Both these studies also demonstrated that, with appropriate monitoring, conventional amphotericin B is reasonably well tolerated, with drug discontinuations in 3% of patients in the first 2 weeks in the Mycoses Study Group trial . Saline and fluid loading equivalent to 1 litre normal saline daily should be given unless contraindicated, to minimize nephrotoxicity , and electrolytes replaced as required. Anaemia, secondary to suppression of erythropoietin transcription , is also a predictable side effect of amphotericin B [65–67]. This may be more clinically significant in populations with lower baseline haemoglobin levels, and where transfusion, when occasionally needed, is difficult.
Flucytosine, at the historically low daily dose of 100 mg/kg, was also well tolerated without real-time drug level monitoring in either trial. A substudy of the Thai trial comparing oral and intravenous flucytosine at the same daily dosage of 100 mg/kg has provided some insight into this observation. In contrast to earlier studies in other patient populations, oral bioavailability of flucytosine in these patients at a late stage of HIV infection was only around 50%, resulting in relatively low serum concentration, of an order not usually associated with toxicity. Nevertheless, despite the lower serum levels, patients on oral formulation had the same rate of clearance of infection as those on intravenous formulation , consistent with evidence for the dose-independent activity of flucytosine [69–71]. The data suggest that even 100 mg/kg daily, if given intravenously, may be in excess of that required for maximal additional fungicidal activity.
If renal impairment does develop, liposomal amphotericin B, at 3 mg/kg daily, provides a less nephrotoxic and equally effective alternative. A small study suggested liposomal amphotericin B, at 4 mg/kg daily, was more active than conventional amphotericin B , but a larger study found no difference in the proportion of patients with sterile CSF at 2 weeks in patients receiving daily liposomal amphotericn B at 3 or 6 mg/kg compared with conventional amphotericin B at 0.7 mg/kg daily .
Unfortunately, in many resource-poor settings, amphotericin B is not available or cannot be used safely because of lack of monitoring, and fluconazole, widely available, through a free access programme or in generic form, is the only treatment option. Outcomes with initial fluconazole monotherapy at 200–400 mg daily have not been good, either in early US-based studies [19,74], including a small randomized study in which 400 mg daily was clinically inferior to amphotericin B plus flucytosine , or in more recent series from Africa [57,75,76]. Although the earlier randomized study comparing amphotericin B with fluconazole found no significant difference in clinical outcomes, time to sterilization was very long for fluconazole (median 64 days), and outcomes for both drugs were poor . Furthermore, the dosages used for both drugs were lower than currently recommended, making interpretation difficult. The 10-week mortality of approximately 50% with initial fluconazole monotherapy reported by Schaars and colleagues  in South Africa represents a minimum estimate in this setting given the retrospective nature of the study with incomplete out-patient follow up. Recent work from Cape Town has demonstrated that 400 mg fluconazole daily is essentially fungistatic over the first 2 weeks of treatment . The resulting prolonged period with a high viable organism load may predispose to the development of fluconazole resistance. Such resistance is a significant problem when initial therapy is with fluconazole . A further concern is that prolonged active infection could also increase the risk of immune reconstitution reactions (see below) following introduction of ART, although data on this point are lacking.
Animal studies suggest a dose–response relationship with increasing fluconazole levels . There is a linear plasma concentration–dose relationship with fluconazole at up to 2 g daily , and doses up to 1600 mg daily have appeared safe in small numbers of patients [79,80]. In addition there is a suggestion of a dose–response relationship in terms of the time to sterilization of CSF: with a median time to CSF sterilization of 64 days with 200–400 mg daily , a mean time of 41 days with 400 mg daily , and 21  and 33 days  with 800 mg daily. On this basis, and given the unsatisfactory results of treatment at lower doses, a dose-escalation study of fluconazole therapy is currently underway in Uganda. In the meantime, in settings where amphotericin B cannot be used safely and fluconazole is the only option, the authors would suggest a starting dose of at least 800 mg daily (Table 1).
The combination of fluconazole plus flucytosine is additive or synergistic in murine models [83,84], although not in a study in rabbits . A clinical study in Uganda suggested benefit with addition of flucytosine to fluconazole, although the dose of fluconazole was low (200 mg daily) ; and in a small series from the United States, the combination of flucytosine and fluconazole at 400 mg daily resulted in a relatively short median time to sterilization of CSF of 23 days, although side effects with the combination appeared frequent . Further comparative trials to examine the fungicidal activity and toxicity of this combination with higher doses of fluconazole are warranted in settings where intravenous amphotericin B-based therapy is not possible.
While not as effective, at conventional dosages, as amphotericin B for initial therapy, fluconazole is highly effective and safe as maintenance therapy [86–88]. Increasing evidence suggests discontinuation of this secondary prophylaxis is safe if there has been a significant and sustained immune reconstitution with ART (CD4 cell count > 200 cells/μl for > 6 months) [89–91].
Significantly raised intracranial pressure is a major problem in cryptococcal meningitis, with over half of patients having pressures > 25 cmH2O and nearly a third pressures > 35 cmH2O in an analysis of the last Mycosis Study Group Trial . Raised CSF pressure was associated with cognitive impairment, more cranial nerve lesions and increased short-term mortality. Prolonged raised CSF pressure usually manifests as severe headache, papilloedema, and progressive loss of vision, hearing impairment and decreased level of consciousness . The mechanisms leading to increased pressure are debated [22,93,94]. Although a marked inflammatory response is not a feature of HIV-associated cryptococcal meningitis, it is possible cerebral oedema plays a role in some patients. Vascular endothelial growth factor, a mediator of vascular permeability, has been measured in the CSF of patients with cryptococcal disease [95,96], although no correlation between levels of this growth factor and CSF opening pressure has been demonstrated. Instead, the primary deficit is likely to be blockage of CSF reabsorption at the arachnoid villi because of the presence of organisms and shed polysaccharide [23–25]. This would be consistent with the association of raised pressure with higher CSF antigen titre and higher rates of India ink positivity , and it would explain why ventricular size usually remains normal, as there is no pressure gradient between the ventricles and the CSF over the convexities of the brain.
In terms of management, few controlled trials have been carried out, so recommendations are based on small series and expert opinion. Current US guidelines suggest daily lumbar punctures for all patients with elevated baseline opening pressures (> 25 cmH2O), with the removal of sufficient CSF to reduce pressures by 50%, continued until pressure has been normal for several days . The maximum volume of CSF that is safe to remove at a single lumbar puncture is unclear but 20–30 ml is probably reasonable . If facilities allow, computed tomographic or magnetic resonance scanning of the head should be done prior to initial lumbar puncture or if suspected raised CSF pressure develops on therapy in order to exclude rare cases of true hydrocephalus and space-occupying lesions. In the rare cases in which hydrocephalus develops, a ventriculoperitoneal shunt should be inserted . When repeated lumbar punctures fail to control pressure and the patient's condition is deteriorating, CSF drainage can be achieved with a ventricular or, less invasive, lumbar drain [99,100]. It is unclear how long the defect in CSF reabsorption persists, but it may be that a significant proportion of patients will respond to relatively short-term drainage with a temporary system . These allow the continual, controlled drainage of high volumes of fluid (approximately 200 ml daily) to a set pressure level, are relatively straightforward to insert, and have a low risk of complications with adequate monitoring and nursing and medical staff who are familiar with their use [101,102].
The use of mannitol, acetazolamide, and corticosteroids for raised CSF pressure is not supported by available evidence . A randomized trial of acetazolamide was terminated early ; and high-dose steroids were associated with higher mortality in patients with elevated CSF pressures in a large, although uncontrolled, study .
The role of IRIS is less in doubt when cryptococcal cultures are negative, but it is likely that immune reconstitution also contributes to the presentation and re-presentation of some patients who are still culture positive .
The occurrence of cryptococcal IRIS has implications for the timing of ART. The apparent increase in the risk of cryptococcal IRIS with earlier initiation of ART has to be balanced against the risk of other HIV-related complications if initiation of ART is delayed. Optimal timing of ART may be earlier in developing countries where rates of death prior to initiation of ART are high [60,117]. Until trials currently underway report, most investigators would start ART from 4 weeks into antifungal therapy, although it is possible earlier ART may be safe if a rapidly fungicidal regimen is used for initial antifungal therapy. Treatment of cryptococcal IRIS is another area requiring further investigation. If clinical progression occurs, despite appropriate antifungal therapy and aggressive management of any raised CSF pressure, short-term steroids, which have been used successfully in case reports [108,118,119], can be considered.
The need for primary antifungal prophylaxis is reducing as access to ART expands, the best prophylaxis being rapid immune reconstitution with ART. However in the absence of ART, or in those who fail to respond to treatment, a strong case exists for primary prophylaxis with fluconazole in those with CD4 cell counts < 100 cells/μl in areas with a high incidence of cryptococcal disease [120,121]. Such a policy was introduced in Thailand prior to widespread availability of ART and is under investigation in east Africa. In areas of high incidence, in view of the significant proportion of patients now presenting after starting ART , a case can also be made for screening with serum cryptococal antigen  prior to ART in order to diagnose and treat subclinical infection before it is unmasked by immune reconstitution. However, studies are needed, and such a strategy is not justified and is not used in areas of lower incidence [18,123].
Reasons for the ongoing high mortality of HIV-related cryptococcal disease include the inadequacy of current antifungal therapy, restricted access to some drugs in many areas , the problem of raised CSF pressure and the lack of data on optimal timing of ART. As discussed above, efforts are underway to address some of these questions.
Regarding access to antifungal drugs, fluconazole is widely available through a free access programme and in generic form. In contrast, although generic amphotericin B is also available, the cost is variable and may be significant in very resource-limited settings . In addition, continuous supply has been an issue in some areas, including the United Kingdom, related perhaps to the reduced market for amphotericin B deoxycholate for treating other fungal infections in the developed world. Flucytosine is a simple and old molecule that nevertheless is not widely available either in Africa or Asia, where the burden of cryptococcal disease is so high. Only one manufacturer markets the drug to our knowledge. In countries where they are not marketed, flucytosine tablets can be obtained on a named patient basis from IDIS World Medicines (www.idispharma.com). If studies, currently underway, comparing high-dose fluconazole with flucytosine as a companion drug to give with amphotericin B show that flucytosine remains the second drug of choice, then advocacy is needed to expand access to flucytosine.
The rate of clearance of infection, or early fungicidal activity, from serial quantitative cultures of CSF provides a means by which the activity of new drugs or combinations for antifungal therapy can be accurately assessed in small numbers of patients; this would enable regimens for testing in phase III trials to be selected on a more rational basis . Such clearance studies are underway to examine whether 1 mg/kg amphotericin B daily is associated with a significant increase in fungicidal activity compared with 0.7 mg/kg daily, and to compare flucytosine and high-dose fluconazole as a second drug to give with amphotericin B. Comparative studies are also needed with new azoles with activity against C. neoformans, such as voriconazole , although interactions with antituberculous and antiretroviral medication are a problem. Minimal inhibitory concentrations, animal model data and penetration into the central nervous system for voriconazole and posaconazole are shown in Table 2. Of note, echinocandins have limited anticryptococcal activity because they target 1–3-β-D-glucan linkages, which are not important in the cryptococcal cell wall .
Given the limitations of current antifungal drugs, and uncertainty over further drug development, there is continuing interest in adjunctive immunotherapy. A monoclonal antibody directed against the capsular polysaccharide of C neoformans has reached phase I human studies ; and a monoclonal antibody fragment, Mycograb, directed against candidal heat shock protein 90, and reported to be beneficial when given with amphotericin B in invasive candidiasis , also has in-vitro activity against C. neoformans. Clinical trials in cryptococcal meningitis are planned.
An alternative approach is use of interferon-γ (IFN-γ). There is direct in-vivo evidence that IFN-γ is important for clearance of cryptococcal infection in HIV-infected patients . A placebo-controlled trial showed that adjuvant IFN-γ therapy was safe and well tolerated, with no detrimental effects on HIV viral load or CD4 cell counts. There was also a trend towards improved mycological outcomes, with 13% of placebo recipients achieving negative cultures at 2 weeks compared with 36% or 32% of those receiving IFN-γ . The trend in favour of IFN-γ was already seen after 2 weeks of treatment, and studies have shown that endogenous IFN-γ in the CSF peaks at day 3 and is virtually undetectable by day 14 , suggesting that short courses of adjuvant IFN-γ, which would be more feasible to implement, may be effective.
Finally, studies continue to identify suitable cryptococcal antigens for vaccine development  and to address the formidable challenges inherent in the vaccination of immunodeficient hosts, such as those with HIV infection .
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