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The association between oral disease and type of antiretroviral therapy among perinatally HIV-infected youth

Shiboski, Caroline H.a; Yao, Tzy-Jyunb; Russell, Jonathan S.b; Ryder, Mark I.a; Van Dyke, Russell B.d; Seage, George R. IIIc; Moscicki, Anna-Barbarae for the Pediatric HIV/AIDS Cohort Study

Author Information
doi: 10.1097/QAD.0000000000001965

Abstract

Introduction

Combination antiretroviral therapy (cART) has been very successful at preserving immune function and controlling opportunistic infections among individuals infected with the HIV [1]. Oral mucosal diseases associated with advanced immunosuppression such as candidiasis and hairy leukoplakia are significantly less common among patients on cART [2–11]. In a recent study among perinatally HIV-infected (PHIV) youth participating in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study (PHACS), oral mucosal lesions were very rare [12]. This was not surprising, as the majority of youth had been on cART for many years. In contrast, this group was found to have a high burden of dental and periodontal disease with 61% having at least one tooth with untreated caries, and over 30% having some form of periodontitis [12,13]. In comparison to perinatally HIV-exposed uninfected (PHEU) youth in AMP, PHIV youth had a greater mean number of untreated decayed teeth, whereas no differences were found between groups with respect to periodontal disease. Of note, there were no differences in cumulative history of caries between HIV-infected and uninfected groups suggesting a more recent influence on the development of current caries. Although these analyses were comprehensive in their consideration of potential risk factors for dental and periodontal disease, the effect of type of ART exposure was not assessed.

To date, 24 Food and Drug Administration-approved drugs, organized into six distinct classes, are available for treatment of HIV-1 infections: nucleoside-analogue reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, fusion inhibitors, integrase inhibitors and coreceptor antagonists [14]. Given the different mechanisms of action of these drugs, their effect on the oral microbiome might vary, which may in turn affect dental and periodontal conditions. Thus, the objective of this study was to examine the association between ART and oral health outcomes (dental and periodontal diseases) among PHIV youth participating in the AMP/PHACS Oral Health Substudy, controlling for indicators of HIV disease severity. We did not include oral mucosal disease as an endpoint given its very low prevalence in this study population [12].

Materials and methods

Study design and population

We conducted a cross-sectional study of oral health among participants in 11 AMP/PHACS sites [12,13]. As described previously, PHACS is a prospective cohort study designed to determine the impact of HIV infection and ART among PHIV youth [15,16].

The study was approved by Institutional Review Boards (IRBs) at clinical sites, and at the Harvard T.H. Chan School of Public Health. Parents or legal guardians provided written informed consent for their child's participation. Youth consented or assented per local IRB guidelines.

Variables and measures

Pediatric HIV/AIDS Cohort Study database and data collection overview

Variables and measures collected as part of the oral study and/or obtained from the PHACS/AMP database have been described previously [12,13]. Sixteen dentists at 11 sites were trained and calibrated on how to perform a standardized oral mucosal, dental and periodontal examination. The mean (SD; range) concordance level was 97.7% (2.4%; 92–100%) for probing depths, 98.3% (2.4%; 92–100%) for gingival margin and 99.2% (1.3%; 96–00%) for the presence/absence of clinically detectable caries [12].

Dental and periodontal endpoints

The decayed-missing-filled-surfaces and teeth index (DMFS/T) was used to assess the prevalence and history of dental caries, and the number of decayed surfaces and teeth was used to assess untreated active caries [17]. The Plaque Index developed by Silness and Löe [18] was measured on all teeth (one buccal and one lingual site per tooth) as an objective measure of oral hygiene. Extensive periodontal parameters were measured on six sites per tooth, including the bleeding on probing (BOP) [13]. The number of teeth with BOP at more than one site was derived. All tooth counts were corrected for missing teeth by multiplying by the ratio of 28 over the number of scored teeth.

On the basis of the periodontal parameters of attachment loss and probing depth, periodontitis was defined as absent, mild, moderate or severe in accordance with the Centers for Disease Control and Prevention and the American Academy of Periodontology (CDC-AAP) case definition [19]. Among those with no periodontitis, we used a definition for gingivitis adapted from work by Offenbacher et al. [20] wherein individuals had to have BOP on at least 10% of the sites scored to be considered as having gingivitis. A 5-min unstimulated whole saliva flow rate was performed [21,22].

Exposure to antiretroviral therapy

The main variables of interest reflected exposure to ART. For this analysis, cART was defined as any regimen containing at least three drugs from at least two drug classes. Classes considered were NRTI, NNRTI, protease inhibitors, fusion inhibitors and integrase inhibitors.

Any regimen that stopped before a cutoff of 6 weeks (42 days) after birth was considered prophylaxis and not considered as part of our analyses. Likewise, any regimen that lasted less than 3 days was not considered.

When exploring history of ART, we considered if a participant had ever received cART and any drug within each class of medication as binary variables. Age at first exposure to any ART, cART and class of medication was explored both as a continuous variable (years), and as a categorized variable: less than 2, 2 to less than 6, 6 years or older.

When exploring the current ART regimen, we defined participants on a specific regimen as ‘current stable ART regimen’ with a start date at least 1 year prior to the oral health examination, and who had no changes to the regimen during that time. To explore the effect of specific classes of medications included in cART, we grouped the regimens by several categorized variables for the most common classes as follows: cART inclusive of an NNRTI vs. cART without NNRTI; cART inclusive of a protease inhibitor vs. cART without protease inhibitor; and cART inclusive of integrase inhibitor vs. cART without integrase inhibitor.

Clinical indicators of history of, and current, HIV disease severity

HIV disease severity history was considered in the characterization of the study participants and in various analyses using the following clinical indicators (among all available lifetime measures up to the time of the oral examination): percentage of HIV RNA measures detectable (>400 copies/ml), CD4+ cell count nadir (dichotomized to <200 or ≥200 cells/μl) and history of a clinical AIDS-defining illness (as defined in CDC Stage 3) [23].

Current HIV disease severity was considered in the characterization of the study sample and in various analyses using the following binary clinical indicators measured at or within 90 days of the oral study visit: HIV RNA viral load (≤400 or >400 copies/ml) and CD4+ cell count (<350 or ≥350 cells/μl).

Statistical analyses

The study population was characterized descriptively for history of ART exposure, current ART exposure, history of HIV disease severity and current HIV disease severity. Summary statistics were calculated for continuous measures, and frequencies were calculated for discrete measures.

Summary statistics of the dental and periodontal tooth count endpoints were calculated. Considering the excess zero and overdispersion relative to Poisson distribution for decayed teeth or other tooth counts, zero-inflated negative binomial (ZINB) models [12,13] were applied to assess the association between each ART exposure measure and dental or periodontal outcomes (SAS proc genmod). We used a directed acyclic graph (DAG) to distinguish between variables, which could play potential confounding vs. mediating roles [24,25]. Thus, all models were adjusted for age, and historical HIV disease severity using two indicators selected on the basis of their associations with the ART exposures and oral health outcomes, the input of the principal investigators and their interpretability: the percentage of detectable HIV RNA measurements over the participant's lifetime up to the oral health visit and CD4+ cell count nadir (< vs. ≥200 cells/μl). An example of DAG drawn in exploring decayed teeth as a primary outcome is shown in supplemental Figure 1, https://links.lww.com/QAD/B340. All variables were only assessed through the negative binomial component of the ZINB models. We used a similar approach, relying on a similar DAG with age and historical HIV disease severity as confounders, to explore the association between age at first cART exposure and dental or periodontal outcomes. We explored both cART and specific drug classes.

Results

Sociodemographic, HIV disease and oral disease characteristics

Among 335 participants enrolled from 11 sites, 209 were PHIV, 53% of the PHIV youth were female, 63% were non-Hispanic blacks, 27% were Hispanic, 10% were white/other, 16% were 10–13 years, 61% were 14–18 years and 23% were 19 years or older at enrolment [12]. Only 38% lived with a caregiver who was their biological parent, 71% had a caregiver who had graduated high school and for 44% the main caregiver's income was $20 000 per year or less.

The median current HIV RNA viral load was 40 copies/mL [first quartile (Q1): 20; third quartile (Q3): 1760], and 66 (32%) PHIV youth had a current viral load more than 400 copies/ml; the median current CD4+ cell count was 626 cells/μl (Q1: 441; Q3: 825), and 38 (18%) had a current CD4+ cell count less than 350 cells/μl (supplemental Table 1, https://links.lww.com/QAD/B340). Over their lifetime, 70 (33%) had a CD4+ cell count nadir less than 200 cells/μl, 51 (24%) had a history of an AIDS-defining illness and the median percentage of lifetime viral load measures that were detectable was 45% (Q1: 20%; Q3: 70%).

As previously described, 61% of PHIV youth had at least one tooth with untreated dental caries, and the mean number of decayed teeth among PHIV was 2.2 (SD 3.3) [12]. The mean number of decayed teeth and DMFT scores were higher in PHIV youth with a CD4+ cell count nadir less than 200 cells/μl (3.2; SD: 4.6) than among those with a nadir at least 200 cells/μl (1.7; SD: 2.4).

History of antiretroviral therapy and current regimens received by perinatally HIV-infected youth

All PHIV youth had received ART at some point since birth, and 198 (95%) were on ART at the time of the oral health visit. All youth received an NRTI at some point in time, the next most common antiretroviral class ever received by this group was a protease inhibitor (91%) followed by an NNRTI (67%; Table 1). The median age when an NRTI was initiated was 0.6 year, and around 3 years for the first protease inhibitor among those who ever received a protease inhibitor, while the median age at first integrase inhibitor was 14.7 years. Nearly three-quarters of PHIV youth had been on the same regimen (or no treatment) for the past year, including 143 (93%) on cART. Among the 143 on stable cART, 78% were receiving a regimen containing protease inhibitor, 30% an NNRTI and 20% integrase inhibitor (Table 2).

T1-7
Table 1:
History of antiretroviral therapy received by 209 perinatally HIV-infected youth participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Studya.
T2-7
Table 2:
Current stable combination antiretroviral therapya regimen (unchanged for past year prior to study entry)b among 153 perinatally HIV-infected youth participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study.

Association between current combination antiretroviral therapy regimen and oral outcomes

Current combination antiretroviral therapy, dental disease and salivary function

Among 143 PHIV youth on the same cART for at least 1 year, cART with protease inhibitor or cART with NNRTI were not associated with either DMFS/T or decayed surface and teeth. However, those who received a cART regimen containing an integrase inhibitor had a significantly higher number of decayed teeth and decayed surface than those receiving cART without integrase inhibitor (P < 0.001 and P = 0.002, respectively), and a higher DMFT score, although this was not statistically significant (Table 3). The mean decayed teeth score for youth who received cART with an integrase inhibitor was 86% higher than those who received cART without integrase inhibitor after adjusting for the lifetime proportion of viral load, which were suppressed and nadir CD4+ cell count (Table 4).

T3-7
Table 3:
Exposure to integrase inhibitors as part of combination antiretroviral therapya regimen by oral health outcomes among 143 perinatally HIV-infected youth participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study and having received the same combination antiretroviral therapy for the past year prior to oral health study entry.
T4-7
Table 4:
Zero-inflated negative binomial multivariable model exploring the association between stable combination antiretroviral therapya with integrase inhibitor and number of decayed teeth, controlling for age, HIV RNA viral load and CD4+ cell count nadir, among 143 perinatally HIV-infected youth participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study and having received the same combination antiretroviral therapy regimen for the past year prior to study entry.

Because a low salivary flow rate is associated with caries, we examined its association with cART. Although no difference was found with respect to unstimulated salivary flow rate between those on cART with an integrase inhibitor and those on cART without, the median flow rate among PHIV youth on the same cART with NNRTI for at least 1 year was 0.5 ml/min (Q1: 0.3 and Q3: 1 mL/min) compared with 0.8 ml/min (Q1: 0.5 and Q3: 1.2 ml/min) among youth on cART without NNRTI (P = 0.007). However, no difference was detected with respect to DMFS/T or decayed surface and teeth between those receiving a cART with NNRTI compared with those receiving a cART without. Similarly, no difference was detected with respect to DMFS/T or decayed surface and teeth among those receiving the same cART with protease inhibitor for at least 1 year compared with those receiving a cART without.

Current combination antiretroviral therapy and periodontal disease

With respect to periodontal disease, there was no difference between those receiving a cART with vs. without an integrase inhibitor, or between those receiving a cART with vs. without protease inhibitor. Mild to moderate periodontitis was diagnosed in 25% of PHIV youth receiving a cART with NNRTI compared with 41% among PHIV youth receiving a cART without NNRTI, and number of teeth with BOP at two to six sites were also lower in youth receiving a cART with NNRTI (mean 7.9 vs. 10.0, Supplemental Table 2, https://links.lww.com/QAD/B340), but this difference was not statistically significant (P = 0.09).

Association between age of first exposure to combination antiretroviral therapy regimen and oral outcomes

PHIV youth with a later initiation of cART had significantly higher DMFS and DMFT scores, and higher number of teeth with multiple BOP sites, than youth whose exposure initiation was at a younger age (Table 5). The DMFS/T difference was particularly notable among PHIV youth with a later initiation of protease inhibitor with a median DMFS of 10 [Q1: 4; Q3: 21] in youth at least 6 years of age at initiation compared with a median DMFS of 7 [Q1 : 2; Q3 : 13] and 4 [Q1: 0; Q3: 8] among those who initiated protease inhibitor between age 2 and 6 years and before age 2 years, respectively (Kruskal–Wallis test, P < 0.001). However, a similar difference was not observed among different age groups of NNRTI initiation, and number of untreated caries (decayed surface and teeth) did not differ across the various initiation age groups.

T5-7
Table 5:
Age of first exposure to combination antiretroviral therapya by dental and periodontal outcomes among 205 perinatally HIV-infected youth ever exposed to combination antiretroviral therapy participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Studyb.

The association between age at first exposure to cART and DMFS/T did not persist after adjusting for age at evaluation, lifetime proportion of unsuppressed viral load and low CD4+ cell count nadir. However, initiating protease inhibitor before the age of 2, or between the ages of 2 and less than 6 years, was associated with a significantly lower DMFT score than participants who initiated at age 6 and older (Table 6).

T6-7
Table 6:
Zero-inflated negative binomial multivariable model exploring the association between age at first protease inhibitor and decayed-missing-filled-teeth score (n = 204), controlling for age at oral health study entry, HIV viral load and CD4+ cell count nadir, among perinatally HIV-infected youth participating in the Oral Health study of the Adolescent Master Protocol of the Pediatric HIV/AIDS Cohort Study.

With respect to periodontal disease, the most notable finding was an association between age at first exposure of cART and BOP. The median number of teeth with at least two sites with BOP was significantly higher among youth who started cART older (Table 5). This association was still significant after adjustment (Table 7). Also of note, the median number of teeth with at least two sites exhibiting BOP was significantly higher among youth who were 6 years and older at the time NNRTI initiation [(7 [Q1: 2; Q3: 15)], and among those ages 2–6 years at NNRTI initiation [9.5 (Q1: 5; Q3: 16)], compared with those who initiated NNRTI younger than 2 years [4.5 (Q1: 2.5; Q3: 9); P = 0.02 using a Kruskal–Wallis test].

T7-7
Table 7:
Zero-inflated negative binomial multivariable model exploring the association between age at first combination antiretroviral therapya and number of teeth with bleeding on probing, 2–6 sites (n = 200), controlling for age at oral health study entry, HIV viral load and CD4+ cell count nadir, among perinatally HIV-infected youth participating in the Oral Health study in the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study.

Discussion

In this unique study exploring the effect of various cART regimens on caries and periodontal outcomes among PHIV youth, those who received a cART regimen containing an integrase inhibitor had a significantly higher number of untreated active caries than those on cART without an integrase inhibitor, after adjusting for age at oral examination, life history of unsuppressed viral load and low CD4+ cell count nadir. Of note, integrase inhibitors were initiated, if ever, at a much older age. Considering lifetime exposure to ART, PHIV youth with a later initiation of a protease inhibitor (the majority of them received a protease inhibitor as part of cART) had significantly higher DMFT/S scores than those initiating a protease inhibitor at an earlier age, after controlling for age at evaluation. With respect to periodontal disease, there was no difference between those receiving cART with vs. without integrase inhibitor. However, those with a later initiation of cART had significantly higher number of teeth with multiple BOP sites than youth whose initial exposure was at a younger age. The associations between age at first cART exposure and BOP persisted after adjusting for current age, lifetime proportion of unsuppressed viral load and low CD4+ cell count nadir.

Although multiple studies among adults with HIV disease have shown that the prevalence of oral mucosal lesions is significantly lower among adult patients on ART in both the developed and developing world [2–11], scarce data addressing this topic have been published among HIV-infected children. The few studies reported among children have been conducted mainly in developing countries [26–31]. Among those that included children receiving ART, while the prevalence of oral mucosal lesions was lower among these children than among those not receiving ART, these estimates were overall much higher than those we observed among PHIV youth, who had almost no oral mucosal lesions [12]. This is likely because PHIV youth in AMP/PHACS were prescribed cART early in life and have remained on it for most of their lives. This is consistent with our finding that the PHIV youth who initiated cART before age 2 had a lower prevalence of gingival inflammation, as suggested by a lower number of teeth with BOP, and those who initiated protease inhibitor earlier in life had a significantly lower score of DMFS/T, which reflects the history of caries. Another possible explanation is that the group of youth who started cART earlier in life may have had better access to care, including dental care, although 87% of PHIV youth who initiated cART before age 2 years reported having a source of dental care at the time of this study, compared with 74% of the youth who initiated cART after age 2 years (data not shown), and adjusting for this factor did not change the estimate of the association.

With respect to our finding that among PHIV youth on the same cART for at least 1 year, those who received cART containing integrase inhibitor had significantly higher numbers of decayed surface and teeth than those on cART without integrase inhibitor: as integrase inhibitors are often used as salvage therapy, the group receiving integrase inhibitor was possibly sicker closer to the time of the oral examination (as they typically initiated integrase inhibitor during adolescence), which could partly explain the higher prevalence of caries in that group, that persisted when explored with a multivariable model. The DMFT/S was not found to be significantly higher in the group receiving integrase inhibitor, presumably because it captures long-term history of caries, rather than more recent active disease. Sicker youth may be less likely to seek dental care due to ascendance of medical concerns, decreased energy. This finding may also reflect decreased ability of caregiver to address medication adherence of youth. Older age may be another possible explanation; however, age was not found to be associated with decayed teeth in our initial multivariable model exploring this association. It may also be that integrase inhibitor alters the oral microbiome to select more cariogenic bacteria. We are currently exploring this hypothesis through ongoing oral microbiome studies. Salivary hypofunction is also a known risk factor for the development of sudden onset caries, and although we did not find that those on integrase inhibitor had lower saliva flow rate than those not receiving integrase inhibitor, a difference may not have been detected reliably given the cross-sectional nature of our study. Furthermore, both groups had an unstimulated salivary flow rate that was above the 0.1 ml/min threshold and were not considered as having salivary hypofunction [22].

Our study is unique in that our team of trained/calibrated dentists performed a comprehensive standardized oral examination (including an oral soft tissue examination, caries assessment and full mouth periodontal evaluation) in a group of PHIV youth with extensive and complete medical history data, including ART, collected at regular time intervals since the onset of the AMP/PHACS project more than a decade ago. The limitation of our study is that it is cross-sectional, which hampers the determination of causality in the associations we uncovered. However, we are in the process of implementing a follow-up visit to our oral AMP/PHACS substudy, which will allow us to further explore some of our findings as youth transition to adulthood.

Studies have shown that early initiation of cART is associated with better health outcomes in children [15,32–34], and the present study suggests that this is also true for oral health outcomes, including dental and gingival health. For instance, we found that PHIV youth who initiated protease inhibitor earlier in life had significantly lower DMFS/T scores, and those who initiated cART before age 2 had a lower prevalence of gingival inflammation. Furthermore, the finding that PHIV youth who received a cART regimen containing integrase inhibitor had a significantly higher number of DT/S than those on cART without integrase inhibitor suggest that youth receiving integrase inhibitor should undergo closer surveillance of their dental status through preventive visits scheduled perhaps as often as three times per year. Daily topical fluoride home applications and/or regular fluoride varnish applications as part of preventive dental visits should be promoted in this group. Meanwhile, further research into the effect of various cART regimens on the oral microbiome are warranted to better understand the pathogenesis of dental caries among PHIV youth exposed to these regimens almost since birth. Such studies are currently ongoing.

Acknowledgements

We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Ellen Chadwick; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson).

C.H.C., M.I.R. and A.-B.M. did study design; data interpretation; manuscript writing; T.-J.Y. did statistical data analysis; data interpretation; manuscript writing; J.S.R. did statistical data analysis; manuscript writing; R.B.vD. and G.R.S. III did study design, manuscript writing.

The following institutions, clinical site investigators and staff participated in conducting PHACS AMP and AMP Up in 2016, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Mirza Baig, Alma Villegas; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia A. Garvie, James Blood; Boston Children's Hospital: Sandra K. Burchett, Nancy Karthas, Betsy Kammerer; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Ray Shaw, Raphaelle Auguste; Rutgers - New Jersey Medical School: Arry Dieudonne, Linda Bettica, Juliette Johnson; St. Christopher's Hospital for Children: Janet S. Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins, Jamie Russell-Bell; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University School of Medicine: Margarita Silio, Medea Gabriel, Patricia Sirois; University of California, San Diego: Stephen A. Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Eric Cagwin, Emily Barr, Alisa Katai; University of Miami: Gwendolyn Scott, Grace Alvarez, Gabriel Fernandez, Anai Cuadra.

Dentist examiners: Drs. Victor Badner, Alvis B. Carter, Susan M. Chialastri, Roopa Gandhi, Ronald Garrett, Ramon Gonzalez, Eric R. Hunt, Ray J. Jurado, Karen Kemp-Posterman, Johnny Kuttab, Kenneth Markowitz, Manwei Ng, Janice Townsend, Ashlee Vorachek, Selene Wun, Jennifer Zeni.

The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or U.S. Department of Health and Human Services.

Conflicts of interest

The authors declare no conflicts of interest.

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Keywords:

caries; combination antiretroviral therapy; HIV; oral disease

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