Oral Manifestations
Current Oral Manifestations of HIV Infection
Mahvash Navazesh, DMD
Copyright 2001 Journal of the California Dental Association.
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The oral manifestations of human immunodeficiency virus infection have changed drastically since the introduction of the highly active anti-retroviral therapy (HAART) in developed countries. Recent studies have documented significant reductions in morbidity and mortality rates among HIV-infected patients on HAART. This article focuses on the latest information about the oral manifestations of HIV infection and will discuss the impact of HAART.
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The oral manifestations of human immunodeficiency virus infection have changed drastically since the introduction of the highly active anti-retroviral therapy (HAART) in developed countries.1-3 This therapy has been effective in suppressing plasma-HIV viral load below a detectable level and elevating CD4 cell counts.4 Recent cohort studies have documented significant reductions in morbidity and mortality rates among HIV-infected patients on HAART.5-12 This article will focus on the latest information about the oral manifestations of HIV infection and will discuss the impact of HAART on the prevalence of these conditions.
Oral Lesions
Much has been written during the past 20 years about the association between the HIV infection and different soft and hard tissue lesions involving the head and neck regions.13-20 Although most of the original publications are based on findings in homosexual men and male intravenous drug users, recent investigations focus on women and children born to HIV-infected mothers.21-26 A summary of oral lesions reported in HIV-infected children and adults is provided in Table 1.
Common Lesions in Adults
Chronic herpetic ulcers (Figure 1), oral hairy leukoplakia (Figure 2), and Kaposi’s sarcoma (Figure 3) have been identified as highly indicative of HIV infection in adults. candidiasis (Figure 4) and herpes zoster (Figure 5) infections are found to be strongly associated with HIV infection.27 Saliva gland pathology including parotid enlargement (Figure 6) is found in some infected adults.
Common Lesions in Children
In pediatric patients, HIV oral manifestations have been divided into three groups.26 The first group includes candidiasis, herpes simplex ulcers, linear gingival erythema, parotid enlargement, and recurrent aphthous ulcers. This group is considered commonly associated with pediatric HIV infection. The second group includes papilloma, xerostomia, and periodontal diseases that are less commonly associated with pediatric HIV infection. The third group includes lesions that are strongly associated with HIV infection in adults but are rarely seen in pediatric patients. This group includes Kaposi’s sarcoma, lymphoma, and oral hairy leukoplakia. More information on the oral manifestations of HIV infection and a picture gallery of clinical presentations are available at http://www.hivdent.org.
Association with Immunosuppression and Relevance to Disease Progression
HIV disease progression is monitored by two key plasma markers: CD4 cell counts and HIV viral loads. Little is known about the relationship between HIV-associated oral lesions and viral loads.28-30 However, some of the oral lesions have been well-studied and have been associated with immunosuppression as measured by CD4 counts.
Adults
Some lesions are more significantly associated than others. Oral candidiasis, oral hairy leukoplakia, and Kaposi’s sarcoma have been reported to be significantly associated with CD4 cell counts of less than 200 cells/ml.31-33 This level of immunosuppression has also been associated with more clinical complications caused by herpes zoster infection and an increase in the number of oral lesions.34,35 Necrotizing ulcerative periodontitis has been associated with CD4 cell counts of less than 100 cell/ml in one study. The mortality rate was reported to be 60 percent within 18 months of a necrotizing ulcerative periodontitis diagnosis in this study.36 In a recent publication, the relationship of immunosuppression to pocket depth, recession, and clinical attachment level was evaluated in 316 HIV-infected dentate patients from North Carolina. Patients with CD4 cell counts of less than 200 cells/ml were 2.8 times more likely to have recession than those with higher CD4 cell counts.37 Oral candidiasis has been associated with linear gingival erythema, and it has been suggested by some that it might be a better predictor of peridontitis than CD4 cell counts.38,39 The prevalence of major salivary gland (parotid, submandibular/sublingual) enlargement, tenderness, and absence of saliva upon palpation was recently investigated in a U.S. multicenter national cohort of 576 HIV-infected women and 152 at-risk HIV-negative women. Unlike previous investigations that are mainly focused on parotid glands, this investigation focused on all major salivary glands and included a variety of clinical indicators of salivary gland disease. Based on the findings from this national study, the authors recommended a multidimensional approach (i.e., enlargement, tenderness and absence of saliva upon palpation) as markers for evaluation of HIV-associated salivary gland disease.21 In the same cohort, the likelihood of a complaint of dry mouth and the absence of unstimulated whole saliva (flow rate equals 0 ml/min) were significantly higher in HIV-positive women than at-risk negatives. Those with CD4 counts less than or equal to 200 cells/ml were at a significantly higher risk for these conditions than those with counts greater than 500 cells/ml.23
Children
Parotid enlargement has been associated with slower progression to AIDS in children. The median time to death has been reported as 3.4 years among patients with oral candidiasis and 5.4 years among those with parotid enlargement.25 In a recent longitudinal study (1995-1998), the prevalence and prognostic significance of oral lesions were examined in 73 children with vertical HIV transmission who were receiving anti-retroviral medications. In this study population, cervical lymphadenopathy, xerostomia, and oral candidiasis were the most prevalent findings. Patients with severe immunosuppression had a more frequent occurrence of oral lesions during the study period. The likelihood of recurrent cervical lymphadenopathy, xerostomia and oral candidiasis was significantly higher in those with a previous (six to 18 months) diagnosis of these conditions.24 In another recent study, 51 HIV-infected children were followed for two years. In this population, the presence of oral candidiasis was significantly associated with the CD4/CD8 cells ratio. Those with a CD4/CD8 ratio less than 0.5 were more prone to development of oral candidiasis.40
HIV viral load is thought to play a role in the occurrence of clinical manifestations as a reliable prognostic indicator of disease progression and anti-retroviral treatment failure.28 Plasma viral load levels equal to or greater than 20,000 copies per/ml have been associated with the presence of oral candidiasis and oral hairy leukoplakia.29 Recently the sensitivity, specificity, and positive predictive value of HIV-associated oral lesions for identifying immunosuppression and viral burden were investigated in 606 HIV-infected men and women in North Carolina. The concurrent presence of oral candidiasis and hairy leukoplakia had the highest (89.3 percent) positive predictive value. Oral candidiasis was significantly associated with plasma viral load equal to or greater than 20,000 copies/ml in this investigation.41 Two recent publications have associated higher viral load levels with a higher likelihood of oral lesions22 and salivary gland disease21 in a large cohort of HIV-infected women in the United States.
Anti-Retroviral Therapy
Benefits
HAART, which usually consists of a combination of three different anti-retroviral agents, has significantly decreased the progression of HIV infection to AIDS and death in the United States. The suppression of viral replication caused by HAART has increased immune function and decreased the incidence of common oral manifestations of the HIV infection. One or more drugs from the protease inhibitor class combined with nucleoside analogs and occasionally a non-nucleoside reverse transcriptase inhibitor constitute the majority of HAART regimens. In a recent study, the overall prevalence of HIV-associated oral lesions was reported to be significantly decreased because of the intervention of protease inhibitors in a cohort of HIV-infected men and women. Hairy leukoplakia, necrotizing ulcerative periodontitis, and stomatitis were among the lesions that were significantly decreased in frequency.41 Oral candidiasis has also been significantly affected by the protease inhibitor and HAART regimens.2 The increase in the CD4 and neutrophil cell counts caused by protease inhibitors and HAART lead to a subsequent increase in the host defense against opportunistic agents. The occurrence of persistent major aphthous ulcers appears to be declining significantly. The management of these lesions has also been improved because of the availability of thalidomide therapy.42
Risks
Despite this good news, there are concerns about the possible adverse effects of HAART. For example, the prevalence of oral warts has been reported to be significantly higher in HIV patients who are on protease inhibitors. An increase in oral warts from 6 percent in 1990-1991 to 26 percent in 1997-1998 is reported in HIV-positive patients evaluated at the University of San Francisco Oral AIDS Center.43 Little information is available about the possible impact of anti-retroviral therapy on oral human papillomavirus. The studies of the impact of HAART on cervical human papillomavirus revealed an inability of HAART to resolve such infections.44 The papilloma viruses are DNA viruses that can produce hyperplastic, verrocoid squamous, and papillomatous lesions involving the skin and mucosa. There are many human papillomavirus types. HPV 1, 2, 4, 6, 7, 11, 13, 16, 18, 32, and 57 have been found in different oral lesions. The major sites of involvement are lips, buccal and labial mucosa, and gingiva (Figure 7). The management of HPV lesions is frustrating for patients and practitioners due to the high rate of recurrences. Surgical removal and cryotherapy are the most common approaches for the management of HPV-associated lesions. Caustic agents such as podophyllin have been used with mixed results. Another concern is the possible association between protease inhibitors and dental caries. A dramatic increase in the rate of cervical and interproximal dental caries (Figure 8) has been reported in some patients who are on protease inhibitors.45 However, the exact cause-and-effect association has not established. Perioral paresthesia, dysgeusia, xerostomia, and oral ulcerations are among other possible adverse effects.46 Protease inhibitors are also associated with abnormal lipid metabolism and distribution that leads to the development of lipodystrophic changes. Peripheral lipodystrophy may be manifested as enlargement of the dorsocervical fat pad (buffalo lump), enlargement of parotid glands (chipmunk face) and increased abdominal girth.47-49 Pancreatitis and insulin resistance are also reported as possible adverse effects associated with HAART (See "Current Concepts in HIV Pathogenesis and Treatment" in this issue.)
Conclusion
The oral manifestations of HIV infection have changed because of the advent of HAART. Many opportunistic infections and neoplasms have resolved or fail to occur as a result of an improved immune system. The HAART regimen is expensive and is not available in many countries. Where it is available, many HIV-infected patients may not have access to it. Therefore, the oral manifestations of HIV infection continue as in the pre-HAART era in these individuals. Oral health care providers should familiarize themselves with the oral signs and symptoms of HIV infection and recognize the significant role that these lesions play in detection, recognition, management, and transmission of HIV infection. Moreover, it is important to be familiar with the adverse effects of anti-retroviral therapy involving the head and neck area because of their impact on the quality and quantity of life for HIV patients.
Acknowledgment
The author would be remiss in not recognizing the considerable contributions of Frank Lucatorto, DDS, MS, in the area of HIV-infected patients. He has indeed been an inspiration to the author as she has pursued her interest in improving the quality of life for such individuals.
Author
Mahvash Navazesh, DMD, is an associate professor and acting chair in the Department of Dental Medicine and Public Health at the University of Southern California School of Dentistry.
References
1. Patton LL, McKaig R, et al, Changing prevalence of oral manifestations of human immunodeficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89(3):299-304, 2000.
2. Aguirre JM, Echebarria M, et al, Reduction of HIV-associated oral lesions after highly active antiretroviral therapy. Oral Surg Oral Med Oral Path 88(2):114-5, 1999.
3. Johnson RA, Human immunodeficiency virus disease in the era of HAART: a re-evaluation of the mucocutaneous manifestations. Curr Clin Topics Infect Dis 19:252-86, 1999.
4. Powderly WG, Landay A, et al, Recovery of the immune system with antiretroviral therapy. The end of opportunism? J Am Med Assoc 280:72-77, 1998.
5. Palella FJ Jr, Delaney KM, et al, Declining morbidity and mortality among patients with advance human immunodeficiency virus infection. N Engl J Med 338:853-60, 1998.
6. Hogg RS, Heath KV, et al, Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. J Am Med Assoc 297:450-4, 1998.
7. Egger M, Hirschel B, et al, Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Br Med J 315:1194-9, 1997.
8. Sendi PP, Bucher HC, et al, Estimating AIDS-free survival in a severely immunosuppressed asymptomatic HIV-infected population in the era of antiretroviral triple combination therapy. J Acquir Immune Defic Syndr Hum Retrovirol 20:376-81, 1999.
9. Brodt HR, Kamps BS, et al, Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 11:1731-8, 1997.
10. Fleming PL, Ward JW, et al, Declines in AIDS incidence and deaths in the USA: A signal change in the epidemic. AIDS 12:555-61, 1998.
11. Jacobson MA, French M, Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy. AIDS 12:S157-163, 1998.
12. Sepkowitz KA, Effect of HAART on natural history of AIDS-related opportunistic disorders. Lancet 351:228-30, 1998.
13. Arendorf T, Holmes H, Oral manifestations associated with human immunodeficiency virus (HIV) infection in developing countries -- are there differences from developed countries? Oral Dis 6:133-5, 2000.
14. Navazesh M, Lucatorto F, Common oral lesions associated with HIV infection. J Cal Dental Assoc 21(9):37-42, 1993.
15. Ceballos A, Aguirre JM, Bagan JV, Oral manifestations associated with human immunodeficiency virus in a Spanish population. J Oral Pathol Med 25:523-6, 1996.
16. Ranganathan K, Reddy BVR, et al, Oral lesions and conditions associated with human immunodeficiency virus infection in 300 south Indian patients. Oral Dis 6:152-7, 2000.
17. Greenspan D, Greenspan JS, HIV-related oral disease. Lancet 348:729-33, 1996.
18. Laskaris G, Hadjivassiliou M, Stratigos J, Oral signs and symptoms in 160 Greek HIV-infected patients. J Oral Pathol Med 21:120-131, 1992.
19. Patton LL, McKaig RG, et al, Oral manifestations of HIV in a southeastern USA population. Oral Dis 4:164-169, 1998.
20. Feigal DW, Katz MH, Greenspan D, et al, The prevalence of oral lesions in HIV-infected homosexuals and bisexual men: three San Francisco epidemiological cohorts. AIDS 5:519-525, 1991.
21. Mulligan R, Navazesh M, et al, Salivary gland disease in human immunodeficiency virus-positive women from the WIHS study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:702-9, 2000.
22. Greenspan D, Komaroff E, et al, Oral mucosal lesions and HIV viral load in the Women’s Interagency HIV Study. JAIDS (accepted for publication), 2000.
23. Navazesh M, Mulligan R, et al, The prevalence of xerostomia and salivary gland hypofunction in a cohort of HIV-positive and at risk women. J Dent Res 79(7):1502-7, 2000.
24. Kozinetz C, Carter A, et al, Oral manifestations of pediatric vertical HIV infection. AIDS Patient Care STDs 14(2):89-94, 2000.
25. Katz MH, Mastrucci MT, et al, Prognostic significance of oral lesions in children with perinatally acquired human immunodeficiency virus infection. Am J Dis Child 147:45-8, 1993.
26. Ramos-Gomez F, Flaitz C, et al, Classification, diagnostic criteria, and treatment recommendations for orofacial manifestations in HIV-infected pediatric patients. J Clin Pediatr Dent 23(2):85-96, 1999.
27. EC-Clearinghouse on Oral Problems Related to HIV infection and WHO Collaborating Center on Oral Manifestations of the Immunodeficiency Virus, Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 22:289-91, 1993.
28. Margiotta V, Campisi G, et al, Plasma HIV-1 RNA and route of transmission in oral candidiasis and oral hairy leukoplakia. Oral Dis 6:194-195, 2000.
29. Patton LL, McKaig RG, et al, Oral hairy leukoplakia and oral candidiasis as predictors of HIV viral load. AIDS 13:2174-6, 1999.
30. Margiotta V, Campisi, G, et al, HIV infection: Oral lesions, CD4+ cell count and viral load in an Italian study population. J Oral Pathol Med 28(4):173-177, 1999.
31. Glick M, Evaluation of prognosis and survival of the HIV-infected patients. Oral Surg Oral Med Oral Pathol 74:386-92, 1992.
32. Glick M, Muzyka BC, et al, Oral manifestations associated with related disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 77:344-9, 1994.
33. Matee MI, Scheutz F, Moshy J, Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians. Oral Dis 6:106-111, 2000.
34. Glesby MJ, Moore RD, Chaissan RE, Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 12:370-5, 1995.
35. Kademani D, Glick M, Oral ulcerations in individuals infected with human immunodeficiency virus: Clinical presentations, diagnosis, management, and relevance to disease progression. Quintessence Int 29(8):523-534, 1998.
36. Glick M, Muzyka BC, et al, Necrotizing ulcerative periodontitis: A marker for immune deterioration and a predictor for the diagnosis of AIDS. J Periodontol 65:393-397, 1994.
37. McKaig RG, Patton LL, et al, Factors associated with periodontitis in an HIV-infected Southeast USA study. Oral Dis 6:158-165, 2000.
38. Grbic J, Mitchell-Lewis D, et al, The relationship of candidiasis to linear gingival erythema in HIV-infected homosexual men and parenteral drug users. J Periodontol 66:30-37, 1995.
39. Lamster IB, Grbic JT, et al, New concepts regarding the pathogenesis of periodontal disease in HIV infection. Ann Periodontol 3:62-75, 1998.
40. Fonseca R, Cardoso A, et al, Frequency of oral manifestations in children infected with human immunodeficiency virus. Quintessence Int 31:419-22, 2000.
41. Patton L, Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:182-8, 2000.
42. Jacobson JM, Greenspan JS, et al, Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 336:1487-93, 1997.
43. Greenspan D, Canchola AJ, et al, Emergence of oral warts in the HAART era. Conference on retroviruses and opportunistic infections, abstract no. 704, 1999.
44. Heard I, Schmitz V, et al, Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy. AIDS 12:1459-1464, 1998.
45. Alves, Mario, Personal communication. March 2000.
46. Porter SR, Scully C, HIV topic update: protease inhibitor therapy and oral health care. Oral Dis 4:159-163, 2000.
47. Henry K, Melroe H, Huebsch J, et al, Severe premature coronary artery disease with protease inhibitors. Lancet 351:1328, 1998.
48. Lo JC, Mulligan K, Tai VW, et al, "Buffalo hump" in men with HIV-1 infection. Lancet 351:867-870, 1998.
49. Miller KD, Jones E, Yanovski JA, et al, Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 351:871-5, 1998.
To request a printed copy of this article, please contact/Mahvash Navazesh, DMD, USC School of Dentistry, 925 W. 34th St., Room 4320, Los Angeles, CA 90089-0641 or at navazesh@hsc.usc.edu
Figure 1. Chronic herpetic lesions involving the midface area.
Figure 2. Hairy leukoplakia involving the lateral border of tongue in a geriatric HIV-infected patient.
Figure 3. Kaposi’s sarcoma involving the palatal mucosa in an HIV-infected male.
Figure 4. Pseudomembranous candidiasis in an edentulous HIV-infected geriatric female.
Figure 5. Herpes zoster skin lesions on the forehead.
Figure 6. Parotid gland enlargement in an HIV-infected female.
Figure 7. Multiple oral papilloma lesions involving the lower lip on a young HIV-infected male.
Figure 8. Rampant cervical caries associated with HAART (courtesy of Dr. Mario Alves).
Table 1. Reported Oral Lesions in Pediatric and Adult HIV-Infected Patients
Candidiasis
Oral hairy leukoplakia
Chronic herpetic ulcers
Papilloma
Kaposi’s sarcoma
Aphthous ulcers (refractory to therapy)
Salivary gland diseases:
Xerostomia (dry mouth)
Glandular enlargement
Glandular tenderness
Diminished or absent saliva output
Cervical lymphadenopathy
Lymphoma
Periodontal diseases:
Linear gingival erythema
Necrotizing ulcerative periodontitis
Necrotizing ulcerative stomatitis
