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The clinical appearances of oral candidiasis vary. The most common presentations include pseudomembranous and erythematous candidiasis, which are equally predictive of the development of AIDS,(12) and angular cheilitis. These lesions may be associated with a variety of symptoms, including a burning mouth, problems eating spicy food, and changes in taste (Figure 1, Figure 2). All three of these common forms may appear in one individual.

Pseudomembranous Candidiasis (Thrush)

Characteristic creamy white, removable plaques on the oral mucosa are caused by overgrowth of fungal hyphae mixed with desquamated epithelium and inflammatory cells. The mucosa may appear red when the plaque is removed. This type of candidiasis may involve any part of the mouth or pharynx.

Erythematous Candidiasis

Erythematous candidiasis appears as flat, red patches of varying size. It commonly occurs on the palate and the dorsal surface of the tongue. Erythematous candidiasis is frequently subtle in appearance and clinicians may easily overlook lesions, which may persist for several weeks if untreated.

Angular Cheilitis

Angular cheilitis appears clinically as redness, ulceration, and fissuring, either unilaterally or bilaterally at the corners of the mouth. It can appear alone or in conjunction with another form of candidiasis.

Hyperplastic Candidiasis

This type of candidiasis is unusual in persons with HIV infection. The lesions appear white and hyperplastic. The white areas are due to hyperkeratosis and, unlike the plaques of pseudomembranous candidiasis, cannot be removed by scraping. These lesions may be confused with hairy leukoplakia. Diagnosis of hyperplastic candidiasis is made from the histologic appearance of hyperkeratosis and the presence of hyphae. Periodic acid-Schiff (PAS) stain is often used to demonstrate hyphae.

Erythematous candidiasis should be differentiated from other red lesions, such as Kaposi's sarcoma or erythroplakia. Histologically, oral candidiasis contains Candida hyphae in the superficial epithelium when viewed under a PAS stain. The inflammatory responses often associated with Candida infection may be absent in immunocompromised patients. The creamy white plaques of pseudomembranous candidiasis are removable; the white lesions of hairy leukoplakia are nonremovable.

Candida is a commensal organism in the oral cavity. Candidiasis is diagnosed by its clinical appearance and by detection of organisms on smears. Smears taken from clinical lesions are examined using potassium hydroxide (KOH), PAS, or Gram's stain. Smears are taken by gently drawing a wooden tongue depressor across the lesion. The specimen is then transferred into a drop of KOH on a glass slide and protected by a cover slip. The smear is examined under the microscope and Candida is detected by finding hyphae and blastospores. Hyphae and spores are only seen in smears from lesions and are rarely seen in the healthy individual in the carrier state. Cultures are grown on specific media, such as Sabouraud's agar; they may be positive and yet reveal very low colony counts. This probably represents a carrier state rather than active infection.(13) Culture is useful for establishing the Candida species but may not be useful for diagnosis.

Oral candidiasis may be treated either topically or systemically.(14) Treatment should be maintained for 7 days. Response to treatment is often good; oral lesions and symptoms may disappear in a fairly short period (ranging from 2 to 5 days), but relapses are common because of the underlying immunodeficiency. As with other causes of oral candidiasis, recurrences are common if the underlying problem persists.

Topical Treatment

Topical treatments are preferred because they limit systemic absorption, but the effectiveness depends entirely on patient compliance. Topical medications require that the patient hold medications in the mouth for 20 to 30 minutes. If the patient uses formulations containing sweetening agents for long periods, consider as concurrent treatment daily fluoride rinses (e.g., ACT or Fluorigard, available as over-the-counter preparations) for 1 minute once a day and then expectorated. Clotrimazole is an effective topical treatment (one oral troche [10-mg tablet]) when dissolved in the mouth five times daily. Used less frequently, one vaginal troche can be dissolved in the mouth daily. Nystatin preparations include a suspension, a vaginal tablet, and an oral pastille. Regimens are nystatin vaginal tablets (one tablet, 100,000 units, dissolved in the mouth three times a day), or nystatin oral pastille (available as a 200,000-unit oral pastille, one or two pastilles dissolved slowly in the mouth five times a day). Nystatin suspension has a high sugar content and cannot be held in the mouth long enough to be effective. Topical creams and ointments containing nystatin, ketoconazole, or clotrimazole may be useful in treating angular cheilitis. Another therapeutic choice is amphotericin B (0.1 mg/ml). Five to 10 ml of oral solution is used as a rinse and then expectorated three to four times daily.

Systemic Treatment

Several agents are effective for systemic treatment. Ketoconazole (Nizoral) is a 200-mg tablet taken with food once daily. Patient compliance is usually good. Careful monitoring of liver function is necessary for long-term use because of reported side effects, including hepatotoxicity. Lack of efficacy of ketoconazole may occur because of poor absorption in those with an abnormally high gastric pH. Fluconazole (Diflucan) is a triazole antifungal agent effective in treating candidiasis (100-mg tablet taken once daily for 2 weeks).(15) Several studies(15) suggest fluconazole is effective as a prophylactic agent, although the most effective prophylaxis dosing regimen is still unclear. Numerous reports,(16) however, describe oral and esophageal candidiasis failing to respond to treatment with fluconazole, and in some of these cases investigators isolated resistant strains.(16,17) Itraconazole (100-mg capsules) may be used for the treatment of oral candidiasis (200 mg daily orally for 14 days).(18) Itraconazole oral suspension is now available (200 mg daily for 2 weeks. Salivary levels of itraconazole are maintained for several hours after administration. Ketoconazole, fluconazole, and itraconazole may interact with other medications including rifampicin, phenytoin, cyclosporin A, terfenadine, digoxin, coumarin-like medications, and oral hypoglycemic medications.

Both erythematous and pseudomembranous oral candidiasis are associated with increased risk for the subsequent development of opportunistic infections classifying the patient as having AIDS as defined by the Centers for Disease Control (CDC).(19)Several studies have shown a statistical correlation between frequency of oral candidiasis in HIV infection and falling CD4+ T-cell counts.(20)

Recurrent herpes labialis occurs on the vermilion border of the lips. The patient may report a history of itching or pain, followed by the appearance of small vesicles. These rupture and form crusts. Recurrent intraoral herpes appears as clusters of painful small vesicles that rupture and ulcerate and usually heal within 1 week to 10 days. The lesions usually occur on the keratinized mucosa, such as the hard palate and gingiva, although lesions may arise on the dorsal surface of the tongue.

Rising antibody titers from initial and convalescent sera confirm primary herpetic gingivostomatitis. Examining smears of lesions (treated with Papanicolaou stain) for multinucleated giant cells confirms recurrent herpes. It is possible to demonstrate herpes simplex type 1 or type 2 by applying monoclonal antibodies to smears from the lesions (the Syva Kit, Syva Corporation, Palo Alto, CA).(23) Swabs taken from fluid-filled vesicles may grow herpes simplex in culture if vesicles are a few days or less old. Clinicians can distinguish between recurrent intraoral herpes simplex lesions, which always occur on keratinized mucosa (such as the hard palate and gingiva), and recurrent aphthous ulcers, which always appear on nonkeratinized mucosa. Recurrent intraoral herpes may appear more frequently in HIV-infected patients. The lesions may be painful and slow to heal.

No treatment will permanently eradicate oral herpes simplex infections, but acyclovir may shorten the healing time for individual episodes. The optimum oral dosage of acyclovir is 1,000 to 1600 mg daily for 7 to 10 days. Topical acyclovir is not useful for treating intraoral lesions and may not be effective for lesions on the lips. Recurrent outbreaks of acyclovir-resistant herpes have been reported, including a case involving the facial skin, lips, nose, and mouth. In this case, the lesions resolved after treatment with foscarnet.(24) Phosphonoformate may also prove effective.

There is no known association between recurrent intraoral herpes and more rapid progression of HIV disease. However, there is a clinical impression that recurrent herpes simplex infections may be more common in patients with symptomatic HIV disease.(25)

Oral herpes zoster generally causes skin lesions. Following a prodrome of pain, multiple vesicles appear on the facial skin, lips, and oral mucosa. Skin and oral lesions are frequently unilateral and follow the distribution of the maxillary and/or mandibular branches of the trigeminal nerve. The skin lesions form crusts and the oral lesions coalesce to form large ulcers. The ulcers frequently affect the gingiva, so tooth pain may be an early complaint.

The appearance of the lesions and their distribution are pathognomonic.

Acyclovir limits the duration of the lesions. For herpes zoster, the standard oral dosage is 800 mg five daily for 7 to 10 days, which is considerably higher than that recommended for treatment of herpes simplex.

HPV lesions in the oral cavity may appear as solitary or multiple nodules. They may be sessile or pedunculated and appear as multiple, smooth-surfaced raised masses resembling focal epithelial hyperplasia or as multiple, small papilliferous or cauliflower-like projections (Figure 3). I have identified HPV types 7, 13, and 32 in some of these oral warts.(26) Malignant transformation of HPV oral lesions has not been reported, but the identification of four new HPV types in these lesions warrants further study.

A biopsy is necessary for histologic diagnosis.

There is no known association between oral HPV lesions and more rapid progression of HIV disease, but oral warts are seen more commonly in HIV-infected persons than in the general population.

Oral HPV lesions can be removed surgically using local anesthetic. Carbon dioxide laser surgery can remove multiple flat warts, but relapses occur and several repeat procedures may be necessary.

Diagnosis of HL is an indication of both HIV infection and immunodeficiency; it is an indication for a work-up to evaluate and treat HIV disease. HL correlates with a statistical risk for more rapid progression of HIV disease. In an early study, 30% of persons with HL progressed to late-stage HIV disease characterized by CDC-defined AIDS within 36 months.(35) In a later study, 47% of a group developed CDC-defined AIDS within 2 years and 67% within four years.(40) Those persons with HL who progressed to CDC-defined AIDS most rapidly, however, were more often anergic to Candida antigen at diagnosis of HL, indicating significant immunosuppression at that time.(41) Progression to CDC-defined AIDS was more rapid in those HIV-infected persons with HL than in those without HL, even after adjustment for CD4+ T-cell count.(34)

The Epstein-Barr virus (EBV) in HL is both unusual in that deletions in the EBNA 2 gene have been described(42,43) and in that to date no viral DNA is found in the basal layers of HIV.(44,45) Intraepithelial Langerhans' cells (LCs) are reduced or absent in the HL lesion, which correlates with the presence of viral antigens.(46) It is not known whether the lack of LCs is a cause of HL or a consequence of EBV infection.

In electron microscopic specimens, investigators have found structures consistent with a herpes group virus.(42) One structure consisted of 100-nm intranuclear virions and 240-nm encapsulated virus particles. Other structures are 48- to 52-nm particles visible in the suprabasal layer.(47) Closer to specimen surfaces, where the nuclei are more condensed, arrays of these particles and herpes group particles occurred in the same cell.(48) Several studies described the appearance of these particles in HL biopsies.(49,50)

HL lesions vary in size and appearance and may be unilateral or bilateral. The surface is irregular and may have prominent folds or projections, sometimes markedly resembling hairs. Occasionally, however, some areas may be smooth and flat. Lesions occur most commonly on the lateral margins of the tongue and may spread to cover the entire dorsal surface (Figure 4, Figure 5). They may also spread downward onto the ventral surface of the tongue, where they usually appear flat. HL lesions can also occur on the buccal mucosa, generally as flat lesions.(48) Rarely, lesions occur on the soft palate.(51) HL usually does not cause symptoms.

Candida albicans may be found in association with many HL lesions, and hyphae can be seen in specimens taken from lesions and examined using potassium hydroxide. Hyphae can be seen in sections stained with periodic acid-Schiff. Administration of antifungal drugs may change the appearance of the lesions but does not cause them to disappear. Clinicians must distinguish them from other white lesions, such as lichen planus, idiopathic leukoplakia, white sponge nevus, dysplasia, and squamous cell carcinoma.

HL should be diagnosed by biopsy for definitive diagnosis. Experienced clinicians can make a presumptive diagnosis of HL in association with HIV disease from the clinical appearance, although HL can be confused with oral candidiasis. The typical microscopic appearance of HL includes acanthosis, marked parakeratosis with the formation of ridges and keratin projections, areas of ballooning cells, and little or no inflammation in the connective tissue. The ballooning changes resemble koilocytosis. Cells are enlarged; some contain enlarged ballooning cells with pyknotic nuclei. Some contain perinuclear haloes.

Definitive diagnosis of HL requires demonstration of EBV.(52) EBV may be readily demonstrated in biopsy specimens by a variety of techniques.(42) Cells taken from the HL lesion by scraping can be used for a noninvasive diagnosis using in situ hybridization.(43)

Hairy leukoplakia usually is asymptomatic and does not require treatment. HL is almost always a manifestation of HIV infection, and clinicians should arrange evaluation of HIV disease and appropriate treatment for patients with HL. HL has disappeared in patients receiving high-dose acyclovir for herpes zoster, presumably because of the anti-EBV activity of acyclovir.(53,54) Doses of acyclovir (2.5 to 3 mg per day for 2 to 3 weeks) usually eliminate HL, but the lesion usually recurs with cessation of treatment.

Elimination or almost complete clinical resolution of the lesion has occurred in patients treated with agents such as desciclovir, an analog of acyclovir,(55) phosphonoformate, Retin A, and podophyllin resin, although lesions tend to recur within a few months. Case reports describe HL disappearing during treatment with ganciclovir, zidovudine, and aerosolized pentamidine.(56) Katz and colleagues have shown that HL both appears and disappears in patients receiving zidovudine,(56) although no case-controlled studies are available.

Occasionally, Candida albicans may be found in HL lesions. Treatment consists of antifungal medications.

LGE and NUP often occur in clean mouths where there is very little plaque or calculus to account for the gingivitis. The onset is often sudden, with rapid loss of bone and soft tissue. In LGE, the gingiva may be reddened and edematous (Figure 6). Patients sometimes complain of spontaneous bleeding. In acute-onset ulcerative gingivitis, ulcers occur at the tips of the interdental papilla and along the gingival margins, and often elicit complaints of severe pain. The ulcers heal, leaving the gingival papillae with a characteristic cratered appearance.

NUP may present as rapid loss of supporting bone and soft tissue. Typically, these losses occur simultaneously with no formation of gingival pockets, sometimes involving only isolated areas of the mouth. Teeth may loosen and eventually fall out, but uninvolved sites can appear healthy.(61) Necrotizing stomatitis may develop, and areas of necrotic bone may appear along the gingival margin. The bone may eventually sequestrate. Patients with NUP and necrotizing stomatitis frequently complain of extreme pain and spontaneous bleeding.(62)

The patient's history and clinical appearance make the diagnosis. It is sometimes difficult to distinguish this type of periodontal disease from non-HIV-related periodontal disease. However, the complaints of severe pain, rapid onset, and rapid destruction in an often extremely clean mouth are unusual for non-HIV-related periodontal disease.

Clinicians should refer patients to a periodontist or dentist for management. The following protocol has achieved reasonable success: plaque removal, local debridement, irrigation with povidone-iodine, scaling and root planing, and maintenance with a chlorhexidine mouth rinse (Peridex-R) once or twice daily. Studies show that the addition of chlorhexidine to this regimen produces significant improvement in periodontal condition. In cases of NUP, metronidazole (one 250-mg tablet four times daily), amoxicillin/clavulanate (Augmentin)(one 250-mg tablet three times daily), or clindamycin (one 300-mg tablet three times daily) should be added to the treatment regimen.(63,64)

The microbiology(65) of periodontal disease in HIV-infected patients has not been fully described.(63) Oral flora associated with LGE and NUP appear to be similar to those associated with periodontal disease seen in non-HIV-infected persons. Recurrences of acute episodes are common and response to conventional treatment may be poor. However, therapeutic strategies and frequent recall appointments can produce effective local treatment of LGE and NUP.(64) There is as yet no known relationship between these conditions and the progression of HIV disease.

KS can appear as a red, blue, or purplish lesion. It may be flat or raised, solitary or multiple. The most common oral site is the hard palate, but lesions may occur on any part of the oral mucosa, including the gingiva, soft palate, and buccal mucosa (Figure 7), and in the oropharynx. Occasionally, yellowish mucosa surrounds the KS lesion. Oral KS lesions may enlarge, ulcerate, and become infected. Good oral hygiene is essential to minimize these complications.

KS must be distinguished from vascular lesions such as hematomas, hemangiomas, other vascular tumors, pyogenic granulomas, bacillary angiomatosis,(69) and pigmented lesions such as oral melanotic macules. Diagnosis is made from histologic examination.(70,71) There are usually no bleeding problems associated with a biopsy of oral KS. However, aspiration of a lesion prior to biopsy may be useful to rule out a hemangioma. Small, flat lesions are probably in early stages, and the histologic appearance is different from the larger, nodular lesions that are probably more advanced. Early lesions may be difficult to diagnose histologically because they resemble endothelial proliferation. KS may appear suddenly, within days of a normal oral examination, in previously uninvolved areas of the mouth.

Providers should ensure that a patient with KS receives evaluation and follow-up care for the underlying HIV disease.(68)

Treatment is determined on the basis of the number, size, and location of the oral KS lesions. The choice of therapy depends on the effect of treatment on the adjacent mucosa, pain associated with treatment, interference with eating and speaking, and the patient's preference. It is important to perform thorough dental prophylaxis before initiating therapy for KS lesions involving the gingiva. Response to therapy is improved if all local plaque and calculus are removed. Local application of sclerosing agents may reduce the size of oral lesions.(72)

Local treatment is appropriate for large oral KS lesions that interfere with eating and talking.(72,73) Oral KS can be treated surgically or with localized intralesional chemotherapy. Surgical removal is suitable for small, well-circumscribed lesions such as gingival or tongue lesions. Surgical removal can be performed under local anesthesia with a blade or with the carbon dioxide laser. Intralesional vinblastine is useful for treating small lesions, particularly on the palate or gingiva. Several studies have documented the effectiveness of one or two injections of 0.1 to 0.2 mg per ml solution of vinblastine. Posttreatment pain is fairly common, but systemic effects are rare.(73) The pain usually disappears several days after therapy.

Radiation therapy may be indicated for large, multiple lesions.(70) A single dose of 800 cGy or an equivalent fractionated dose is frequently used and produces a good response. Side effects include xerostomia and mucositis,(74) although both conditions usually improve with cessation of radiation therapy.

The ulcers may present a diagnostic problem. Herpetiform RAUs may resemble the lesions of coxsackievirus infection, and major RAUs may require biopsy to exclude malignancy, such as lymphoma, or opportunistic infection, such as histoplasmosis. The ulcers usually occur on nonkeratinized mucosa; this characteristic differentiates them from those caused by herpes simplex.

The RAU type ulcers usually respond well to topical steroids such as fluocinonide (0.05%) ointment mixed with equal parts Orabase applied six times daily or clobetasol (0.05%) ointment mixed with equal parts Orabase applied three times per day. Dexamethasone elixir (0.5 mg/5 ml) used as a mouth rinse and then expectorated two to three times daily is helpful for multiple ulcers and for those where topical ointments are hard to apply.(81) For HIV-infected persons with oral and gastrointestinal aphthous-like ulcers, systemic steroid therapy (prednisone 40 to 60 mg/day for 7 to 10 days) has been reported as helpful.(82) The risks of steroid therapy, however, must be considered before administration to individuals in this population. Thalidomide (50 to 200 mg) has been used in Europe and is the subject of clinical trials in the United States (ACTG 251).(83)

Petechiae, ecchymoses, and hematoma can occur anywhere on the oral mucosa. Spontaneous bleeding from the gingiva can occur, and patients may report finding blood in their mouths on waking.

The clinician must distinguish ITP from other vascular lesions and KS. Because of potential bleeding risk, the clinician should obtain blood and platelet counts before performing other diagnostic procedures. (Treatment and prognostic significance are discussed elsewhere.)

Removal of the enlarged parotid glands is rarely recommended. For individuals with xerostomia, the use of salivary stimulants such as sugarless gum or sugarless candies may provide relief. Candies that are acidic should be avoided as frequent use may lead to loss of tooth enamel. The use of salivary substitutes may also be helpful. An increase in caries can occur, so fluoride rinses (that can be bought over the counter) should be used daily, and visits to the dentist should occur two to three times per year.