Once-daily topical tablet as effective as systemic drugs for oral thrush

Michael Carter
Published: 27 January 2004

A daily slow release topical oral treatment is as effective a treatment for oropharyngeal candida as systemic anti-fungal therapy in severely immunosuppressed individuals according to a study published in the February edition of the Journal of Acquired Immune Deficiency Syndrome.

It’s estimated that as many as 90% of HIV-positive individuals will develop oropharyngeal candida at some point during advanced disease, and oral treatment consisting of nystatin or gentian violet are World Health Organisation-recommended standard of care. Both have their drawbacks. Nystatin must be dosed five times a day due to rapid clearance by saliva, whilst gentian violet stains the mouth and saliva, effectively announcing that someone is HIV-positive and receiving treatment for oral thrush.

Although systemic therapies are highly effective in HIV-positive individuals, even in the presence of severe immune suppression, they have significant interactions with both antiretroviral drugs and medicines used to treat AIDS-defining illnesses, most notably some anti-tuberculosis drugs.

To address these drawbacks in treatment, researchers from the Belgian company Tibotec developed a formulation of the anti-fungal miconazole that could be stuck to the wall of the mouth and would slowly release miconazole into the saliva to maintain adequate drug levels throughout the day.

Investigators from Belgium and Uganda compared the effectiveness of the slow-release mucoadhesive tablet containing miconazole with systemic ketoconazole therapy in a randomised non-inferiority study involving 306 individuals in Uganda. All the patients had oropharyngeal candida.

The primary end-point of the study was cure after seven days of treatment. Secondary outcomes were treatment response at 14 days, clinical response by CD4 cell count, and resolution of painful swallowing.

All the patients were assumed to be HIV-positive, and confirmatory HIV test results were available for 299 individuals. The median CD4 cell count was 36 cells/mm3 for the study population, indicative of a high degree of immune suppression.

At day seven, 92.8% of patients treated with miconazole and 96.4% of ketoconazole-treated patients had responded to treatment. The difference in response rate was not statistically significant. End of treatment (day 14) response rates were also comparable between the two study arms at 93% and 96% respectively, and the investigators also found a similar treatment response for the two drugs when results were stratified by CD4 cell count.

Relapse rate was 30.8% for the miconazole group and 23% for the ketaconazole group. The difference was not statistically significant.

Microscopic smears also indicated that the two drugs were comparable. At day seven 70% of miconazole patients and 75% of ketaconazole patients had negative microscopic examinations.

Oral thrush is often characterised by pain on swallowing. By day 14 only 1% of both study arms still had this symptom.

There were no serious side-effects reported and the incidence of the most frequently reported adverse events, such as fever and headache was comparable between the two arms of the study. However, the incidence of vomiting was only 1% in the miconazole group versus 8% in the ketaconazole group.

Although the miconazole tablet was mucoadhesive, attaching to the gum, the investigators found no signs of local irritation.

The investigators note, “the clinical response rate at day seven and the end of treatment demonstrated that miconazole nitrate was not significantly inferior to ketoconazole.” They add, “the administration of a miconazole mucoadhesive tablet represents a breakthrough in topical therapy by combining the user-friendliness of a tasteless once-daily regimen with the effectiveness of a systemic anti-fungal.”

The investigators also note that the P450 enzyme is used by the body to metabolise ketaconazole and other systemic anti-fungals, and that this enzyme is also employed by some anti-HIV and anti-TB drugs, potentially causing interactions, which would be avoided by the use of the topical miconazole therapy.

Availability

The miconazole slow-release tablet is available through the International Dispensary Association and a number of other international non-profit pharmacy organisations. It costs around $1 for a course of treatment, and Tibotec, a subsidiary of Johnson & Johnson, is providing the drug on a not-for-profit basis.

Further information on this website

Candida - factsheet

Anti-fungal drugs - menu of information

Reference

Van Roey J et al. Comparative efficacy of topical therapy with a slow-release mucoadhesive buccal tablet containing miconazole nitrate versus systemic therapy with ketoconazole in HIV-positive patients with oropharyngeal candidiasis. JAIDS 35: 144 – 150, 2004.

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