1. Esophageal Candidiasis in Patients with AIDS

2. Case 32-year-old male with AIDS CD4 50 cells/mm3 Reports severe pain and difficulty swallowing “It feels like food gets stuck below my throat” Denies other symptoms Reports history of oral candidiasis What is the most likely diagnosis?

3. Esophageal Candidiasis

4. Objectives Upon completion of this activity, participants should be able to: – Recognize symptoms of esophageal candidiasis – Review methods for diagnosing esophageal candidiasis – Discuss treatments for esophageal candidiasis

5. Overview Candida ssp is an opportunistic fungus (yeast) Candida albicans is the most common etiology of esophagitis in patients with AIDS Candida tropicalis, Candida Krusei, Candida glabrata, and Candida parapsilosis can also cause esophagitis

6. Overview Occurs in 20–40% of patients with AIDS Patients usually have CD4 <100 cells/mm3

7. Esophagitis – Other Causes Less common causes: HSV, CMV and aphthous ulcerations Rare causes: lymphoma, KS, PCP, Cryptosporidia, TB, histoplasmosis, M. avium Consider non-HIV-related causes if CD4 >200 cells/mm3 (e.g., gastro esophageal reflux disease—GERD, medication- and food-induced)

8. Clinical Presentation Odynophagia (painful swallowing) Dysphagia (difficulty swallowing) Diffuse retrosternal pain Occasional nausea and vomiting Oral candidiasis often present but not required

9. Diagnosis Usually made clinically based on symptoms Endoscopy only if empirical azole therapy fails Response to empiric treatment precludes need for endoscopic esophageal candidiasis diagnosis When needed, diagnosis by endoscopy is made based on visual appearance of white pseudomembranous plaques in the esophagus

10. Diagnosis Brushings or biopsy can be taken during endoscopy for microscopy or culture Fungal culture of esophageal pseudomembranous plaques is useful for identification of Candida species and resistance testing (when available)

11. Treatment – Basic Principles No place for topical treatment Treat empirically with systemic drugs Azoles are first-line of therapy – Fluconazole included in class HAART reduces relapses

12. First Line Therapy Fluconazole 200 mg po daily (preferred) x 14–21 days Itraconazole solution 200 mg po daily x 14–21 days – Itraconazole also available in capsule but better absorption with liquid formulation – Ketoconazole rarely used due to erratic absorption

13. Second Line Therapy Amphotericin B 0.3-0.7 mg/kg IV daily – Or lipid formulations of amphotericin If available, can also use – Echinocandins Caspofungin, micafungin – Alternative azoles with increased activity against fluconazole-resistant Candida Voriconazole, posaconazole, itraconazole

14. Treatment Assess response to therapy within 5–7 days Continue therapy for 14–21 days after clinical improvement Use intravenous drugs for patients unable to swallow

15. If no Response to Fluconazole Check medication adherence Reconsider diagnosis Refer for endoscopy Consider resistance to azole therapy – especially if repeated courses of azole treatment or if maintenance therapy used

16. Other Treatment Considerations Azoles prone to drug interactions through the cytochrome P450 (CYP450) pathway The CYP450 enzymes are involved in the metabolism of most commonly prescribed drugs Check package insert for drug interactions when prescribing azoles

17. Other Treatment Considerations Absorption of itraconazole capsules is pH dependent. Absorption affected by: 1. Antipeptic Ulcer Drugs H2 blockers Proton pump inhibitors Antacids 2. Antiretroviral Drugs Buffered didanosine Liquid formulation better absorbed but must be taken on an empty stomach (preferred)

18. Other Treatment Considerations Fluconazole absorption is not affected by food or gastric pH Hepatotoxicity and gastrointestinal intolerance can occur with azole therapy

19. Other Treatment Considerations Amphotericin B is renally eliminated Amphotericin B is not a substrate, inhibitor or inducer of the CYP450 enzymes Thus, amphotericin B is not prone to drug interactions through the CYP450 enzymes

20. Other Treatment Considerations Common side effects of amphotericin B – Nephrotoxicty – Electrolyte abnormalities – Infusion-related chills – Injection site pain and irritation – Phlebitis Increased risk for amphotericin B-induced nephrotoxicity when given concurrently with other nephrotoxic drugs

21. Prophylaxis Prophylaxis/maintenance not generally recommended, but consider if frequent recurrences Fluconazole 100–200 mg po daily Itraconazole liquid 200 mg po daily can be used as an alternative

22. Additional Considerations Use analgesic therapy for pain relief Reinforce importance of maintaining adequate nutrition Avoid foods that are hot/cold/spicy to avoid exacerbating discomfort caused by dysphagia and odynophagia Favor pureed/mashed foods and liquids served at room temperature

23. Summary Candida albicans is the most common etiology of esophagitis in patients with AIDS Treat empirically with fluconazole If no response to treatment, consider alternative etiology, inadequate adherence, drug resistance Azoles are prone to drug interactions through the CYP450 pathway Azoles can cause gastrointestinal and hepatic toxicity

24. Summary Amphoterycin B for second line therapy Amphoterycin B is not prone to drug interactions through the CP450 pathway Common side effects include nephrotoxicity, infusion-related chills and fever, phlebitis and electrolyte abnormalities

25. Summary Prophylaxis usually not recommended Reinforce the importance of adequate nutrition Pain management is crucial HAART reduces relapses

26. References Ally R, Schurmann D, Kreisel W, et al. 2001. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 33:1447-1454. Arathoon EG, Gotuzzo E, Noriega LM, et al. 2002. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis. Antimicrob Agents Chemother. 46:451-457. Bonacini M, Young T, Laine L. 1991. The causes of esophageal symptoms in human immunodeficiency virus infection. A prospective study of 110 patients. Arch Intern Med. 151:1567-1572.

27. References Clinical Infectious Diseases 2004; 38:165-89. Connoly GM, Hawkins D, Harcourt-Webster JN et al. Oesophageal symptoms, their causes, treatment, and prognosis in patients with the acquired immunodeficiency syndrome. Gut. 1989;30:1033-1039. de Wet N, Llanos-Cuentas A, Suleiman J, et al. 2006. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis. 42:1179-1186. de Wet N, Llanos-Cuentas A, Suleiman J, et al. 2004. A randomized, double-blind, parallel-group, dose- response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis. 39:842-849.

28. References Maenza JR, Keruly JC, Moore RD, et al. 1996. Risk factors for fluconazole-resistant candidiasis in human immunodeficiency virus-infected patients. J Infect Dis. 174:219-221. Vazquez JA. 2000. Therapeutic options for the management of oropharyngeal and esophageal candidiasis in HIV/AIDS patients. HIV Clin Trials. 1:47-59. Villanueva A, Arathon EG, Gotuzzo, et al. 2001. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 33:1529- 1535.