Oral Manifestations of HIV Disease

Perspective – Oral Manifestations Volume 13 Issue 5 December 2005/January 2006

Perspective Oral Manifestations of HIV Disease

HIV-related oral conditions occur in a large proportion of patients, and fre- incidence of oral ulcers. quently are misdiagnosed or inadequately treated. Dental expertise is nec- Some of the oral conditions encoun- essary for appropriate management of oral manifestations of HIV infection tered in HIV-infected individuals are or AIDS, but many patients do not receive adequate dental care. Common discussed below. A good resource for or notable HIV-related oral conditions include xerostomia, candidiasis, oral information on these and other condi- hairy leukoplakia, periodontal diseases such as linear gingival erythema tions is www.hivdent.org. and necrotizing ulcerative periodontitis, Kaposi’s sarcoma, human papilloma virus-associated warts, and ulcerative conditions including herpes sim- Xerostomia plex virus lesions, recurrent aphthous ulcers, and neutropenic ulcers. This article summarizes a presentation on oral manifestations of HIV disease Xerostomia is a major contributing made by David A. Reznik, DDS, at the 8th Annual Clinical Conference for factor in dental decay in HIV-infected Ryan White CARE Act Clinicians in New Orleans in June 2005. individuals. More than 400 medications lead to symptoms of xerostomia. Approximately 30% to 40% of HIV- In 2000, US Surgeon General David HIV-related oral abnormalities are infected individuals experience mod- Satcher stated, “Those who suffer the present in 30% to 80% of HIV-infected erate to severe xerostomia in associa- worst oral health include poor individuals, and these abnormalities are tion with the effects of medications Americans. Members of racial and eth- often inaccurately described in medical (eg, didanosine) or the proliferation of nic groups also experience a dispro- care. Rates of treatment for oral condi- CD8+ cells in the major salivary portionate level of oral health prob- tions are also very low; findings in 1424 glands. Changes in the quantity and lems. And people with disabilities and adults in the AIDS Cost and Utilization quality of saliva, including diminished complex health conditions are at Study indicated that only 9.1% received antimicrobial properties, lead to rapid- greater risk for oral diseases that, in treatment for oral manifestations of HIV ly advancing dental decay and peri- turn, further complicate their health.” disease (Mascarenhas, Oral Surg Oral odontal disease (Figure 1). Dental expertise is necessary for Med Oral Pathol Oral Radiol Endod, Use of crystal methamphetamine is proper management of oral complica- 1999). Factors predictive of receiving associated with increased risk of HIV tions in HIV infection or AIDS. Medical oral care included education beyond a acquisition, and its use by infected clinicians should be able to recognize high school level, participation in clin- individuals can be associated with HIV-associated oral disease and to pro- ical trials, and utilization of support rapid dental decay known as “meth vide appropriate care and referral. services such as medical social work- mouth” (Figure 2). The primary factor Factors that predispose to HIV-related ers. African-Americans and Hispanic- in this condition is probably xerosto- oral conditions include CD4+ cell Americans were significantly less like- mia, with contributions from bruxism, count of less than 200/µL, plasma HIV- ly to receive treatment than were poor diet, sugar cravings, and the cor- RNA levels greater than 3000 white patients. The overall prevalence rosive constituents of crystal metham- copies/mL, xerostomia, poor oral of oral manifestations of HIV disease phetamine—ie, lithium, muriatic and hygiene, and smoking. For individuals has changed since the advent of sulfuric acids, and lye. with unknown HIV status, oral mani- potent antiretroviral therapy. One festations may suggest possible HIV study by Patton and colleagues noted Candidiasis infection, although they are not diag- a reduction of oral lesions from 47.6% nostic of infection. For persons living pre-potent antiretroviral therapy to The 3 common presentations of oral with HIV disease who are not yet on 37.5% during the potent antiretroviral candidiasis are angular cheilitis, ery- therapy, the presence of certain oral therapy era (Oral Surg Oral Med Oral thematous candidiasis, and pseu- manifestations may signal progression Pathol Oral Radiol Endod, 2000). domembranous candidiasis. of HIV disease. For patients on Overall, there appears to be a reduced Angular cheilitis presents as ery- antiretroviral therapy, the presence of incidence of candidiasis, Kaposi’s sar- thema or fissuring of the corners of certain oral manifestations may signal coma, oral hairy leukoplakia, and the mouth (Figure 3). It can occur with an increase in the plasma HIV-1 RNA necrotizing ulcerative periodontitis; an or without erythematous or pseu- level. increased incidence of salivary gland domembranous candidiasis, and can disease, oral warts, and dental caries persist for an extensive period of time Dr Reznik is the Chief of Dental Services at in the form of “brittle teeth syn- if left untreated. Treatment involves Grady Health Systems in Atlanta, Georgia. drome;” and a relatively unchanged the use of a topical antifungal cream

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applied directly to the affected areas 4 Table 1. Topical and Systemic Agents for Oral Candidiasis times a day for the 2-week treatment period. Topical agents (mild to moderate oral candidiasis) Erythematous candidiasis may be Clotrimazole troches 10 mg: Dispense 70, dissolve 1 troche in mouth 5 the most underdiagnosed and misdiag- times a day for 14 days nosed oral manifestation of HIV dis- Nystatin oral suspension 500,000 units: Swish 5 mL in mouth as long as possi- ease. The condition presents as a red, ble then swallow (optional), 4 times a day for 14 days flat, subtle lesion on the dorsal surface of the tongue or on the hard or soft Nystatin pastilles 100,000 units: Dispense 56, dissolve 1 in mouth 4 palates (Figure 4). It may present as a times a day for 14 days “kissing” lesion—if a lesion is present on the tongue, the palate should be Systemic agents examined for a matching lesion, and Fluconazole 100 mg: Dispense 15 tablets, take 2 tablets on day 1, vice versa. The condition tends to be followed by 1 tablet a day for the remainder of the symptomatic, with patients complain- ing of oral burning, most frequently 14-day treatment period while eating salty or spicy foods or Itraconazole oral suspension 10 mg/10 mL: Dispense 140 mL, swish and swallow drinking acidic beverages. Clinical diag- 10 mL per day for 7 to 14 days. Take medication nosis is based on appearance, as well without food as on the patient’s medical history and Voriconazole 200 mg: Dispense 14 tablets, take 1 tablet twice daily virologic status. The presence of fungal for 2 weeks or at least 7 days following resolution of hyphae or, more likely, blastospores symptoms can be confirmed by performing a potassium hydroxide (KOH) prepara- Drug interactions tion. Contraindications: rifampin, rifabutin, ritonavir, and efavirenz (all are potent CYP450 Pseudomembranous candidiasis (or inducers). Drug interactions are most significant with voriconazole and present with thrush) appears as creamy, white, curd- itraconazole oral suspension, but less critical with fluconazole like plaques on the buccal mucosa, tongue, and other oral mucosal sur- faces. The plaques can be wiped away, of fluconazole resistance (Table 1). on the lateral borders of the tongue; typically leaving a red or bleeding Figure 6A shows disease with flucona- the lesion cannot be wiped away underlying surface. The most common zole-resistant Candida albicans; its (Figure 7). There has been a marked organism involved is Candida albicans; attachment to tissue is stronger, and it decrease in the incidence of oral however, there are increasing reports of is more difficult to wipe away than hairy leukoplakia in the potent involvement of non-albicans species. As azole-susceptible candidiasis. Figure 6B antiretroviral era. This condition is with erythematous candidiasis, diagno- shows disease due to Candida glabrata, normally asymptomatic and does sis is based on appearance. Figure 5A which is intrinsically azole-resistant. not require therapy unless there are shows a mild to moderate case; Figure Factors associated with azole-resistant cosmetic concerns. However, it is 5B shows more severe disease. disease include prior exposure to important to note that the condition Topical treatments for mild to mod- azoles, low CD4+ cell count, and pres- is observed with immune deteriora- erate cases of both erythematous and ence of non-albicans species. tion and that patients presenting pseudomembranous candidiasis The primary lesson to be learned in with it while on antiretroviral thera- include clotrimazole troches, nystatin the treatment of any candidiasis— py may thus be experiencing failure oral suspension, and nystatin pastilles whether it be with a topical agent for of their current regimen. (Table 1). It should be noted that the mild to moderate disease or a systemic common nystatin oral suspension con- agent for more severe disease—is that Periodontal Disease tains 50% sucrose, which is cariogenic; treatment must be continued for at this is less of a potential problem if flu- least 2 weeks in order to reduce organ- Linear gingival erythema oride is prescribed along with the nys- ism colony-forming units to levels low tatin. The clotrimazole oral treatment is enough to prevent recurrence. Linear gingival erythema, or “red formulated with fructose, which is less band gingivitis,” presents as a red cariogenic. Systemic agents for moder- Oral Hairy Leukoplakia band along the gingival margin and ate to severe disease consist of flucona- may or may not be accompanied by zole, the most widely used drug; itra- Oral hairy leukoplakia, which is occasional bleeding and discomfort conazole; and voriconazole, the latter caused by Epstein-Barr virus, pre- (Figure 8). It is seen most frequently in of which should be reserved for cases sents as a white, corrugated lesion association with anterior teeth, but

144 Perspective – Oral Manifestations Volume 13 Issue 5 December 2005/January 2006 commonly extends to the posterior Table 2. Management of Necrotizing teeth. It can also present on attached Ulcerative Periodontitis ment of warts may be related to and non-attached gingiva as petechia- immune reconstitution. The warts like patches. Some data indicate a rela- Initial visit may be cauliflower-like, spiked, or tionship between sub-gingival colo- raised with a flat surface (Figure 11). nization of Candida species and •Prescribe narrow spectrum antibiotics Treatment may involve surgery, laser HIV-related periodontal conditions such as metronidazole 500 mg, dispense surgery, or cryotherapy. It should be including linear gingival erythema. 14 to 20 tablets, take 1 tablet twice noted that HPV survives in aerosol. The most recent American Academy daily for 7 to 10 days. Other antibiotic Topical 5-fluorouracil treatment has of Periodontology classification of options include clindamycin and amoxi- been used on external lesions, but periodontal diseases groups linear gin- cillin should be avoided in African- gival erythema under “gingival disease • Pain management is extremely impor- American patients since it can cause of fungal origin.” However, antifungals tant hyperpigmentation. It should be typically are not needed for treatment. • Nutritional supplementation or counsel- noted, however, that this is a special- Treatment includes debridement by a ing may be necessary ized treatment and should only be dental professional, twice-daily rinses used by those experienced with the with a 0.12% chlorhexidine gluconate Follow-up visits use of this topical medication. Lesions suspension for 2 weeks, and improved tend to recur after treatment. home oral hygiene. • Detailed periodontal care, such as scaling and root planing Ulcerative Diseases Necrotizing Ulcerative Periodontitis Kaposi’s sarcoma can be macular, Herpes simplex virus nodular, or raised and ulcerated, with Although necrotizing gingivitis and color ranging from red to purple Herpes simplex virus (HSV)-1 infection necrotizing periodontitis may reflect (Figure 10); early lesions tend to be is widespread and oral lesions are the same disease entity, they are dif- flat, red, and asymptomatic, with the common. Recurrent intraoral HSV out- ferentiated by the rapid destruction of color becoming darker as the lesion breaks start as a small crop of vesicles soft tissue in the former condition and ages. Diagnosis is frequently missed that rupture to produce small, painful hard tissue in the latter. Necrotizing in African-American patients due to ulcerations that may coalesce. Lesions ulcerative periodontitis is a marker of lesion coloration. Progressing lesions on the lip are fairly easy to recognize. severe immune suppression. The con- can interfere with the normal func- In the mouth, lesions on keratinized, dition is characterized by severe pain, tions of the oral cavity and become or fixed, tissues, including the hard loosening of teeth, bleeding, fetid symptomatic secondary to trauma palate and gums, should prompt sus- odor, ulcerated gingival papillae, and or infection. Definitive diagnosis picion of HSV infection (Figure 12). rapid loss of bone and soft tissue requires biopsy. Treatment ranges Herpetic ulcerations are often self-lim- (Figure 9). Patients often refer to the from localized injections of iting, although the use of an antiviral pain as “deep jaw pain.” Treatment chemotherapeutic agents, such as medication such as acyclovir is some- includes removal of dental plaque, cal- vinblastine sulfate, to surgical times necessary to control the out- culus, and necrotic soft tissues utiliz- removal. Oral hygiene must be break. ing a 0.12% chlorhexidine gluconate stressed. Systemic chemotherapy or 10% povidone-iodine lavage, and may be the treatment of choice for Aphthous ulcerations institution of antibiotic therapy (Table patients with extraoral and intraoral 2). Pain management is crucial, as is Kaposi’s sarcoma. Recurrent aphthous ulcerations appear attention to nutrition in these patients. on non-keratinized, or non-fixed, tis- Timely referral to primary care is indi- Oral Warts—Human Papilloma sues, such as the labial or buccal cated to rule out other systemic oppor- Virus mucosa, floor of the mouth, ventral sur- tunistic infections. face of the tongue, posterior orophar- The incidence of oral warts due to ynx, and maxillary and mandibular Kaposi’s Sarcoma human papillomavirus (HPV) has dra- vestibules (Figure 13). Their cause is matically increased in the potent unknown. The lesions are character- Kaposi’s sarcoma is still the most fre- antiretroviral therapy era. Studies at ized by a halo of inflammation and a quent HIV-associated oral malignancy, the author’s institution indicate that yellow-gray pseudomembranous cov- although its incidence has dramatically the risk of HPV-associated oral warts is ering. They are very painful, especial- decreased in the potent antiretroviral associated with a 1-log10 or greater ly during consumption of salty, spicy, therapy era. Kaposi’s sarcoma-associ- decrease in plasma HIV RNA level or acidic foods and beverages, or ated herpesvirus (KSHV) has been within the 6 months prior to oral HPV hard or rough foods. In immunocom- identified as the etiologic agent. diagnosis, suggesting that the develop- promised patients, these lesions tend

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Figure 1. Cervical caries occurring in associ- Figure 5a. Pseudomembranous candidia- Figure 8. Linear gingival erythema. ation with xerostomia. sis—mild or moderate disease.

Figure 2. Dental decay in less than 1 year Figure 5b. Pseudomembranous candidia- Figure 9. Necrotizing ulcerative periodonti- (from left to right) with “meth mouth.” sis—more severe disease. tis.

Figure 3. Angular cheilitis. Figure 6a. Oral candidiasis due to flucona- Figure 10a. Kaposi’s sarcoma. zole-resistant Candida albicans.

Figure 4a. Erythematous candidiasis. Figure 6b. Oral candidiasis due to flucona- Figure 10b. Kaposi’s sarcoma. zole-resistant Candida glabrata.

Figure 4b. Erythematous candidiasis. Figure 7. Oral hairy leukoplakia. Figure 11a. HPV-associated warts.

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the cause of this increase in frequency remains unknown. Large, unusual- looking, or fulminant ulcers in the oral cavity that cannot otherwise be identified or explained should prompt suspi- cion of this condition. Patients should receive granulocyte colony-stimulating factor treatment prior to systemic or topical steroid treatment, depending Figure 11b. HPV-associated warts. Figure 13b. Aphthous ulceration. on the size and location of the lesion.

Pain in ulcerative disease

Pain management is a crucial compo- nent of treating ulcerative oral diseases. Pain usually is treated with topical anesthetics or systemic analgesics. However, relief provided by topical anesthetics is usually of short dura- tion. Furthermore, anesthetic mouth rinses numb the taste buds, resulting Figure 11c. HPV-associated warts. Figure 14a. Neutropenic ulcerations in a in a decreased desire to eat, and patient before therapy. diminished nutritional intake can have a significant negative impact on overall well-being for many patients. Systemic analgesics are also some- what effective, but do not specifically address localized pain. One product that has been found to be effective in ulcer pain control is a rinse composed of polyvinylpyrrolidone, hyaluronic acid, and glycyrrhetinic acid. If other topical treatments are to be used (eg, Figure 12a. HSV-1 lesion. Figure 14b. Neutropenic ulcerations in the topical steroids), they should be patient shown in Figure 14a after therapy. applied prior to use of this rinse, since to persist for longer than the 7- to 14- the barrier formed by the product will day period observed in immunocom- prevent penetration of the other topi- petent individuals. Treatment for cal medications. milder cases involves the use of topical corticosteroids such as dexametha- Conclusion sone elixir (0.5 mg/5 mL) 5 mL swished for 1 minute and then Oral conditions seen in association expectorated, 2 to 3 times daily until with HIV disease are still quite preva- symptoms resolve. For more severe lent and clinically significant. A thor- occurrences, systemic corticosteroids ough examination of the oral cavity Figure 12b. HSV-1 lesion. such as prednisone are used. can easily detect most of the common lesions. An understanding of the Neutropenic ulcerations recognition, significance, and treatment of said lesions by primary health Neutropenic ulcerations are very care providers is essential for the painful ulcerations that can appear on health and well-being of people living both keratinized and non-keratinized with HIV disease. tissues, and are associated with abso- lute granulocyte counts of less than Presented by David A. Reznik, DDS, in June 800/µL (Figure 14). These lesions are 2005. First draft prepared from transcripts being found with increasing frequency by Matthew Stenger. Reviewed and edited by Figure 13a. Aphthous ulceration. in the HIV-infected population, although Dr Reznik in November 2005.

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Financial Disclosure: Dr Reznik has received Glick M, Muzyka BC, Salkin LM, Lurie D. McDowell MA and Centers for Disease Control and grant and research support from and served Necrotizing ulcerative periodontitis: a marker Prevention National Center for Health Statistics. as a consultant to or is on the speakers’ for immune deterioration and a predictor for the 1996 update: The Third National Health and bureau of Bristol-Myers Squibb and Colgate diagnosis of AIDS. J Periodontol. 1994;65:393- Nutrition Examination Survey (NHANES III). Oral Pharmaceuticals. 397. Available at: http://www.nal.usda.gov/fnic/food- comp/conf/NDBC21/p3-2.pdf. Accessed: May 26, Greenspan D, Canchola AJ, MacPhail LA, Cheikh 2005. Suggested Reading B, Greenspan JS. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet. Patton LL, McKaig R, Strauss R, Rogers D, Eron Aguirre JM, Echebarria MA, Ocina E, Ribacoba 2001;357:1411-1412. JJ, Jr. Changing prevalence of oral manifestations L, Montejo M. Reduction of HIV-associated oral of human immuno-deficiency virus in the era of lesions after highly active antiretroviral therapy. King MD, Reznik DA, O'Daniels CM, Larsen NM, protease inhibitor therapy. Oral Surg Oral Med Oral Surg Oral Med Oral Pathol Oral Radiol Osterholt D, Blumberg HM. Human papillo- Oral Pathol Oral Radiol Endod. 2000;89:299-304. Endod. 1999;88:114-115. mavirus-associated oral warts among human immunodeficiency virus-seropositive patients in Powderly WG, Mayer KH, Perfect JR. Diagnosis Arendorf TM, Bredekamp B, Cloete CA, Sauer G. the era of highly active antiretroviral therapy: an and treatment of oropharyngeal candidiasis in Oral manifestations of HIV infection in 600 emerging infection. Clin Infect Dis. 2002;34:641- patients infected with HIV: a critical reassess- South African patients. J Oral Pathol Med. 648. ment. AIDS Res Hum Retroviruses. 1999;15:1405- 1998;27:176-179. 1412. Kutcher MJ, Ludlow JB, Samuelson AD, Baillargeon J, Deng JH, Hettler E, et al. Campbell T, Pusek SN. Evaluation of a bioadhe- Tappuni AR, Fleming GJ. The effect of antiretro- Seroprevalence of Kaposi's sarcoma-associated sive device for the management of aphthous viral therapy on the prevalence of oral manifes- herpesvirus infection among blood donors from ulcers. J Am Dent Assoc. 2001;132:368-376. tations in HIV-infected patients: a UK study. Oral Texas. Ann Epidemiol. 2001;11:512-518. Surg Oral Med Oral Pathol Oral Radiol Endod. Lamster IB, Grbic JT, Mitchell-Lewis DA, Begg 2001;92:623-628. Cartledge JD, Midgley J, Gazzard BG. Non-albi- MD, Mitchell A. New concepts regarding the cans oral candidosis in HIV-positive patients. J pathogenesis of periodontal disease in HIV Yeung SC. HIV infection and periodontal disease. Antimicrob Chemother. 1999;43:419-422. infection. Ann Periodontol. 1998;3:62-75. Ann R Australas Coll Dent Surg. 2000;15:331-334.

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