A randomised double blind study in Thailand has shown that primary prophylaxis with the anti-fungal drug fluconazole reduced the risk of death fourfold in people with advanced HIV disease, but did not significantly reduce the incidence of cryptococcal meningitis (the main opportunistic infection that fluconazole prophylaxis might prevent).
The study recruited 90 Thai patients with CD4 cell counts below 100 cells/mm3 who were positive for cryptococcal antigen. Pregnant and breastfeeding women were excluded from the study, as were individuals with liver enzymes more than five times the upper limit of normal.
Participants were randomised to receive either 400mg of fluconazole (n=44) once a week or placebo (n=46), and were evaluated every four to eight weeks for possible fungal infections. The primary endpoint in the study was the measurement of cryptococcosis, but the effect of treatment on the development of penicilliosis, histoplasmosis and oesophageal candidiasis was also measured as a secondary endpoint.
The mean CD4 cell count was 28 cells/mm3 and follow-up lasted a median of 152 days in the fluconazole group (range 1-554) and 136 days in the placebo group (range 1-540).
One patient in the fluconazole group and five patients in the placebo group were receiving antiretroviral therapy at baseline, and approximately 85% of patients in each arm of the study had already experienced at least one AIDS-defining illness.
The study was terminated before it could recruit 52 patients to each arm, due to a decision by the Thai government to introduce antifungal prophylaxis as a result of a trial of itraconazole prophylaxis. That study found that itraconazole prophylaxis was associated with a lower incidence of systemic fungal infections, but had no survival advantage (Chariyalertsak 2002).
In contrast, the study of fluconazole found that whilst there was a trend towards a lower incidence of cryptococcal meningitis in fluconazole-treated patients, the only significant advantage to fluconazole treatment lay in improving survival. Patients in the placebo group were 4.3 times more likely to die.
Three cases of oesophageal candidiasis were diagnosed (one in the fluconazole group and two in the placebo group), and one fluconazole-treated patient developed penicilliosis, a fungal infection that is widespread in South East Asia. Fluconazole shows limited activity against either penicillium marneffei or histoplasma capsulatum (unlike itraconazole).
Although the study shows a survival advantage for fluconazole-treated patients, comparison of causes of death in the two groups shows that whilst nine people died in the placebo group, only two of those deaths were attributable to cryptococcal meningitis. One was due to cerebral toxoplasmosis. The remaining six were attributed to `progression of HIV disease`.
In the fluconazole group, two deaths occurred – one due to mycobacterium avium complex infection and one due to `progression of HV disease`.
The results of this study suggest that a larger study is needed to clarify the role of primary prophylaxis against fungal infections in patients with advanced HIV infection, comparing the relative benefits of fluconazole and itraconazole.
In an accompanying editorial, Dr Lawrence John of the Chelsea and Westminster Hospital in London notes that cryptococcal meningitis accounts for 38% of AIDS-defining illnesses amongst hospital admissions, while 17% of deaths in a Ugandan adult cohort were due to the infection.
However, the relative burden of other fungal infections varies more widely from region to region, and it may be important to consider this both in the design of studies and the implementation of prophylaxis. Penicillium marneffei is largely confined to South East Asia, while histoplasma capsulatum v.duboisii is largely confined to Central Africa (between Zimbabwe and the Sahara). Another histoplasma variant is common in South Africa.
Comparisons between studies and antifungals are difficult.
Previous studies of itraconazole have not provided conclusive results. Whilst a US study reported in 1999 found that itraconazole 200mg once daily reduced the incidence of invasive fungal infections (p=0.04) and delayed the time to onset of histoplasmosis and cryptococcosis, it did not find that itraconazole improved survival compared with a placebo. Patients in this study had slightly higher median CD4 counts than the Thai study (73 cells/mm3 in the placebo group, and around one-fifth had CD4 counts above 100 cells/mm3.
A UK study of similar size found that whilst itraconazole (200mg daily) reduced the incidence of oral candida, it did not reduce the incidence of deep fungal infections. However, since very few were reported, the investigators remained uncertain about the value of primary prophylaxis with itraconazole (Smith 2001). Patients in this study had substantially higher CD4 counts than in the Thai study; anyone with a CD4 count below 300 cells/mm3 was eligible to join.
Fluconazole access
Pfizer, the manufacturer of fluconazole (Diflucan) makes the drug available free of charge for the treatment of cryptococcal meningitis and oesophageal candidiasis. The drug is not available free of charge for use as primary prophylaxis.
In Thailand, a generic version of fluconazole is available at a cost of approximately US$0.29 per 200mg tablet (compared with an approximate cost of $12 per tablet for Diflucan, according to the HIV Medicine editorial).
Where generic versions of fluconazole are not available, the editorial’s authors point out that, as antiretroviral regimens fall in price, the use of antiretrovirals to prevent opportunistic infections is likely to prove far more cost-effective than the use of fluconazole as primary prophylaxis.
However, where ARVs are not yet available, or where their use must be rationed due to cost constraints, there are likely to be demands for more realistic pricing of fluconazole, together with support for studies that define more clearly when primary prophylaxis with antifungal drugs may be useful and cost-effective.
Further information on this website
Cryptococcus - overview of the opportunistic infection and its treatment.
Fluconazole - drug information.
Itraconazole - drug information.
References
Chariyalertsak S et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Inf Dis 34: 277-84, 2002.
Chetchtisakd P et al. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Medicine 5: 140-3, 2004.
McKinsey DS et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 28(5): 1049-56, 1999.
Smith DE, Itraconazole Prophylaxis Study Group. A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection. HIV Medicine 2(2):78-83, 2001.