Management of Cryptococcal Meningitisin Sub-Saharan Africa

Arthur Jackson & Mina C. Hosseinipour

Published online: 8 June 2010# Springer Science+Business Media, LLC 2010

Abstract Cryptococcal meningitis (CM) is a common formof meningitis in sub-Saharan Africa due to the highprevalence of HIV/AIDS. This report outlines the manage-ment of CM with a focus on resource-limited settings.Sections covered include epidemiology and diagnosis,pharmacotherapy, management of complications, timing ofantiretrovirals, and primary and secondary prevention ofCM. Emphasis has been given to recent articles andlandmark trials, and opinion is given from the authors’own experiences.

Keywords Cryptococcal meningitis .Cryptococcusneoformans . Resource-limited settings . Sub-SaharanAfrica . Amphotericin B . Fluconazole . Flucytosine . Earlyfungicidal activity . Immune reconstitution inflammatorysyndrome . HIV. AIDS . Lumbar puncture . Intracranialpressure . Cryptococcal antigen

Introduction

Cryptococcal meningitis (CM) is a common and oftendevastating disease in areas of high HIV prevalence, suchas sub-Saharan Africa. Prospective studies from Africahave shown that 10% to 20% of deaths among HIV-infected patients are attributable to CM [1, 2]. The mortalityrate remains unacceptably high, especially in resource-poor

areas, with an estimation that more than half a milliondeaths globally per year can be attributed to CM [3•].Efforts need to be coordinated to both reduce theincidence of CM and better treat individual cases withevidence-based regimens. Management must thereforedeal with early diagnosis, antifungal pharmacotherapy,treatment of complications, optimally timed therapy to restoreimmune function, and the ultimate goal should be preventionof disease.

Epidemiology and Diagnosis

Epidemiology

Cryptococcus neoformans is an ubiquitous environmentalfungus found throughout the world that has been specificallyassociated with pigeon excreta and various tree species,including types of eucalyptus [4]. The causative fungi forCM have recently been divided into two separate species: C.neoformans and Cryptococcus gattii (previously C. gattii hadbeen considered as serotypes B and C of C. neoformans).C. neoformans variant grubii causes most disease amongthe severely immunocompromised and in the developingworld.

Cryptococcal capsular polysaccharide and proteinantigen are antibody stimulant, with presence of theseantibodies implying prior exposure to Cryptococcus.High seroprevalence has been encountered in manypopulations, with a majority of children older than 2 yearsshown to have been exposed/infected in an urban USstudy. For children older than 5 years, the prevalence was70% [5]. In less developed settings there are few dataregarding seroprevalence. In Manila, capital of thePhilippines, the seroprevalence among a small cohort of

A. Jackson :M. C. Hosseinipour (*)University of North Carolina Project, Kamuzu Central Hospital,100 Mzimba Road, Private Bag A/104,Lilongwe, Malawie-mail: Mina_hosseinipour@med.unc.edu

A. Jacksone-mail: arthurjackson@yahoo.com

Curr HIV/AIDS Rep (2010) 7:134–142DOI 10.1007/s11904-010-0052-6

children receiving tuberculosis treatment (median ages inyears: 12.8 for girls, 14 for boys) was 18% [6]. Thisreinforces the belief that primary infection can beasymptomatic, or mistaken for a nonspecific viral illness,and that cryptococcal disease is caused by a reactivation oflatent disease during profound immunosuppression.

In the developing world, in tandem with the HIVpandemic, CM is extremely common and is the mostcommonly diagnosed meningitis in many African countries.It accounted for 40% of meningitis cases in a recent largestudy from Malawi [7].

Clinical Presentation

CM usually presents as an indolent meningitis in aprofoundly immunocompromised host. Symptoms typicallyprecede presentation to hospital by 2 to 4 weeks. However,these symptoms are very nonspecific and not reliablypresent especially in advanced HIV, in which theinflammatory response is limited. Classical meningismusis present in less than one third of patients. Featuresreflecting increased intracranial pressure are common,such as severe headache, reduced level of consciousness,seizures, papilledema, and sixth cranial nerve palsies.

Diagnostic Tests

Due to the nonspecific nature of the signs and symptoms,one must have a low threshold for suspecting CM inpatients with a low CD4 count (<100 cells/mL) who areunwell. Cerebrospinal fluid (CSF) examination throughlumbar puncture (LP) is the mainstay of diagnosis. Whilebrain imaging is commonly recommended in resource-richsettings, resource-limited settings do not have this serviceavailable and clinicians feel the diagnostic and therapeuticbenefits of LP outweigh the potential risks.

An LP will classically reveal a raised opening pressure,and a lymphocytic pleocytosis. The CSF protein may beelevated. With HIV-associated immunosuppression theremay be blunting of the inflammatory response with normalor less protein elevation, and pleocytosis may be absent.India ink examination of CSF will reveal a characteristicstaining pattern: the capsule repels the ink, leaving a visible“halo” around the individual yeast cells. This method ishighly sensitive when experienced technicians are availableand disease burden is high.

Cryptococcal antigen (CrAg) can bemeasured in the serumand the CSF. When detected in the CSF it is also highlysensitive and specific. A serum CrAg with a titre of > 1:8suggests disseminated disease. Rare false positives can occur.

Confirmation of diagnosis can be made by culturingCSF on Sabouraud agar plates, where characteristiccolonies should grow after approximately 36 h. A useful

method to determine the extent of the disease burden inan individual case is to do quantitative cultures, bydiluting aliquots of CSF and plating onto Sabouraudagar. By counting the individual colonies growing froma specific dilution of CSF one can calculate thenumber of colony-forming units (CFUs) in the initialundiluted CSF. This can give diagnostic information,helping to differentiate between immune reconstitutioninflammatory syndrome (IRIS) and relapse of CM, andcan give prognostic information, with higher initialfungal burden associated with worse outcome. The rateof clearance of infection, as calculated by plotting thelog of the CFU counts/mL CSF against time over thefirst 14 days, is a valuable tool called the earlyfungicidal activity (EFA), the magnitude of which isinversely associated with mortality at 2 and 10 weeks[8••]. This method also gives a measure of drug activityfor research purposes and is discussed again later.

Prognostic Indicators

The most significant negative prognostic indicators arereduced level of consciousness and increased fungal burdenin CSF. Other negative prognostic indicators include aprevious history of significant weight loss, a history ofconvulsions prior to treatment, and raised intracranialpressure [9, 10].

Treatment

Treatment of the patient with CM focuses on antifungalpharmacotherapy (Table 1), measures aimed towardnormalizing intracranial pressure, and an appropriatelytimed reconstitution of the immune system.

Antifungal Pharmacotherapy

A case series in Malawi from 1994 highlights the rapidlyfatal course of untreated HIV-associated CM. Of patientsnot receiving antifungal treatment, none survived longerthan 30 days after diagnosis of CM (the median time beingonly 4 days) [11].

Based on the findings of a landmark clinical trial from1997, the antifungal therapy of immunocompromised patientswith CM can be divided into three phases: induction,consolidation, and maintenance [10]. The induction phase isthe initial intensive period lasting at least 2 weeks, and theconsolidation phase should last at least 8 weeks. Maintenancetherapy may need to be prolonged.

The primary aim of antifungal pharmacotherapy shouldbe to achieve rapid fungicidal activity and CSF sterility.The importance of rapid clearance of infection is supported

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by studies showing the association of 2-week culture statuswith 10-week outcome [12], and more recent studies usingserial quantitative cultures of CSF to derive the rate ofclearance of infection in individual patients. In a large,combined cohort, greater EFAwas associated with decreased2-week and 10-week mortality independent of the other majorprognostic factors. The EFA for those who died at 2 weekswas −0.17 log10 CFU per day compared to −0.40 log10 CFUper day for those who survived at 2 weeks (significantlydifferent). Non-survivors at 10 weeks had a mean EFA of−0.27 log10 CFU, compared to −0.41 log10 CFU amongsurvivors at 10 weeks. What remains unclear is whether thisis a linear relationship, or if there is a value of EFA abovewhich one no longer confers additional benefit [8••].

Some experts suggest a follow-up LP after 2 weeks, andprolongation of the induction phase if the CSF culture is notsterile [13]. The importance of cryptococcal clearancesupports this recommendation, but requires more researchas continuing induction beyond 14 days in all patients,pending culture results, may potentially increase treatmenttoxicity.

Initial Antifungal Pharmacotherapy

Current international guidelines recommend that immuno-suppressed patients with CM should receive amphotericinB deoxycholate (AmB) 0.7 to 1.0 mg/kg/day intravenouslyplus flucytosine (5-FC) 100 mg/kg/day for at least 2 weeks,followed by fluconazole, 400 mg orally daily, for aminimum of 8 weeks.

When AmB is used, careful monitoring is essential, withroutine fluid and saline loading and electrolyte replacement.Blood transfusions are occasionally needed. If dose-limitingtoxicity does occur (almost always in the second week),doses can be deferred, and recommenced once renalfunction has recovered. In general, our team uses acreatinine cut-off of 2.5 mg/dL to decide on deferringAmB treatment. Liposomal formulations of AmB, while

accepted and useful in certain situations in developedcountries, are not available in resource-limited settings.

Unfortunately, amphotericin B is rarely available in sub-Saharan Africa, and even in places where it is available,limited monitoring facilities often preclude its use. While 5-FC has been shown to improve fungal clearance, it is notwidely available in resource-limited settings. Hence, manycenters in Africa still rely on fluconazole monotherapy.Fluconazole is currently available free through the Pfizerdonation program (see www.diflucanpartnership.org) or asan inexpensive generic form. However, previously useddosages of fluconazole (up to 400 mg/day) have beenshown to be essentially fungistatic [14•] and associatedwith poor outcomes [14•, 15], and also carry a significantrisk of the development of secondary fluconazole resistance[16]. Therefore, recent research has focused on evaluatingstrategies to simplify the CM treatment to include high-dose fluconazole, oral-only combination therapy, andshortened or reduced-dose courses of AmB in combinationwith oral agents (Table 2). In some trials, the novel use ofquantitative culture and early fungicidal activity has alloweddirect comparison across these various treatment regimens.

When resources are limited, 1 week of AmB may bepreferable to no AmB. A substantial reduction in organismload can be achieved with 1 week of high-dose AmB [14•],while toxicity usually only develops in the second week.

Recently, Bicanic et al. [17], in South Africa, directlycompared 0.7 mg/kg/day with 1 mg/kg/day, for 14 days,both given with 5-FC. A dose of 1 mg/kg/day resulted inmore rapid fungal killing. However, there was increasedanemia in the higher-dose group, of borderline statisticalsignificance, although the study was not powered to detectdifferences in adverse events. This gives some rationale forusing the higher dose, especially in settings where 5-FC is notavailable or if a full 2-week induction course is not possible.

Addition of 5-FC to anti-cryptococcal treatments hasshown improved rates of clearance of disease [10, 18, 19••],although a significant mortality benefit has yet to be shown

Table 1 Common recommended pharmacotherapy regimens in resource-limited settings

Scenario Induction Consolidation Maintenance

Optimal therapy available AmB (0.7–1 mg/kg/d) for 14 days +flucytosine (100 mg/kg/d) for 14 days

Fluconazole 800 mg/dfor 8 weeks

Fluconazole 200–400 mg/duntil immune reconstitution

Flucytosine unavailable AmB 1 mg/kg for 2 weeksAmB 0.7 mg/kg for 2 weeks + fluconazole800 mg/d for 2 weeks

Polyene unavailable,flucytosine unavailable

Fluconazole 800–1,200 mg/d for 2 weeks Fluconazole 800–1,200 mg/dfor 8 weeks

Polyene unavailable,flucytosine available

Fluconazole 800–1,200 mg/d + flucytosine100 mg/kg/d for 2 weeks

AmB amphotericin B

(Adapted from Perfect et al. [13], Infectious Diseases Society of America guidelines 2010)

136 Curr HIV/AIDS Rep (2010) 7:134–142

in a randomized trial. When added to AmB, 5-FC has alsobeen shown to be associated with a lower rate of treatmentfailure at 2 weeks than AmB alone [10, 20].

Unfortunately, 5-FC is not currently available outside ofclinical trials in Africa, despite its likely benefit. It is hopedthat the growing body of evidence supporting its use willlend weight to its registration in African countries and themanufacturing of a cheap, generically made version of thisoff-patent drug with a relatively simple molecular structure.

Fluconazole given at doses up to 2 g/day has beenstudied in small numbers of patients, with preliminaryevidence for a dose response and reasonable safety up to1,600 mg/day [21•]. Recently, 1,200 mg/day was shown to

be more rapidly fungicidal than 800 mg/day in a trial inUganda, without apparent toxicity [22•], and another studyinvestigating the combination of 5-FC and fluconazoledemonstrated optimal fungicidal activity at fluconazoledoses of 800 to 1,200 mg [21•]. While 1,200 mg/dayfluconazole was found to be a safe and tolerable dose withoptimal efficacy, the fungicidal activity of fluconazole1,200 mg/day is still below that for AmB regimens.

Combinations of AmB and fluconazole have been studied.AmB with fluconazole 400 mg/day was more rapidlyfungicidal than AmB alone, although the difference did notreach statistical significance [18]. AmB plus fluconazole800 mg/day is a more promising combination. In a phase 2

Table 2 A selection of CM treatment studies applicable to resource-limited settings

Year Author Type of study Location Induction regimenscompared

EFA [logCFU/mL/d]

Conclusion

2010 Nussbaumet al. [19••]

RCT Malawi FLUCO 1,200 mg −0.11 Addition of oral 5-FC to 1,200 mg/dayFLUCO for induction results in greaterEFA, and there was a trend toward lowermortality at 2 weeks

FLUCO 1,200 mg +5-FC 100 mg/kg/d

−0.28

2009 Pappaset al. [23•]

RCT Thailand, USA AmB 0.7 mg/kg/d N/A AmB (0.7 mg/kg) plus FLUCO 800 mg/dhad a trend toward better outcomes whencompared with AmB alone

AmB + FLUCO 400 mg/dAmB + FLUCO 800 mg/d

2008 Bicanicet al. [17]

RCT South Africa AmB 0.7 mg/kg/d +5-FC 100 mg/kg/d

−0.45 1 mg/kg AmB results in significantly greaterEFA than 0.7 mg/kg AmB, although withincreased adverse effectsAmB 1 mg/kg/d +

5-FC 100 mg/kg/d

−0.56

2008 Longleyet al. [22•]

Clinical trial Uganda FLUCO 800 mg/d −0.07 1,200 mg/d FLUCO is more rapidlyfungicidal than 800 mg/dFLUCO 1,200 mg/d −0.18

2008 Milefchiket al. [21•]

RCT Zambia FLUCO 800 mg/d ±5-FC 100 mg/kg/d

N/A Doses of FLUCO are safe and welltolerated up to 2,000 mg; additionof 5-FC associated with better outcomeFLUCO 1,200 mg ±

5-FC 100 mg/kg/d

FLUCO 1,600 mg/d ±5-FC 100 mg/kg/d

FLUCO 2,000 mg ±5-FC 100 mg/kg/d

2007 Dromeret al. [20]

Prospectiveobservational

France Multiple regimens(not specified)

N/A Addition of 5-FC appears to be associatedwith lower rates of treatment failure

2004 Brouweret al. [18]

RCT Thailand AmB 0.7 mg/kg/d −0.31 AmB (0.7 mg/kg/d) + 5-FC (100 mg/kg/d)resulted in greater EFA than AmB +FLUCO (400 mg) and AmB +FLUCO + 5-FC

AmB 0.7 mg/kg/d +5-FC 100 mg/kg/d

−0.54

AmB 0.7 mg/kg/d +FLUCO 400 mg/d

−0.39

AmB 0.7 mg/kg/d +FLUCO 400 mg/d +5-FC 100 mg/kg/d

−0.38

1997 Van der Horstet al. [10]

RCT United States AmB 0.7 mg/kg/d N/A Optimal initial therapy for CM is 2 weeksof AmB + 5-FC; divide treatment intoinduction, consolidation, and maintenancephases; use FLUCO for consolidationtreatment

AmB 0.7 mg/kg/d +5-FC 100 mg/kg/d

5-FC flucytosine; AmB amphotericin B; CFU colony-forming units; CM cryptococcal meningitis; EFA early fungicidal activity; FLUCOfluconazole; N/A not applicable; RCT randomized controlled trial

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trial, this combination had the highest percentage success rate(defined as sterile CSF plus survival plus neurologicalstability or improvement) at 2, 6, and 10 weeks, comparedwith AmB alone and AmB plus fluconazole 400 mg/day[23•]. A phase 3 trial is needed, given the widespreadavailability and safety of fluconazole. In the meantime, AmBplus fluconazole 800 mg/day for 14 days may be consideredas an alternative to AmB alone when 5-FC is not available.We are currently evaluating the EFAs of regimens of short-course AmB (7 days) plus fluconazole 1,200 mg/day(14 days), both with and without 5-FC (14 days).

A Cochrane review has assessed the evidence behind sixdifferent anti-cryptococcal regimens in resource-limitedsettings. As there were no trials directly comparing AmBto fluconazole therapy, they did not recommend onetherapy as superior to the other in these settings [24]. Thechoice of most appropriate antifungal regimens remains adifficult decision in such areas where availability andaffordability of regimens varies greatly, as does the abilityto safely monitor potentially toxic events.

Consolidation Therapy

If optimal therapy of AmB and 5-FC is available for at least2 weeks of induction therapy, then consolidation therapy canconsist of 8 weeks of fluconazole at 400mg once daily.Withoutthis optimal regimen, which is almost never available inresource-limited settings, doses of fluconazole, ≥800 mg/day,should be used for consolidation treatment [13].

It is important to note that in the setting of concurrentrifampicin-containing tuberculosis treatment, one shouldincrease the dosage of fluconazole by 50% in theconsolidation phase. This is due to rifampicin increasingfluconazole metabolism [25].

Maintenance Therapy

Without maintenance treatment, there is an unacceptablyhigh rate of relapse of HIV-associated CM followingapparently successful initial treatment. In the pre-antiretroviral therapy (ART) era, fluconazole was shownto be effective at preventing relapse, with 15% of casesrelapsing in the placebo arm and no relapses in thefluconazole arm [26]. Fluconazole 200 mg/day was shownto be superior as a maintenance therapy to weekly AmB[27], and to itraconazole 200 mg/day [28].

In the pre-ART era, lifelong maintenance therapy wasadvised after successful treatment of HIV-associated CM.With the advent of ART and the realization of immunerestoration, this is no longer considered necessary. Prospectivetrials [29, 30] suggest that it is safe to discontinuemaintenance treatment after ≥1 year of antifungal therapy ifthe patient has a sustained undetectable viral load and CD4+

cell count >100 cells/μL. In developing world settings withless access to laboratory monitoring, fluconazole 200 mg/dayis often continued indefinitely.

Management of Complications

Raised CSF Pressure

A total of 19% to 27% of patients with CM have a CSFpressure >35 cm H2O [9, 31]. This is associated with moresevere symptoms and increased early mortality. Treating theraised pressure is sometimes the onlyway to relieve symptomsand can remove the adverse effect on mortality [31].

The degree of symptoms is not always an indicator ofintracranial pressure, and therefore it is very important toformally measure opening pressure when performing LP inpatients with CM. If a specialized manometer is unavail-able, as is often the case in developing world settings,opening pressure can be accurately estimated by measuringthe vertical height reached by a column of CSF rising in anintravenous giving set that has been attached to the end ofthe spinal needle and held vertically.

A defect in resorption at the arachnoid villi due to fungaldetritus is the expected mechanism behind raised intracranialpressure, supported by a recent pathology study [32], and bythe finding that higher fungal burden is associated withraised opening pressure [31]. Therefore, it is recommendedthat repeated mechanical drainage of CSF through repeatedLPs be the initial approach when faced with this problem.Current guidelines recommend repeat daily LP for those withpressures >25 cm H2O, with the aim to reduce pressure by50% or to <20 cm H2O. The pressure should be recheckedafter every 10 mL of CSF to a maximum of 30 mL drainedat any one time [13].

Even if CSF pressure declines initially, it is common forit to recur in the second week regardless of decline in CSFfungal burden. If daily LPs are not effective, a temporarylumbar drain can allow the safer removal of larger volumesof CSF over 24 h, although with a small risk of infectionassociated. Usually these can be removed without recur-rence of raised intracranial pressure after about 7 days [33].Permanent ventricular shunts can be reserved for patientswho develop true hydrocephalus as a result of obstructionearlier in the pathway of CSF recirculation [34]. Acetazol-amide, steroids, and mannitol have no role in themanagement of raised CSF pressure in CM [9, 35].

Antiretroviral Considerations

Timing of ART

Optimal timing of ART after HIV-associated CM is unclear.The balance lies between the risk of further HIV-related

138 Curr HIV/AIDS Rep (2010) 7:134–142

illness and death if ART is delayed, and the possibility ofmore frequent or severe IRIS (discussed later) if ART isstarted earlier. There have been conflicting data on thetopic. The known very high HIV-related mortality in Africain the months prior to initiation of ART may favor earlierART in this setting. Survival among patients with a firstdiagnosis of CM was improved among patients who wereon ART prior to the time of the diagnosis. However, thisnonrandomized study does not address the optimal timingof ART [36]. A randomized study that included over 30CM patients receiving AmB therapy compared startingART within 2 weeks versus after initial treatment gave a(nonsignificant) trend toward more favorable outcomewith earlier treatment [37]. Conversely, in a recent studyfrom Zimbabwe in which the antifungal treatment wasfluconazole, 800 mg/day, starting nevirapine-based ARTwithin 72 h of diagnosis compared with its initiation at10 weeks was associated with over twice the risk ofmortality (82% vs 37%) [38]. It is possible that the slowfungicidal activity of fluconazole predisposes to IRIScompared to AmB-based therapy, leading to a worseoutcome with earlier treatment as an explanation for thesedivergent results.

Current guidelines from the Southern African HIVClinicians Society recommend starting ART between 2and 4 weeks after antifungal therapy [39], which iscompatible with current Infectious Diseases Society ofAmerica guidelines [13].

If nevirapine-based ART is started during the consolidationphase, the basic fluconazole dose should be reduced to400 mg/day due to a potential drug interaction wherein thenevirapine could attain supra-therapeutic levels, althoughmost studies do not show a dose-dependent toxicity fornevirapine [40, 41]. In our opinion, although there are nosupporting clinical trials, if CM develops in a patient beingtreated with nevirapine-based ART without an option formodification, then normal doses of fluconazole should beused for the induction phase, as the risk of under-treating theCM is probably greater than the risk of potential nevirapinetoxicity.

IRIS

An IRIS occurs in approximately 15% to 30% of HIV-associated cases of CM, at a median of approximately1 month after starting ART [42]. As well as symptoms ofworsening meningitis, one must be aware that IRIS canmanifest at extrapulmonary sites such as lungs, skin, andlymph nodes. Fever is common and CSF opening pressureand white cell counts may be raised, and patients typicallyshow an increased CD4.

Although cultures are usually negative, active infectionand IRIS may coexist, especially if a less rapidly fungicidal

regimen is used as initial therapy and, as in “unmaskingIRIS,” when (usually culture-positive) CM presents for thefirst time soon after the start of ART. In some Africancenters, one third of all CM cases now fall into thiscategory [14•, 36].

Risk factors for IRIS include more severe initialcryptococcal disease, cryptococcemia, a low nadir andrapid rise in CD4+ cell count, lack of sterilization of CSFat 2 weeks, and earlier commencement of ART [43].

CM-IRIS is a diagnosis of exclusion, distinguished fromother causes of symptomatic recurrence, most notablyrelapse due to non-receipt of maintenance fluconazole orsecondary fluconazole resistance (rare following AmBinduction), or alternative diagnoses, in particular concom-itant tuberculous meningitis. An LP should be performedfor evaluation of pressure, cell counts, antigen, and fungaland mycobacterial culture. Depending on severity, whileawaiting culture results, AmB may be restarted. Any raisedCSF pressure should be managed as described above. ARTshould be continued. If fungal cultures are negative and noother diagnosis is apparent, fluconazole consolidation/maintenance can be continued or resumed. Most episodesof IRIS will resolve with time, but if symptoms are severeor progressing, then the use of corticosteroids may bebeneficial. The optimal steroid dose or duration has notbeen determined by a clinical trial, but some expertsrecommend 40 to 60 mg/day until clinical improvement,followed by a tapering course for a total of 2 to 6 weeks.CM-IRIS, although potentially fatal, is usually manageableif recognized early.

Primary Prevention of CM

HIV-associated CM could be prevented if all HIV-infectedpatients were diagnosed and started on ART before theirCD4+ cell counts fell to <100 cells/mL3. However, evenwith increasing access to ART, many programs are onlyjust keeping pace with the number of new patientsprogressing to stage IV HIV disease. Thus, the numberof patients vulnerable to the development of CM is not yetdecreasing, and the issue of CM needs to be specificallyaddressed.

Previous trials of primary prophylaxis with fluconazoleor itraconazole (in the absence of ART) in patients with lowCD4+ cell counts have shown a reduction in CM, althoughno clear survival benefit [44, 45]. The World HealthOrganization recommends consideration of azole prophy-laxis if the incidence of cryptococcal disease is high [46],and Thailand adopted a policy of such prophylaxis forpatients with low CD4 counts, prior to the widespreadavailability of ART. A recent trial in east Africa, lookingonly at cryptococcal serum antigen-negative patients, again

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showed a reduction in CM with fluconazole, although alarge number of patients needed to be treated to prevent onecase and there was no survival benefit [47].

Presumptive Treatment

An alternative attractive strategy, yet to be implemented inlarge programs, regards the detection of asymptomaticcryptococcal antigenemia in susceptible individuals. Thisis found to precede clinical disease, and is detectable a medianof 22 days before symptoms (and for over 100 days in 11% ofpatients) [2]. Antigenemia is a strong independent risk factorfor death [48].

A recent retrospective study from an ART cohort inSouth Africa with median CD4 of 97 cells/mL measuredthe prevalence of CrAg in stored plasma samples from over700 patients. Seven percent were positive for CrAg, whichwas found to be 100% sensitive and 96% specific forpredicting incident CM during the first year of ART andwas an independent predictor of mortality [49••].

Serious consideration has been given to using CrAg as ascreening test among highly immunosuppressed patients atthe time of ART initiation. Cost effectiveness of thisapproach was calculated in a study by Meya et al. [50••].They found that 15% of all patients with a CD4 <100cells/µL had serum CrAg positivity, and treatment of thosewith asymptomatic antigenemia prevented clinical disease.The vast majority of those who did not receive treatmentdeveloped CM. In this study, the number needed to treat(NNT) to avoid one case was 6.5, and the NNT to avoidone death was 10. Extrapolating to situations where CrAgprevalence is >3.5%, the cost predicted to avoid one deathwas $300, which is seen as affordable and couldpotentially be integrated into ART rollout programs.

Conclusions

Incidence and mortality of CM remain unacceptably highin resource-limited areas, such as sub-Saharan Africa.Adherence to established guidelines should be a priorityto clinicians working in such areas, as well as applyingnovel research findings where possible. Emphasis shouldbe placed on the training of local clinicians in anapproach to CM management as outlined above: optimalavailable pharmacotherapy, management of complicationsincluding raised intracranial pressure, and immunerestoration (and its optimal timing). Steps must be takento reduce incidence—first by applying internationalstandards so ART would start before catastrophicimmunological decline, and secondly by consideringnovel approaches such as CrAg screening for those atspecific risk.

Disclosure No potential conflicts of interest relevant to this articlewere reported.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Okongo M, Morgan D, Mayanja B, et al.: Causes of death in arural, population-based human immunodeficiency virus type 1(HIV-1) natural history cohort in Uganda. Int J Epidemiol 1998,4:698–702.

2. French N, Gray K, Watera C, et al.: Cryptococcal infection in acohort of HIV-1-infected Ugandan adults. AIDS 2002, 16:1031–1038.

3. • Park BJ, Wannemuehler KA, Marston BJ, et al.: Estimation ofthe current global burden of cryptococcal meningitis amongpersons living with HIV/AIDS. AIDS 2009, 23:525–530. Thisarticle highlights the devastating effect of this underappreciateddisease in resource-limited areas.

4. Ellis DH, Pfeiffer TJ: Ecology, life cycle, and infectious propaguleof Cryptococcus neoformans. Lancet 1990, 336:923–925.

5. Goldman DL, Khine H, Abadi J, et al.: Serologic evidence forCryptococcus neoformans infection in early childhood. Pediatrics2001, 107:E66.

6. Davis J, Zheng WY, Glatman-Freedman A, et al.: Serologicevidence for regional differences in pediatric cryptococcalinfection. Pediatr Infect Dis J 2007, 26:549–551.

7. Scarborough M, Gordon SB, Whitty CJ, et al.: Corticosteroids forbacterial meningitis in adults in sub-Saharan Africa. N Engl J Med2007, 357:2441–2450.

8. •• Bicanic T, Muzoora C, Brouwer AE, et al.: Independentassociation between rate of clearance of infection and clinicaloutcome of HIV-associated cryptococcal meningitis: analysis of acombined cohort of 262 patients. Clin Infect Dis 2009, 49:702–709. This article validates a useful tool for assessing efficacy ofanticryptococcal regimens.

9. Graybill JR, Sobel J, Saag M, et al.: Diagnosis and managementof increased intracranial pressure in patients with AIDS andcryptococcal meningitis. The NIAID Mycoses Study Group andAIDS Cooperative Treatment Groups. Clin Infect Dis 2000,30:47–54.

10. van der Horst CM, Saag MS, Cloud GA, et al.: Treatment ofcryptococcal meningitis associated with the acquired immunode-ficiency syndrome. National Institute of Allergy and InfectiousDiseases Mycoses Study Group and AIDS Clinical Trials Group.N Engl J Med 1997, 337:15–21.

11. Maher D, Mwandumba H: Cryptococcal meningitis in Lilongweand Blantyre, Malawi. J Infect 1994, 28:59–64.

12. Robinson PA, Bauer M, Leal MA, et al.: Early mycologicaltreatment failure in AIDS-associated cryptococcal meningitis. ClinInfect Dis 1999, 28:82–92.

13. Perfect JR, Dismukes WE, Dromer F, et al.: Clinical practiceguidelines for the management of cryptococcal disease: 2010update by the Infectious Diseases Society of America. Clin InfectDis 2010, 50:291–322.

14. • Bicanic T, Meintjes G, Wood R, et al.: Fungal burden, earlyfungicidal activity, and outcome in cryptococcal meningitis inantiretroviral-naive or antiretroviral-experienced patients treated withamphotericin B or fluconazole. Clin Infect Dis 2007, 45:76–80. Thisarticle supports the use of AmB when possible for CM and

140 Curr HIV/AIDS Rep (2010) 7:134–142

highlights the fact that lower doses of fluconazole are veryineffective at clearing disease.

15. Mwaba P, Mwansa J, Chintu C, et al.: Clinical presentation,natural history, and cumulative death rates of 230 adults withprimary cryptococcal meningitis in Zambian AIDS patientstreated under local conditions. Postgrad Med J 2001, 77:769–773.

16. Bicanic T, Harrison T, Niepieklo A, et al.: Symptomatic relapse ofHIV-associated cryptococcal meningitis after initial fluconazolemonotherapy: the role of fluconazole resistance and immunereconstitution. Clin Infect Dis 2006, 43:1069–1073.

17. Bicanic T, Wood R, Meintjes G, et al.: High-dose amphotericin Bwith flucytosine for the treatment of cryptococcal meningitis inHIV-infected patients: a randomized trial. Clin Infect Dis 2008,47:123–130.

18. Brouwer AE, Rajanuwong A, Chierakul W, et al.: Combinationantifungal therapies for HIV-associated cryptococcal meningitis: arandomised trial. Lancet 2004, 363:1764–1767.

19. •• Nussbaum JC, Jackson A, Namarika D, et al.: Combinationflucytosine and high-dose fluconazole compared with fluconazolemonotherapy for the treatment of cryptococcal meningitis: arandomized trial in Malawi. Clin Infect Dis 2010, 50:338–344. Thisarticle shows the most effective combination of oral therapies forCM to date, with EFA of fluconazole 1200 mg/day plus flucytosineapproaching that of AmB alone. It lends weight to the call forflucytosine to be made available in resource-limited settings.

20. Dromer F, Mathoulin-Pelissier S, Launay O, Lortholary O:Determinants of disease presentation and outcome during crypto-coccosis: the CryptoA/D study. PLoS Med 2007, 4:e21.

21. • Milefchik E, Leal MA, Haubrich R, et al.: Fluconazole alone orcombined with flucytosine for the treatment of AIDS-associatedcryptococcal meningitis. Med Mycol 2008, 46:393–395. Thisarticle supports the use of high-dose fluconazole with flucytosine.

22. • Longley N, Muzoora C, Taseera K, et al.: Dose response effectof high-dose fluconazole for HIV-associated cryptococcal menin-gitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556–1561. This article demonstrates the safety and efficacy of higherdoses of fluconazole.

23. • Pappas PG, Chetchotisakd P, Larsen RA, et al.: A phase IIrandomized trial of amphotericin B alone or combined withfluconazole in the treatment of HIV-associated cryptococcalmeningitis. Clin Infect Dis 2009, 48:1775–1783. This study showsimproved efficacy of AmB combined with fluconazole 800 mg overAmB alone.

24. Sloan D, Dlamini S, Paul N, Dedicoat M: Treatment of acutecryptococcal meningitis in HIV infected adults, with an emphasison resource-limited settings. Cochrane Database Syst Rev 2008,4:CD005647.

25. Apseloff G, Hilligoss DM, Gardner MJ, et al.: Induction offluconazole metabolism by rifampin: in vivo study in humans. JClin Pharmacol 1991, 31:358–361.

26. Bozzette SA, Larsen RA, Chiu J, et al.: A placebo-controlled trialof maintenance therapy with fluconazole after treatment ofcryptococcal meningitis in the acquired immunodeficiency syn-drome. California Collaborative Treatment Group. N Engl J Med1991, 324:580–584.

27. Powderly WG, Saag MS, Cloud GA, et al.: A controlled trial offluconazole or amphotericin B to prevent relapse of cryptococcalmeningitis in patients with the acquired immunodeficiencysyndrome. The NIAID AIDS Clinical Trials Group and MycosesStudy Group. N Engl J Med 1992, 326:793–798.

28. Saag MS, Cloud GA, Graybill JR, et al.: A comparison ofitraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergyand Infectious Diseases Mycoses Study Group. Clin Infect Dis1999, 28:291–296.

29. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al.: Discon-tinuation of secondary prophylaxis for cryptococcal meningitis inhuman immunodeficiency virus-infected patients treated withhighly active antiretroviral therapy: a prospective, multicenter,randomized study. Clin Infect Dis 2003, 36:1329–1331.

30. Aberg JA, Price RW, Heeren DM, Bredt B: A pilot study of thediscontinuation of antifungal therapy for disseminated cryptococ-cal disease in patients with acquired immunodeficiency syndrome,following immunologic response to antiretroviral therapy. J InfectDis 2002, 185:1179–1782.

31. Bicanic T, Brouwer AE, Meintjes G, et al.: Relationship ofcerebrospinal fluid pressure, fungal burden and outcome inpatients with cryptococcal meningitis undergoing serial lumbarpunctures. AIDS 2009, 23:701–706.

32. Loyse A, Wainwright H, Jarvis JN, et al.: Histopathology of thearachnoid granulations and brain in HIV-associated cryptococcalmeningitis: correlation with cerebrospinal fluid pressure. AIDS2010, 24:405–410.

33. Manosuthi W, Sungkanuparph S, Chottanapund S, et al.:Temporary external lumbar drainage for reducing elevatedintracranial pressure in HIV-infected patients with cryptococcalmeningitis. Int J STD AIDS 2008, 19:268–271.

34. Park MK, Hospenthal DR, Bennett JE: Treatment of hydroceph-alus secondary to cryptococcal meningitis by use of shunting. ClinInfect Dis 1999, 28:629–633.

35. Newton PN, Thai le H, Tip NQ, et al.: A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatmentof elevated intracranial pressure in cryptococcal meningitis. ClinInfect Dis 2002, 35:769–772.

36. Bisson GP, Nthobatsong R, Thakur R, et al.: The use of HAARTis associated with decreased risk of death during initial treatmentof cryptococcal meningitis in adults in Botswana. J AcquirImmune Defic Syndr 2008, 49:227–229.

37. Zolopa A, Andersen J, Powderly W, et al.: Early antiretroviraltherapy reduces AIDS progression/death in individuals with acuteopportunistic infections: a multicenter randomized strategy trial.PLoS One 2009, 4:e5575.

38. Makadzange A, Ndhlovu CE, Takarinda K, et al.: Early vsdelayed initation of antiretroviral therapy for concurrent HIVinfection and cryptococcal meningitis in sub-saharan Africa. ClinInfect Dis 2010, 50:1532–1538.

39. McCarthy K, Meintjes G: Guidelines for the prevention, diagnosisand management of cryptococcal meningitis and disseminatedcryptococcosis in HIV-infected patients. Southern African J HIVMed 2007, 25–35.

40. Wakeham K, Parkes-Ratanshi R, Watson V, et al.: Co-administration of fluconazole increases nevirapine concentrationsin HIV-infected Ugandans. J Antimicrob Chemother 2010,65:316–319.

41. Manosuthi W, Athichathanabadi C, Uttayamakul S, et al.: Plasmanevirapine levels, adverse events and efficacy of antiretroviraltherapy among HIV-infected patients concurrently receivingnevirapine-based antiretroviral therapy and fluconazole. BMCInfect Dis 2007, 7:14.

42. Bicanic T, Meintjes G, Rebe K, et al.: Immune reconstitutioninflammatory syndrome in HIV-associated cryptococcal meningi-tis: a prospective study. J Acquir Immune Defic Syndr 2009,51:130–134.

43. Lortholary O, Fontanet A,Memain N, et al.: Incidence and risk factorsof immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005, 19:1043–1049.

44. Powderly WG, Finkelstein D, Feinberg J, et al.: A randomizedtrial comparing fluconazole with clotrimazole troches for theprevention of fungal infections in patients with advanced humanimmunodeficiency virus infection. NIAID AIDS Clinical TrialsGroup. N Engl J Med 1995, 332:700–705.

Curr HIV/AIDS Rep (2010) 7:134–142 141

45. Chariyalertsak S, Supparatpinyo K, Sirisanthana T, Nelson KE: Acontrolled trial of itraconazole as primary prophylaxis for systemicfungal infections in patients with advanced human immunodeficien-cy virus infection in Thailand. Clin Infect Dis 2002, 34:277–284.

46. Essential Prevention and Care Interventions for Adults andAdolescents Living With HIV in Resource-Limited Settings.World Health Organization; 2008.

47. Parkes-Ratanshi R, Kamali A, Wakeham K, et al.: Successfulprimary prevention of cryptococcal meningitis using fluconazoleprophylaxis in HIV-infected Ugandan adults [abstract]. Confer-ence on Retroviruses and Opportunistic Infections. 2009, Inpress.

48. Liechty CA, Solberg P, Were W, et al.: Asymptomatic serumcryptococcal antigenemia and early mortality during antiretro-

viral therapy in rural Uganda. Trop Med Int Health 2007,12:929–935.

49. •• Jarvis JN, Lawn SD, Vogt M, et al.: Screening for cryptococcalantigenemia in patients accessing an antiretroviral treatment programin South Africa. Clin Infect Dis 2009, 48:856–862. This studysuggests an approach to reduce the incidence of clincial CM inresource-limited settings by screening for CrAg in at-risk individuals.

50. •• Meya DB, Castelnuovo B, Kambugu A, et al.: Serumcryptococcal antigen (CRAG) screening: Cost-effective methodto prevent death in HIV-infected persons with CD4 ≤100/μL insub-Saharan Africa. Cape Town, South Africa: International AIDSSociety; 2009. This study shows the cost-benefit implications of aCrAg screening approach in resource-limited settings. It is shownto be a cost-effective method.

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