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Oral Lesions of HIV Disease and HAART in Industrialized Countries

T.A. Hodgson^1,*, D. Greenspan², and J.S. Greenspan²

¹ Unit of Oral Medicine, UCL Eastman Dental Institute and UCLHT Eastman Dental Hospital, 256 Gray’s Inn Road, London, WC1X 8LD, UK; and
² Department of Orofacial Sciences and the Oral AIDS Center, School of Dentistry, The University of California, San Francisco, CA 94143-0422, USA

Correspondence: ^* corresponding author, t.hodgson{at}eastman.ucl.ac.uk

	Abstract

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
The epidemiology of HIV-related oral disease in industrialized nations has evolved following the initial manifestations described in 1982. Studies from both the Americas and Europe report a decreased frequency of HIV-related oral manifestations of 10–50% following the introduction of HAART (highly active antiretroviral therapy). Evidence suggests that HAART plays an important role in controlling the occurrence of oral candidosis. The effect of HAART on reducing the incidence of oral lesions, other than oral candidosis, does not appear as significant, possibly as a result of low lesion prevalence in industrialized countries. In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in patients on HAART has been reported from the USA and the UK. HIV-related salivary gland disease may show a trend of rising prevalence in the USA and Europe. The re-emergence of HIV-related oral disease may be indicative of failing therapy. A range of orofacial iatrogenic consequences of HAART has been reported, and it is often difficult to distinguish between true HIV-related oral disease manifestations and the adverse effects of HAART. A possible association between an increased risk of oral squamous cell carcinoma and HIV infection has been suggested by at least three epidemiological studies, with reference to the lip and tongue. These substantial and intensive research efforts directed toward enhancing knowledge regarding the orofacial consequences of HIV infection in the industrialized nations require dissemination in the wider health care environment.

KEY WORDS: Oral • HIV • AIDS • HAART • industrialized

	Introduction

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Current interest regarding oral human immunodeficiency virus (HIV) disease epidemiology in industrialized nations focuses on: the effects of anti-HIV therapies on the prevalence, incidence, and types of oral lesions; the oral aspects of complications of HIV therapy; whether oral cancer may become a long-term complication of HIV infection; the nature and significance of HIV salivary gland disease; and whether the HIV-infected individual is at risk of increased caries. Health services research and oral-health-promotion-related questions requiring further clarification include: the effects of oral HIV disease on quality of life; resource implications of the oral disease burden in the HIV-infected population; the role of oral lesion surveillance in HIV prevention programs; the role of oral lesions in HIV early diagnosis; the most cost-effective therapy for oral lesions; access to oral and dental care for HIV-infected people; and dental health professionals’ attitudes toward and acceptance of HIV-infected persons as patients.

The intent of this review is additive to that published in 2002 regarding information on oral HIV lesions in the industrialized nations, and the roles occupied by these lesions in the natural history and approaches to prevention and control of HIV infection (Greenspan and Greeenspan, 2002). Reports detailing oral lesions in HIV-infected individuals in resource-poor countries, specifically affecting women or children, can be found elsewhere (Hodgson and Rachanis, 2002; Holmes and Stephen, 2002; Ramos-Gomez, 2002; Shiboski, 2002; Exposito-Delgado et al., 2004; Ranganathan and Hemalatha, 2006).

	Significance

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Oral lesions are readily accessible, and many can be diagnosed reliably from the clinical features alone. The presence of oral hairy leukoplakia (OHL) and oral candidosis (OC) paralleling the decline in CD4 cell count and increase in HIV viral load, but also independent of these laboratory indices, indicates progression to AIDS (Greenspan and Greenspan, 2002; Chattopadhyay et al., 2005a,b). These lesions feature in all classifications of HIV disease currently in use (Amirali et al., 2004), as well as in staging and prognosis (Birnbaum et al., 2002). More recently, in a Spanish cohort, multivariate analysis associating the presence of OC with progression to AIDS failed to reach a predictive value (Fernandez-Feijoo et al., 2005). Oral examination of all individuals at risk of infection, potentially infected, and diagnosed HIV-infected by health care workers at each clinical interaction is mandatory. These lesions are recognized in both HIV prevention and intervention programs (Badri et al., 2001). The presence and development of oral lesions are used as entry criteria and end-points for prophylaxis, therapy, and vaccine trials. Furthermore, many HIV-related oral lesions are reduced in frequency with highly active antiretroviral therapy (HAART), and recur or develop de novo with HAART failure and multi-drug resistance.

	Oral Lesions as Indicators of HIV Infection

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
During examination of an asymptomatic at-risk individual or patient presenting with a specific oral mucosal complaint, health care professionals may detect signs consistent with underlying immunosuppression. North American and European adult studies have reported that the presence of OC, OHL, and Kaposi’s sarcoma (KS) strongly suggests HIV infection in the absence of systemic immunosuppressive pharmacotherapy (Klein et al., 1984; Feigal et al., 1991; Ficarra et al., 1994; Shiboski et al., 1994; Greenspan, 1997; Greenspan and Greenspan, 2002). This led to the consensus guidelines defining oral lesions associated with HIV infection (Greenspan et al., 1992; EC Clearinghouse, 1993).

	Oral Lesions as Early Clinical Features of HIV Disease

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Oropharyngeal lesions frequently occur in individuals soon after seroconversion, as part of the acute or primary HIV infection syndrome (Vanhems et al., 1997). The indirect approach of determining the CD4 count or other laboratory values at which oral lesions are found in cross-sectional studies is a circular argument but, despite this, has yielded valuable data (Skolasky et al., 2001).

	Oral Lesions Predict Progression

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Oral lesions have been shown to be associated with increased risk of progression of HIV disease, and the majority of longitudinal studies from North America have demonstrated an association between the presence of OC and OHL and a decreased CD4 lymphocyte count in HIV-infected adult subjects (Lifson et al., 1994; Begg et al., 1996, 1997; Hilton et al., 1997; Rabeneck et al., 1997; Schuman et al., 1998; Shiboski et al., 1999), as have studies from Europe (Moniaci et al., 1990; Plettenberg et al., 1990; Morfeldt-Mansen et al., 1991; Husak et al., 1996; Ravina et al., 1996; Munoz-Perez et al., 1998). Cross-sectional studies have associated low CD4 lymphocyte counts with the presence of oral KS (Glick et al., 1994), non-Hodgkin’s lymphoma (Flaitz et al., 1996; Lozada-Nur et al., 1996), or necrotizing ulcerative periodontitis (Glick et al., 1994). The oral health care professional diagnosing these lesions in a known HIV-infected client should be alerted to possible disease progression which may lead to review of laboratory markers of immune deterioration.

	Oral Lesions in Anti-HIV and Anti-opportunistic Therapy

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Many sets of recommendations for the initiation of anti-HIV and anti-opportunistic infection prophylaxis and therapy have used OC and OHL as criteria (Greenspan and Greenspan, 2002).

	Oral Lesions in HIV Staging and Classification Schemes

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Certain oropharyngeal lesions, notably oral candidiasis and hairy leukoplakia, feature in all HIV/AIDS classifications, staging, and prognosis systems currently in use (Greenspan and Greenspan, 2002).

	Oral Lesions and HIV Viral Load

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
So far, data on the relationship between oral disease and HIV viral load come predominantly from cross-sectional studies. The North Carolina Oral AIDS group has sequentially reported the presence of HL and OC correlates with higher HIV viral load, which may be independent of CD4 cell count (Patton et al., 1999; Patton, 2000; Chattopadhyay et al., 2005a,b). The US Women’s Interagency HIV Study (WHIS) suggests that HL presence is associated with high viral load (Greenspan et al., 2000, 2004). In a small and as-yet-unreproduced study of 39 HIV-infected individuals (28 intravenous drug users), greater levels of periodontal destruction and caries were associated with higher HIV viral loads (Baqui et al., 1999). Clearly, more extensive studies of these relationships are needed, particularly in longitudinal cohorts. However, accounts continue to indicate that the sentinel oral lesions continue to bear significant relationships to other measures of HIV infection. A biological explanation for this association remains unclear.

	HIV Infection and Caries Risk

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Reports comparing dental caries indices in HIV-infected with non-HIV-infected adults are rare, with reports in children much more common. The results of the WIHS suggest no significant difference in coronal or root caries by HIV status, nor did the results support a relationship between antiretroviral therapy and increased dental caries risk (Phelan et al., 2004). In Pittsburgh, PA (USA), HIV-infected individuals receiving HAART had a lower occurrence of dental caries than did patients not taking these medications (Bretz et al., 2000). Other reports from North America suggest a relationship between antiretroviral medication and increased risk of dental caries (Glick et al., 1998), and an association between decreased salivary flow and HAART in the WIHS oral cohort has been reported as a factor for increased caries risk (Navazesh et al., 2003).

	Oral Health and Quality of Life

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
It is assumed that oral disease affects the quality of life in HIV-infected individuals, and that treatment results in a measurable symptomatic improvement. However, the impact of oral disease in HIV infection is poorly documented. In Australia, patients with HIV experienced more discomfort than a comparable sample of the general population (Coates et al., 1996). In multivariate analyses, the presence of oral symptoms had a significant impact on health-related quality of life (Lorenz et al., 2001; Coulter et al., 2002). In addition, an improvement in oral health was significantly associated with improvements in both physical and mental health (Coulter et al., 2002). Therefore, based on the available evidence, oral health care professionals play a role in improving and maintaining health-related quality of life in HIV-infected patients. This topic is further discussed in "Implications of HIV disease for oral health services" (Robinson, 2006), elsewhere in this issue.

	Non-discriminatory Access to Oral Health Care

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Although access to dental treatment has significantly improved for HIV-infected patients in North America and Europe, some oral health care practitioners remain unwilling to accept this patient group for treatment, and HIV-infected individuals continue to experience discrimination by health care professionals (Hodgson et al., 2006). While, in the United States, the number of dentists willing to treat HIV-infected patients has nearly doubled to 83% from 1984 to 2003 (Gerbert, 1987; Seacat and Inglehart, 2003), a trend mirrored in many European countries (Angelillo et al., 1994; Scheutz and Langebaek, 1995), a recent study from central England suggests that only 55% of dentists would accept HIV-infected patients for treatment without hesitation (Crossley, 2004).

	Oral Lesions and HAART

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
Post-introduction of specific anti-HIV therapies, there have been well-documented changes in the frequency and character of the oral complications of HIV disease. Antiretroviral drugs increase CD4+ T-cell count, decrease HIV RNA viral load, and result in a decreased frequency and severity of opportunistic disease (Powderly et al., 1998). It was therefore expected that HAART would reduce most HIV-related oral disease (unless associated with immunological reconstitution). Studies from both the Americas and Europe reported a decreased frequency of HIV-related oral manifestations of 10 to 50% following the introduction of HAART (Ceballos-Salobrena et al., 2000; Patton et al., 2000; Tappuni and Fleming, 2001; Ramirez-Amador et al., 2003; Zakrzewska and Atkin, 2003). The re-emergence of HIV-related oral disease may be indicative of failing therapy (Eyeson et al., 2002; Greenwood et al., 2002; Manfredi, 2004; Gaitan-Cepeda et al., 2005; Flint et al., 2006).

HAART plays an important role in controlling the occurrence of oral candidosis (Flint et al., 2006; Hodgson et al., 2006). Prospective studies and a single retrospective study show significant decreases in oral candidosis incidence after the initiation of HAART (Arribas et al., 2000; Schmidt-Westhausen et al., 2000; Greenspan et al., 2001; Ramirez-Amador et al., 2003; Greenspan et al., 2004; Nicolatou-Galitis et al., 2004). A UK cross-sectional study showed a higher prevalence of oral candidosis in adults not on any antiretroviral medication, compared with those on HAART (Tappuni and Fleming, 2001). The largest cohort, followed over 12 years, showed a 50% decrease in OC (Ramirez-Amador et al., 2003). The relative risk of having OC was halved in subjects on HAART compared with untreated women in San Francisco, and the rate of recurrence reduced independently of both CD4 count and HIV-RNA viral load (Greenspan et al., 2004).

Protease inhibitor (PI) therapy has been demonstrated to decrease both frequency and recurrence of oral candidosis in HIV-infected individuals (Diz et al., 1999; Patton et al., 2000). The ability of PI to inhibit Candida infection may be related to similarities between candidal secreted aspartic proteinases and HIV proteinase, and the inhibition of both by protease inhibitors (Munro and Hube, 2002). Clinical studies provide further evidence for a direct effect of PI on control of oral candidosis (Cassone et al., 2002). Studies from the United States and Italy suggested a reduction of fluconazole- and itraconazole-resistant Candida strains following HAART therapy (Martins et al., 1998; Tacconelli et al., 2002), probably secondary to the decreased need for azole therapy. The impact of HAART may thus not only lessen the likelihood of Candida infection but also reduce the virulence of opportunistic fungal strains (Cassone et al., 2002).

The effect of HAART on reducing the incidence of oral lesions, other than OC, does not appear to be as significant, possibly as a result of the low prevalence for most of these lesions in HIV-positive patients in industrialized countries. In populations from Germany and Mexico with high baseline HL prevalence, a significant prospective decrease following HAART initiation was demonstrated (Schmidt-Westhausen et al., 2000; Ramirez-Amador et al., 2003), but this was not demonstrated in women enrolled in the WIHS (Greenspan et al., 2004). One cross-sectional study in North America found a significantly lower prevalence of HL (Patton et al., 2000).

In a Spanish population, no oral KS lesions were documented in patients taking HAART (Ceballos-Salobrena et al., 2000). A prospective German study reported a significant decrease in the prevalence of KS after initiation of HAART, from 9% to 1% (Schmidt-Westhausen et al., 2000). Studies from the USA (Patton et al., 2000) and Mexico (Ramirez-Amador et al., 2003) found no significant change in the occurrence of KS with HAART. The prevalence of HIV-associated periodontal disease was reported to decrease significantly in an American cohort with HAART (Patton et al., 2000), in concordance with reports on selected European populations (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001; Nicolatou-Galitis et al., 2004).

In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in subjects on HAART has been reported from the USA and the UK (Patton et al., 2000; Greenspan et al., 2001; Greenwood et al., 2002; King et al., 2002; Zakrzewska and Atkin, 2003). However, in a Mexican population, similar detection rates of oral warts were documented in subjects on HAART, compared with those not on therapy (Ramirez-Amador et al., 2003), and this was also demonstrated in the prospective multi-center Women’s Interagency study, which showed no change in incidence with the initiation of HAART therapy (Greenspan et al., 2004). In HIV-infected individuals, the risk factors for oral HPV infection are: male sex, herpes simplex virus-2 seropositivity, and oro-genital contact with more than one partner in the preceding year (King et al., 2002; Kreimer et al., 2004). An association between oral HPV infection and hepatitis B virus seropositivity also suggests the sexual transmission of HPV (King et al., 2002).

The development of HPV-related oral mucosal lesions in HIV-infected individuals may be related to a decreased HIV viral load (King et al., 2002) and/or CD4+ cell count (King et al., 2002; Kreimer et al., 2004). The mechanism by which a reduction in HIV viral load may lead to an increased risk of oral warts remains unclear, but may represent a form of immune reconstitution syndrome (Race et al., 1998; King et al., 2002). The multiple lesions are often refractory to management, and, more recently, the use of topical cidofovir (Husak et al., 2005) and powered shaver (Miller and Tami, 2005) has been suggested.

HIV-related salivary gland disease may show a trend of rising prevalence in the USA and Europe (Patton et al., 2000; Greenspan et al., 2001; Nicolatou-Galitis et al., 2004); however, this was not supported by studies in Mexico (Ramirez-Amador et al., 2003). HIV-infected women are at a significantly higher risk of xerostomia and salivary gland hypofunction than are non-infected women, and HAART is a significant risk factor for these conditions (Navazesh et al., 2003).

	The Orofacial Adverse Effects of HAART

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
A range of orofacial iatrogenic consequences-usually not severe-has been reported with HAART. Lipodystrophy syndrome disfigurement may result in therapeutic non-compliance (Scully and Diz Dios, 2001). It remains difficult to distinguish between true HIV-related oral disease manifestations and the adverse effects of HAART (Flint et al., 2006).

The oral adverse effects of the nucleoside reverse-transcriptase inhibitors (NRTI) may be related to bone marrow suppression. Recurrent oral ulceration secondary to neutropenia may affect up to 30% of patients prescribed zalcitabine (McNeely et al., 1989). Xerostomia has been reported in 30% of patients taking didanosine (ddI) (Allan et al., 1993). Erythema multiforme and toxic epidermal necrolysis are rare events associated with NRTI, as are lichenoid reactions, particularly related to zidovudine (Fischl et al., 1990). Zidovudine can also give rise to mucocutaneous hyperpigmentation (Greenberg and Berger, 1990; Poizot-Martin et al., 1991).

Oral adverse effects seem to be less commonly associated with the non-nucleoside reverse-transcriptase inhibitors; however, erythema multiforme has been described following treatment with Nevirapine (Wetterwald et al., 1999; Fagot et al., 2001).

Notable protease-inhibitor-related oral adverse effects include: dysgeusia, affecting up to 20% of patients (Schiffman et al., 1999); circumoral paresthesia, especially with ritonavir (Scully, 2000); chelitis, which may affect up to 57% patients prescribed Indinavir (Calista and Boschini, 2000); and xerostomia (Danner et al., 1995). To date, no adverse oral effects have been reported for the fusion inhibitors, the latest addition to HAART (Leao et al., 2004).

	Oral Premalignancy and Carcinoma in HIV Infection

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
A possible association between the increased risk of oral squamous cell carcinoma and HIV infection has been suggested by at least three epidemiological studies, with reference to the lip and tongue. Cancer registry data examined from 11 regions in the USA found an association between immunosuppression secondary to HIV infection and the risk of developing lip cancer (relative risk of 3.1; 95% confidence interval, 1.9–4.8) (Frisch et al., 2001). A similar method in Australia found an increased risk of lip cancer of 2.6 times the standard incidence rate (Grulich et al., 2002). Cancer registry data from New York demonstrated that HIV-infected individuals developing cancer (lung, skin, penis, larynx, tongue, colon, and rectum) were, on average, over a decade younger than non-infected individuals (47.5 years vs. 60.3 years; p = 0.04) (Demopoulos et al., 2003). These and a series of case reports suggest the possibility of a future increased incidence of oral epithelial malignancies in the aging HIV-infected population whose disease is controlled by current and emerging antiretroviral therapies (Anil et al., 1996; Kao et al., 1999).

Human papilloma virus (HPV) is more commonly isolated from the oral cavity of HIV-infected than immunocompetent individuals, and often, in this group, more than one genotype and more high-risk genotypes are carried (Kreimer et al., 2004). The common occurrence of clinical lesions secondary to oral HPV infection in HIV-infected individuals, especially on HAART (Greenspan et al., 2001; Hagensee et al., 2004; Kreimer et al., 2004), and the suggested etiological significance of the virus in oral cavity carcinogenesis (Ha and Califano, 2004) raise the question of a possible increased incidence of HPV-associated premalignant oral lesions and squamous cell carcinoma. In contrast to the oral cavity, HAART-induced reduction in HIV load is associated with a decreased risk of HPV-related cervical cytological abnormalities in HIV-infected women (Luque et al., 2000). HPV types 16 and 51 have been demonstrated within labial carcinoma in situ, arising within a condyloma (Casariego et al., 2002). This is in contrast to HPV genotypes 11, 16, 18, and 31, which are most commonly associated with anogenital condylomata (Palefsky et al., 2001).

Notwithstanding the known association of Epstein-Barr virus (EBV) with epithelial malignancies such as nasopharyngeal carcinoma and the role of EBV in oncogenesis, there is little evidence to support the notion that HL is premalignant. No convincing individual case reports of such a transformation have yet been published. The histopathology is that of a benign, hypertrophic, and hyperplastic lesion, and numerous longitudinal observational studies have failed to reveal oral cancer arising in this lesion. The EBV genome in the epithelial cells is that of a fully replicating form of the virus, with no evidence for the kind of incorporation into the host genome that is seen in epithelial malignancies associated with EBV (Greenspan et al., 1985; Walling et al., 2004). Furthermore, laboratory studies indicate a stable epithelial phenotype rather than a premalignant one (Cruchley et al., 1998).

	Conclusion: Clinical Applications of Oral Lesions in AIDS Medicine

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
The clinical application of this substantial body of information regarding oral lesions in HIV infection is dependent on two premises. The first is that clinicians caring for those who may be or are HIV-infected, presumably predominantly physicians, should be capable of diagnosing the documented oral lesions, and the second is that they should be knowledgeable in the application of that information on behalf of their patients. Unfortunately, the available data do not justify optimism. Medical examiners were significantly less successful in identifying oral lesions than were their dental colleagues (Cruz et al., 1996; Hilton et al., 2001), indicating that the stage of HIV disease assigned could well be erroneous. It should be noted that physical signs in North America and Europe would not determine stage alone, but rather would suggest to the attending physician the necessity to revisit the CD4 cell count and HIV RNA viral load as further evidence of immune deterioration. Physical sign detection and interpretation should be of greater value in the resource-poor environment, especially in those without access to sophisticated laboratory measurements. However, as in the studies discussed above, in a study of the ability of primary care physicians to recognize physical findings associated with HIV infection, despite being directed by presenting histories to sites of the lesions, only 26% of physicians evaluating a patient with KS and 23% of those evaluating a patient with OHL detected and correctly diagnosed the abnormality (Paauw et al., 1995). Clearly, the substantial and intensive efforts which have been directed toward enhancing knowledge regarding the orofacial consequences of HIV infection have failed to be widely recognized by physicians, and alternative approaches should be resourced. From a patient’s perspective, the importance of a knowledge of oral disease affecting the HIV-infected individual broadens the physicians’ AIDS experience and is a significant factor in patient survival (Kitahata et al., 1996).

	Acknowledgments

 
This work was supported by funding from the USPHS-NIH-NIDCR-DE07946 and by the University of California AIDS Research Program (UCSF California AIDS Research Center).

	References

TOP Abstract Introduction Significance Oral Lesions as Indicators... Oral Lesions as Early... Oral Lesions Predict Progression Oral Lesions in Anti-HIV... Oral Lesions in HIV... Oral Lesions and HIV... HIV Infection and Caries... Oral Health and Quality... Non-discriminatory Access to... Oral Lesions and HAART The Orofacial Adverse Effects... Oral Premalignancy and Carcinoma... Conclusion: Clinical... References

 
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