Oropharyngeal candidiasis ("thrush"), a fungal disease of the oral mucosa and tongue, is the most common intraoral lesion among persons infected with HIV. In the absence of other known causes of immunosuppression, oral thrush in an adult is highly suggestive of HIV infection. Although thrush in the absence of esophageal disease is not an AIDS-defining condition, it usually occurs with CD4 counts of <200 cells/µL. Three clinical presentations of thrush are common in people with HIV: pseudomembranous, erythematous, and angular cheilitis. Candida also may infect the esophagus in the form of esophageal candidiasis, which causes dysphagia (difficulty with swallowing) or odynophagia (pain with swallowing). Esophageal candidiasis is an AIDS-defining condition, generally occurring in individuals with CD4 counts of <200 cells/µL. It is the most common cause of esophageal infection in persons with AIDS.
Oropharyngeal and esophageal candidiasis are caused most commonly by Candida albicans, although non-albicans species increasingly may cause disease and may be resistant to first-line therapies.
The patient may complain of painless white patches on the tongue and oral mucosa, smooth red areas on the dorsal tongue, burning or painful areas in the mouth, a bad or unusual taste, sensitivity to spicy foods, or decreased appetite.
The patient complains of difficulty or pain with swallowing, or the sensation that food is "sticking" in the retrosternal chest. Weight loss is common, and nausea and vomiting may occur. Fever is not common with candidal esophagitis and suggests another cause. The patient may note symptoms of oral candidiasis (as above).
Perform a thorough oropharyngeal examination. Patients presenting with oral candidiasis may be totally asymptomatic, so it is important to inspect the oral cavity thoroughly. Patients with esophageal candidiasis usually have oral thrush and often experience weight loss.
Lesions can occur anywhere on the hard and soft palates, under the tongue, on the buccal mucosa or gums, or in the posterior pharynx.
Pseudomembranous oral candidiasis appears as creamy white, curdlike plaques on the buccal mucosa, tongue, and other mucosal surfaces. Typically, the plaques can be wiped away, leaving a red or bleeding underlying surface. Lesions may be as small as 1-2 mm, or they may form extensive plaques that cover the entire hard palate.
Erythematous oral candidiasis presents as one or more flat, red, subtle lesions on the dorsal surface of the tongue or the hard or soft palate. The dorsum of the tongue may show loss of filiform papillae.
Angular cheilitis causes fissuring and redness at one or both corners of the mouth and may appear alone or in conjunction with another form of oral Candida infection.
A partial differential diagnosis for the two conditions is as follows:
- Oral hairy leukoplakia
- Abrasion of the mucosa or a topical burn
- Bacterial gingivitis
- Cytomegalovirus (CMV)
- Herpes simplex virus (HSV)
- Aphthous ulceration
Clinical examination alone usually is diagnostic. If the diagnosis is unclear, organisms may be detected on smear or culture if necessary.
- On a potassium hydroxide (KOH) preparation of a smear collected by gentle scraping of the affected area with a wooden tongue depressor, visible hyphae or blastospheres on KOH mount indicate Candida infection.
- Culture is diagnostic and may detect non-albicans species in cases resistant to first-line therapies. Sensitivities also may be needed in such cases to diagnose azole-resistant infections.
A presumptive diagnosis usually can be made with a recent onset of typical symptoms, especially in the presence of thrush, and empiric antifungal therapy may be started as a diagnostic trial. If the patient fails to improve clinically after 3-7 days of therapy, endoscopy should be performed for a definitive diagnosis.
Treatment of oropharyngeal candidiasis
- Oral therapy is convenient and very effective as first-line treatment. Note that azole antifungal drugs are not recommended for use during pregnancy. Topical therapy is less expensive, safe for use during pregnancy, and effective for mild to moderate disease. All therapies should be given for 7-14 days.
- Preferred oral therapy: Fluconazole 100 mg PO QD
- Preferred topical therapy:
- Clotrimazole troches 10 mg dissolved in the mouth 5 times daily
- Miconazole mucoadhesive tablet 50 mg PO QD
- Alternative oral therapy:
- Itraconazole oral solution 200 mg PO QD
- Posaconazole oral solution 400 mg PO BID for 1 day, then 400 mg PO QD
(Note: These agents may present a greater risk of drug interactions (see "Potential ARV Interactions," below) and hepatotoxicity than do fluconazole or topical treatments)
- Alternative topical therapy: Nystatin oral suspension 4-6 mL "swish and swallow" QID or 1-2 pastilles 4-5 times daily
Treatment of esophageal candidiasis
- Duration of therapy: 14-21 days
- Preferred therapy:
- Fluconazole 100 mg PO (up to 400 mg) QD; IV therapy can be given if the patient is unable to swallow pills.
- Itraconazole oral solution 200 mg PO QD
- Alternative therapy:
- Voriconazole 200 mg PO or IV BID
- Posaconazole 400 mg PO BID
- IV therapy with an echinocandin (caspofungin, micafungin, anidulafungin), or amphotericin, if the patient is unable to tolerate PO therapy (Note: Treatment with echinocandins is associated with a higher rate of relapse; see "Potential ARV Interactions," below, regarding potential drug-drug interactions between voriconazole or posaconazole and ARVs)
Treatment of refractory candidiasis
Oral or esophageal candidiasis that does not improve after at least 7-14 days of appropriate antifungal therapy can be considered refractory to treatment. The primary risk factors for development of refractory candidiasis are CD4 counts of <50 cells/µL and prolonged, chronic antifungal therapy (especially with azoles). In such cases, it is important to confirm the diagnosis of candidiasis. As noted, other infections such as HSV, CMV, and aphthous ulcerations can cause similar symptoms. Once refractory candidiasis is confirmed, several treatment options are available, including the following:
- Posaconazole 400 mg PO BID
- Itraconazole oral solution ≥200 mg PO QD
- Voriconazole 200 mg PO or IV BID (see "Potential ARV Interactions," below)
- Therapy with an echinocandin (caspofungin 50 mg QD; micafungin 150 mg QD; anidulafungin 100 mg for 1 dose, then 50 mg QD), or amphotericin B deoxycholate or lipid preparation
(Note: Treatment with echinocandins is associated with a higher rate of relapse. See "Potential ARV Interactions," below, for information on potential drug interactions.)
The choice of treatment depends upon anticipated drug-drug interactions, the patient's preferences and tolerability, availability of medications, and the provider's experience. Consult with an HIV or infectious disease expert for advice about treatment regimens.
Use caution when considering chronic maintenance therapy, because it has been associated with refractory and azole-resistant candidiasis, as noted above. Fluconazole 100 mg PO QD or TIW can be effective for patients who have had multiple or severe recurrences of oral disease (azole sensitive). Fluconazole 100-200 mg PO QD or posaconazole 400 mg PO BID (see "Potential ARV Interactions," below) can be considered for patients who have had frequent or severe recurrent esophageal candidiasis.
There are no data to guide this decision; it is reasonable to discontinue maintenance therapy in patients who achieve immunologic responses on fully suppressive ART (i.e., with an increase in CD4 count to ≥200 cells/µL). Patients with fluconazole-refractory oropharyngeal or esophageal disease who respond to IV echinocandins are recommended to take posaconazole or voriconazole suppression until they achieve immune reconstitution on ART, because of high relapse rates.
Potential ARV Interactions
There may be significant drug-drug interactions between certain systemic antifungals (particularly itraconazole, voriconazole, and posaconazole) and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), elvitegravir/cobicistat, or maraviroc. Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both. Check for adverse drug interactions before prescribing. For example, voriconazole use is not recommended for patients taking ritonavir-boosted PIs, and dosage adjustment of both voriconazole and NNRTIs may be required when voriconazole is used concurrently with NNRTIs. See relevant tables in the U.S. Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, or consult with an expert.
- Patients should maintain good oral hygiene by brushing teeth after each meal.
- A soft toothbrush should be used to avoid mouth trauma.
- Advise patients to rinse the mouth of all food before using lozenges or liquid medications.
- Tell patients to avoid foods or liquids that are very hot in temperature or very spicy.
- Patients who have candidiasis under a denture or partial denture should remove the prosthesis before using topical agents such as clotrimazole or nystatin. When not in use, the prosthesis should be stored in a chlorhexidine solution.
- Pregnant women and women who may become pregnant should avoid azole drugs (e.g., fluconazole, itraconazole, voriconazole) during pregnancy because they can cause skeletal and craniofacial abnormalities in infants.
- Patients should be informed of proper storage of oral solutions (e.g., refrigeration requirements).
- Aberg JA, Gallant JE, Ghanem KG et al.; HIV Medicine Association of the Infectious Diseases Society of America. Primary Care Guidelines for the Management of Persons Infected With HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jan;58(1):e1-e34.
- Klein RS, Harris CA, Small CB, et al. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med. 1984 Aug 9;311(6):354-8.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed December 1, 2013.
- Pappas PG, Kauffman CA, Andes D, et al.; Infectious Diseases Society of America . Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Mar 1;48(5):503-35.
- Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis. 2007 Feb 15;44(4):607-14.