Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children

Background

Oral candidiasis (OC) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Left untreated these lesions contribute considerably to the morbidity associated with HIV infection. Interventions aimed at preventing and treating HIV-associated oral candidal lesions form an integral component of maintaining the quality of life for affected individuals.

Objectives

To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection.

Search strategy

The search strategy was based on that of the HIV/AIDS Cochrane Review Group. The following electronic databases were searched for randomised controlled trials for the years 1982 to 2005: Medline; AIDSearch; EMBASE and CINAHL. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched through May 2005. The abstracts of relevant conferences, including the International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections, as indexed by AIDSLINE, were also reviewed. The strategy was iterative, in that references of included studies were searched for additional references. All languages were included.

Selection criteria

Randomised controlled trials (RCTs) of palliative, preventative or curative therapy were considered, irrespective of whether the control group received a placebo. Participants were HIV positive adults.

Data collection and analysis

Two authors independently assessed the methodological quality of the trials and extracted data. Study authors were contacted for additional data where necessary.

Main results

Four trials were conducted in developing countries with eleven of the trials conducted in the United States of America. Twenty eight trials (n=3225) were included. Nineteen trials investigated treatment and nine trials the prevention of OC. One trial, comparing fluconazole and ketoconazole, investigated the treatment of OC in children. Eighteen of the included studies reported CD4 cell counts. None of the included studies investigated the effects of HAART or any other form of antiretroviral treatment on OC treatment or prevention.

Treatment
Treatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one trial. Compared to nystatin, fluconazole favoured clinical cure in adults(1 RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole compared to ketoconazole (2 RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (2 RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16) or clotrimazole (2 RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42). When compared with clotrimazole, both fluconazole (2 RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (1 RCT; n=123; RR 2.20; 95% CI 1.43 to3.39) proved to be better for mycological cure. Both gentian violet (1 RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (1 RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure.

Prevention
Successful prevention was defined as the prevention of a relapse while receiving prophylaxis. Fluconazole was compared with placebo in one trial (5 RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) and with no treatment in another (1 RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (1 RCT; n=62; RR 0.37; 95% CI 0.15 to 0.92), prevention is favoured by the continuous treatment.

Authors' conclusions

Implications for practice
Due to only one study in children it is not possible to make recommendations for treatment or prevention of OC in children. Amongst adults, there were few studies per comparison. Due to insufficient evidence no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole with regard to OC prophylaxis. In comparison to placebo, fluconazole is an effective preventative intervention. However, the potential for resistant Candida organisms to develop, as well as the cost of prophylaxis, might impact the feasibility of implementation. No studies were found comparing fluconazole with other interventions. Direction of findings suggests that ketoconazole, fluconazole, itraconazole and clotrimazole improved the treatment outcomes.

Implications for research
There is an urgent need for gentian violet and other less expensive anti-fungal drugs for OC treatment to be evaluated in larger studies. More well designed treatment trials with larger sample size are needed to allow for sufficient power to detect differences in not only clinical, but also mycological response and relapse rates. There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive. More research on the effectiveness of less expensive interventions also needs to be done in resource-poor settings. Currently few trials report outcomes related to quality of life, nutrition, or survival. Future researchers should consider measuring these when planning trials. Development of resistance remains under-studied and more work must be done in this area.
It is recommended that trials be more standardised and conform more closely to CONSORT as this will improve research and also clinical practice.