since 0.5 mg/kg/day was not directly

compared with 0.7 mg/kg/day in the above mentioned clinical trial [9]. However, comparison of

0.7 mg/kg/day with 1 mg/kg/day amphotericin B demonstrated no difference in mortality at 10 weeks in

a small trial among 64 HIV-infected patients with cryptococcal meningoencephalitis [20].

Fluconazole is generally preferred over itraconazole since the bioavailability of itraconazole varies

significantly from person to person and drug monitoring is generally needed to assure appropriate

serum levels have been achieved. In addition, itraconazole is associated with significant

gastrointestinal symptoms, and its penetration into the CSF compartment is substantially less than

fluconazole. (See "Pharmacology of azoles".)

Maintenance therapy — Early in the AIDS epidemic, primary therapy for cryptococcal

meningoencephalitis was followed by frequent relapse after treatment discontinuation [21]. In 1991, 84

AIDS patients with a history of cryptococcal meningoencephalitis 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) [21].

Subsequent trials comparing fluconazole with either weekly intravenous amphotericin B or

oral itraconazole for cryptococcal meningoencephalitis demonstrated that fluconazole was the most

efficacious antifungal agent for maintenance therapy [7,13,22]. For example, in one clinical trial of 108

HIV-infected patients, the relapse rate among those treated with itraconazole was 23 percent

compared with 4 percent of those taking fluconazole [13].

APPROACH TO ANTIFUNGAL TREATMENT

Induction and consolidation

●The initial preferred approach to the patient with cryptococcal meningoencephalitis includes

combination antifungal therapy for the induction phase of therapy followed by consolidation

therapy with fluconazole alone [2,7]. Dosing for patients with renal insufficiency is discussed

below. (See 'Patients with established renal insufficiency' below.)

●For most patients, we recommend induction therapy with liposomal amphotericin B (3 to

4 mg/kg intravenously [IV] daily) plus flucytosine (100 mg/kg per day orally in four divided doses)

for a minimum of two weeks, followed by consolidation therapy with fluconazole at a dose of 400

mg orally once daily for a minimum of eight weeks. However, amphotericin B deoxycholate

(0.7 mg/kg IV daily) can be used if liposomal amphotericin is not available (eg, because of

cost) and/or the patient isnot at risk for developing nephrotoxicity. (See 'Patients without risk of

nephrotoxicity' below.)

●If flucytosine is not available, we recommend liposomal amphotericin B (3 to 4 mg/kg IV daily) or

amphotericin B deoxycholate (0.7 mg/kg IV daily) plus fluconazole(800 mg daily orally) for a

minimum of two weeks, followed by consolidation therapy with fluconazole at a dose of 800 mg

orally daily for a minimum of eight weeks.

Induction therapy should be continued if clinical improvement is not yet observed or if cerebrospinal

fluid (CSF) sterilization has not yet been achieved at two weeks [2]. The regimen and the length of re-

induction will be guided by the clinical and microbiological response. Use of intrathecal or

intraventricular amphotericin B is not advised since systemic administration demonstrates good

efficacy and these other direct routes can be associated with arachnoiditis [23]. Such patients should

be managed in consultation with an Infectious Disease physician who has experience in treating

cryptococcal disease.

A discussion on how to manage patients who cannot tolerate amphotericin B and/or flucytosine is

found below. (See 'Patients who are intolerant of amphotericin B and/or flucytosine' below.)

There is no role for empiric glucocorticoids during induction therapy. This is in contrast to other

conditions (eg, tuberculous meningitis) where they 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 [24]. Patients received amphotericin

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 immune reconstitution inflammatory syndromes (IRIS) between the two groups at 10 weeks; in

addition, patients who received adjunctive glucocorticosteroids were less likely to have a good

neurologic outcome (13 versus 25 percent; odds ratio 0.42, 95 CI 0.25 to 0.69). Patients who received

dexamethasone also had significantly slower rates of fungal 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 events). The use of glucocorticoids for the management of patients who

develop IRIS is discussed elsewhere. (See "Clinical management and monitoring during antifungal

therapy of the HIV-infected patient with cryptococcal meningoencephalitis".)

Maintenance — At the completion of eight weeks, maintenance therapy with lower-

dose fluconazole (200 mg daily) should be continued for long-term suppression (minimum of one

year). Maintenance therapy can be discontinued if the patient has achieved sufficient immunologic

recovery (ie, CD4 count >100 cells/microL) with effective antiretroviral therapy (ART).

(See 'Discontinuation of maintenance therapy' below.)

SPECIAL TREATMENT CONSIDERATIONS

Patients without risk of nephrotoxicity — Amphotericin B deoxycholate and liposomal amphotericin

B are both effective for the treatment of cryptococcal meningitis [25]. We suggest induction therapy

with liposomal amphotericin B rather than the deoxycholate formulation for patients with baseline

normal renal function and without risk factors for renal failure (eg, diabetes, uncontrolled hypertension,

HIV nephropathy, and/or being administered other nephrotoxic drugs). The use of liposomal

amphotericin is associated with less toxicity (eg, nephrotoxicity, infusion reactions, anemia) [25,26].

Thus, it is more likely that induction therapy will be uninterrupted with the use of the lipid formulation,

which is an important factor for the successful management of cryptococcal meningoencephalitis [27].

Amphotericin B deoxycholate (0.7mg/kg IV daily) can be used for patients with normal renal function

who are without risk of nephrotoxicity if liposomal amphotericin is not available.

However, guidelines differ with regard to the preferred type of amphotericin B preparation that they

recommend for patients at low risk of nephrotoxicity:

●The guidelines from the Infectious Disease Society of America recommend the use of

amphotericin B deoxycholate as the preferred preparation for most individuals with cryptococcal

meningoencephalitis [2]. The rationale for this choice is that there is extensive clinical experience

with this preparation, and that dosages of 0.7mg/kg per day administered with adjunctive saline

infusions are generally well tolerated for a period of two weeks.

●The guidelines from the Centers for Disease Control and Prevention, the National Institutes of

Health, and the HIV Medicine Association of the Infectious Diseases Society of America

recommend the liposomal amphotericin B preparation for all individuals [7]. This view is based on

the growing body of evidence that lipid formulations are effective in patients with disseminated

disease and are associated with a decreased risk of nephrotoxicity. However, there are no

comparative studies with the combination of lipid formulations of amphotericin B

and flucytosine together for cryptococcal meningoencephalitis.

●Guidelines from the World Health Organization consider liposomal amphotericin

B (3 mg/kg/day) as an alternative strategy to amphotericin B deoxycholate since both

formulations are effective and the liposomal formulations are much more costly [28].

Patients at risk of renal insufficiency — During the induction phase, we recommend lipid

formulations of amphotericin B for patients at risk for renal failure (eg, those with diabetes or

uncontrolled hypertension, patients taking other nephrotoxic drugs, or patients with suspected HIV

nephropathy) [2,7]. All formulations of amphotericin B can cause renal functional impairment, including

decreases in the glomerular filtration rate. However, compared with standard amphotericin B

deoxycholate, lipid formulations of amphotericin B are associated with comparable efficacy and a lower

incidence of acute kidney injury and renal tubular dysfunction, although at increased drug acquisition

cost [25,29,30]. (See "Amphotericin B nephrotoxicity".)

We agree with the guidelines that recommend 3 to 4 mg/kg IV daily of liposomal amphotericin B for

HIV-infected patients with cryptococcal meningoencephalitis [2,7], based upon clinical trials

demonstrating clinical equivalence between this regimen and 0.7 mg/kg/day of standard amphotericin

B deoxycholate [25,30]. Amphotericin B lipid complex (5 mg/kg IV daily) or Ambisome (6 mg/kg IV

daily) are acceptable alternatives [2].

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; 6mg/kg/day in a third arm) among 267

HIV-infected patients with cryptococcal meningoencephalitis [25]. The mean serum creatinine amongst

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.

Patients with established renal insufficiency — We strongly recommend lipid formulations of

amphotericin B for patients with renal dysfunction to reduce the risk of nephrotoxicity. (See 'Patients at

risk of renal insufficiency' above.)

Although difficult to use in patients with renal impairment, the dose of amphotericin B for treatment

does not need to be adjusted for renal dysfunction. However, the dose of flucytosine should be

adjusted in patients with reduced kidney function. Dose modifications are discussed in the Lexicomp

drug information topic within UpToDate and within the individual topic review. (See "Pharmacology of

flucytosine (5-FC)", section on 'Dose modification'.)

A discussion on the management of patients who develop renal insufficiency while receiving

amphotericin B is found elsewhere. (See "Clinical management and monitoring during antifungal

therapy of the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Amphotericin

B'.)

ADVERSE EVENTS — Amphotericin B deoxycholate is frequently associated with electrolyte

disturbances, anemia, renal insufficiency, and infusion site reactions, such as drug fever and rigors.

These adverse events are reduced when liposomal preparations are used [25]. 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

intravenously). The risk of renal dysfunction associated with amphotericin B may be reduced with

infusion of normal saline before and during therapy. (See "Pharmacology of amphotericin B", section

on 'Infusion-related reactions' and "Clinical management and monitoring during antifungal therapy of

the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Monitoring for drug

toxicity' and "Amphotericin B nephrotoxicity".)

Flucytosine is mainly associated with gastrointestinal intolerance. Laboratory abnormalities include

elevations in aminotransferases, anemia, leukopenia, and thrombocytopenia. (See "Clinical

management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis", section on 'Monitoring for drug toxicity'.)

Fluconazole is generally well tolerated [18]; patients occasionally may develop rash or abnormal

aminotransferases. 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 flucytosine (5-FC)" and "Pharmacology of azoles".)

Patient and laboratory monitoring during induction/consolidation and maintenance is discussed

elsewhere. (See "Clinical management and monitoring during antifungal therapy of the HIV-infected

patient with cryptococcal meningoencephalitis".)

PATIENTS WHO ARE INTOLERANT OF AMPHOTERICIN B AND/OR FLUCYTOSINE — Some

patients have difficulty tolerating amphotericin B and/or flucytosine. Alternative regimens are available;

however, they appear suboptimal for cerebrospinal fluid (CSF) sterilization [2,18,31,32] (see 'Induction

and consolidation' above and'Adverse events' above). As examples:

●In an open-label study of high-dose fluconazole (400 to 800 mg daily) combined

with flucytosine for induction/consolidative therapy, 25 percent of patients still had positive

cultures after 10 weeks of treatment and 13 percent died [31,32]. In another small clinical trial,

there were a lower number of deaths in the combination therapy arm compared with fluconazole

alone (200 mg daily), but overall mortality rates were high (16 versus 40 percent) [32].

●When measuring rates of CSF sterilization, the combination of amphotericin B

plus fluconazole (400 mg daily) was found to be inferior to amphotericin B

plusflucytosine for induction/consolidation, but more effective than amphotericin B monotherapy

[14].

Thus, before changing a patient’s regimen, it is important to see if any of the individual’s adverse

reactions can be managed without a change in therapy.

●The use of lipid amphotericin may reduce the risk of adverse events related to amphotericin B

deoxycholate. Discussions on the management of infusion reactions and nephrotoxicity are found

elsewhere. (See 'Adverse events' above and "Clinical management and monitoring during

antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis", section on

'Monitoring for drug toxicity' and "Pharmacology of amphotericin B", section on 'Infusion-related

reactions' and"Amphotericin B nephrotoxicity", section on 'Salt loading'.)

●For those with an adverse reaction to flucytosine, serum levels may be helpful to assess if a

dose adjustment is required. Additional discussions of the management of adverse reactions

related to flucytosine are found elsewhere. (See 'Adverse events' above and "Clinical

management and monitoring during antifungal therapy of the HIV-infected patient with

cryptococcal meningoencephalitis", section on 'Monitoring for drug toxicity' and "Pharmacology of

flucytosine (5-FC)", section on 'Management of toxicities'.)

If the patient is still unable to tolerate amphotericin B plus flucytosine, the regimen can be modified.

●For those who are unable to tolerate flucytosine, amphotericin B plus fluconazole (800 mg per

day) is the preferred polyene-azole combination [18]. The adverse events associated with

amphotericin B plus fluconazole are mainly related to those expected with amphotericin B

administration.

●For those unable to tolerate amphotericin B, we administer fluconazole 800 mg daily

with flucytosine (100 mg/kg daily in four divided doses orally). On rare occasion when neither

amphotericin nor flucytosine can be tolerated, fluconazole alone (1200 mg daily) can be used [7].

Since these modified regimens appear to be less effective, it is important that patients are monitored

closely for evidence of treatment failure. (See "Clinical management and monitoring during antifungal

therapy of the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Sterilization of

cerebrospinal fluid' and "Clinical management and monitoring during antifungal therapy of the HIV-

infected patient with cryptococcal meningoencephalitis", section on 'Clinical monitoring during

treatment'.)

WHEN TO INITIATE ANTIRETROVIRAL THERAPY — Immune recovery is an important part of the

successful treatment of cryptococcal meningitis. However, initiation of ART can be associated with an

immune reconstitution inflammatory syndrome (IRIS). The timing of when to initiate ART to minimize

the risks of IRIS is discussed elsewhere. (See "Clinical management and monitoring during antifungal

therapy of the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Timing of

antiretroviral therapy'.)

DRUG INTERACTIONS — Before starting antiretroviral therapy, drug-drug interactions must be

checked and considered, particularly with the azoles. (See "Pharmacology of azoles".)

THERAPEUTIC COMPLICATIONS — Multiple complications can occur during antifungal therapy

related to adverse drug-related events. In addition, patients with severe cryptococcal

meningoencephalitis may develop increased intracranial pressure, which can lead to significant

morbidity and mortality. Furthermore, some patients who initiate antiretroviral therapy (ART) can

develop an inflammatory cerebrospinal fluid (CSF) profile with symptomatic increased intracranial

pressure that is related to immune recovery. A full discussion of the symptoms, signs, and

management of these IRIS complications are found elsewhere. (See "Clinical management and

monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis".)

DISCONTINUATION OF MAINTENANCE THERAPY — We agree with guidelines that recommend

discontinuing maintenance therapy for individuals on antiretroviral therapy (ART) who have a CD4 cell

count greater than 100 cells/microL, who have an undetectable viral load on ART for greater than three

months, and have received a minimum of one year of azole maintenance therapy [2,7].

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 [33,34]. CD4 cell counts are usually monitored every three to four months. (See "Patient

monitoring during HIV antiretroviral therapy", section on 'Frequency of immunologic and virologic

monitoring'.)

●In a prospective trial, 42 AIDS patients in Thailand were randomly assigned to continue or

discontinue maintenance therapy when the CD4 cell count had risen to >100 cells/microL along

with HIV viral suppression for three months [33]. There were no relapses in either arm after 48

weeks of observation.

●In an observational study, 4 of 100 patients who discontinued maintenance therapy had a

clinical relapse of cryptococcal infection [34].

●In an observational cohort of 358 patients who discontinued prophylaxis for various

opportunistic infections, 39 had a history of cryptococcal meningitis [35]. The absolute CD4 cell

count was 100 to 199 in 8 patients and >200 cells/microL in 28 patients at the time of

discontinuation of maintenance therapy; none of the patients relapsed.

With discontinuation of azole maintenance therapy, the clinician must continue to follow patients

closely, and 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 titer.

(See "Clinical management and monitoring during antifungal therapy of the HIV-infected patient with

cryptococcal meningoencephalitis", section on 'Monitoring of serum cryptococcal antigen'.)

PREVENTING SYMPTOMATIC DISEASE

Primary prevention — The best way to prevent cryptococcal disease in HIV-infected individuals is

through early initiation of antiretroviral therapy (ART). Antiretroviral therapy 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 HIV-infected patients".)

We suggest not using routine antifungal prophylaxis for primary prevention of cryptococcal infection.

This is supported by major guideline panels because of the lack of overall survival benefit, drug

interactions, adverse effects, potential antifungal drug resistance, and cost [2,7,28]. A Cochrane

systematic review identified five randomized controlled trials using antifungal interventions for the

primary prevention of cryptococcal disease in a total of 1316 HIV-infected patients [36]. The incidence

of cryptococcal disease decreased significantly in patients taking either fluconazole or itraconazole;

however, there was no significant effect on mortality. Similar findings regarding lack of survival benefit

have been observed in resource-limited settings [37].

Screening and treatment of early infection — In addition to starting ART, a strategy involving serum

cryptococcal antigen (CrAg) screening and antifungal therapy may reduce the risk of developing

cryptococcal meningitis in patients who are at high risk for developing disease [7,28,38-41].

Cryptococcal antigen is detectable in serum at least three weeks prior to the onset of neurologic

symptoms.

We suggest serum CrAg screening for asymptomatic patients not receiving ART with a CD4 count

<100 cells/microL if they are from resource-limited settings where the prevalence of cryptococcal

antigenemia is >3 percent. Although evidence is limited, this approach to screening is in agreement

with recommendations from the World Health Organization [28]. For patients in the United States,

guidelines state that screening should be considered in patients with a CD4 count

<100 cells/microL(especially those with a CD4 count <50 cells/microL) if the prevalence of

cryptococcal antigenemia is approximately 3 percent, which has been reported within some United

States cohorts [7,42,43]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus

neoformans meningoencephalitis in HIV-infected patients".)

Patients who test negative for serum CrAg should initiate ART. 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 (regardless of signs and symptoms) to evaluate for the

presence of CSF CrAg or positive CSF cryptococcal cultures. Antiretroviral therapy should be held

pending return of the cerebrospinal fluid (CSF) studies, but antifungal therapy with fluconazole 400 mg

daily should be started.

●If the LP is negative (ie, negative CSF CrAg and culture), antifungal therapy

with fluconazole (400 mg daily) should be continued and ART can be started concurrently. 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 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. (See 'Approach to antifungal treatment' above and "Clinical management

and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal

meningoencephalitis", section on 'Timing of antiretroviral therapy'.)

In certain resource-limited settings, it may not be possible to perform a lumbar puncture on all

asymptomatic patients, and then the decision to initiate fluconazole must be based upon the absence

of clinical disease. For such patients, we initiate ART two to four weeks after pre-emptive therapy with

fluconazole has been started.

Small studies in resource-limited settings have suggested a clinical benefit of using screening and a

pre-emptive therapeutic strategy to prevent development of cryptococcal meningitis [7,28,38-41];

however, there are no high quality data to demonstrate the efficacy of this approach. As examples:

●In a study of 295 antiretroviral (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 [38]. 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% to 89%). In the five CRAG-positive persons who were not

treated with fluconazole, all died within two months of ART initiation.

●In another study that evaluated approximately 2000 patients in Tanzania and Zambia with a

CD4 count <200 cells/microL, an intervention that included ART, community support, and CrAg

testing with pre-emptive fluconazole was compared with standard of care (ART plus clinic based-

visits) [41]. 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). However, it

is unclear if the mortality benefit was from screening and pre-emptive therapy for cryptococcal

disease or from enhanced community support.

●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 lateral flow assay (LFA) and 21

received antifungal therapy [40]. Ten patients agreed to LP and four tested positive for CrAg in

the CSF and received amphotericin. Of the remaining 17, all received fluconazole and none

developed cryptococcal meningitis. These findings were compared with a historical control where

7 of 25 serum CrAg-positive patients (28 percent) who did not receive pre-emptive antifungal

therapy went on to develop cryptococcal meningoencephalitis [44].

Studies evaluating cost-effectiveness have suggested that this screen and treat strategy can be cost-

effective in resource-limited areas where the prevalence of cryptococcal antigenemia is >3 percent

[38,39,45,46]. These findings were based upon reductions in mortality found in some of the studies

above [38,39]. However, the low quality of the evidence results in substantial uncertainty as to the true

effect of this approach on mortality. As such, the cost-effectiveness results are similarly uncertain.

SUMMARY AND RECOMMENDATIONS

●Cryptococcal meningoencephalitis occurs mainly in HIV-infected patients with advanced

immunosuppression related to untreated AIDS. (See 'Introduction' above.)

●The main antifungal agents used for the treatment of cryptococcal meningitis include

intravenous amphotericin B deoxycholate and its lipid formulations, oralflucytosine, and

oral fluconazole. Amphotericin B and flucytosine are fungicidal (inhibition leads to cell death),

while fluconazole is only fungistatic (ie, inhibits without killing). Lipid formulations of amphotericin

B are preferred for patients with renal dysfunction and at risk for renal failure and in all patients

where induction therapy might be at risk for interruption. (See 'Antifungal agents' above.)

●Cryptococcal meningoencephalitis is uniformly fatal if untreated. The therapeutic approach

includes three phases: induction and consolidation for a total of 10 weeks to decrease early

mortality and to rapidly sterilize the cerebrospinal fluid (CSF), followed by maintenance therapy to

prevent relapse of infection. (See 'General principles' above.)

●For patients with cryptococcal meningoencephalitis, we recommend intravenous (IV)

amphotericin B with oral flucytosine during the two-week induction phase of therapy (Grade 1A).

The dose of flucytosine is 100 mg/kg per day in four divided doses, adjusted for renal function. If

flucytosine is not available, or if it is not tolerated, we recommend fluconazole (800 mg daily

orally) in addition to amphotericin B during the two-week induction phase of therapy (Grade 1B).

It is important that induction therapy not be interrupted. (See 'Induction and consolidation' above.)

•For patients with normal renal function, we suggest liposomal amphotericin B (3 to

4 mg/kg IV daily) rather than amphotericin B deoxycholate (Grade 2B). However,

amphotericin B deoxycholate (0.7 mg/kg IV daily) is a suitable alternative for such patients if

liposomal amphotericin is not available. (See 'Patients without risk of nephrotoxicity' above.)

•For patients with baseline renal dysfunction and for those at risk for renal failure (eg, those

with diabetes or uncontrolled hypertension or patients taking other nephrotoxic drugs), we

recommend liposomal amphotericin B (3 to 4 mg/kg IV daily) rather than amphotericin B

deoxycholate (Grade 1B). The incidence and severity of decreased renal function is

reduced with liposomal amphotericin B compared with amphotericin deoxycholate,

particularly among patients at increased risk of nephrotoxicity. (See 'Patients at risk of renal

insufficiency' above and 'Patients with established renal insufficiency' above.)

●If there is clinical improvement during the two-week induction therapy period, amphotericin B

and flucytosine can be discontinued and oral azole therapy initiated for the eight-week

consolidation phase of treatment. For patients who received amphotericin B plus flucytosine

during the induction phase of therapy, we recommendfluconazole (400 mg per day orally) rather

than itraconazole during the consolidation phase (Grade 1B). For patients who received

amphotericin B plus fluconazole during the induction phase of therapy, we suggest fluconazole at

a dose of 800 mg orally daily rather than itraconazole or fluconazole at a lower dose (Grade 2C).

(See 'Induction and consolidation' above.)

●After the completion of induction/consolidation phases of therapy, we

recommend fluconazole (200 mg daily) for maintenance treatment compared with no therapy

(Grade 1A). Long-term chronic suppression should be continued for a minimum of one year.

(See 'Maintenance therapy' above.)

●We discontinue maintenance fluconazole therapy in asymptomatic patients who have CD4 cell

counts >100 cells/microL, who have an undetectable viral load on antiretroviral therapy (ART) for

greater than three months and who have received a minimum of one year of azole maintenance

therapy. Close follow-up is advised, and fluconazole should be reinitiated if the CD4 cell count

declines to <100 cells/microL. (See 'Discontinuation of maintenance therapy' above.)

●We suggest not routinely administering antifungal prophylaxis for primary prevention of

cryptococcal disease (Grade 2B). However, for asymptomatic patients with a CD4 count

<100 cells/microL not receiving ART, who are from resource-limited settings where the

prevalence of cryptococcal antigenemia is >3 percent, we suggest a strategy involving serum

cryptococcal antigen screening prior to initiation of ART (Grade 2C). The management of patients

who screen positive for cryptococcal antigen is discussed above. (See 'Preventing symptomatic

disease' above.)

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