12.1. Background
12.1.1. Epidemiology
Oropharyngeal candidiasis, or thrush, is a common local infection seen in infants, older adults who wear dentures, patients treated with antibiotics, chemotherapy or radiation therapy to the head and neck, and those with cellular immune deficiency states, such as HIV infection (Shay et al., 1997; Epstein et al., 1993; Iacopino & Wathen, 1992; Sangeorzan et al., 1994).
Several studies have shown that oropharyngeal candidiasis can occur in 45% to 90% of HIV-infected adults in the absence of ART (Yang et al., 2006). It is not only common, but also recurs frequently (Arribas et al., 2000; Greenspan et al.,1992; Gennaro et al., 2008; Reznik, 2005/2006), often presenting as an initial manifestation of the disease (Coogan et al., 2005; Epstein & Polsky, 1998; Nittayananta & Chingpanich, 1997; Rachanis, 2001).
Similarly, in HIV-infected children the prevalence can be as high as 81% (Christine Henneberg, personal communication, 2010). If left untreated, these lesions contribute considerably to the morbidity associated with HIV infection (Oude Lashof, 2004). Interventions aimed at preventing and treating HIV-associated oral candida lesions form an integral component of maintaining the quality of life for affected individuals.
12.1.2. Clinical features
The clinical manifestations include a soft white coating or pseudomembrane on the mucosal surface of the mouth which reveals a red, raw surface when wiped off; depapillation or red/raw surface on the tongue; or thick white plaque which cannot be rubbed off, which is most challenging to diagnose. Though Candida albicans is most commonly implicated, other organisms have also been identified.
In patients with oropharyngeal candidiasis a presumptive diagnosis of Candida esophagitis can be made if the patient has dysphagia (difficulty in swallowing). Endoscopy is required for definitive diagnosis. Most patients with esophageal candidiasis respond to antifungal therapy within three to seven days (Rabeneck & Laine 1994). If the patient fails to improve with appropriate systemic antifungal therapy, then endoscopy is indicated to exclude other causes of esophagitis including herpes simplex virus or cytomegalovirus, both common causes of esophagitis in immunocompromised populations.
12.2. Recommendations
Specific therapy
In adults
Oral fluconazole 100–150 mg for seven to 14 days is recommended as the preferred treatment.
When fluconazole is not available or contraindicated, alternatives include topical therapy with nystatin suspension or pastilles, or clotrimazole troches.
(Strong recommendation, moderate quality evidence)
In children
Oral fluconazole 3 mg/kg for children for seven to 14 days is recommended as the preferred treatment.
When fluconazole is not available or contraindicated, alternatives include topical therapy with nystatin suspension or pastilles, or clotrimazole troches.
In children with mild oropharyngeal candidiasis, topical therapy with nystatin suspension or pastilles (alternatively clotrimazole troches) is recommended.
(Strong recommendation, low quality evidence)
ART eligibility
Prompt ART initiation is recommended in all HIV-infected adults (including pregnant and breastfeeding women), adolescents and children with oropharyngeal candidiasis (see SECTION 3).
(Strong recommendation, high quality evidence)
Remarks
When there is no response to fluconazole after 14 days of treatment, consider a higher dose. If still no response, consider fluconazole resistance. Itraconazole may be an alternative regimen, but precautions regarding drug interactions should be observed. When there are difficulties in swallowing, oesophageal candidiasis should be considered and treatment should be provided for a longer duration, 14–30 days. The use of maintenance therapy is not recommended.
In HIV-infected patients with oropharyngeal candidiasis, always ask for a history of dysphagia to rule out oesophageal candidiasis, which is always treated with systemic antifungals (fluconazole 3–6 mg/kg per day for 14 days). A diagnostic trial of systemic antifungal treatment is appropriate before performing an endoscopic examination.
The use of gentian violet is no longer recommended.
Relevant drug interactions are described in
ANNEX 2.
Check the breasts of a breastfeeding woman when she or her infant has oropharyngeal candidiasis and treat accordingly.
In addition to the drug treatment, ensure that the patient has adequate hydration and nutrition.
These recommendations apply to HIV-negative children and adults as well.
12.3. Review question and summary of evidence
The systematic review was based on the PICO question: in children and adults living with HIV infection (receiving or not receiving ART) (P) do antifungals (fluconazole, itraconazole, clotrimazole, posaconazole, nystatin, gentian violet) or ART (I) compared to another drug or no treatment (C) achieve complete resolution of the disease, achieve mycological cure or reduce or prevent recurrence (O).
The systematic review (Pienaar et al., 2013) included 34 studies: 23 assessing treatment and 11 assessing prevention of oropharyngeal candidiasis. Six studies were done in developing countries, 16 in the USA and the remainder in Europe.
Treatment of oropharyngeal candidiasis
Treatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one study. Compared to nystatin, fluconazole favoured clinical cure in adults (one RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole and ketoconazole (two RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (two RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16), clotrimazole (two RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42) or posaconazole (one RCT; n=366; RR1.32; 95% CI 0.36 to 4.83). Two trials compared different dosages of fluconazole with no difference in clinical cure. When compared with clotrimazole, both fluconazole (two RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (one RCT; n=123; RR 2.20; 95% CI 1.43 to 3.39) proved to be better for mycological cure. Both gentian violet (one RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (one RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure. A single study compared miconazole with clotrimazole with no difference between the groups for clinical cure.
Two trials, De Wit and colleagues (1993) (n = 56) and Hamza and colleagues (2008) (n=220) compared different dosages of fluconazole. In De Wit and colleagues’ study one arm was given 50 mg per day for seven days, and the other arm was given 150 mg as a single dose. Hamza and colleagues compared 150 mg per day for 14 days with 750 mg as a single dose. There was no clear superiority between the dosages for both clinical and mycological cure. Based on clinical experience and the evidence from the systematic review, the GDG recommended a fluconazole dose of 100–150 mg daily for seven to 14 days.
Recurrence of oropharyngeal candidiasis
Eleven trials identified in the review investigated the prevention of recurrence of oropharyngeal candidiasis in adults. Fluconazole was compared with placebo in five studies (five RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) (Leen et al., 1990; Stevens et al., 1991; Marriott et al., 1993; Pagani et al., 2002; Schuman et al., 1997) and with no treatment in another (one RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34) (Ramsay et al., 2003). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (two RCTs; n=891; RR 0.65; 95% CI 0.23 to 1.83) (Goldman et al., 2005; Revankar et al., 1998), there was no significant difference between the two treatment arms. Chlorhexidine was compared with normal saline in a single study with no significant difference between the treatment arms (Nittayanta et al., 2008).
There were no trials investigating prevention of recurrence in children, including in HIV-infected children.
Impact of ART
One systematic review compared the incidence of oropharyngeal candidiasis before and after the widespread introduction of ART, and showed a significant reduction in the incidence in both adults and children (Andrea Low & Marie-Renee Lajoie, unpublished data, 2014). In general, after ART immune reconstitution, recurrence is infrequent.
None of the studies included in the systematic review investigated the individual effects of ART or any other form of ART on oropharyngeal candidiasis response and rate of recurrence. Oral lesions associated with HIV form part of the clinical spectrum of immune reconstitution associated with ARV use. Protease inhibitors have been shown to directly attenuate the adherence of Candida albicans to epithelial cells in vitro (Bektic et al., 2001; Cauda et al., 1999; Cassone et al.,1999). The systematic review’s authors considered that the impact of this intervention warrants further investigation with regard to clinical presentation and mycological effect.
12.4. Rationale for recommendations
The evidence suggests that ketoconazole, fluconazole, itraconazole and clotrimazole are all effective in the treatment of oropharyngeal candidiasis in HIV-infected persons. Oral fluconazole is highly effective, and as a single daily dose is more convenient. Itraconazole is as effective as, but less well tolerated than, fluconazole. Both ketoconazole and itraconazole capsules are less effective than fluconazole because of their variable absorption. Ketoconazole oral tablets were excluded from the recommendation because of their severe adverse effects (e.g. Smith et al., 1991) and significant drug interactions with ART (WHO, 2013).
In a previously published review, Patton and colleagues (2001) found that the efficacy of fluconazole ranged from 87% to 100%, bringing about a complete clinical response, which is the absence of signs or symptoms of oropharyngeal candidiasis, or both. This is similar to the findings in the review by Pienaar and colleagues (2013), namely that the effectiveness of fluconazole in bringing about clinical cure of oropharyngeal candidiasis is the highest, followed by itraconazole.
Even though the only trial on gentian violet, by Nyst and colleagues (1992), showed that it is equally effective as nystatin and ketoconazole, the GDG reached expert consensus that it is no longer effective based on clinical experience and should not be recommended.
Although fluconazole is an effective preventive intervention, the potential for resistant Candida organisms to develop as well as the cost of prophylaxis might impact on the feasibility of implementation. Therefore, antifungal prophylaxis is not recommended for oropharyngeal candidiasis.
It is not possible to make recommendations for treatment or prevention of oropharyngeal candidiasis in children based on evidence from the review as there is only one study in children. However, based on expert clinical experience, the GDG recommended oral fluconazole as the preferred treatment in children. When fluconazole is not available or contraindicated, nystatin suspension or pastilles, or clotrimazole troches are alternate treatments. Although rated as a strong recommendation, the evidence is graded as low quality.
Adverse effects, costs, availability and other implementation considerations
The resources required to implement this recommendation are small (see ANNEX 3). There may be an issue with availability of antifungals, and also with drug interactions (e.g. with methadone). Overall, the desirable effects of the recommended medicines are probably large relative to any undesirable effect, and this recommendation would probably be acceptable to key stakeholders. Based on the evidence and the above-mentioned factors this recommendation for fluconazole as the first choice of treatment for oropharyngeal candidiasis is rated as strong with moderate quality evidence.
12.5. Research gaps
More research is needed in the following areas:
Well-designed treatment trials to detect differences in not only clinical, but also mycological response and relapse rates;
Treatment and prevention of oropharyngeal candidiasis in HIV-infected children and adolescents;
Development of resistance to current treatments.
