Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Last Updated: October 18, 2017; Last Reviewed: October 18, 2017
Oropharyngeal and esophageal candidiasis are common in HIV-infected patients.1,2 The vast majority of such infections are caused by Candida albicans, although infections caused by non-albicans Candida species have also been reported in recent years worldwide.3-6 The occurrence of oropharyngeal or esophageal candidiasis is recognized as an indicator of immune suppression and is most often observed in patients with CD4 T lymphocyte (CD4) cell counts <200 cells/mm3, with esophageal disease typically occurring at lower CD4 counts than oropharyngeal disease.1,2 In contrast, vulvovaginal candidiasis—whether a single episode or recurrent—is common in healthy, adult women and does not suggest HIV infection. The advent of antiretroviral therapy (ART) has led to a dramatic decline in the prevalence of oropharyngeal and esophageal candidiasis and a marked diminution in cases of refractory disease.
Fluconazole (or azole) resistance is predominantly the consequence of previous exposure to fluconazole (or other azoles), particularly repeated and long-term exposure.7-9 In this setting, the vast majority of cases relate to acquisition of C. albicans resistance, however, prior exposure to azole therapy has also been associated with a gradual emergence of non-albicans Candida species, particularly Candida glabrata, as a cause of refractory mucosal candidiasis in patients with advanced immunosuppression and low CD4 counts.7,10
Oropharyngeal candidiasis is characterized by painless, creamy white, plaque-like lesions that can occur on the buccal surface, hard or soft palate, oropharyngeal mucosa, or tongue surface. Lesions can be easily scraped off with a tongue depressor or other instrument. Less commonly, erythematous patches without white plaques can be seen on the anterior or posterior upper palate or diffusely on the tongue. Angular cheilosis also can be caused by Candida. Because a proportion of HIV-infected patients with oropharyngeal candidiasis also manifest esophageal involvement, clinicians should ascertain whether there are symptoms suggestive of esophageal disease in patients with oropharyngeal candidiasis. Esophageal candidiasis generally presents with retrosternal burning pain or discomfort along with odynophagia; occasionally esophageal candidiasis can be asymptomatic. Endoscopic examination reveals whitish plaques similar to those observed with oropharyngeal disease. On occasion, the plaques may progress to superficial ulcerations of the esophageal mucosa with central or peripheral whitish exudates.
In HIV-infected women, Candida vulvovaginitis usually presents with white adherent vaginal discharge associated with mucosal burning and itching of mild-to-moderate severity and sporadic recurrences. In women with advanced immunosuppression, episodes may be more severe and recur more frequently. In contrast to oropharyngeal candidiasis, vulvovaginal candidiasis is less common and rarely refractory to azole therapy.
Oropharyngeal candidiasis is usually diagnosed clinically based on the characteristic appearance of lesions. In contrast to oral hairy leukoplakia, the white plaques of oropharyngeal candidiasis can be scraped off the mucosa. If laboratory confirmation is required, scrapings can be examined microscopically for characteristic yeast or hyphal forms, using a potassium hydroxide preparation. Cultures of clinical exudative material yield the species of Candida present.
The diagnosis of esophageal candidiasis is often made empirically based on symptoms plus response to therapy, or visualization of lesions plus fungal smear or brushings without histopathologic examination. The definitive diagnosis of esophageal candidiasis requires direct endoscopic visualization of lesions with histopathologic demonstration of characteristic Candida yeast forms in tissue and confirmation by fungal culture and speciation.
Vulvovaginal candidiasis usually is diagnosed based on the clinical presentation coupled with the demonstration of characteristic blastosphere and hyphal yeast forms in vaginal secretions when examined microscopically after potassium hydroxide preparation. Culture confirmation is rarely required but may provide supportive information. Self-diagnosis of vulvovaginitis is unreliable; microscopic and culture confirmation is required to avoid unnecessary exposure to treatment.
Candida organisms are common commensals on mucosal surfaces in healthy individuals. No measures are available to reduce exposure to these fungi.
Data from prospective controlled trials indicate that fluconazole can reduce the risk of mucosal disease (i.e., oropharyngeal, esophageal, and vulvovaginal) in patients with advanced HIV.11-14 However, routine primary prophylaxis is not recommended because mucosal disease is associated with very low attributable morbidity and mortality and, moreover, acute therapy is highly effective. Primary antifungal prophylaxis can lead to infections caused by drug-resistant Candida strains and introduce significant drug-drug interactions. In addition, long-term oral prophylaxis is expensive. Therefore, routine primary prophylaxis is not recommended (AIII). Administration of ART and immune restoration is an effective means to prevent disease.
Oral fluconazole is as effective or superior to topical therapy for oropharyngeal candidiasis. In addition, oral therapy is more convenient than topical therapy and usually better tolerated. Moreover, oral therapy has the additional benefit over topical regimens in being efficacious in treating esophageal candidiasis. Oral fluconazole at 100 mg once a day is considered the drug of choice to treat oropharyngeal candidiasis except during pregnancy (AI). One to two weeks of therapy is recommended for oropharyngeal candidiasis; two to three weeks of therapy is recommended for esophageal disease.15
Using topical agents to treat oropharyngeal candidiasis reduces systemic drug exposure, diminishes risk of drug-drug interactions and systemic adverse events, and may reduce the likelihood that antifungal resistance develops. Unfavorable taste and multiple daily dosing such as in the cases of clotrimazole and nystatin may lead to decreased tolerability of topical therapy. As an alternative to oral fluconazole, once-daily miconazole in 50-mg mucoadhesive buccal tablets (BI) or five-times-per-day clotrimazole troches can be used to treat oropharyngeal candidiasis (BI); these regimens were equivalent as shown in a multicenter, randomized study.16 Nystatin suspension or pastilles four times daily remains an additional alternative (BII).17
Itraconazole oral solution for 7 to 14 days is as effective as oral fluconazole for oropharyngeal candidiasis but less well tolerated (BI).17 Posaconazole oral suspension18 is also as effective as fluconazole and generally better tolerated than itraconazole solution, although both posaconazole and itraconazole have more drug-drug interactions compared to fluconazole (BI). Both antifungals are alternatives to oral fluconazole, although few situations require that these drugs be used in preference to fluconazole solely to treat mucosal candidiasis. In a multicenter, randomized study, posaconazole was found to be more effective than fluconazole in sustaining clinical success after antifungal therapy was discontinued.18 A new solid oral delayed-release tablet formulation of posaconazole is now available, which exhibits less variable absorption compared to the oral suspension.19 Whether it offers any advantage for the treatment of oropharyngeal candidiasis is unknown and it currently is indicated only for prophylaxis of invasive Apsergillus and Candida infection.20 Itraconazole capsules are less effective than fluconazole because of their more variable absorption and they are associated with more drug-drug interactions than fluconazole.
Systemic antifungals are required for effective treatment of esophageal candidiasis (AI). A 14- to 21-day course of either fluconazole (oral or intravenous [IV]) or oral itraconazole solution is highly effective (AI). However, patients with severe symptoms initially may have difficulty swallowing oral drugs. As with oropharyngeal candidiasis, itraconazole capsules for esophageal candidiasis are less effective than fluconazole because of variable absorption (CII). A two-week course of the newer triazole isavuconazole, given orally at an initial loading dose of 200 mg, followed by 50 mg; or a loading dose of 400 mg followed by 100 mg once-daily; or 400 mg once-weekly, is also as effective as fluconazole for uncomplicated esophageal candidiasis (BI); a higher rate of gastrointestinal adverse effects was seen with the 100 mg once-daily isavuconazole regimen compared to fluconazole and the other isavuconazole regimens.21 Voriconazole, amphotericin B (either deoxycholate or lipid formulations) and the echinocandins caspofungin, micafungin, and anidulafungin all effectively treat esophageal candidiasis (BI); however, esophageal candidiasis appears to have a higher relapse rate after treatment with the echinocandins.22,23 Therefore, oral or IV fluconazole remains the preferred therapy for esophageal candidiasis (AI). Although other pathogens (e.g., cytomegalovirus, herpes simplex virus esophagitis) can mimic the symptoms of esophageal candidiasis, a diagnostic and therapeutic trial of antifungal therapy is usually warranted before endoscopy. In those who do not respond to antifungal therapy, endoscopy is recommended to identify different causes of esophagitis or drug-resistant Candida (AII).
In most HIV-infected women, vulvovaginal candidiasis is uncomplicated and responds readily to short-course oral or topical treatment with any of several therapies, including:
- Oral fluconazole (AII)
- Topical azoles (i.e., clotrimazole, butoconazole, miconazole, tioconazole, or terconazole) (AII)
- Itraconazole oral solution (BII)
Severe or recurrent episodes of vaginitis should be treated with oral fluconazole or topical antifungal therapy for ≥7 days (AII). For more information, see the Vulvovaginal Candidiasis section in the Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention (CDC).
Special Considerations with Regard to Starting ART
There are no special considerations regarding initiation of ART in patients with mucocutaneous candidiasis. Specifically, there is as yet no evidence that treatment with ART needs to be delayed until treatment for candidiasis has been completed.
Monitoring of Response to Therapy and Adverse Events (Including IRIS)
For most patients with mucocutaneous candidiasis, response to antifungal therapy is rapid; signs and symptoms improve within 48 to 72 hours. Short courses of topical therapy rarely result in adverse effects, although patients may experience cutaneous hypersensitivity reactions characterized by rash and pruritus. Oral azole therapy can be associated with nausea, vomiting, diarrhea, abdominal pain, or transaminase elevations. Periodic monitoring of liver function studies should be considered if azole therapy is anticipated for >21 days, especially in patients with other hepatic comorbidities (AII). The echinocandins appear to be associated with very few adverse reactions: histamine-related infusion toxicity, transaminase elevations, and rash have been attributed to these drugs. No dose adjustments are required in renal failure.
Immune reconstitution inflammatory syndrome with ART has not yet been reported for mucocutaneous candidiasis in HIV-infected patients. Indeed, ART is associated with a markedly reduced incidence of candidiasis.
Managing Treatment Failure
Antifungal treatment failure is typically defined as the persistence of signs or symptoms of oropharyngeal or esophageal candidiasis after 7 to 14 days of appropriate antifungal therapy. Refractory disease occurs in approximately 4% to 5% of HIV-infected patients with oral or esophageal candidiasis, typically those with CD4 cell counts <50 cells/mm3 and who have received multiple courses of azole antifungals.8 Confirmatory culture and, in the case of esophageal candidiasis, endoscopy are necessary to confirm treatment failure due to azole resistance or other causes of esophagitis, especially if these procedures were not initially performed.
Posaconazole immediate-release oral suspension (400 mg twice daily for 28 days) is effective in 75% of patients with azole-refractory oropharyngeal or esophageal candidiasis (AI).24 Again, although the new solid delayed-release tablet formulation has been recently made available, it is not known if it offers an advantage over the suspension for treating this particular disease. Alternatively, oral itraconazole solution is effective, at least transiently, in approximately two-thirds of patients with fluconazole-refractory mucosal candidiasis (BII).17 If necessary, azole-refractory esophageal candidiasis also can be treated with anidulafungin (BII), caspofungin (BII), micafungin (BII), or voriconazole (BII).
IV amphotericin B is usually effective for treating refractory disease (BII). Both amphotericin B deoxycholate and the lipid preparations of amphotericin B have been used successfully (BII). Amphotericin B oral suspension (1 mL of the 100-mg/mL suspension 4 times daily) is sometimes effective in patients whose oropharyngeal candidiasis does not respond to itraconazole (BII), but this product is not commercially available in the United States.
When to Start Secondary Prophylaxis
A randomized clinical trial14 in HIV-infected patients with CD4 counts <150 cells/mm3 documented a significantly lower number of episodes of oropharyngeal candidiasis and other invasive fungal infections with continuous fluconazole therapy (3 times a week) compared with episodic fluconazole treatment for recurrences. This clinical trial also demonstrated no difference in the risk of developing clinically significant fluconazole resistance between the two groups among those receiving ART.
However, secondary prophylaxis (chronic suppressive therapy) is not recommended by most HIV specialists for recurrent oropharyngeal or vulvovaginal candidiasis unless patients have frequent or severe recurrences (BIII) because therapy for acute disease is effective, mortality associated with mucocutaneous disease is low, potential exists for drug interactions and for the development of antifungal-resistant Candida, and prophylaxis is costly.
If recurrences are frequent or severe, oral fluconazole can be used as suppressive therapy for either oropharyngeal (BI), esophageal (BI), or vulvovaginal (BII) candidiasis.11-13 Oral posaconazole twice daily is also effective for esophageal candidiasis (BII).25 The potential for development of secondary azole resistance should be considered when contemplating chronic maintenance therapy using azoles in HIV-infected patients who are severely immunocompromised. Several important factors should be taken into account when making the decision to use secondary prophylaxis. These include the effect of recurrences on the patient’s well-being and quality of life, the need for prophylaxis against other fungal infections, cost, adverse events and, most importantly, drug-drug interactions.26
Rates of relapse are high in patients with azole-refractory oropharyngeal or esophageal candidiasis who have initially responded to echinocandins, voriconazole, or posaconazole therapy. In such patients, secondary prophylaxis should be instituted until ART produces immune reconstitution (AIII).
When to Stop Secondary Prophylaxis
In situations where secondary prophylaxis has been instituted, no data exist to guide recommendations regarding its discontinuation. On the basis of experience with other opportunistic infections, it would be reasonable to discontinue secondary prophylaxis when the CD4 count has risen to >200 cells/mm3 following initiation of ART (AIII).
Special Considerations During Pregnancy
Pregnancy increases the risk of vaginal colonization with Candida species. Diagnosis of oropharyngeal, esophageal, and vulvovaginal candidiasis is the same in pregnant women as in those who are not pregnant.
Topical therapy is preferable for treatment of oral or vaginal candidiasis in pregnancy, when possible (AIII). Although single-dose, episodic treatment with oral fluconazole has not been associated with birth defects in humans,27 its use has not been widely endorsed.28 Five cases of a syndrome consisting of craniosynostosis, characteristic facies, digital synostosis, and limb contractures (fluconazole embryopathy) have been reported in women chronically prescribed fluconazole at doses of 400 mg daily or higher in pregnancy.29 A report from a national cohort register in Denmark found an increased hazard ratio of 1.48 (95% CI 1.23 – 1.77) for spontaneous pregnancy loss with any exposure to oral fluconazole from 7 to 22 weeks of pregnancy compared to unexposed, matched controls.30 An increased hazard ratio of 1.47 (95% CI 1.22 – 1.77) was also noted with low dose (150 – 300 mg cumulative dose) exposure. No increase in stillbirth was seen with fluconazole exposure broadly, but an increase in risk of stillbirth (HR 4.10, 95% 1.89 – 8.90) was noted with fluconazole doses above 300 mg. On the basis of these data, substitution of amphotericin B for high-dose fluconazole in the first trimester is recommended for invasive or refractory esophageal Candidal infections (AIII). Neonates born to women receiving chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.
Itraconazole has been shown to be teratogenic in animals at high doses, but the metabolic mechanism accounting for these defects is not present in humans, so these data are not applicable. Case series in humans do not suggest an increased risk of birth defects with itraconazole,31 but experience is limited. Human data are not available for posaconazole; however, the drug was associated with skeletal abnormalities in rats and was embryotoxic in rabbits when given at doses that produced plasma levels equivalent to those seen in humans. Voriconazole is considered a Food and Drug Administration Category D drug because of its association with cleft palate and renal defects seen in rats, as well as embryotoxicity seen in rabbits. Human data on the use of voriconazole are not available, so use in the first trimester is not recommended. Multiple anomalies have been seen in animals exposed to micafungin, and ossification defects have been seen with use of anidulafungin and caspofungin.32 Human data are not available for these drugs, thus their use in human pregnancy is not recommended (AIII).
Chemoprophylaxis, either chronic maintenance therapy or secondary prophylaxis, against oropharyngeal, esophageal, or vaginal candidiasis using systemically absorbed azoles should not be initiated during pregnancy (AIII). Furthermore, prophylaxis with systemic azoles should be discontinued in HIV-infected women who become pregnant (AIII).
Treating Mucosal Candidiasis
Oropharyngeal Candidiasis: Initial Episodes (Duration of Therapy: 7–14 days)
Esophageal candidiasis (Duration of Therapy: 14–21 days)
Note: A higher rate of esophageal candidiasis relapse has been reported with echinocandins than with fluconazole.
Uncomplicated Vulvovaginal Candidiasis
Note: Severe or recurrent vaginitis should be treated with oral fluconazole (100–200 mg) or topical antifungals for ≥7 days (AII)
Chronic Suppressive Therapy
If Decision Is To Use Suppressive Therapy
Key to Acronyms: ARV = antiretroviral; BID = twice daily; CD4 = CD4 T lymphocyte; IV = intravenous; OI = opportunistic infection; PO = orally; QID = four times daily
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