8.1. Background
8.1.1. Epidemiology
Dermatophytes, specifically trichophyton, epidermophyton and microsporum species, are responsible for most superficial fungal infections (Weitzman & Summerbell, 1995). The term “tinea” refers exclusively to dermatophyte infections. Tinea infections are classified according to the affected body site, such as tinea capitis (scalp), tinea barbae (beard area), tinea corporis (skin other than bearded area, scalp, groin, hands or feet), tinea cruris (groin, perineum and perineal areas), tinea pedis (feet), tinea manuum (hands) and tinea unguium (nails).
Tinea infections are seen throughout the world, with a higher prevalence of tinea corporis in warmer and more humid conditions (Aly, 1994). It is estimated that 10% to 20% of the world’s population is affected by fungal skin infections (Drake et al.,1996).
Tinea infections are common in HIV-infected patients; however, the incidence has not been found to be higher in HIV-infected people compared to those who are HIV uninfected. Dermatophyte infections in HIV-infected populations are often more severe and may have an unusual presentation (Coldrion & Bergstresser, 1989).
8.1.2. Clinical features
Tinea corporis, tinea cruris, tinea pedis (all dermatophyte infections of the skin), tinea unguium (infection of nails) and tinea capitis (infection of scalp hair) all occur in patients with HIV infection.
Tinea pedis, the most common type of dermatophytosis in patients with symptomatic HIV disease, is usually manifested by typical interdigital maceration with scaling and diffuse hyperkeratosis of the sole.
Tinea cruris presents as an expanding scaling plaque of the upper thighs and groin, with central clearing and an erythematous elevated border. In HIV-infected patients, tinea corporis is often an extension of infection from the groin to the trunk. In severely immunosuppressed patients the lesions may have little inflammation and lack the typical elevated border and central clearing of tinea.
Infection of the nail is common in HIV-infected individuals. The nails often appear discoloured; they may be thickened and brittle. Nail infection has been associated with advanced HIV disease and considered a clinical marker of HIV infection (Weismann et al., 1988).
8.2. Recommendations
In children and adults (including pregnant women) with tinea infections that are not extensive, topical treatment with terbinafine 1% cream/gel (for two weeks) or miconazole (for three to four weeks) should be initiated.
(Strong recommendation, low quality evidence)
In children and adults (see comment below regarding pregnant women) with extensive tinea infections or hair/nail involvement, oral griseofulvin should be considered.
(Conditional recommendation, very low quality evidence)
If there is no response, then oral terbinafine or itraconazole should be used.
(Conditional recommendation, very low quality evidence)
In children and adults having tinea infections with unknown HIV status, an HIV test should be offered (see
SECTION 3).
(Strong recommendation, low quality evidence)
Remarks
A variety of topical antifungals are considered efficacious. Topical miconazole and topical terbinafine are listed in the recommendations specifically as they are part of the WHO Model list of essential medicines.a
Griseofulvin
Griseofulvin may be used in children aged 2 years and older.
Griseofulvin should be avoided in pregnancy as it may be teratogenic. It is labeled as a Pregnancy Category C drug. There is no evidence of excretion into human milk.
Other side effects of griseofulvin include gastrointestinal upsets (which may be reduced by administration with food) and photosensitivity in some patients.
Ointment preparations are preferred for thickened, hyperkeratotic lesions. Lotions and solutions are preferred for intertriginous areas and hairy areas of the body, and also appropriate for treating moist, oozy, weepy lesions. Cream formulations are beneficial in the treatment of scaling, non-oozing lesions.
These recommendations apply to HIV-negative children and adults as well.
8.3. Review question and summary of evidence
The PICO question considered was: in HIV-infected adults and children with tinea infections (either receiving or not receiving ART) (P), does treatment with topical antifungals such as terbinafine, naftifine, azoles, allylamines and benzylamines and oral antifungals such as griseofulvin, terbinafine and itraconazole (I) compared to no intervention or any of the individual antifungals or combined with corticosteroids (C) lead to clinical cure or mycological cure (O).
A Cochrane review (El-Gohary et al., 2014) that examined this question included 129 studies comprising 18 086 participants over 18 years of age. Although all of the studies were RCTs, 27 had a placebo arm, 98 an active control treatment arm and four included both arms. A range of interventions was covered. Antifungals evaluated included azoles (e.g. ketoconazole 1%, miconazole 2%, clotimazole 1% and others), allylamines (terbinafine 1%, naftifine 1%), benzylamines (butenafine 1%), hydroxypyridones (ciclopirox olamine 1%), thiocarbamates (tolnaftate 1%) and others (griseofulvin, itraconazole, fluconazole and others). There was a clear over-representation of the azole group among the interventions evaluated. Participants living with HIV were not included in this review.
Almost all active interventions were effective at achieving mycological cure after two to four weeks compared to a placebo. There appeared to be little difference between active interventions in achieving this outcome, although duration of treatment varied. Clinical cure was also assessed in most studies, and similarly, most active interventions were superior when compared to placebo.
Direct comparisons of allylamines versus azoles show allylamines to be generally more efficacious. Trials directly comparing the two compounds demonstrate the superiority of allylamines. There is little evidence of superiority at two weeks, but this effect becomes detectable in outcomes taken six weeks after treatment begins and appears to remain at 12 weeks. Comparisons between different regimes of allylamines provided little evidence that any one regime is more effective than another.
The Cochrane Review (El-Gohary et al., 2014) compared active interventions for three treatment classes of antifungals (topical azoles, allylamines, benzylamines) and also azoles combined with corticosteroids. Few of the included studies assessed duration of treatment until clinical cure, and none of the studies included participants living with HIV infection. The results suggested that all achieved high mycological cure rates, with either very low or moderate quality of evidence supporting any difference in results. There was no difference in clinical cure rates between azoles and allylamines (RR 0.99; 95% CI 0.95 to 1.03; and RR 0.97; 95% CI 0.92 to 1.02) respectively, nor mycological cure between azoles and benzylamines (RR 1.01; 95% CI 0.94 to 1.07). Clinical cure slightly favoured azole and steroid combination treatments compared to azoles alone (RR 0.67; 95% CI 0.53 to 0.84), but there was no difference in mycological cure rate (RR 0.99; 95% CI 0.93 to 1.05).
Adverse effects were minimal and were mainly irritation and burning with no differences between active interventions and placebo, nor between different classes of treatment.
8.4. Rationale for recommendations
The evidence suggests that all classes of commonly-used topical antifungals achieve substantial mycological and clinical cure rates. However, there is currently not enough evidence to be able to determine if one particular class or individual topical antifungal is superior in terms of mycological and clinical cure. Topical miconazole and topical terbinafine are listed in the recommendations specifically as they are part of the WHO Model list of essential medicines.1 In addition, topical terbinafine may be more appealing as it requires fewer applications and a shorter duration of treatment, and there is widespread global availability of the intervention. Also, side effects of local antifungal creams are minimal. The recommendation of topical miconazole 2% or terbinafine 1% for non-extensive tinea corporis is therefore a strong recommendation.
The participants identified in the review were a fairly representative sample, and the GDG did not have any significant concerns about the directness of the evidence. Participants living with HIV were not included in this review. The evidence for the effectiveness of antifungal treatment of tinea infections is strong. However, in view of the more extensive and varied differences in clinical presentation of tinea infections in HIV-infected individuals, the evidence for the effects of these interventions may not be extrapolated directly to immunocompromised participants. The panel, therefore, decided to grade the evidence for HIV populations as low.
For treatment of extensive tinea infections, the panel favoured griseofulvin rather than terbinafine because of the latter’s higher cost. The recommendation was made conditional as a result.
Overall, the benefits of treatment would normally outweigh the potential harms, and this recommendation would probably be acceptable to key stakeholders. The cost of the various groups of antifungals that appear to achieve similar outcomes is not significantly different (see ANNEX 3).
Adverse effects, costs, availability and other implementation considerations
Griseofulvin is easily available at low cost and has a favorable safety profile. It may be used in children aged 2 years and older. However, griseofulvin should be avoided in pregnancy as it may be teratogenic and is labeled as a Pregnancy Category C drug. When used for treatment durations of up to eight weeks, laboratory monitoring is not necessary. Other side effects of griseofulvin include gastrointestinal upset (which may be reduced by administration with food) and photosensitivity in some patients.
Potential limitations for terbinafine and itraconazole include an increased potential for drug-drug interaction and possible hepatotoxicity if treatment duration is more than six weeks, although studies confirm that these are not common occurences. Another more practical limitation of terbinafine and itraconazole is their cost.
8.5. Research gaps
The gaps identified included:
Well-designed, prospective, blinded RCTs in HIV-infected adults and children to provide high quality evidence upon which to base clinical decision-making;
Establishment of a standardized outcome measure (e.g. time to resolution of the lesions or resolution after three months) to ensure studies are easier to compare.
Large RCTs to compare the effectiveness of topical amorolfine and butenafine in order to establish an alternative to oral treatments for toenail infections, in both HIV-infected and the general population.
Better formulations/vehicles for topical therapy for nail infections;
The effectiveness of specific oral antifungal drugs on specific dermatophytes, which would require future investigators to report the types of dermatophytes cultured at the last outcome assessment for the proportion of participants not cured;
Treatment doses and frequency for all antifungals, including griseofulvin, in the HIV-infected and general population;
Issues around development of resistance to drugs.
