Age-specific associations with dental caries in HIV-infected, exposed but uninfected and HIV-unexposed uninfected children in Nigeria

The oral health of children living with HIV has been the focus of several recent investigations [1‐6]. Oral pathologies including candidiasis, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis, necrotizing stomatitis, hairy leukoplakia, and oral ulcers have been well characterized among HIV-infected (HI) individuals. However, childhood caries, oral mucosal lesions, and periodontal disease have been studied less [7, 8]. This represents a knowledge gap, because dental caries is the most prevalent disease globally, and the most common oral disease in children [1, 9]. Early childhood caries (ECC) is the tenth most prevalent disease globally; and when untreated, can be painful, expensive to treat, and can lead to tooth loss, impaired nutrition [10, 11] and a diminished quality of life [1, 9, 12].

We and other researcher teams have reported observations of higher levels of ECC in HI compared to uninfected children [4, 13‐18]. These higher rates for caries may be due to the higher rates of hyposalivation and hypoplasia observed in PLWH [14] when compared to their uninfected counterparts; compounded by the sustained consumption of sucrose-based (antiretroviral therapy) ART syrups and suspensions, hypoplastic teeth due to the immunological impact of HIV infection [17, 18], low salivary flow [19] and cariogenic oral microbiota, including bacterial-fungal components of dysbiosis [20‐23]. In spite of this emerging evidence, there is no clear consensus on whether the impact of perinatal HIV infection on caries risk in the primary dentition persists, diminishes, or accentuates in the permanent dentition.

Recent studies compared HI children to uninfected children [3, 4, 13, 18, 24, 25] while only one study included a comparison with HIV-exposed-but-uninfected (HEU) children [9]. Our earlier findings suggested that the immune status of HI (as reflected in CD4 + percentages and counts) had the greatest influence on the differences in salivary community composition between HI and uninfected children [20]. These initial observations were based on studies including the primary dentition in early childhood. In the present study, we sought to expand upon earlier findings, and examine the relationship between caries and HIV infection in older children and including the mixed dentition. Accordingly, we sought to quantify HIV infection-associated differences in the prevalence and severity of dental caries in the primary and permanent dentition in a cohort of 544; 4–11-year-old Nigerian children who were HI, HIV-exposed-but-uninfected (HEU), and HIV-unexposed-and-uninfected (HUU). Additionally, we studied the influence of age-specific factors such as dentition and duration on ART on the association between HIV exposure/infection and caries. Our hypothesis was that compared to HUU children, caries experience of HI children would be higher, and this association would persist in both primary and permanent teeth.

Dental Caries and its association with Oral Microbiomes and HIV in young children—Nigeria (DOMHaIN) study is a prospective cohort study of young children in Nigeria aimed at investigating aspects of the dental caries-associated microbiome in children infected or exposed to HIV [26]. Eligible children were recruited from the University of Benin Teaching Hospital (UBTH), Edo State, Nigeria, in three groups: HI, HEU, and children that were unexposed and uninfected (HUU). HI, children receiving treatment at the Special Treatment Clinic (STC) within the eligible age range were approached for recruitment. Children who were uninfected but receiving care at the STC were recruited as HEU children (i.e., perinatally exposed to HIV) after confirmation of HIV status of the mother at the time of birth. Additional HI and HEU children were recruited from the HIV/AIDS pediatric clinic or by referral by mothers attending adult ART clinic at UBTH. Age-matched HUU children were recruited from well-child and pediatric clinics at UBTH.

The study population comprised 544 unrelated children with mean age of 7 years. Half of participating children were male, 181 (33%) were HI, 177 (33%) HEU, and 186 (34%) were HUU children (Table 1). Sixty-eight mothers were deceased at the time of enrollment. Among those for which we had records or who are still living, most (85%) had at least a primary school education and were married. Children in the 3 study groups differed significantly with respect to mode of delivery, early infant feeding, birth weight, current anthropometric measurements and CD4 counts. There were no significant associations of HIV infection and exposure status with sex, socioeconomic status or age (Table 1).

None of the participating children had undergone dental extractions or received dental treatment prior to our study; meanwhile, 129 (24%) had at least one caries lesion and a third of those had decay visibly involving the dentine. Additional file 1: Table S1 highlights the additional dental findings across study groups. Among children > 6 years of age, 100/376 were diagnosed with caries compared to 29/168 among those aged ≤ 6 years (27% vs. 17%, p = 0.024). Among caries-affected children aged > 6, 85% had at least one primary carious tooth (i.e., overall, 23% caries prevalence in primary teeth among children aged > 6 years) while, as expected, all caries-affected children aged 6 years or younger had at least one primary carious tooth. In terms of quantitative caries experience, study participants had an average of 5 (SD = 8.4) caries-affected teeth, including 2.6 in the primary dentition and 2.9 in the permanent dentition. Among caries-affected children, the dmft index ranged from 1 to 10, while the DMFT index ranged from 1 to 8.

The prevalence of caries was highest in HI compared to HEU (p = 0.03) and HUU (p = 0.02) children. Notably, HEU children had a lower prevalence than HI or HUU children (12% vs. 22%, p = 0.03, Additional file 1: Table S1). The prevalence of caries lesions involving dentine was significantly higher in HI children compared to their HEU counterparts (24% vs 8%; p < 0.0001) and HUU counterparts (24% vs 15%; p < 0.0001). While these patterns remained consistent when examining age-specific groups, the strongest difference in caries experience between HIV groups was observed in children aged > 6 years (p = 0.002).

In further investigating these age-specific associations, we sought to evaluate dentition-specific differences. Table 2 highlights the independent association between study groups and caries prevalence in the primary and permanent dentition based on results from simple and multivariable logistic regression models. HIV infection remained independently associated with caries in the permanent dentition (p = 0.005). There was no significant association between HIV infection and sex; however, the association between age and hyposalivation differed by type of dentition. Enamel defects was an independent significant risk indicator for caries prevalence in the primary dentition (Table 2).

Caries severity differed by type of dentition and study group (Fig. 1A, B). Compared to HUU, HEU children had a significantly lower dmft indices in the primary dentition (beta coefficient = − 0.29, p = 0.04); Table 3). Age was not associated with the number of carious teeth in primary dentition. In permanent teeth, caries severity was associated with HIV infection [adjusted mean ratio, AMR (95% confidence interval (CI); 5.4 (1.4–20.3)], hyposalivation and age. The presence of enamel defects was consistently associated with caries severity in both dentitions.

Greater caries severity scores of the permanent dentition were observed in HI compared with HUU with predominance in molars (Fig. 2A, B). Caries prevalence was significantly greater among participants with low (≤ 500 cells/mm³) compared to higher CD4 counts (OR = 2.2, 95% CI, 1.0–5.1). However, in all multivariable analyses where study groups were excluded (due to collinearity with immune status), CD4 + T cell measurements were independently associated with caries prevalence or severity (Additional file 1: Tables S2 and S3).

To our knowledge, this is the first comparative study of HI, HEU and HUU children investigating the association of perinatal HIV exposure and infection with dental caries in school-aged children or in children with mixed dentition. Our study results showed that the positive association of perinatal HIV infection with dental caries was more pronounced in children with permanent dentition (> 6 years of age). A more extensive analysis revealed that not only did HI children have significantly greater caries prevalence, but they also had a higher caries experience in terms of the number of caries-affected teeth. We noted distinct patterns of caries experience in the primary and the permanent dentitions highlighting the need to address specific caries prevention strategies at each dentition phase in immunocompromised children.

While a wide range of caries prevalence has been reported in school-aged children in sub-Saharan Africa, several studies report estimates ranging 10–22% [11, 31‐34]. Results from several studies of children perinatally infected with HIV, including ours of early childhood [4, 20], are consistent with our findings of a higher caries prevalence in HIV-infected children [2, 3, 8, 13, 17, 18, 35‐41]. While a non-comparative study [42] observed a low prevalence of early childhood caries in children with perinatal HIV infection, several comparative studies [4, 13, 25, 37, 43] have reported elevated risk of dental-related diseases, including caries, in PLWH compared to their uninfected counterparts. The mechanism behind this elevated caries risk associated with HIV infection is not clear and has not been adequately investigated. Studies in younger children suggest that HI children are more susceptible to ECC when compared to their HIV-uninfected counterparts due to an increased level of Streptococcus mutans [44, 45]. Candida albicans also has been implicated in driving the risk of dental caries in PLWH by facilitating the colonization of S. mutans [46]. Significant changes in salivary microbial composition have been reported between in PLWH when compared with people not living with HIV, likely increasing the risk for caries in PLWH [20, 47]. The persistently defective immune responses or chronic immune activation experienced in PLWH on ART could also play a significant role in increasing this risk. There is correlation between low levels of CD4 + T cells and caries severity [3], gingivitis [48] and xerostomia and hyposalivation [49, 50]. People living with HIV are susceptible to xerostomia and hyposalivation due to adversely affect salivary gland output [51, 52]. While the etiology of hyposalivation and xerostomia associated with caries has been well-described [45], we were only able to assess hyposalivation as many children did not report a symptom of dry mouth/xerostomia. In addition, xerostomia can occur with hyposalivation [54, 55] or without hyposalivation [45] and be associated with caries. Also, some syrup- or suspension-based antiretroviral medications are sucrose-based [1, 53]. While most HI children in our study were receiving zidovudine-based regimens (AZT/3TC/NVP or EFV) as their first-line regimens, integrase-inhibitor dolutegravir-based regimens are currently being rolled out for children in Nigeria [54]. This is particularly important as the US Pediatric HIV/AIDS Cohort Study (PHACS) cohort had previously reported a higher caries risk among youth receiving integrase-inhibitors, compared to those who did not [38]. Furthermore, PHACS cohort reported lower dmft scores in children who initiated protease inhibitors (PIs) before age 6 when compared to those who did not initiate PIs before age 6 [38]. Such data adds to growing evidence that PI-based ART confers favorable clinical and immunological outcomes [55].

All these aforementioned factors, in addition to other dietary and socioeconomic related factors, could explain the higher prevalence of caries observed in HI children that may differentiate the study groups [56, 57]. These factors require further examination in future studies.

Perinatal HIV exposure alone did not appear to increase the risk of dental caries in this population as observed in other studies [1, 9]. In fact, in the younger age group (≤ 6 years), we observed a lower prevalence of caries in the primary teeth of HEU children compared to their unexposed counterparts. While this observation needs to be further investigated based on our previous report [4], there are several reasons that could explain this finding. It is likely that HUU children in this study population might have heightened levels of unmeasured risk factors that include nutritional status, immunological markers and genetics associated with caries compared to HI and HEU children. In addition, although speculative, it is reasonable to posit as a hypothesis that the development and training of the immune system via the oral microbiota [20], and perhaps the gut microbiota [58], in HEU children via maternal ART exposure in-utero and lower likelihood of breast feeding (observed in mothers of HEU children) might be protective of caries [4]. Our thoughts are based on results from a previous analysis of younger children suggesting a higher odds of caries in children delivered after a spontaneous membrane rupture and in those who were breastfed for longer durations [4]. It is very interesting to note that in that study, HEU children were least likely to be delivered via spontaneous membrane rupture or vaginal delivery. These findings however require further investigations.

Given our previous work that showed immune status (CD4 lymphocyte counts) had a stronger impact (compared to HIV infection) on caries [4] and the salivary microbiota [20], we examined the association between CD4 counts or percentages and caries experience without including HIV infection and exposure status in the models. In these models, low CD4 + cell counts were consistently associated with higher caries prevalence and severity. While salivary pH levels were not assessed in this study, our observations suggest that a higher salivary pH level, is essential for the prevention of dental caries, and is associated with a better immune status, while a worse dental health status is closely associated with a poorer immune status. A prior study has indicated this possibility [59]. Notably, impaired immunity or immunodeficiency may lead to a decrease in salivary flow, impeding the recovery of the salivary pH level after eating [59]. This phenomenon has been reported in patients with other immunodeficiency associated diseases such as end-stage renal disease [60].

This study’s findings suggest that HIV status is associated with higher prevalence and severity of dental caries mainly in the permanent dentition; and the impact of HIV infection and exposure may differ with age/dentition phase and HIV exposure. Building upon earlier reports, here we provide additional evidence, using a sizeable community-based cohort of HI, HEU, and HUU children. Our findings suggest the need for specific and targeted oral health care for children who are HI, HEU and HUU with respect to caries prevention in early and middle childhood. Finally, this study lays the foundation for investigating and identifying key contributory factors, including environmental, microbial and dietary factors, that may contribute to caries development in children exposed to and infected with HIV.