Most common oral manifestations in pediatric patients HIV positive and the effect of highly active antiretroviral therapy

This integrative literature review aims to identify the main oral lesions affecting pediatric patients with HIV, and describe the effect of highly active antiretroviral therapy (HAART) on these injuries, comparing it to antiretroviral therapy (ART). A search was conducted in PubMed and Scielo databases, following predetermined inclusion and exclusion criteria. 19 papers were selected and the main information on the prevalence and frequency of oral manifestations in HIV-positive pediatric patients and effect of therapy applied were extracted. The most frequent injuries were oral candidiasis, gingivitis, parotid gland enlargement and linear gingival erythema. The use of HAART shown to reduce the prevalence of oral manifestations in pediatric patients with HIV and be more effective than ART. The findings of this study suggest that the most frequent oral manifestation in HIV-infected children is oral candidiasis, followed by changes such as gingivitis and enlargement parotid glands. The use of HAART appears to reduce the prevalence of these oral lesions, showing more effective results than ART.


Introduction
Acquired Immunodeficiency Syndrome (AIDS) is a systemic disease caused by the Human Immunodeficiency Virus (HIV), which affects the individual's immune system and makes him/her more susceptible to other diseases of systemic origin, such as oral lesions 1 .
First cases of AIDS were reported in the mid-1980s and its heterosexual transmission has grown over time, affecting a large number of women of childbearing age and capable of transmitting HIV virus to their children 2 .This vertical transmission, from mother to child,is considered the main factor for the increasing prevalence of this disease in pediatric patients [2][3][4] and it can occur during pregnancy, childbirth or through breastfeeding 5,6 .
HIV infection currently affects more than 2 million children under the age of 15 years old worldwide and it is associated with numerous life-long comorbidities for this population 6,7 .Early identification of oral manifestations, which usually are the first signs of this infection or its progression in children 2 , may assist in choosing appropriate therapy and reducing its morbidity 6 .
Immunosupressed patients are more susceptible to opportunistic infections, especially those that affect the oral cavity, such as oral candidiasis 8 .This problem becomes worse when it comes to HIV-positive pediatric patients because they present an immature immune system that makes them more prone to severe immunosuppression and rapid disease progression 2,6 .Some oral manifestations in pediatric patients present a different prevalence of adult patients 9 .The prevalence of oral lesions is, on average, 63% 1,10 , ranging from 20% to 80% 11 .This variation may occur according to the region or country and type of treatment instituted, such as whether patients have access to more potent antiretroviral drugs 4 or not.
Introduction of antiretroviral therapy (ART) regarding the treatment of HIV-infected patients brought enhancements in their oral health quality of life, reducing frequency of the disease's oral manifestations 6 .Subsequently, it was created a combination therapy known as highly active antiretroviral therapy (HAART).This one delivered more effective results, altering the prevalence of some oral lesions caused by HIV, besides improving the immune function, which reduced opportunistic infections, morbidity and mortality 10,12 .
A wide variety of oral lesions in HIV-infected pediatric patients are reported in the literature, such as: candidiasis 8,10-12 , gingivitis [12][13][14] , oral hairy leukoplakia 9,13 ,Kaposi's sarcoma 5,10,15 ,parotid enlargement 1,4,14,16 , herpes simplex 1,2 .This data also reveal divergence of information regarding which ones are the most frequent oral manifestations and how the antiretroviral therapies act on them.For this reason, this present study aims to identify the main oral lesions affecting pediatric patients with HIV, as well as the effects of ART and HAART on said lesions.

Methodology
This integrative review consisted of a bibliographic survey in the PubMed and SciELO databases.Adopting "advanced search" mode, the following keywords were used blended and standalone: "oral manifestations", "HIV", "children", "childhood", "prevalence", "HAART", "antiretroviral therapy" in both Portuguese and English.
Inclusion criteria for the articles were: descriptive, cross-sectional, and comparison studies reporting oral manifestations in HIV-infected children published in Portuguese or English between 2004 and 2014.
After the initial selection, repeated articles were excluded from the sample, along with those which did not include at least three keywords in the title or abstract, were not published in full and did not present the investigated issue as main subject.Last selection step consisted of reading the texts in full, followed by the construction of tables using most relevant information of each selected article.

Results
A total of 367 articles were identified in the databases searched.After excluding duplicate articles and those that did not meet predetermined inclusion and exclusion criteria, there were 24 articles left for full reading.After analyzing the content of each one of them, 19 scientific articles that addressed investigated issues were selected for this review.Most relevant subjects raised were: • Identification of oral manifestations affecting HIV-positive pediatric patients, highlighting the most frequent ones; • ART and HAART effects on oral lesions of HIV-positive children, especially HAART in the prevalence of these oral manifestations.
Most frequent lesions in HIV-positive pedi-atric patients were oral candidiasis, gingivitis, parotid enlargement and linear gingival erythema, being oral candidiasis considereda predictor of disease progression.The use of HAART has been shown to decrease the prevalence of oral manifestations in pediatric patients with HIV and to be more effective than ART.Main information contained in each article were described in the form of Charts 1 to 4 and sorted according to their publication year.

Discussion
Cross-sectional and prospective studies have shown that pediatric HIV-infected patients will present some type of oral lesion in non-specific phases of their childhood, which will help to identify the correct diagnosis of the syndrome 1,2,17 and, consequently, to find the most suitableantiretroviral therapy treatment 4,9,11 .

Vaseliu et al. 2005
Longitudinal study To evaluate the presence of oral manifestations associated with HIV infection in children.

Literature review
To discuss over the classification, prevalence and treatment of oral manifestations in HIVpositive children.
Oral lesions serve as markers for the deterioration of the immune system and progression of HIV.
The prevalence differs between regions.Three common orofacial lesions in children: oral candidiasis, enlargement of the parotid glands and lymphadenopathy.There is a significant association between the occurrence of oral lesions and immune suppression.

Retrospective cohort study
To assess whether HAART changes the patterns and prevalence of oral lesions in HIVpositive children.
Oral candidiasis was the most prevalent lesion.HAART use may be associated with a lower prevalence of oral lesions (especially oral hairy leukoplakia) compared to the use of ART.

Crosssectional study
To assess the accuracy of oral lesions related to HIV to predict the immunologic and virologic failure in HIVinfected children on HAART.
31.6% of children had oral lesions.Oral manifestations of HIV may be important markers for immunological suppression and for virological failure in Brazilian children on HAART.In all the studies analyzed, although they occurred in different regions and countries, oral manifestations were highlighted as a common feature in children infected with HIV virus.Most commonly found lesions were oral candidiasis in various forms 3,7,14,18 , gingivitis 2,13,14,16 , acute her-petic gingivostomatitis 2 , linear gingival erythema 1,10,17 , oral hairy leukoplakia 5,9,13 , Kaposi's sarcoma 1,5,15 and parotid enlargement 4,13,15,19 .However, almost all of them reported oral candidiasis as the most frequent manifestation, corroborating with the findings in literature.This fact can be ob- served in the analysis of Charts 1 to 4 and it will be further discussed in the course of this article.
Regarding periodontal conditions, it can be observed that when it comes to immunosuppressed patients, gingivitis can occur even when the patient is well hygienised and there is no bio-film, which does not happen with healthy children 2 .
In a longitudinal study, Vaseliu et al. 13 found that gingivitis was the most frequent oral lesion (49%), however, the authors suggest that the relevance of gingivitis in pediatric infection scenario is still unknown.On the other hand, Sowole et al. 16 found gingivitis (25.5%) as the second most prevalent lesion, followed by enlargement of parotid glands (3.6%).
Linear gingival erythema has also been described by some authors as a common oral manifestation in these patients 1,17 , besides also being considered as a unique feature of seropositive Enlargement of the parotid glands seems to be common even on ART (16.4%).The most frequent lesion was oral candidiasis (52.6%).patients by Tonelli et al. 1 .These characteristics reinforce the need for a careful clinical evaluation of periodontal condition for a possible early diagnosis ofthe HIV virus' presence in pediatric patients.
Oral candidias is and its pseudomembranous, angular cheilitis, erythematous and oropharyngeal variants were reported in most studies 1,2,16,17,19 .The first three variants have been described as the types known to be associated with HIV infection nowadays 11 .
Thus, it is possible to affirm that the opportunistic lesion most commonly associated with HIV-infected patients is oral candidiasis and that this finding is fundamental for the early diagnosis of AIDS [1][2][3]10,14,16,18,19 . In addition, tis oral manifestation may serve as a marker of disease progression and immunosuppression 2,5,13,15 since its prevalence is related to lower values ofTCD4+ lymphocytes 1 .
According to Konstantyner et al. 8 , candidias is has a considerable importance in the clinical prognosis of HIV infection, besides being a good indicator to show the non-efficacy of antiretroviral treatment.In their study, antiretroviral therapy (mono, double or triple/highly active) proved to be a significant protective factor against oral manifestations and the latter (triple/highly active) demonstrated a better beneficial effect to prevent candidias is in HIV-positive pediatric patients.
According to Pinheiro et al. 11 , the use of HAART significantly reduces oral manifestations associated with AIDS, because an improvement in the immune systemoccurs and consequently a decrease in the incidence and prevalence of opportunistic infections.Such finding was reported in other studies that compared oral manifestations in HIV-positive children with or without the use of this therapy, where those who received the medication had a lower prevalence of oral disorders than children who did not receive said treatment 9,10,12 .
Corroborating with the affirmative protective action of antiretroviral drugs, Meless et al. 19 observed in their study a low prevalence of oral lesions, possibly because all the children in the study were being treated with this type of medication.Jose et al. 6 compared patients that used and did not use HAART and observed that those on this medication had oral manifestations with moderate intensity, with a lower occurrence of oral candidiasis.In addition, there was a significant reduction in the presence oflesions when the treatment time with HAART was longer, especially in periods that exceed five months.
Ogumbosi et al. 3 study showed that the high number of deaths was related to pre-antiretroviral era and that lower mortality rates were observed when ART was instituted.On the other hand, Ponnamet al. 12 observed that the administration of HAART increased thedisease's free time, with a consequent raise in patients' survival rates.However, it is important to point out that unusual clinical manifestations of oral lesions may appear due to the immune response restoration, known as immune reconstitution syndrome (IRS).This may occur a few weeks after starting the treatment 11 and professionals involved should watch out for this adverse effect.
It is important to highlight that the use of HAART may be associated with a lower prevalence of oral lesions compared to the use of ART 9 .Therefore, it is possible to say that HAART plays a key role in reducing the prevalence of oral manifestations in HIV-positive pediatric patients, contributing substantially to give saidimmunosuppressed patients a better quality of life 11,18 .

Final Considerations
The findings of this study suggest that the most frequent oral manifestation in HIV-infected children is oral candidiasis, followed by alterations such as gingivitis and parotid glandsenlargement, being candidiasis regarded as a marker of disease progression.It is relevant to point out that oral manifestations are common in seropositive pediatric patients and treating them is fundamental to improve these children quality of life.In addition, HAART seems to reduce the prevalence of said oral lesions, making its use beneficial for patients.