| Abstract|| |
Aims: The aim was to assess the prevalence of oral lesions in HIV-infected children undergoing highly active anti-retroviral therapy (HAART), and the association between the duration of HAART usage and oral lesions.
Subjects and Methods: Totally, 111 medical and dental records of HIV-infected children, aged from 2 to 16 years old were reviewed for medical data, presence of oral lesions, and caries prevalence. According to the type of medication, the children were grouped as follows: 51 were under HAART (G1), 46 were using anti-retroviral medication (G2), and 14 were using no medication (G3).
Results: The majority of the HIV children had AIDS (65.8%), of which 86.3% were in G1, 63% in G2, and 0% in G3. The mean length of therapy was 34.4 months, with no difference between groups (Kruskal-Wallis; P = 0.917). The prevalence of the oral lesions was 23.4%, namely, G1 was 27.5%, G2 was 21.7%, and G3 was 14.3% (P > 0.05). Gingivitis was the most common oral manifestation (15.3%) seen in the three groups, followed by gingival linear erythema and pseudomembranous candidiasis in G1 and G2. The mean values regarding deft and DMFT indexes were, respectively, 3.2 and 1.9 (G1), 2.8 and 1.6 (G2), and 3.8 and 3.0 (G3). For the patients without AIDS (n = 38), oral manifestations were seen in 29.4% of G2 compared to G1, with 0% (Chi-square; P > 0.05). In terms of therapy duration, 47.65% of the patients who had been under HAART for 18 months or less had oral manifestations, compared to 13.3% of those who had been treated for a longer time (Chi-square; P = 0.007).
Conclusions: Although the prevalence of oral lesions was similar between the groups, it was less in patients without AIDS and those under HAART. The duration of HAART usage had a significant influence on the prevalence of these lesions.
Keywords: Anti-retroviral therapy, child, highly active, Human immunodeficiency virus, oral manifestations
|How to cite this article:|
Oliscovicz NF, Pomarico L, de Ara˙jo Castro GB, Souza IR. Effect of highly active antiretroviral therapy use on oral manifestations in pediatric patients infected with HIV. Indian J Dent Res 2015;26:200-4
There are approximately 33.3 million people in the world infected with HIV, and approximately 2.5 million of them are children under 15 years old.  In Brazil, there are around 19,203 children aged 13 years old or less with AIDS.  Within this scenario, there are a great variety of drugs to fight this virus.
|How to cite this URL:|
Oliscovicz NF, Pomarico L, de Ara˙jo Castro GB, Souza IR. Effect of highly active antiretroviral therapy use on oral manifestations in pediatric patients infected with HIV. Indian J Dent Res [serial online] 2015 [cited 2020 Jul 2];26:200-4. Available from: http://www.ijdr.in/text.asp?2015/26/2/200/159169
The highly active anti-retroviral therapy (HAART) was introduced in 1995  and changed the infection into a chronic disease.  This triple therapy interferes with progression and suppression of the viral load in these patients, , and is characterized by the association of protease inhibitors and nucleosides reverse transcriptase or nonnucleoside reverse transcriptase inhibitors. Although, some patients on this therapy showed an improvement in their immune system, they also presented other infection-related diseases, thus characterizing a picture of an immune reconstitution syndrome. ,
Oral manifestations related to HIV are numerous and they usually occur precociously. ,, One such manifestation is candidiasis, which is often associated with the initial phase of the infection. , Many studies on oral lesions in HIV-infected patients were made before the introduction of HAART. ,,,,,,,,,, The influence of HAART caused significant differences in relation to these lesions. ,,, In fact, a decrease of 10-50% in the rate of HIV-related oral manifestations has been reported following the introduction of HAART. This suggests that this therapy plays an important role in controlling oral candidiasis. 
However, the reduction in the incidence of oral lesions with the use of HAART in industrialized countries is not significant, except for candidiasis. This is possibly due to the low prevalence of oral lesions in these countries. In contrast to other HIV oral manifestations, an increase in the prevalence of oral condylomas and salivary gland diseases in patients on HAART has been reported in the USA and UK. The re-emergence of HIV-related oral diseases may indicate treatment failure. In fact, a range of orofacial iatrogenic consequences of HAART therapy have been reported, and it is difficult to distinguish the actual oral manifestations related to HIV from those due to the adverse effects of HAART. 
Therefore, the objective of the present work was to determine the prevalence of oral lesions in HIV-infected children who are on HAART, as well as the influence of treatment time on the lesions.
| Subjects and Methods|| |
The medical and dental records of all the patients who attended the pediatric AIDS Outpatient Clinic of a Public University Hospital in Rio de Janeiro, Brazil, were reviewed by means of retrospective analysis. Our sample consisted of 111 medical and dental records of HIV-infected children aged from 2 to 16 years old, selected by convenience, based on the frequency in which these patients attended the outpatient clinic during a 7-month period. All children had been definitively diagnosed with HIV infection according to criteria established by the Center of Disease Control and Prevention. 
The following data were collected from the children's medical records: Personal information, medical history (diagnosis of AIDS), type of anti-retroviral (ARV) therapy and results (the closest ones to the sample collection time) of laboratory tests (CD4 count and viral load). We considered AIDS when a patient has a CD4 count <15% and patients were considered to be using HAART when the ARV therapy involved the use of three or more drugs. According to the type of ARV drugs used, the sample was divided into three groups: HAART group (G1) with 51 patients, ARV (up to 2 ARV drugs) (G2) with 46 patients and G3 (no medication) with 14 patients. With regard to the length of time under medication, the children were regrouped into: Short period (taking ARV therapy for a period ranging from 1 to 18 months) and long period (taking the drugs for more than 18 months). However, when there was no clinical and/or laboratorial indication for treatment, according to criteria by the Brazilian Consensus of ARV Treatment for Children, no medications were used. 
Clinical oral data, including caries and oral lesions, were obtained from outpatient records regarding dental examinations performed by the dentist every 3 months during visits for tooth brushing with fluoride dentifrice and topical application of 1.23% acidulated phosphate fluoride gel. During the dental visits, both children and their caregivers were instructed about tooth brushing and oral hygiene. Furthermore, examinations for oral lesions  and determination of deft/DMFT indexes based on diagnostic criteria for caries in enamel and dentine were realized. , After such examinations, all the children received dental treatment according to their needs.
The collected data were entered and stored in a database created by the Epi Info TM 6.04. Kruskall-Wallis and Chi-square tests were performed to analyze the variables between and within groups, at a significance level of 5%.
| Results|| |
The sample consisted of 111 medical records of the children, all divided into three groups as follows: G1 (45.9%), G2 (41.4%), and G3 (12.6%). The mean age of the sample was 112.5 months and more than half were male (61.3%).
Overall, 65.8% of the children had AIDS, and most of them were in the G1 group (Qui-square, P < 0.05). The mean length of time on medication was 34.4 months, with no difference observed between groups G1 and G2 (Kruskal-Wallis, P > 0.05). [Table 1] lists data by groups.
|Table 1: General characteristics of the sample, whose children were divided into G1 (HAART), G2 (ARV), and G3 (no medication) |
Click here to view
With regard to the prevalence of oral manifestations, 23.4% showed some type of oral lesion related to the infection. Gingivitis (15.3%) was the most common manifestation found in the three groups, followed by parotid hypertrophy. Linear gingival erythema also had a high prevalence (9.8%) in G1 [Table 2].
|Table 2: Prevalence of oral manifestations and deft/DMFT indexes distributed between the three groups (%) |
Click here to view
When only considering patients without AIDS (n = 38), 29.4% of those who were using up to 2 ARV medications (G2) showed some type of lesion compared to 0% of those on HAART (G1) (Chi-square, P > 0.05). Furthermore, 47.65% of the children who had been taking HAART for a short time (<18 months) had lesions compared to 13.3% of the children who had being treated for a long period (Chi-square, P < 0.05). The deft/DMFT indexes data by groups is presented in [Table 2].
| Discussion|| |
Oral diseases can affect the quality of life of HIV-infected patients, and one of the objectives of their treatment is to improve such symptoms,  thus improving the patient's overall health. In the present study, gingivitis was the most commonly found lesion, followed by parotid hypertrophy and linear gingival erythema; this latter lesion had a high prevalence in G1. In another study, also involving children, the most commonly found lesions were parotid hypertrophy (19.6%), oral candidiasis (11.8%), and Kaposi sarcoma (3.9%).  In the study conducted by Miziara et al.,  however, oral candidiasis (11.5%) was the most prevalent lesion, followed by parotid hypertrophy and angular cheilitis. The presence and development of such oral lesions are usually used as a criterion for starting prophylaxis and drug therapy. Among the therapeutic approaches developed for these patients, one can highlight HAART. The indication for this therapy takes into account the clinical presence of lesions such as oral candidiasis and pilous leukoplakia,  since these opportunistic infections are directly related to the immunosuppression in HIV-infected individuals  and the infection progress. Therefore, HAART is used in more severely immunosuppressed patients. 
The frequency of many of these HIV-related lesions can be reduced with HAART therapy.  The prevalence of lesions such as oral candidiasis, oral pilous leukoplakia, Kaposi sarcoma, and HIV-related periodontal diseases have been reported to decrease with the use of HAART. ,,,,,,, On the other hand, salivary gland diseases, human papillomavirus (HPV), xerostomy, and recurrent oral ulcers have shown an increase in their prevalence. ,,,, However, there are also some reports indicating no change in the occurrence of these lesions in children on HAART. , The reasons for such different results are not fully understood. Some authors have associated these variations with differences in oral care habits, social and demographic factors, HIV-transmission mode, types of co-infections, disease stage, and immune reconstitution. ,, In the present work, a great difference in oral manifestations between HIV-infected patients and those on HAART or using ARV medications was found as no oral lesions were observed in the former, whereas the latter had 29.4%. Similar results were also reported by Miziara et al.,  who found percentages of 24.7% and 37.6%, respectively-a statistically significant difference. On the other hand, Hamza et al.  found no significant difference between children using HAART and those using no medication, although higher values were observed among the latter group.
Nevertheless, one should emphasize that oral lesions may develop again due to HAART failure and multi-drug resistance.  The results found in the literature on this issue are controversial. For instance the effect of HAART on reducing the incidence of oral lesions, including candidiasis, does not seem to be significant in industrialized countries, probably because of the low percentage of these oral manifestations in such nations.  Based on the positive results with HAART life expectancy of HIV-infected patients has increased. However, oral cancer seems to be a common clinical complication in these patients over time,  a finding also observed by Hamza et al.  and Olaniyi and Sunday,  who found the presence of oral warts and Kaposi sarcoma, respectively. In the present study, however, such lesions were not found.
Another factor to be taken into consideration is the length of time that the patient has been taking HAART. In the present work, among those children who had used HAART for up to 18 months, 47.65% had oral lesions compared to 13.3% of those who had used it for a longer time (Chi-square P = 0.007). Another study, however, reported no relationship between time of HAART use and decrease in oral manifestations, although the methodologies employed were different. In the latter case, the short time of HAART was considered to be between 24 and 28 weeks. 
However, despite the decrease in the presence of oral lesions following introduction of HAART, some factors must be considered. The first factor has to do with the long-term consequences of hyposalivation for patients on this therapy. The second factor is the increase in the prevalence of oral warts, which is directly related to HPV, as commented earlier. The third factor is the fact that the CD4 cell counts and oral manifestations no longer correlate over time. In view of this, surgeon-dentists should check the oral health of these patients carefully, mainly for any early signs of oral cancer- a fact which has been recently linked to infection, and pay attention to lesions commonly related to HIV.  This is relatively simple due to the fact that the oral cavity can be investigated easily with a clinical examination. Thus, oral lesions indicating important signs of infection progression can be diagnosed earlier, and a prompt intervention can then be carried out.
| Conclusion|| |
The prevalence of oral lesions was found to be similar between the groups, but less frequent in those patients without AIDS or who were on HAART. However, the length of time on HAART significantly influenced the prevalence of such lesions.
| References|| |
UNAIDS. Global Report: UNAIDS Report on the Global AIDS Epidemic; 2010. Available from: http://www.unaids.org
. [Last accessed on 2015 Dec 06].
Brasil, Ministério da Saúde. Epidemiological Report - AIDS/DST. Ano VII, n. 1. Brasil:Brasília; 2010.
Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995;333:450-1.
Patton LL, Shugars DC. Immunologic and viral markers of HIV-1 disease progression: Implications for dentistry. J Am Dent Assoc 1999;130:1313-22.
Jordan R, Gold L, Cummins C, Hyde C. Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy. BMJ 2002;324:757.
Rutherford GW, Sangani PR, Kennedy GE. Three-or four-versus two-drug antiretroviral maintenance regimens for HIV infection (Cochrane review). Cochrane Database Syst Rev 2003:CD002037.
Gaitan Cepeda LA, Ceballos Salobreña A, López Ortega K, Arzate Mora N, Jiménez Soriano Y. Oral lesions and immune reconstitution syndrome in HIV+/AIDS patients receiving highly active antiretroviral therapy. Epidemiological evidence. Med Oral Patol Oral Cir Bucal 2008;13:E85-93.
Lawn SD, Wilkinson RJ. Immune reconstitution disease associated with parasitic infections following antiretroviral treatment. Parasite Immunol 2006;28:625-33.
Greenspan JS, Barr CE, Sciubba JJ, Winkler JR. Oral manifestations of HIV infection. Definitions, diagnostic criteria, and principles of therapy. The U.S.A. Oral AIDS Collaborative Group. Oral Surg Oral Med Oral Pathol 1992;73:142-4.
Classification and diagnostic criteria for oral lesions in HIV infection. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. J Oral Pathol Med 1993;22:289-91.
Ramos-Gomez FJ, Flaitz C, Catapano P, Murray P, Milnes AR, Dorenbaum A. Classification, diagnostic criteria, and treatment recommendations for orofacial manifestations in HIV-infected pediatric patients. Collaborative Workgroup on Oral Manifestations of Pediatric HIV Infection. J Clin Pediatr Dent 1999;23:85-96.
Vaseliu N, Carter AB, Kline NE, Kozinetz C, Cron SG, Matusa R, et al.
Longitudinal study of the prevalence and prognostic implications of oral manifestations in Romanian children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J 2005;24:1067-71.
Pomarico L, Cerqueira DF, de Araujo Soares RM, de Souza IP, de Araujo Castro GF, Socransky S, et al.
Associations among the use of highly active antiretroviral therapy, oral candidiasis, oral Candida
species and salivary immunoglobulin A in HIV-infected children. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:203-10.
Hodgson TA. HIV-associated oral lesions: Prevalence in Zambia. Oral Dis 1997;3 Suppl 1:S46-50.
Tukutuku K, Muyembe-Tamfum L, Kayembe K, Odio W, Kandi K, Ntumba M. Oral manifestations of AIDS in a heterosexual population in a Zaire Hospital. J Oral Pathol Med 1990;19:232-4.
Itula PF, Mackenzie SB, Lewis K, Mortimer PP. Orofacial manifestations and seroprevalence of HIV infection in Namibian dental patients. Oral Dis 1997;3 Suppl 1:S51-3.
Matee MI, Scheutz F, Moshy J. Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians. Oral Dis 2000;6:106-11.
Schiødt M, Bakilana PB, Hiza JF, Shao JF, Bygbjerg IB, Mbaga I, et al.
Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. Oral Surg Oral Med Oral Pathol 1990;69:591-6.
Matee MI, Moshi J, Kalyanyama B. Oro-facial lesions occurring in HIV-infected individuals in Dar es Salaam. East Afr Med J 1996;73:813-5.
Kamiru HN, Naidoo S. Oral HIV lesions and oral health behaviour of HIV-positive patients attending the Queen Elizabeth II Hospital, Maseru, Lesotho. SADJ 2002;57:479-82.
Adurogbangba MI, Aderinokun GA, Odaibo GN, Olaleye OD, Lawoyin TO. Oro-facial lesions and CD4 counts associated with HIV/AIDS in an adult population in Oyo State, Nigeria. Oral Dis 2004;10:319-26.
Butt FM, Chindia ML, Vaghela VP, Mandalia K. Oral manifestations of HIV/AIDS in a Kenyan Provincial Hospital. East Afr Med J 2001;78:398-401.
Jonsson N, Zimmerman M, Chidzonga MM, Jonsson K. Oral manifestations in 100 Zimbabwean HIV/AIDS patients referred to a specialist centre. Cent Afr J Med 1998;44:31-4.
Arendorf TM, Bredekamp B, Cloete CA, Sauer G. Oral manifestations of HIV infection in 600 South African patients. J Oral Pathol Med 1998;27:176-9.
Tappuni AR, Fleming GJ. The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients: A UK study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:623-8.
Hamza OJ, Matee MI, Simon EN, Kikwilu E, Moshi MJ, Mugusi F, et al.
Oral manifestations of HIV infection in children and adults receiving highly active anti-retroviral therapy [HAART] in Dar es Salaam, Tanzania. BMC Oral Health 2006 18;6:12.
Miziara ID, Filho BC, Weber R. Oral lesions in Brazilian HIV-infected children undergoing HAART. Int J Pediatr Otorhinolaryngol 2006;70:1089-96.
Olaniyi TO, Sunday P. Oral manifestations of HIV infection in 36 Nigerian children. J Clin Pediatr Dent 2005;30:89-92.
Hodgson TA, Greenspan D, Greenspan JS. Oral lesions of HIV disease and HAART in industrialized countries. Adv Dent Res 2006;19:57-62.
CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43:1-19.
Brasil, Ministério da Saúde, Secretaria de Políticas de Saúde. National STD and AIDS. Clinical Guider fot the treatment of HIV infection in children; 2004. p. 49.
Carvalho JC, Thylstrup A, Ekstrand KR. Results after 3 years of non-operative occlusal caries treatment of erupting permanent first molars. Community Dent Oral Epidemiol 1992;20:187-92.
Bjørndal L, Larsen T, Thylstrup A. A clinical and microbiological study of deep carious lesions during stepwise excavation using long treatment intervals. Caries Res 1997;31:411-7.
Greenspan JS, Greenspan D. The epidemiology of the oral lesions of HIV infection in the developed world. Oral Dis 2002;8 Suppl 2:34-9.
Gaitán-Cepeda L, Cashat-Cruz M, Morales-Aguirre JJ, Sánchez-Vargas L, Aquino-Garcia S, Fragoso-Ríos R, et al.
Prevalence of oral lesions in Mexican children with perinatally acquired HIV: Association with immunologic status, viral load, and gender. AIDS Patient Care STDS 2002;16:151-6.
Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Anaya-Saavedra G, González-Ramírez I, Ponce-de-León S. The Changing Clinical Spectrum of Human Immunodeficiency Virus (HIV)-Related Oral Lesions in 1,000 Consecutive Patients: A 12-Year Study in a Referral Center in Mexico. Medicine (Baltimore) 2003;82:39-50.
Patton LL, McKaig R, Strauss R, Rogers D, Eron JJ Jr. Changing prevalence of oral manifestations of human immuno-deficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:299-304.
Nicolatou-Galitis O, Velegraki A, Paikos S, Economopoulou P, Stefaniotis T, Papanikolaou IS, et al.
Effect of PI-HAART on the prevalence of oral lesions in HIV-1 infected patients. A Greek study. Oral Dis 2004;10:145-50.
Shetty K, Leigh J. The changing face of oral lesions in HIV/AIDS patients undergoing highly active antiretroviral treatment. AIDS Patient Care STDS 2000;14:627-35.
Hood S, Bonington A, Evans J, Denning D. Reduction in oropharyngeal candidiasis following introduction of protease inhibitors. AIDS 1998;12:447-8.
Hoegl L, Thoma-Greber E, Röcken M, Korting HC. HIV protease inhibitors influence the prevalence of oral candidosis in HIV-infected patients: A 2-year study. Mycoses 1998;41:321-5.
Revankar SG, Sanche SE, Dib OP, Caceres M, Patterson TF. Effect of highly active antiretroviral therapy on recurrent oropharyngeal candidiasis in HIV-infected patients. AIDS 1998;12:2511-3.
Diz Dios P, Ocampo A, Miralles C, Otero I, Iglesias I, Rayo N. Frequency of oropharyngeal candidiasis in HIV-infected patients on protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:437-41.
Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet 2001;357:1411-2.
King MD, Reznik DA, O′Daniels CM, Larsen NM, Osterholt D, Blumberg HM. Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: An emerging infection. Clin Infect Dis 2002;34:641-8.
Eyeson JD, Warnakulasuriya KA, Johnson NW. Prevalence and incidence of oral lesions - The changing scene. Oral Dis 2000;6:267-73.
Flanagan MA, Barasch A, Koenigsberg SR, Fine D, Houpt M. Prevalence of oral soft tissue lesions in HIV-infected minority children treated with highly active antiretroviral therapies. Pediatr Dent 2000;22:287-91.
Khongkunthian P, Grote M, Isaratanan W, Piyaworawong S, Reichart PA. Oral manifestations in 45 HIV-positive children from Northern Thailand. J Oral Pathol Med 2001;30:549-52.
Marcus M, Maida CA, Freed JR, Younai F, Coulter ID, Der-Martirosian C, et al.
Oral white patches in a national sample of medical HIV patients in the era of HAART. Community Dent Oral Epidemiol 2005;33:99-106.
Sroussi HY, Epstein JB. Changes in the pattern of oral lesions associated with HIV infection: Implications for dentists. J Can Dent Assoc 2007;73:949-52.
Ceballos A, Gaitán L, Ceballos L. Oral lesions in HIV+/AIDS patients under highly active antiretroviral therapy for long time. J Dent Res 2002 (80 th
IADR General Session); abstract #1744.
Prof. Luciana Pomarico
Department of Pediatric Dentistry and Orthodontics, Universidade Federal do Rio de Janeiro, Rio de Janeiro
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]