Integrated therapy for HIV and cryptococcosis
Antifungal therapy
Cryptococcus is susceptible to polyenes, flucytosine, and azoles. Among these drugs, azoles exhibit the least fungicidal activity. Antifungal treatment for cryptococcosis varies according to the disease extent, severity, as well as host immune status. Although there are some clinical distinctions between cryptococcosis due to C. neoformans and C. gattii, recommended treatment regimens for both species are currently identical. Some experts suggest that a longer duration of induction and consolidation therapy should be used in C. gattii infection [71, 72]. Fluconazole monotherapy is recommended for mild-to-moderate pulmonary disease. In contrast, treatment of disseminated disease, severe pulmonary disease, and meningitis/meningoencephalitis consists of three phases: induction, consolidation, and maintenance. A combination of two drugs is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases (Table 1) [2].
Antifungal therapy for cryptococcosis in HIV-infected patients
aFor cerebral cryptococcoma, consider induction treatment for ?6 weeks and consolidation and maintenance treatment for 6–18 months; for isolated cryptococcal antigenemia, consider (1) induction treatment with oral fluconazole at the dose of 800 mg/day for 2 weeks, then proceed to consolidation and maintenance treatment, or (2) oral fluconazole at the dose of 400 mg/day for 12 months
bLiposomal amphotericin B (3–4 mg/kg/day; as high as 6 mg/kg/day) or Amphotericin B lipid complex (5 mg/kg/day) serves as an alternative to amphotericin B deoxycholate, with less nephrotoxicity and infusion reaction
cPatients should have suppressed or very low viral load, and have CD4 counts 100 cells/?l for at least 3 months before discontinuing maintenance treatment
Amphotericin B plus flucytosine has been shown to be the most potent and advocated regimen for the induction phase [2, 9, 73–77]. Intravenous amphotericin B deoxycholate should be given at a dose of 0.7–1 mg/kg/day [2, 9]. Liposomal amphotericin B at a dose of 3–4 mg/kg/day or amphotericin B lipid complex at a dose of 5 mg/kg/day can be used as a substitute for amphotericin B deoxycholate, as these formulations cause less nephrotoxicity and infusion reaction, while demonstrating similar, if not better, efficacy [78, 79]. Flucytosine should be used at a dose of 100 mg/kg/day, given in four divided doses. Alternative regimens for the induction phase include amphotericin B plus fluconazole, amphotericin B monotherapy, fluconazole plus flucytosine, and high-dose fluconazole monotherapy [2, 9]. Unfortunately, flucytosine is not available in many countries in resource-limited settings and cannot be used in patients with bone marrow suppression and liver enzyme elevations. Amphotericin B deoxycholate at a dose of 0.7 mg/kg/day plus 800 mg/day of fluconazole might have better efficacy than amphotericin B alone [73, 79–81]. A high fluconazole dosage at 800 mg/day is also associated with high serum and CSF fluconazole concentration and appears to be associated with increased survival and treatment success [82]. Moreover, no additional toxicity was observed [73, 79–81]. If the patient cannot tolerate amphotericin B or the drug is not available, the induction phase can be achieved by fluconazole plus flucytosine, or high-dose fluconazole monotherapy (Table 1) [2, 9]. However, these two regimens have lowered efficacy. As a result, higher doses of fluconazole and longer durations of treatment are suggested [2, 9, 83]. Fluconazole plus flucytosine has proven better than fluconazole monotherapy [84–86].
After the Induction phase of treatment, the consolidation phase commences. Longer durations of induction should be considered if clinical improvement is not evident and/or CSF culture at 2 weeks is still positive [2, 9]. Patients who fail to achieve negative CSF culture after 2 weeks were shown to have higher risks for treatment failure at 10 weeks [87]. Fluconazole is the drug of choice during this phase (Table 1). It is noted that 800 mg/day, rather than 400 mg/day, of fluconazole should be used if amphotericin B plus fluconazole regimen is selected for induction. The consolidation phase continues for at least 8 weeks. Then, the fluconazole dose should be reduced to 200 mg/day during the maintenance phase. As long as the patients’ CD4 cell counts remain low, they are still at high risk for relapse. The maintenance phase can be safely discontinued in patients who have been treated for at least 12 months, have suppressed or very low viral load, and have CD4 counts 100 cells/µL for at least 3 months [88–92].
Other azoles, such as itraconazole, voriconazole, posaconazole, and isavuconazole, also possess anti-cryptococcal activity. However, given the scarcity of studies of clinical efficacy, potential drug interactions, CNS penetration, and bioavailability, they are reserved for refractory cases only [2, 9, 75, 93–99].
Resistance to antifungal drugs was previously rare. However, recent reports described increased MICs of C. neoformans isolates to fluconazole and, to a lesser extent, amphotericin B over the past decade [100, 101]. Whether this has an impact on clinical outcomes is not known. Furthermore, clinical breakpoints of Cryptococcus spp. to antifungal drugs are not yet established. Some small studies suggested that worse treatment outcomes might be associated with higher MICs to antifungal drugs, although this is still controversial [100–105]. Currently, testing for antifungal susceptibility might be considered only in patients with persistent or relapse disease [2, 9]. An MIC of ?16 µg/mL for fluconazole may be considered resistant, and alternative treatment is suggested, e.g. intravenous amphotericin B deoxycholate at a dose of 1 mg/kg/day until CSF, blood, and/or other sites are sterile [2]. An MIC of ?32 µg/mL for flucytosine may be considered resistant, and the induction phase with non-flucytosine-containing regimen may be selected [2].
Cerebral cryptococcoma should be treated with the same regimen used for cryptococcal meningitis, but with an extended duration of therapy (Table 1) [2]. This should also be guided by clinical response and imaging during treatment. The recommended dose of fluconazole during consolidation is 400–800 mg/day [2]. Surgery is rarely necessary, except when other etiologies are suspected and histopathological diagnosis is required, or mass effect is observed. It is noteworthy that an MRI of the brain may not show a decrease in lesion size for many months [106]. Adjunctive treatment with corticosteroids with gradual tapering might be considered in patients with significant perilesional edema [2].
Pulmonary cryptococcosis in HIV-infected patients is frequently a manifestation of disseminated disease. Hence, these patients should be evaluated for CNS involvement and disease dissemination, even if they are asymptomatic. A CSF examination, culture, as well as testing for cryptococcal antigen in the CSF and serum should be performed. Disseminated disease should be treated with the same regimen as that of cryptococcal meningitis [2, 9]. For isolated pulmonary cryptococcosis, treatment varies according to severity. Pulmonary cryptococcosis with severe symptoms and/or diffuse pulmonary infiltrates should be treated with regimens identical to those for disseminated disease and meningitis [2, 9]. For pulmonary cryptococcosis with mild-to-moderate symptoms, a dosage of 6 mg/kg/day of oral fluconazole for 12 months is recommended [2, 9]. Surgical removal and drainage of pleural effusion caused by Cryptococcus are rarely required [107].
Similar to pulmonary cryptococcosis, cryptococcal infection of other organs is often a manifestation of disseminated disease, especially in HIV-infected patients. These patients should be evaluated for CNS involvement and disease dissemination as well [2, 9]. For ocular cryptococcosis, combined antifungal agents using systemic amphotericin B with high-eye penetration drugs, such as flucytosine or fluconazole, are recommended [2].
Positive serum cryptococcal antigen has been shown to be associated with subsequent cryptococcal disease [108–110]. Screening for serum cryptococcal antigen in asymptomatic HIV-infected patients with CD4 counts 100 cells/µL and preemptive treatment of those who test positive lead to more favorable outcomes and more cost-effectiveness [63–65, 108, 109, 111–113]. Antifungal regimens have been proposed [9, 114] although sparse data exist: (1) oral fluconazole at the dose of 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks, and 200 mg/day thereafter until CD4 count is 200 cells/µL [65], or (2) oral fluconazole at the dose of 400 mg/day for 1 year. HIV-infected patients with serum antigen titer ?1:512 may be treated as CNS disease [2].
Pregnant women with cryptococcosis represent a special population. Amphotericin B can be used safely without risk of teratogenicity in humans (FDA pregnancy category B) [2, 9, 115]. Use of other antifungal agents, however, should be considered when the benefits outweigh fetal risks. Flucytosine is classified as category C by the FDA. Although animal studies showed teratogenic effect of flucytosine, limited studies in humans showed no adverse fetal outcomes after exposure [112]. Fluconazole is classified as category D. There are few reports of fetal anomalies in pregnant women who had received ?400 mg/day of fluconazole [116]. Use of fluconazole, as well as other azoles, is thereby discouraged during pregnancy, especially in the first trimester [2, 9, 112]. Neonates born to patients receiving amphotericin B at delivery should be evaluated for renal function and electrolytes [9].