Single high dose fluconazole equivalent to 14 day treatment for oropharyngeal candidiasis

A single 750mg dose of fluconazole is just as effective at curing thrush in the mouth and upper throat as a 14-day course of the drug at a lower dose of 150mg, a randomised study conducted in Tanzania has shown.

The findings, published in the journal Clinical Infectious Diseases, could make it easier and cheaper to treat one of the most common infections in people with advanced HIV disease in resource-limited settings, the Tanzanian and Dutch study investigators say.

Candidiasis, or thrush, is the most frequent warning sign that the immune system of a person infected with HIV has suffered a serious decline. It tends to appear in the mouth and upper throat above the voice-box (the pharynx) with increasing frequency when the CD4 cell count falls below 200 cells/mm³.

It may still be present even in people who have recently started HIV treatment.

A more severe form, which affects the oesophagus, was covered in a recent edition of HIV & AIDS Treatment in Practice.

The recommended treatment in many countries, including Tanzania, is a 14-day course of fluconazole at a dose of 150mg per day. However a 14-day treatment course is inconvenient to patients and is problematic if the patient is taking an antiretroviral regimen that includes nevirapine, since fluconazole doubles nevirapine levels. This is particularly problematic if an individual is starting nevirapine treatment, because nevirapine dosing must be scaled up carefully after 14 days to avoid early toxicity.

Alternatives to fluconazole include nystatin, ketoconazole and miconazole. Miconazole has been formulated into a patch that is applied to the inside of the mouth. This formulation has been shown to be equivalent to ketoconazole for treatment of oropharyngeal candidiasis, and is available at cost-only price from manufacturer Tibotec through a range of non-profit distributors including the International Dispensary Association (IDA), Missionpharma and UNICEF.

The Tanzanian study of fluconazole, conducted at Muhimbili National Hospital in Dar es Salaam in 2006 and 2007, recruited 220 HIV-positive patients with a clinical and microbiological diagnosis of oropharyngeal candidiasis. They were randomised in equal groups to receive either a single 750mg dose of fluconazole (in a generic form manufactured by Shelys Pharmaceuticals) and then a placebo course for 14 days, or a 14-day course of fluconazole at 150mg once daily, plus a dummy dose of five placebo tablets on the first day of treatment.

Patients underwent four oral examinations, oral swabs and blood tests during the treatment period and a follow-up exam 42 days after beginning the treatment course. Adherence was monitored by pill counts at each clinic visit.

The primary study endpoints were clinical and mycological cure.

A clinical response to treatment was measured according to the clearance of oropharyngeal lesions. The extent of lesions was graded as absent, mild, moderate and severe. Mycological response to therapy was measured at day 14, with any presence of candida albicans in oral lesions classified as treatment failure.

The median CD4 cell count among participants was 100 cells/mm³. Two-thirds (67.7%) had moderate oropharyngeal lesions, 27.7% severe lesions and 4.5% had mild lesions. Candida albicans was identified in the lesions of 90% of patients at baseline. Half had received some previous treatment with an antifungal drug of the azole class. Thiry-six per cent were receiving antiretroviral therapy (74% of regimens contained nevirapine, and 55% of patients had been receiving treatment for less than three months). There were no significant differences in any demographic variables between the study arms.

After treatment was completed 94.5% of the single dose group and 95.5% of the single-dose group were clinically cured, a non-significant difference. There was a significant association between baseline fluconazole resistance and cure, but previous azole exposure did not affect the cure rate.

Mycological cure was seen in 84.5% of the single dose group and 75.5% of the 14-day group (a non-significant difference).

Plasma fluconazole levels were significantly higher on days 1, 7 and 14 in the single dose group.

Twenty-four patients experienced a relapse of symptoms after completing treatment.There was no significant difference in relapse rates between days 14 and 42 according to the study treatment. (During the follow-up phase four patients died from AIDS-related illnesses and 11 patients were lost to follow-up). The vast majority of those experiencing relapse (70%) were not receiving antiretroviral therapy, and two-thirds had a CD4 cell count below 100 cells/mm³.

There was no significant difference in adverse events between the two treatment groups. Only one patient (taking nevirapine) experienced an increase in liver enzyme levels, and in this patient liver enzyme levels returned to normal after fluconazole treatment was completed.

The investigators conclude by noting that single-dose therapy is less costly than a 14-day course of treatment, and has the additional advantage that it can be given as a directly-observed treatment by medical personnel.