Oropharyngeal Candidiasis in Patients with AIDS Welcome to this training module on oropharyngeal candidiasis in patients with AIDS. Before continuing it should be noted that Pfizer‘s antifungal medicine Diflucan (fluconazole) is made available free of charge through the Diflucan Partnership Program only for the treatment of cryptococcal meningitis and esophageal candidiasis, two opportunistic infections associated with HIV/AIDS. This donated Diflucan is not to be used in the treatment of oral thrush or other indications. Information on oral thrush is included in this learning tool for educational purposes only. It is not one of the indications for which Diflucan is donated. And remember, you can access and print supporting materials for this and other modules from the “Resources for Site-based Training” tab, above.

Case 29-year-old male with AIDS CD4 198 Complaining of painful cracks at the corners of the mouth A 29-year-old male with AIDS and a CD4 count of 198 cu mm/cells is referred to your clinic to be evaluated for painful cracks at the corners of his mouth, which he has had for two days. What is your diagnosis? What is your diagnosis?

Oropharyngeal Candidiasis: Angular Cheilitis This slide shows a picture of the patient’s mouth. The cracks in the labial commissures, or corners of the mouth, are consistent with angular cheilitis, one of the many clinical presentations of oropharyngeal candidiasis.

Learning Objectives Upon completion of this activity, participants should be able to: Describe symptoms of oropharyngeal candidiasis Discuss methods for diagnosing oropharyngeal candidiasis Review treatments for oropharyngeal candidiasis After going through this module about oropharyngeal candidiasis, you as a participant in this learning activity will be able to: Describe common symptoms of oropharyngeal candidiasis Discuss methods used to diagnose oropharyngeal candidiasis Review treatments for oropharyngeal candidiasis

Overview on Oropharyngeal Candidiasis Candida albicans is the most common cause of oropharyngeal candidiasis Oral candidiasis is broadly known as thrush Candida albicans is a mouth commensal The fungus Candida albicans is the most common cause of oropharyngeal candidiasis in patients with AIDS. Oral candidiasis is also known as thrush. Candida albicans is a mouth commensal, meaning that under normal circumstances it colonizes the mouth without causing harm to its host. However, it can cause infection in immune-compromised patients.

Overview Common risk factors include CD4 <250, chronic antibiotic and/or steroid use, diabetes and cancer Differential diagnosis: oral HSV, hairy leukoplakia, and aphthous ulcerations Usually a recurrent process Patients with AIDS having a CD4 count of less than 250 cu mm/cells are at risk for orophayngeal candidiasis Other potential risk factors include chronic use of antibiotics and steroids, or having cancer or diabetes. In diagnosing oropharyngeal candidiasis in patients with AIDS, one needs to consider other common mouth pathologies/pathogens, including Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), hairy leukoplakia and aphthous ulcerations. Oropharyngeal candidiasis is often recurrent and therefore, clinicians should educate their patients about it, and also perform routine oral examinations.

Clinical Presentation Discovered on routine examination Often asymptomatic but patients may experience: Burning sensation in mouth Taste alteration Pain Oropharyngeal candidiasis is usually asymptomatic and is often found during a routine medical examination. However, some patients presenting with oropharyngeal candidiasis can experience burning sensation in their mouths, pain and/or report changes in taste perception.

Clinical Presentations of Oropharyngeal Candidiasis We are now going to review the clinical presentations of oropharyngeal candidiasis.

Pseudomembranous Candidiasis White/Grey Plaques on the Hard Palate (Pseudomembranous candidiasis) This slide shows a patient with oropharyngeal candidiasis with white/gray plaques on the hard palate known as pseudomembranous candidiasis. This is the most common clinical presentation of oral candidiasis. The white/gray plaques can be easily removed by scraping them off with a tongue depressor. Occasionally, there is an erythematous area and/or bleeding under the area that was previously covered by the white/gray plaque.

Erythematous Candidiasis Erythematous Candidiaisis Affecting the Hard Palate This slide shows erythemathous candidiasis affecting the hard palate. This is a less common presentation of oropharyngeal candidiasis. These lesions have a red appearance and cannot be scraped off.

Angular Cheilitis Corners of the Mouth Angular Cheilitis This slide shows a patient with angular cheilitis. This is also a less common presentation of oropharyngeal candidiasis characterized by cracks in the mouth.

Diagnosis Diagnosis usually clinical Easily removable white/grey plaques with erythematous base Scraping away these plaques reveals raw ulcerated area Can also present atypically as erythematous patches and angular cheilitis The diagnosis of oropharyngeal candidiais is usually clinical. As outlined in previous slides, the diagnosis is based on the presence of whitish/gray patches, known as (pseudomembranous candidiasis) erythemathous, areas, known as erythematous candidiaisis and cracks in the mouth commissure known as angular cheilitis.

Diagnosis Fungal culture of mouth lesions not useful for diagnostic purposes since positive results may be due to high rates of mouth colonization Fungal culture of mouth lesions used for identification of Candida species and resistance testing Because of the high rates of mouth colonization by Candida albicans, fungal cultures of mouth lesions are not routinely obtained to diagnose oropharyngeal candidiasis. A positive fungal culture of mouth lesions may only reflect colonization and not active disease. Fungal cultures of the mouth can be useful when treatment resistant Candida infections are suspected, and drug sensitivity testing is needed to guide therapy.

Diagnosis If laboratory confirmation needed, exudates of epithelial scrapings may be examined microscopically for yeast and/or pseudohyphae by 10% KOH (potassium hydroxide) wet mount preparation Although the diagnosis of oropharyngeal candidiasis is generally clinical, wet mount preparations with 10% potassium hydroxide solution can be used to confirm the diagnosis. Microscopic examination of epithelial scrapings from the mouth lesions (scrapings from the buccal mucosa) reveals the presence of yeast cells or pseudohyphae as shown in this picture. However, most of the time clinical diagnosis will suffice and laboratory confirmation is rarely necessary.

Treatment Use oral topical treatments as initial therapy Systemic therapy seldom required and only use if absolutely necessary Relapse common, therefore prescribe intermittent treatment rather than continuous Depending on which medications are locally available and affordable to the patient, there are several options for treating oropharyngeal candidiasis. Initially, the preferred 1st line treatment for oropharyngeal candidiasis is topical nystatin or clotrimazole. Systemic therapy should only be used for patients who do not respond to topical treatments. Because of the high rate of relapse, there may be need for maintenance therapy.

Treatment Preferred First Line Therapy Topical nystatin or clotrimazole The first line therapy for oropharnygeal candidiasis is topical nystatin or clotrimazole. Clinicians should consult the local pharmacopeia to obtain dosing information, strengths and the locally available formulations since they may vary from country to country.

Second Line Therapy for Refractory Cases Fluconazole 100 mg po daily for 7–14 days after clinical improvement (preferred) Itraconazole 200 mg po daily for 7– 14 days after clinical improvement Alternative therapies are indicated for patients who fail to respond to the first line topical treatments. A number of treatment options exist for the management of refractory cases of oropharyngeal candidiasis. Fluconazole is the drug of choice. The patient should be prescribed 100mg a day to be taken orally for 7 to 14 days after clinical improvement. Itraconazole can also be used as an alternative to fluconazole, taken 200 mg daily orally and continued for 7 to 14 days after clinical improvement.

Second Line Therapy for Refractory Cases Topical amphotericin B OR Amphotericin B 0.3 mg/kg per day IV for 7–14 days after clinical improvement Patients who are refractory or cannot take azoles, can also be treated with topical or intravenous amphotericin. Clinicians should check the local pharmacopeia to obtain dosing information, strengths and formulations for locally available topical amphotericin B.

Treatment If no Response to Alternative Therapy Check adherence Reconsider diagnosis Consider resistance to azole and/or amphotericin It is important to check adherence prior to transitioning from first to second line therapy. If the patient is not responding to second line therapy, also assess medication adherence. For instance, ask the patient how often they take their medication; confirm the dosage and whether the patient filled his/her prescription. Inquire whether they completed treatment as prescribed. If you determine that the second line therapy medication is taken properly but without improvement, reconsider your diagnosis and evaluate for other common oral pathologies/pathogens such as HSV, CMV, aphthous ulcerations, and hairy leukoplakia. If you suspect that resistant Candida is the cause of treatment failure, obtain culture of mouth lesions (if available) for drug sensitivity testing and select future therapy according to sensitivity results. However, if you confirm poor medication adherence, intervene to improve medication adherence and restart treatment with close follow-up.

Drug Interactions Azoles are prone to drug interactions through the cytochrome P450 (CYP450) enzymes The CYP450 pathway is involved in the metabolism of commonly prescribed drugs Check package insert for drug interactions when prescribing azoles concurrently with other drugs Azoles can be associated with hepatotoxicity and gastrointestinal intolerance It is important that clinicians check the package insert for drug interactions with azoles, especially for the commonly prescribed medications. Azoles are prone to drug interactions through the cytochrome P450 metabolic pathway. Azoles can inhibit the cytochrome 3A4 enzyme (CYP3A4), a pathway involved in the metabolism of a large number of commonly prescribed drugs. Inhibition of CYP3A4 activity can lead to an increase in the plasma concentrations of drugs that are substrates for that enzyme and potentially increase their toxicity. There is a need to alert patients for the possibility that azoles may have gastrointestinal side effects and/or cause hepatotoxicity. Patients taking these medications need close follow-up during treatment.

Drug Interactions: Absorption Itraconazole capsules require gastric acid for absorption. Absorption affected by Buffered didanosine, proton pump inhibitors, H2 blockers and antacids Itraconazole liquid is better absorbed and should be taken on an empty stomach Fluconazole absorption is not affected by food or gastric pH Itraconazole absorption is affected by a number of drugs. One of these drugs, didandosine, or ddI, is an antiretroviral medication that is available in two formulations: enteric coated (ddI EC) or buffered ddI. The buffer in the ddI formulation can change the gastric pH and affect absorption of a number of commonly prescribed drugs, including itraconazole. Other medications that can interact with itraconazole include drugs used for the treatment of GERD and peptic ulcer disease such as H2 blockers, proton pump inhibitors and antacids. Itraconazole liquid is better absorbed than the capsule formulation, but must be taken on an empty stomach. Clinicians should refer to pack inserts for more information on what drugs interfere with the optimal absorption of itraconazole. Fluconazole has no specific food requirements, and it is not as affected by gastric acidity.

Treatment Side Effects Clotrimazole Generally well tolerated Occasionally can cause gastrointestinal toxicity Nystatin Bitter taste Can be associated with gastrointestinal toxicity Patients need to be advised that nystatin has a bitter taste, and that both clotrimazole and nystatin can cause gastrointestinal toxicity. Although these side effects are usually self-limited, they can negatively affect medication adherence. Therefore, it is important that patients understand the common side effects associated with these drugs and strategies to minimize them.

Maintenance Therapy Generally not recommended Occasionally needed if recurrence frequent Topical therapy preferred Maintenance therapy is generally not recommended for oropharyngeal candidiasis unless the patient experiences frequent recurrences. In occasional situations when maintenance therapy is needed, topical agents are the therapy of choice.

Maintenance Therapy If refractory to topical therapy consider azoles Fluconazole or itraconazole 100 mg po daily Chronic use of azoles can lead to resistance Optimal prevention is immune reconstitution with ART Systemic therapy should only be used for refractory cases. Fluconazole is the preferred choice for systemic therapy but itraconazole can also be used. It is also important to remember that chronic therapy with azoles can lead to the development of Candida resistance. Most cases of oropharyngeal candidiasis will improve once the patient’s immune system has been restored with the initiation of antiretroviral therapy.

Additional Considerations Reinforce importance of maintaining adequate nutrition Educate the patient on good mouth hygiene Counsel the patient on which foods may be difficult to chew as they can exacerbate mouth discomfort In addition to medical treatment, patients with oropharyngeal candidiasis should be counseled on proper oral hygiene, including the brushing of teeth, and the importance of maintaining a healthy diet.

Summary Common in patients with AIDS Diagnosis usually clinical Treat with topical agents Preserve systemic treatment and only use if absolutely necessary Relapse common To summarize, the key points of oropharyngeal candidiasis in patients with AIDS are: Oropharyngeal candidiasis is a common disease in patients with AIDS Oropharyngeal candidiasis is usually diagnosed clinically Topical anti-fungals such as nystatin and clotrimazole are the first line of treatment Azole antifungals and amphotericin B are second line agents Fluconazole is the preferred azole agent Relapse is common and patients should be counseled and screened accordingly

Summary Maintenance generally not recommended Reinforce the importance of good oral hygiene Optimal prevention is immune reconstitution with ART Other key points include: There may be need for maintenance therapy in those with frequently recurrent oropharyngeal candidiasis Initiation of ARVs will lead to reconstitution of the immune system and consequently will diminish recurrence of oropharyngeal candidiasis.

References Bartlett, J and Gallant, J. 2007. Medical Management of HIV Infection. Johns Hopkins University. Baltimore, MD. Boon, NA et al. 2006. Davidson’s Principles and Practice of Medicine. Elsevier Science Health Science div. 20th Edition. pg 373-375. The Hopkins HIV Guide: http://www.hopkins-hivguide.org Ramírez-Amador, V. et al. 2003. The Changing Clinical Spectrum of Human Immunodeficiency Virus (HIV)-Related Oral Lesions in 1,000 Consecutive Patients: A 12-Year Study in a Referral Center in Mexico. Medicine. 82: 39-50. Vazquez, JA. 2000. Therapeutic options for the management of oropharyngeal and esophageal candidiasis in HIV/AIDS patients. HIV Clin Trials. Jul-Aug; (1): 47-59. This slide provides suggested sources of additional reading material about oropharyngeal candidiasis.