Fluconazole prophylaxis: resistance risk lower than fungal disease risk

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Long-term prophylaxis against fungal infections using fluconazole may prove cost-effective in countries with a high burden of fungal diseases among people with advanced HIV disease, according to an editorial in the November 15th edition of Clinical Infectious Diseases.

Commenting on a randomised study of continuous versus episodic fluconazole therapy in HIV-positive people with a history of oropharyngeal candidiasis, Dr Samuel Bozette of the University of California San Diego suggests that studies are needed to determine whether fluconazole prophylaxis is effective in reducing the burden of invasive fungal infections among HIV-positive people in resource-limited settings.

His comments accompany an analysis of ACTG323, a US study which compared the impact of continuous or episodic fluconazole treatment on the time to development of either an invasive fungal infection or a fungal infection resistant to treatment with fluconazole. The analysis sought to determine whether fluconazole prophylaxis resulted in a high rate of resistance if it was used indefinitely, and whether the risk of resistance outweighed the benefit in terms of disease and death.

Glossary

fungi

A group of organisms, including the yeasts which cause candidiasis and cryptococcosis.

invasive

In medical terms, going inside the body.

candidiasis

A common yeast infection of moist areas of the body, caused by the fungi of the candida family such as Candida albicans. Most common in the vagina, where it is known as thrush, but also occurs in the mouth and skin folds.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

mucosal tissue

Moist layer of tissue lining the body’s openings, including the genital/urinary and anal tracts, the gut and the respiratory tract.

ACTG323 randomised 829 people with CD4 cell counts below 150 cells/mm3 to continuous treatment or to receive fluconazole treatment only when they developed an invasive fungal infection. All participants had been diagnosed previously with oropharyngeal candidiasis (invasive thrush in the mouth and upper throat). Eighty-two per cent were receiving antiretroviral therapy at baseline.

Treatment discontinuation was relatively high in both arms of this study. Only 53% of patients completed the full follow-up period, providing 1273 patient years of follow-up on fluconazole treatment and resistance, but all patients continued to be followed in order to record survival. Median follow-up duration was 24 months.

There was no significant difference in survival between treatment arms, nor in the rate of non-fungal opportunistic infections, but patients who received continuous fluconazole treatment had a significantly smaller CD4 cell increase during the follow-up period (median of +56 cells vs +101 cells, p=0.02), and were more likely to develop thrombocytopenia.

Significantly fewer invasive fungal infections occurred in the group who received continuous fluconazole (15 vs 28, p=0.04). Fluconazole-resistant fungal infections did not occur any more frequently in the continuous treatment group than in the episodic treatment group. The primary endpoint of the study was the time to development of fluconazole-refractory oropharyngeal or oesophageal candidiasis, which was defined as lack of response to 200mg fluconazole given daily for 14 or 21 days, respectively.

The authoprs comment: “In industrialized nations, given the reduction in fungal infections associated with HAART and the lack of survival benefit associated with continuous fluconazole, the routine use of continuous fluconazole treatment cannot be recommended.”

“In resource-poor settings…it is our opinion that the decision to use azole prophylaxis should not be based on a concern for excess risk for [fluconazole refractory infections]; rather, it should be based on the frequency of mucosal candidiasis and invasive infections.”

A review of previous studies of antifungal prophylaxis can be viewed by following this link.

References

Goldman M et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323 / Mycoses Study Group Study 40. Clinical Infectious Diseases 41: 1473-1480, 2005.