Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis

Abstract

Summary

Highly active antiretroviral therapy has decreased the morbidity and mortality related to HIV infection, including oral opportunistic infections. This paper offers an analysis of the scientific literature on the epidemiological aspects of oral candidiasis in HIV-positive children in the combination antiretroviral therapy era. An electronic databases search was made covering the highly active antiretroviral therapy era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with highly active antiretroviral therapy and HIV/AIDS children. The following data were collected from each paper: year and country in which the investigation was conducted, antiretroviral treatment, oral candidiasis prevalence and diagnostic parameters (clinical or microbiological). Prevalence of oral candidiasis varied from 2.9% in American HIV-positive children undergoing highly active antiretroviral therapy to 88% in Chilean HIV-positive children without antiretroviral therapy. With respect to geographical location and antiretroviral treatment, higher oral candidiasis prevalence in HIV-positive children on combination antiretroviral therapy/antiretroviral therapy was reported in African children (79.1%) followed by 45.9% reported in Hindu children. In HIV-positive Chilean children on no antiretroviral therapy, high oral candidiasis prevalence was reported (88%) followed by Nigerian children (80%). Oral candidiasis is still frequent in HIV-positive children in the highly active antiretroviral therapy era irrespective of geographical location, race and use of antiretroviral therapy.

Keywords

Oral candidiasis HIV AIDS treatment opportunistic infection children highly active antiretroviral therapy oral lesions

Introduction

Human immunodeficiency virus (HIV) infection, one of the most important pandemics in the history of humanity, has been directly responsible for 35 million deaths from 1981 to date. Presently there are approximately 35.3 million people living with HIV.¹ In the mid-90s, the introduction of protease inhibitors of HIV-1 in antiretroviral therapy and their subsequent combination with other antiretroviral drugs resulted in the implementation of the so-called highly active antiretroviral therapy (HAART). The introduction of HAART resulted in a dramatic decrease in morbidity and mortality associated with HIV as well as in a reduction in the progression of the disease (AIDS).² HAART was beginning to shift a fatal disease to a chronic disease. Use of HAART has reduced the prevalence of opportunistic infections, including the oral infections, in both adults and children. This was reflected in an increase in life expectancy. A study in a cohort of American HIV-positive children prenatally infected showed a decrease in annual mortality and a prolongation in their survival.³ In high-income countries, HAART has caused an important decrease in the rate of vertical transmission (mother-child) of HIV and therefore in the incidence of paediatric AIDS,^4,5 due to its usefulness as antiretroviral prophylaxis during pregnancy. Vertical transmission rates decreased 35% in 2012 in comparison to 2009.¹ However, in 2010 there were approximately 2.3 million children living with HIV, 90% of them in the sub-Saharan region. HIV-positive children represent one of the most vulnerable sectors of our society.^6,7

Since the beginning of the HIV pandemic, oral lesions, specifically opportunistic infections, have been an important part of the clinical picture of the disease and in consequence oral health is considered an integral and inseparable part of the overall health of HIV patients. A compromised oral health affects quality of life, complicates the treatment of medical conditions and causes or exacerbates psychosocial and nutritional problems. Children with lesions in the oral mucosa manifest discomfort during eating; this situation may reduce their food intake. Malnutrition is an important mortality risk factor. The prevention and early diagnosis of oral infections increases the life expectancy and the welfare of HIV patients.⁸ Oral candidiasis (OC) has been attributed with important diagnostic and prognostic values for HIV infection and as a marker of antiretroviral therapy failure and therefore their clinical presence can be used as a criterion to make important therapeutic decisions.⁹ Therefore, and due to the fact that OC is the most frequent oral opportunistic infection in HIV-positive/AIDS-affected children, and with the purpose of updating scientific information on this issue, the present study offers a literature review on the prevalence of oral candidiasis in HIV-positive children in the HAART era.

Material and methods

The present study offers a literature review on the prevalence of OC in HIV-positive/AIDS children, with the purpose to update scientific information about OC in children infected with HIV in the HAART era. An electronic database (Medline-PubMed and Cochrane) search was conducted covering the HAART era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with HAART and HIV-positive/AIDS children. The following data were obtained from each paper: year in which the investigation was conducted, type of antiretroviral treatment employed, reported prevalence of oral candidiasis and diagnostic parameters used. In those papers which did not specify the year of the study, the year of publication of the article was used. When the paper was a cohort study and only bearing in mind the purpose of the present work, the final year of study of the cohort was used. With respect to antiretroviral therapy, HAART was defined as the combination of three or more antiretroviral drugs. Any other antiretroviral therapy was defined as antiretroviral therapy (ART). Only for research purposes inherent to this paper, the OC prevalence was used regardless of distribution of intraoral clinical forms reported. In such a way oral candidiasis included the pseudomembranous, erythematous or hyperplastic clinical form. In cases when prevalence of OC was not reported, but number of subjects studied and the number of cases of oral candidiasis were reported, and only for the research purposes of this study, the OC prevalence was calculated following the formula: prevalence = number of cases/number of subjects examined × 100 (%). The diagnostic technique employed was defined as microbiological when it included the microbiological culture and/or direct or indirect microscopic identification of Candida spp. With respect to the country where the study was conducted, studies were grouped according to their geographical location.

Results

It is commonly accepted that HAART/ART produce a decline in the prevalence of OC in HIV-positive children, however analyses of scientific literature in HAART era (1998 onwards) show varied figures of prevalence: from 2.9%¹⁰ in American children undergoing HAART to 88% in Chilean HIV-positive children with no ART.¹¹ This substantial variation could be justified by several facts: geographical distribution, characteristics of the studied population, type and time under antiretroviral treatment. The analyses of data in relation to their geographical location and type of antiretroviral treatment show different distribution. In Africa the prevalence of OC in HIV-positive children undergoing HAART/ART varied from 3.8%¹² to 79.1%;¹³ both data were provided from two different populations of Nigerian HIV-positive children. With respect to HIV-positive children without antiretroviral therapy reported in Africa, the lowest prevalence was observed in South African children (13.8%)¹⁴ and the highest one was reported in Nigerian HIV-positive children (80%)¹⁵ (Table 1). In Asia, with respect to children undergoing HAART, the lowest OC prevalence (3.1%) was reported in a multicentric study which involved the following countries: Cambodia, India, Indonesia, Malaysia and Thailand.²³ The highest OC prevalence was 45.9% reported in India.²⁴ On the other hand, the lowest OC prevalence reported in HIV-positive children not on ART was 13.5%²⁵ and the highest was 57.6%.²⁶ Both data were obtained from two different populations of Hindu HIV-positive children (Table 2). These data suggest that the prevalence of OC is high in some populations, whether or not they are undergoing antiretroviral therapy. Those data, even coming from the same country, may vary.

Table 1.

Prevalence of oral candidiasis in African HIV+ children in the HAART era.

HAART/ART					Not on ART
Country (year)	N	THER	OC (%)	DIAG	Country (year)	N	OC (%)	DIAG
West Africa (2012)¹⁶	420	ART	4.8	CLIN	South Africa (2000)¹⁷	69	40.5	CLIN
Uganda (2009)⁷	118	HAART	19.5	CLIN	South Africa (2001)¹⁸	169	55	CLIN
Uganda (2013)¹⁹	368	HAART	50.5	CLIN	South Africa (2007)¹⁴	87	13.8	CLIN/MICRO
Nigeria (2006)¹³	105	HAART (61.9%)	79.1	CLIN	South Africa (2010)²⁰	56	33.9	CLIN
Nigeria (2013)¹²	155	HAART	3.8	CLIN/MICRO	Uganda (2009)⁷	119	37	CLIN
Nigeria (2013)¹⁵	112	ART	40.1	CLIN	Nigeria (2001)²¹	31	38.2	CLIN
Dem Rep Congo (2004)²²	299	ART	38.4	CLIN	Nigeria (2013)¹⁵	15	80	CLIN

YEAR: year when the research was done or year of publication; N: number of patients; THER: therapy; HAART: highly active antiretroviral therapy; ART: antiretroviral therapy; OC: oral candidiasis; (%): prevalence; DIAG: diagnostic; CLIN: clinical; MICRO: microbiological.

Table 2.

Prevalence of oral candidiasis in Asian HIV-positive children in the HAART era.

HAART/ART					Not on ART
Country (year)	N	THER	OC (%)	DIAG	Country (year)	N	OC (%)	DIAG
Thailand (2000)²⁷	45	15 ART (30%)	35.5	CLIN	India (2003)²⁴	58	43.1	CLIN
Asia (2009)²³	1480	HAART	3.1	CLIN	India (2004)²⁵	1768	13.5	CLIN
Asia (2009)²³	272	ART	18.3	CLIN	India (2005)²⁸	212	56.1	CLIN/MICRO
India (2003)²⁴	37	ART (25.9%)	45.9	CLIN	India (2013)²⁶	53	57.6	CLIN
India (2012)²⁹	95	HAART	16.8	CLIN	India (2012)²⁹	95	28.4	CLIN
India (2013)²⁶	47	HAART	42.4	CLIN	India (2013)³⁰	50	32	CLIN
India (2013)³⁰	50	ART	14	CLIN	Thailand (2000)³¹	120	33	CLIN/MICRO
India (2013)³²	326	ART	20.8	CLIN	Thailand (2002)³³	40	45	CLIN/MICRO

With respect to children on HAART in North America the OC prevalence varied from 2.9% in USA¹⁰ to 24.2% in Mexican HIV-positive children³⁴ (Table 3); while in South America it was 4.7%³⁸ to 38.4%,³⁹ both data coming from Brazil. In South American HIV-positive children without ART the lowest prevalence was 27.4% (Brazilian children)⁴⁰ and the highest one was showed by HIV-positive children from Chile (88%)¹¹ (Table 4).

Table 3.

Prevalence of oral candidiasis in North American HIV-positive children in the HAART era.

Country (year)	N	THER	OC (%)	Diagnoses
USA (2000)¹²	102	HAART	2.9	CLIN
USA (2000)³⁵	38	HAART	24	CLIN/MICRO
USA (2004)³⁶	38	HAART/ART	23.6	CLIN/MICRO
Mexico (1999)³⁷	48	ARTV	20.8	CLIN/MICRO
Mexico (2007)³⁴	64	HAART	24.2	CLIN/MICRO

Table 4.

Prevalence of oral candidiasis in South American HIV-positive children in the HAART era.

HAART/ART					None ARTV
Country (year)	N	THER	OC (%)	DIAG	Country (year)	N	OC (%)	DIAG
Brazil (2001)⁴¹	38	ART	18.4	CLIN	Brazil (2000)⁴²	20	35	CLIN
Brazil (2002)³⁹	52	HAART	38.4	CLIN/ MICRO	Brazil (2001)⁴⁰	51	27.4	CLIN/ MICRO
Brazil (2002)⁴³	58	HAART/ART	12	CLIN	Brazil (2000)⁴⁴	143	37	CLIN
Brazil (2004)⁴⁵	223	HAART	10.3	CLIN	Venezuela 2010⁴⁶	41	73	CLIN
Brazil (2004)⁴⁵	236	ART	12.7	CLIN/MICRO	Chile (2002)¹¹	37	88	CLIN
Brazil (2008)³⁸	42	HAART/ART	4.7	CLIN
Brazil (2010)⁴⁷	65	HAART	10.7	CLIN/MICRO
Brazil (2011)⁴⁸	117	HAART	5.9%	CLIN/MICRO

In Europe, the reports on this issue topic are scarce. The highest OC prevalence was reported in Romanian HIV-positive children with no ART (50%)⁴⁹ while the lowest was reported in English HIV-positive children undergoing HAART (8.5%)⁵⁰ (Table 5).

Table 5.

Prevalence of oral candidiasis in European HIV-positive children in the HAART era.

HAART/ART					None ART
Country (year)	N	THER	OC (%)	DIAG	Country (year)	N	OC (%)	DIAG
UK (2000)⁵⁰	35	ART	8.5	CLIN	Rumania (2000)⁴⁹	48	50	CLIN
Rumania (2000)⁴⁹	56	ART	41	CLIN	Rumania (2001)⁵¹	173	29	CLIN
Rumania (2001)⁵²	238	ART	11	CLIN

Although the main objective of this work is focused on the epidemiology and therefore a microbiological analysis is beyond the scope of this paper, it is important to point out that high prevalence (from 88% to 100%) of oral carriers of Candida spp. in HIV-positive children in the HAART era are independent of ethnicity, geographical location or antiretroviral therapy.^47,48,33,53 Although C. albicans is still the most frequently isolated species in the HAART era, non-albicans species, specifically C. tropicalis,⁴⁸ C. glabrata and C. krusei,³³ represent from 18% to 40% of oral cultures.^33,54

Discussion

Our literature search suggests that the prevalence of OC is different in respect to geographical areas. It has been suggested that those countries located in tropical or equatorial regions show different patterns of infectious diseases. Tropical regions in general are areas where factors that favor opportunist infections are present, such as poor nutritional status, endemic tropical diseases (e.g. diarrhoea and tuberculosis), poor health care quality and other socio-economic factors.⁵⁵ Due to this apparent geographical distribution it has been suggested to incorporate the analysis and interpretation of OC prevalence, besides the obvious influence of HAART/ART availability, several important socio-demographic factors, e.g. nutritional status, endemic tropical diseases and health care quality to design better preventive strategies for HIV-infected children in developing countries.⁵⁶ The impact of specific issues related to the care of HIV-infected children in resource-poor settings, such as malnutrition, diagnosis of tuberculosis and antiretroviral dosing have not been sufficiently studied. Few reports have addressed the challenges of paediatric ART programmes outside of well-equipped settings, including the influence of social and structural aspects such as inadequate access to potable water, food and quality health care, and therefore the need for holistic interventions to reduce HIV-related mortality.

When the OC prevalence in the HAART era is analysed using the year data as the only parameter of research (1998 onwards), there are more scientific reports conducted in populations coming from developing countries and fewer data coming from developed countries. It is likely that this decrease in research on HIV-positive children could be related to a real decline in HIV paediatric patients associated with the establishment of successful strategies of prevention of mother-child transmission in countries with high resources.⁵⁷ Our review of scientific literature revealed a significant number of HIV-positive children who are not on ART including HAART. The availability and accessibility to antiretroviral drugs continues to be a very important factor, probably the most important, in the interpretation of the HAART era data. However, in spite of well-documented association of HAART with decrease of opportunistic infections, our information search yielded reports where HIV-positive children showed high prevalence of OC even when on HAART.^13,24 These results should not always be interpreted as failure of HAART because they could be related to the guidelines of ART treatment of these particular populations. Guidelines for initiating therapy may differ depending on the characteristics of the countries’ resources. In some countries the ART/HAART starts in patients with advanced disease or AIDS. For example HIV-positive children aged >5 years received ART if their CD4 count is <350 cells/mm³,²⁵ or they are in the stage 3 or 4 in the WHO clinical staging. The presence of OC has been proposed as a clinical proxy for immunosuppression and oesophageal candidiasis, and is currently considered a stage 3 disease in the WHO clinical staging. Hence it was reported, as opposed to the accepted position, that a major risk factor for the development of OC by paediatric HIV patients is ART.²⁵ In a study involving 65 HIV-positive Brazilian children recurrent OC was diagnosed more frequently in HAART^47,58 users and in African HIV-positive children with 2 years of HAART use it was reported that the incidence of OC had remained stable.⁵⁸ This high prevalence of OC in HIV-positive children on HAART could be related to drug interactions, complex dosing schedules, adverse effects and high costs of ART/HAART⁴; xerostomia associated with use of antidepressants, anxiolytics or analgesics and the individual response to ART/HAART regarding change in their immunological status.

Notwithstanding the epidemiological data, a decrease in the clinical episodes of OC in HIV patients undergoing HAART including protease inhibitors (PIs) has been reported.^58,59 Two mechanisms have been proposed to justify OC decrease: immune improvement and a direct antifungal effect of PIs. HIV-positive children appear to be able to induce normal mucosal responses to oral microorganisms, including Candida spp.⁶⁰ It has been observed that levels of Candida-specific secretory IgA in saliva are elevated in HIV-positive children as a response to oral yeast, suggesting that responsiveness of the secretory IgA system is maintained during HIV infection.⁵⁸ With respect to putative antifungal mechanism of PIs, these antiretroviral drugs inhibit fungal secretory aspartyl proteinases (SAPs). SAPs of C. albicans hydrolyse host protein components to facilitate the epithelial adherence, growth and tissue invasion. HIV-1 aspartyl protease and C. albicans SAPs belong to the superfamily of aspartic proteinases.⁶¹ Indinavir has been suggested as the most potent inhibitor of candidal adhesion to human epithelial cells, followed by saquinavir and ritonavir.⁶¹ However, because high concentrations of PIs (concentrations not reached in vivo) are required to inhibit C. albicans adherence in vitro, the aforementioned inhibitory mechanism would not be possible.⁶² It is likely that bioavailability of PIs in the saliva of HIV-positive children play an important role in their anticandidal effect. Future research is necessary in this field.

Although high prevalence of oral carriers of Candida spp. in HIV-infected children has been reported,^47,48,33,53 data are not conclusive. To date and to our knowledge there is no explanation to justify why some populations have high prevalence of oral carriers but decreased clinical episodes of oral candidiasis or why some populations of HIV-positive children show high prevalence of candida colonisation but others do not; however some mechanism have been suggested. De Bernardis et al.⁶³ found that HAART strongly inhibited the expression of SAP's influence on candida virulence without exerting any effect on the Candida spp. isolation. On the other hand, local factors like presence of dentinal carious teeth increase the probability of oral colonisation of Candida spp.⁴⁷ Further research should be aimed to confirm this interesting proposal.

In spite of C. albicans being the most frequently isolated species in the HAART era, Candida species mixed cultures have been observed in HIV-positive children.⁴⁷ The most common non-albicans Candida (NAC) species reported in HIV-positive children are C. tropicalis,⁴⁸ C. glabrata and C. krusei.³³ The prevalence of clinical antifungal resistance has increased in recent decades (HAART era) possibly related to the use of more azole antifungal drugs.^64,65 Candida spp. isolated from the oral cavity of HIV-positive children exhibited more resistance to fluconazole, followed by itraconazole, 5-fluorocytosine, ketoconazole and amphotericin B.⁶⁶ In an Mexican HIV population, C. glabrata and C. parapsilosis were resistant to itraconazole and to fluconazole,⁶⁵ while C. albicans isolates from Cambodian HIV-positive children on HAART were resistant to 5-fluorocytosine (5-FC) and NAC exhibited resistance to fluconazole, 5-FC, itraconazole and voriconazole.⁶⁷ Cross-resistance among azole antifungal agents correlates with refractory mucosal candidiasis and therefore is an additional cause for concern. The emergence of cross-resistance to ketoconazole, fluconazole, itraconazole, voriconazole⁶⁸ and clotrimazole⁶⁹ has been reported in HIV-positive children with OC.

Analysis of the literature showed very heterogeneous and socially different populations studied with different methodology. The data may be partial with respect to whether the children were on ART or not when they were orally examined, and in the case they were undergoing ART, which type of therapies were used and the time of utilisation. More well-designed treatment trials with larger samples are needed to identify similarities and differences in clinical, mycological and relapse rates. There is also a strong need for more research to be conducted on the treatment and prevention of OC in children.⁵⁸

The effect of HAART on the evolution of HIV disease was such that the HIV epidemic has been artificially separated into two eras: pre-HAART era (1981 to 1997/98) and HAART era (1998 onwards). Although the exact date indicating the beginning of the HAART era and therefore the end of the pre-HAART era has not been established, this date could be located in 1997/1998, when the clinical use of PIs was authorised and its combination with two nucleoside analogue reverse transcriptase nucleoside drugs was recommended. However, in the 15 or 16 years of the HAART era not all countries have availed themselves at the same time the different antiretroviral drugs and therefore the availability and accessibility of HAART has been partial. While the term “era” implies a time issue, in the case of the HAART era the term “era” depends on the availability and accessibility to different antiretroviral drugs. Consequently in 2014 there are countries that are “living in the HAART era” and countries that continue in the pre-HAART era. This gives rise to the question of whether to consider these results as representative of the HAART era?

Conclusions

The analyses of scientific literature show that HIV-positive children in the HAART era show a high prevalence of OC irrespective of geographical location, race and use of antiretroviral therapy. There are also populations that have limited accessibility or even more some that have no access to HAART. HIV-positive children where these oral opportunistic infections are still present could eventually present a clinically different picture or have different clinical behavior. Advances in medicine allowed increasing survival time of HIV-positive children, so it is expected that changes should occur in the clinical spectrum of the disease, as well as in the oral manifestations. Therefore, it seems very likely that HIV-positive children will continue to suffer opportunistic infections, including oral ones, unless there is a renewed effort to increase the availability of HAART.⁵⁷

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2013, Switzerland: WHO Library Cataloguing-in-Publication Data, 2013.

Montaner

JSG

Lima

Harrigan

. Expansion of HAART coverage is associated with sustained decreases in HIV/AIDS morbidity, mortality and HIV transmission: the “HIV Treatment as Prevention” experience in a Canadian setting. PLoS One 2014; 9: e87872–e87872.

Kapogiannis

Soe

Nesheim

. Mortality trends in the US Perinatal AIDS Collaborative Transmission Study (1986--2004). Clin Infect Dis 2011; 53: 1024–1034.

Gona

Van Dyke

Williams

. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006; 296: 292–300.

Stringer

Ekouevi

Coetzee

. Coverage of nevirapine-based services to prevent mother-to-child HIV transmission in 4 African countries. JAMA 2010; 304: 293–302.

Desclaux

Alfieri

. L'annonce du statut VIH de l'enfant: expériences des mères et interprétations des soignants au Burkina Faso. SAHARA J 2013; 10: S81–S92.

Rwenyonyia

Kutesaa

Muwazia

. Oral Manifestations in HIV/AIDS-Infected Children. Eur J Dent 2011; 5: 291–298.

Walker

Mulenga

Sinyinza

. CHAP Trial Team: Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial. J Acquir Immune Defic Syndr 2006; 42: 637–645.

Gaitán-Cepeda

Martínez-González

Ceballos-Salobreña

. Oral candidosis as a clinical marker of immune failure in patients with HIV/AIDS on HAART. AIDS Patient Care STDS 2005; 19: 70–77.

10.

Okunseri

Badner

Wiznia

. Prevalence of oral lesions and percent CD4+ T-lymphocytes in HIV-infected children on antiretroviral therapy. AIDS Patient Care STDS 2003; 17: 5–11.

11.

Tassara

Alarcón

Larrañaga

. Digestive pathology in children infected with the human immunodeficiency virus (HIV), in Santiago de Chile. Rev Med Chil 2003; 131: 19–24.

12.

Katibi

Ogunbiyi

Oladokun

. Mucocutaneous disorders of pediatric HIV in South West Nigeria: surrogates for immunologic and virologic indices. J Int Assoc Provid AIDS Care. Epub ahead of print 20 Sep 2013. DOI: 10.1177/2325957413502540.

13.

Adebola

Adeleke

Mukhtar

. Oral manifestation of HIV/AIDS infections in paediatric Nigerian patients. Niger Med J 2012; 53: 150–154.

14.

Blignaut

. Oral health needs of HIV/AIDS orphans in Gauteng, South Africa. AIDS Care 2007; 19: 532–538.

15.

Oladokun

Okoje

Osinusi

. Oral lesions and their association with CD4 count and viral load in HIV positive Nigerian children. Oral Health Dent Manag 2013; 12: 200–204.

16.

Meless

Faye

. Oral lesions among HIV-infected children on antiretroviral treatment in West Africa. Trop Med Int Health 2014; 19: 246–255.

17.

Van Gend

Haadsma

Sauer

. Evaluation of the WHO clinical case definition for pediatric HIV infection in Bloemfontein, South Africa. J Trop Pediatr 2003; 49: 143–147.

18.

Naidoo

Chikte

. Oro-facial manifestations in paediatric HIV: a comparative study of institutionalized and hospital outpatients. Oral Dis 2004; 10: 13–18.

19.

Nabbanja

Gitta

Peterson

. Orofacial manifestations in HIV positive children attending Mildmay Clinic in Uganda. Odontology 2013; 101: 116–120.

20.

Duggal

Abudiak

Dunn

. Effect of CD4+ lymphocyte count, viral load, and duration of taking anti-retroviral treatment on presence of oral lesions in a sample of South African children with HIV+/AIDS. Eur Arch Paediatr Dent 2010; 11: 242–246.

21.

Ojukwu

Ogbu

. HIV infection in hospitalized children with endemic diseases in Abakaliki, Nigeria: the role of clinically directed selective screening in diagnosis. AIDS Care 2007; 19: 330–336.

22.

Callens

Shabani

Lusiama

. Mortality and associated factors after initiation of pediatric antiretroviral treatment in the Democratic Republic of the Congo. Pediatr Infect Dis J 2009; 28: 35–40.

23.

Prasitsuebsai

Kariminia

Puthanakit

. Impact of antiretroviral therapy on opportunistic infections of HIV-infected children in the TREAT Asia pediatric HIV observational database. Pediatr Infect Dis J 2013. Epub ahead of print 30 Dec. DOI: 10.1097/INF.0000000000000226.

24.

Madhivanan

Mothi

Kumarasamy

. Clinical manifestations of HIV infected children. Indian J Pediatr 2003; 70: 615–620.

25.

Rajasekaran

Jeyaseelan

Raja

. Demographic & clinical profile of HIV infected children accessing care at Tambaram, Chennai, India. Ind J Med Res 2009; 129: 42–49.

26.

Jose

Chandra

Puttabuddi

. Prevalence of oral and systemic manifestations in pediatric HIV Cohorts with and without Drug Therapy. Curr HIV Res 2013; 11: 498–505.

27.

Khongkunthian

Grote

Isaratanan

. Oral manifestations in 45 HIV-positive children from Northern Thailand. J Oral Pathol Med 2001; 30: 549–552.

28.

Ranganathan

Umadevi

Saraswathi

. Oral lesions and conditions associated with human immunodeficiency virus infection in 1000 South Indian patients. Ann Acad Med Singapore 2004; 33: 37–42.

29.

Ponnam

Srivastava

Theruru

. Oral manifestations of human immunodeficiency virus in children: an institutional study at highly active antiretroviral therapy centre in India. J Oral Maxillofac Pathol 2012; 16: 195–202.

30.

Baghirath

Krishna

Gannepalli

. Oral manifestations of HIV in children receiving anti-retroviral therapy in Hyderabad, India. Eur Arch Paediatr Dent 2013; 14: 389–395.

31.

Wananukul

Thisyakorn

. Mucocutaneous manifestations of HIV infection in 91 children born to HIV-seropositive women. Pediatr Dermatol 1999; 16: 359–363.

32.

Kumar

Mohan

Reddy

. Associated oral lesions in human immunodeficiency virus infected children of age 1 to 14 years in antiretroviral therapy centers in Tamil Nadu. Contemp Clin Dent 2013; 4: 467–471.

33.

Pongsiriwet

Iamaroon

Sriburee

. Oral colonization of Candida species in perinatally HIV-infected children in northern Thailand. J Oral Sci 2004; 46: 101–105.

34.

Gaitán-Cepeda

Domínguez-Sánchez

Pavía-Ruz

. Oral lesions in HIV+/AIDS adolescents perinatally infected undergoing HAART. Med Oral Patol Oral Cir Bucal 2010; 15: e545–e550.

35.

Flanagan

Barasch

Koenigsberg

. Prevalence of oral soft tissue lesions in HIV-infected minority children treated with highly active antiretroviral therapies. Pediatr Dent 2000; 22: 287–291.

36.

Barasch

Safford

Dapkute-Marcus

. Efficacy of chlorhexidine gluconate rinse for treatment and prevention of oral candidiasis in HIV-infected children: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 97: 204–207.

37.

Gaitán-Cepeda

Cashat-Cruz

Morales-Aguirre

. 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: 151–156.

38.

Silva-Boghossian

Castro

Teles

. Salivary microbiota of HIV-positive children and its correlation with HIV status, oral diseases, and total secretory IgA. Int J Paediatr Dent 2008; 18: 205–216.

39.

Melo

Taguchi

Culhari

. Oral candidiasis of HIV-infected children undergoing sequential HIV therapies. Med Mycol 2009; 47: 149–156.

40.

Fonseca

Cardoso

Pomarico

. Frequency of oral manifestations in children infected with human immunodeficiency virus. Quintessence Int 2000; 31: 419–422.

41.

Magalhães

Bueno

Serra

. Oral manifestations of HIV positive children. J Clin Pediatr Dent 2001; 25: 103–106.

42.

Gondim

Zonta

Fortkamp

. Otorhinolaryngological manifestations in children with human immunodeficiency virus infection. Int J Pediatr Otorhinolaryngol 2000; 54: 97–102.

43.

de Araújo Castro

de Souza

. Pediatric HIV-related oral manifestations: a five-year retrospective study. Braz Oral Res 2004; 18: 6–11.

44.

Grando

Yurgel

Machado

. Oral manifestations, CD4+ T-lymphocytes count and viral load in Brazilian and North-American HIV-infected children. Pesqui Odontol Bras 2002; 16: 18–25.

45.

Miziara Id Weber

. Oral lesions as predictors of highly active antiretroviral therapy failure in Brazilian HIV-infected children. J Oral Pathol Med 2008; 37: 99–106.

46.

Dávila

Gil

. Oral manifestations and dental caries in children exposed to human immunodeficiency virus. Rev Salud Pública (Bogota) 2011; 13: 833–843.

47.

Cerqueira

Portela

Pomarico

. Oral Candida colonization and its relation with predisposing factors in HIV-infected children and their uninfected siblings in Brazil: the era of highly active antiretroviral therapy. J Oral Pathol Med 2010; 39: 188–194.

48.

Domaneschi

Massarente

De Freitas

. Oral colonization by Candida species in AIDS pediatric patients. Oral Dis 2011; 17: 393–398.

49.

Chen

Flaitz

Wullbrandt

. Association of dental health parameters with oral lesion prevalence in human immunodeficiency virus-infected Romanian children. Pediatr Dent 2003; 25: 479–484.

50.

Gelbier

Lucas

Zervou

. A preliminary investigation of dental disease in children with HIV infection. Int J Paediatr Dent 2000; 10: 13–18.

51.

Flaitz

Wullbrandt

Sexton

. Prevalence of orodental findings in HIV-infected Romanian children. Pediatr Dent 2001; 23: 44–50.

52.

Vaseliu

Carter

Kline

. 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: 1067–1071.

53.

Cerqueira

Portela

Soares

. Comparison of techniques to evaluate the quantification of Candida spp. in HIV-infected children. Gen Dent 2009; 57: 438–441.

54.

Gaitán-Cepeda

Sánchez-Vargas

Pavia-Ruz

. Oral Candida in Mexican children with malnutrition, social marginalization, or HIV/AIDS. Rev Panam Salud Publica 2012; 31: 48–53.

55.

Alarcón

Freimanis-Hance

Krauss

. Opportunistic and other infections in HIV-infected children in Latin America compared to a similar cohort in the United States. AIDS Re Hum Retroviruses 2012; 28: 282–288.

56.

De Beaudrap

Boullé

Lewden

. Morbidity after antiretroviral therapy initiation in HIV-1–infected children in West Africa: temporal trends and relation to CD4 count. Pediatr Infect Dis J 2013; 32: 354–360.

57.

Pienaar

Young

Holmes

. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst Rev 2010; 11: CD003940–CD003940.

58.

Pomarico

Ferraz Cerqueira

. 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: 203–210.

59.

Ceballos-Salobreña

Gaitán-Cepeda

Ceballos-Garcia

. Oral lesions in HIV/AIDS patients undergoing highly active antiretroviral treatment including protease inhibitors: a new face of oral AIDS? AIDS Patient Care STDS 2000; 14: 627–635.

60.

Alves

Simões

Soares

. Salivary lactoferrin in HIV-infected children: Correlation with Candida albicans carriage, oral manifestations, HIV infection and its antifungal activity. Arch Oral Biol 2014; 59: 775–782.

61.

Tsang

CSP

Hong

. HIV protease inhibitors differentially inhibit adhesion of Candida albicans to acrylic surfaces. Mycoses 2010; 53: 488–494.

62.

Cerqueira

Portela

Pomarico

63.

De Bernardis

Tacconelli

Mondello

. Anti-retroviral therapy with protease inhibitors decreases virulence enzyme expression in vivo by Candida albicans without selection of avirulent fungus strains or decreasing their anti-mycotic susceptibility. FEMS Immunol Med Microbiol 2004; 41: 27–34.

64.

Mulu

Kassu

Anagaw

. Frequent detection of ‘azole’ resistant Candida species among late presenting AIDS patients in northwest Ethiopia. BMC Infect Dis 2013; 13: 82–82.

65.

Sánchez-Vargas

Ortiz-López

Villar

. Point prevalence, microbiology and antifungal susceptibility patterns of oral Candida isolates colonizing or infecting Mexican HIV/AIDS patients and healthy persons. Rev Iberoam Micol 2005; 22: 83–92.

66.

Bosco

Birman

Cury

. Yeasts from the oral cavity of children with AIDS: exoenzyme production and antifungal resistance. Pesqui Odontol Bras 2003; 17: 217–222.

67.

Shahum

Liskova

Kalavsky

. Voriconazole resistant Candida spp. and Saccharomyces spp. isolates from oropharyngeal candidiasis from Cambodian children with AIDS not pretreated with azoles (letter). Scand J Infect Dis 2007; 39: 286–287.

68.

Müller

Weig

Peter

. Azole cross-resistance to ketoconazole, fluconazole, itraconazole and voriconazole in clinical Candida albicans isolates from HIV-infected children with oropharyngeal candidosis. J Antimicrob Chemother 2000; 46: 338–340.

69.

Pelletier

Peter

Antin

. Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations. J Clin Microbiol 2000; 38: 1563–1568.