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Keywords:

  • candidiasis;
  • Candida albicans;
  • non-albicans Candida;
  • oesophagitis

7.1 Methods

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References

The PubMed database was searched under the following headings: HIV or AIDS and candidosis, candidiasis, Candida spp, Candida albicans, non-albicans Candida, oropharyngeal candidiasis and mucosal candidiasis.

7.2 Background and epidemiology

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References

Candida species are common commensals in the general population and may be cultured using selective media from the oral cavity and genital tracts of up to 75% of individuals [1]. Such cultures are not clinically helpful. Oropharyngeal candidiasis is the commonest opportunistic infection to affect HIV-seropositive individuals, occurring in 80–90% of patients in the pre-HAART era [2]. Oesophageal candidiasis in the pre-HAART era was the AIDS-defining illness in 11% of cases [3].

7.3 Presentation

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References

Oral candidiasis is associated with worsening immunodeficiency [4] and in the absence of HAART predicts the development of AIDS at a median of 25 months [5]. The most familiar clinical appearance of oral candidiasis is of easily removable curdy white plaques, underneath which lies raw or bleeding mucosa. Other presentations include an erythematous form, with patchy reddening of the mucosa, and depapillation of the dorsal surface of the tongue [6]; hyperplastic candidiasis, where there are white plaques that cannot be scraped away; and angular cheilitis with painful fissuring of the commissures. The symptoms are of pain in the tongue or surrounding structures or the presentation may be asymptomatic with just the clinical appearance of oral candidiasis.

Vaginal candidiasis is common in HIV-seropositive women and presents with vaginitis with itching and curd-like exudate. Management is as for HIV-seronegative individuals [7].

Typically the patient with oesophageal candidiasis complains of dysphagia and/or odynophagia. Oesophageal candidiasis without oral evidence of plaques is infrequent and where a patient complains of typical symptoms in the absence of oral candidiasis other diagnoses must be considered. However, in a minority of cases oesophageal candidiasis may occur without oral involvement [8].

Invasive candidiasis is seen in more immunocompromised patients, in particular those with central venous catheters, prolonged antimicrobial usage or intensive care unit admission.

7.4 Diagnosis

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References
  • Oral and oesophageal candidiasis are clinical diagnoses (category IV recommendation).
  • Microbiological confirmation and susceptibility testing of Candida spp is required when symptoms of candidiasis persist or develop whilst the patient is taking antifungal therapy (category IV recommendation).

Oral and oesophageal candidiasis are clinical diagnoses, and microbiological confirmation is not advised due to the likelihood of positive cultures in the absence of clinical disease. Candida cultures should be requested only for studies of resistance in individuals not responding to standard therapy. C. krusei is always fluconazole-resistant, and may be cross-resistant to itraconazole and ketoconazole. C. glabrata sensitivity is more variable with many strains showing fluconazole resistance [9]. Susceptibility testing is recommended for patients with clinical disease from whom these species are isolated and for cases in which there is a slow response to therapy or development of candidiasis despite azole therapy for some other reason.

  • Oesophageal candidiasis can be diagnosed clinically if oropharyngeal candidiasis is present (category IV recommendation).
  • Confirmation by endoscopy can be reserved for cases with symptoms of oesophageal candidiasis who fail to respond to initial therapy, do not have concomitant oropharyngeal candidiasis or those in which an additional oesophageal condition is suspected (category IIb recommendation).

Endoscopy should reveal white patches. The main value of endoscopy is to exclude other causes of oesophageal symptoms that may be present with or without oesophageal candidiasis or obtain samples for susceptibility testing if response to therapy is not detected.

7.5 Treatment

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References
  • Azoles and topical treatment are equally effective at treating oropharyngeal candidiasis but azole therapy is associated with a lower risk of relapse (category Ib recommendation).

Azoles are the mainstay of treatment for HIV-seropositive patients with oral or oesophageal candidiasis. Topical nystatin or amphotericin are of little benefit for oesophageal candidiasis, and although as effective as azoles for oropharyngeal candidiasis, are associated with slower clearance of yeast from the mouth and a higher relapse rate [10].

Fluconazole (50–100 mg/day), ketoconazole (200 mg bd) and itraconazole (200 mg od) are the most commonly selected orally absorbable systemic azoles, and all have efficacy against oropharyngeal candidiasis when prescribed for 7–14 days [11–16]. Fluconazole is most often recommended. Itraconazole may be used in select cases when fluconazole resistance has been demonstrated. Ketoconazole is mainly of historical interest. Studies have suggested greater efficacy with fluconazole and oral solution of itraconazole than with ketoconazole or itraconazole tablets [11,16,17]. Both fluconazole and itraconazole have demonstrated efficacy in the treatment of oesophageal candidiasis with fluconazole providing greater short-term response [18].

Ketoconazole and itraconazole capsules require gastric acid to facilitate absorption, and achlorhydria, which is associated with advanced HIV disease, will impair the efficacy of these agents [19,20]. Itraconazole oral solution shows better bioavailability [17]. Patients with low CD4 T-cell counts are thus best treated with fluconazole, as are those requiring systemic antacid preparations.

Ketoconazole and itraconazole are metabolized via cytochrome P450 enzymes and therefore should not be co-prescribed with hepatic enzyme-inducing agents such as rifamycins. Fluconazole is excreted predominantly unchanged in the urine and is therefore the azole of choice in patients requiring treatment with such enzyme inducers. It is advisable to use fluconazole, as the least hepatotoxic agent, in patients with liver disease. Ketoconazole is teratogenic in laboratory animals, is contraindicated in pregnancy and like other azoles can cause hepatitis [21].

Individuals with fluconazole-refractory candida may respond to itraconazole cyclodextrin (oral) solution 200 mg bd [22,23]. Where this is not possible, clotrimazole pessaries (100 mg) have been used orally (sucked rather than swallowed) or clotrimazole troches (10 mg), available in the US, may be effective (Cartledge JD, personal communication). Alternatively amphotericin B oral solution or lozenges may be used [24]. In patients with severe oesophageal symptoms, or those with severe oropharyngeal candidiasis who do not respond to itraconazole solution or clotrimazole cloches, or those with strains with elevated minimum inhibitory concentration (MIC) to fluconazole and itraconazole intravenous therapy with amphotericin B, echinocandins or newer azoles may be effective.

  • Voriconazole, posaconazole or the echinocandins (caspofungin, micafungin and anidulafungin) should be reserved for cases in which the organism is resistant to fluconazole but sensitive to the newer agent, to cases which fail to respond clinically to fluconazole despite sensitivity or where the individual is intolerant of fluconazole therapy (category IV recommendation).

There are a number of antifungal drugs that can be considered for the treatment of fluconazole-refractory disease [25]. These include the azoles, voriconazole and posaconazole, and the echinocandins, caspofungin, micafungin and anidulafungin, which have shown efficacy in randomized clinical trials against oesophageal candidiasis although cost means their use should be reserved for cases where traditional fluconazole therapy is ineffective, not tolerated or where infection is due to organisms with altered susceptibility to first-line agents. In clinical trials of oesophageal candidiasis caspofungin was as effective but less toxic than amphotericin B [26] and was active against fluconazole-resistant strains [27]. Caspofungin, micafungin and anidulafungin have shown efficacy comparable to fluconazole in treatment of oesophageal candidiasis [28–30]. Only micafungin has resulted in a relapse rate comparable to fluconazole; caspofungin shows a trend towards, and anidulafungin is associated with a significantly higher relapse rate [26,29,30]. However, interpretation of these differences is hampered by the different doses of fluconazole used in the different studies [25]. Voriconazole is also active against resistant strains [31] and was as effective but more toxic than fluconazole [32], and posaconazole also showed efficacy against oropharyngeal/oesophageal candidiasis [33], including candidiasis refractory to fluconazole/itraconazole [34].

There are no clinical trial data to guide the treatment of invasive candidiasis in HIV-seropositive individuals. In general, they should be treated with systemic antifungal therapy as in other immunocompromised patients (category IV recommendation). The British Society for Medical Mycology has published proposed standards of care for invasive fungal infections, including Candida [35].

7.6 Prophylaxis

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References
  • Routine prophylaxis is not warranted and is associated with the emergence of resistance (category III recommendation).

Ongoing prescription of azole antifungals between episodes of recurrent candidiasis is not recommended as this is associated with emergence of azole-resistant candidiasis [36–38]. In the pre-HAART era, azole-unresponsive candidiasis was increasingly common in patients who had received prolonged prophylaxis with azole antifungals, and was either due to infection with species other than C. albicans [39–41], such as C. krusei and C. glabrata, or resistant strains of C. albicans [42–45].

7.7 Impact of HAART

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References

As with other opportunistic infections, effective antiretroviral therapy prevents relapses of symptomatic candidiasis. Thus the most successful strategy for managing patients with candidiasis is HAART (see Table 7.1). There are rare reports of candidiasis associated with IRIS, including a case of Candida meningitis leading to fatal vasculitis [46].

Table 7.1.   Candida infection treatment and antiretroviral drug interactions
Drug nameInteraction with antiretroviralAction required
  1. Antiretroviral drugs, especially the NNRTIs and boosted PIs, have several important drug–drug interactions. This table lists some examples of drug–drug interactions with antiretrovirals and antifungals. As the azole antifungal compounds are metabolized via the cytochrome P450 enzyme system they are likely to interact with both NNRTIs and PIs. There are few published data on potential drug interactions with the newer antifungal agents. As data and advice changes frequently, this information should always be interpreted in conjunction with the manufacturer's information (http://www.medicines.org.uk). Other useful web-based reference sources include the Liverpool HIV drug information website (http://www.hiv-druginteractions.org) and the Toronto Clinic (http://www.hivclinic.ca/main/drugs_interact.html).

Antifungals
 AmphotericinTenofovirCaution – increased risk of renal toxicity with concurrent or recent use.
 ItraconazoleRitonavir increases itraconazole exposureAvoid high doses of itraconazole Caution with boosted PIs – some PI levels increased
Efavirenz, etravirine and nevirapine reduce itraconazole levelsConsider alternative, or increase dose Monitor clinical effect
Maraviroc levels increasedReduce maraviroc dose (150 mg bd)
 VoriconazoleEfavirenz levels increased and voriconazole levels reducedNot recommended to be used together. Seek HIV specialist pharmacist advice
Etravirine and voriconazole levels are both increasedNo dose adjustment required – monitor
Lopinavir/ritonavir reduces voriconazole levelsNot recommended to be used together. Seek HIV specialist pharmacist advice
 FluconazoleZidovudine levels increasedCaution – monitor for adverse effects
Nevirapine levels increasedCaution – monitor for adverse effects
 PosaconazoleEfavirenz reduces posaconazole levelsAvoid combination unless benefit to patient outweighs risk
Atazanavir levels increased Other PIs – levels possibly increasedCaution – additional monitoring for toxicity (bilirubin levels) Monitor for signs of increased toxicity
 CaspofunginEfavirenz and nevirapine reduce levels.Increase caspofungin dose to 70 mg od, for those <80 kg

7.8 References

  1. Top of page
  2. 7.1 Methods
  3. 7.2 Background and epidemiology
  4. 7.3 Presentation
  5. 7.4 Diagnosis
  6. 7.5 Treatment
  7. 7.6 Prophylaxis
  8. 7.7 Impact of HAART
  9. 7.8 References
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