Viral suppression after early initiation of combination antiretroviral therapy (cART) is the primary goal of antiretroviral therapy in children. In addition to improving long-term clinical outcomes, there are data to suggest that early and sustained viral suppression (SVS) in children may limit the viral reservoir [1–3], with case reports of SVS off treatment after early initiation of cART in infants [4–6]. There is therefore tremendous interest in the strategy of early and SVS among children with perinatal HIV infection as a means of both controlling the viral reservoir, and improving clinical outcomes.
However, the time to, and durability of viral suppression among early-treated children (<12 months age) has not been well described. Children with perinatal HIV infection face unique challenges as compared with adults, including variability in children's weight and antiretroviral pharmacokinetics [7,8], higher pretreatment viral loads in infancy , limited liquid or granule formulations for use in infancy [10,11], and poor palatability of existing formulations . Moreover, adherence in children is uniquely influenced by the family structure and more easily susceptible to social influences and disruption [13,14], as well as parental nonadherence to their own antiretroviral regimens . Studies have shown lower rates of viral suppression after cART among children whose parents did not have viral suppression , among orphaned children [17,18] and among those in sicker households .
A limited number of studies have reported viral suppression rates ranging from 89 to 92% among children living in high-income countries [20,21]; however, these have largely been cross-sectional rather than longitudinal analyses. Moreover, the time to viral suppression, and durability beyond 24 months after cART initiation has not well been described. In response, the primary objective of this study was to determine the time to, and durability of, viral suppression, among Canadian children living with HIV after initiation of cART. Secondary objectives were to identify factors predictive of shorter time to suppression, as well as those risk factors for subsequent viral rebound.
The EPIC4 (Early Pediatric Initiation Canada Child Cure Cohort) study was a prospective, multicenter Canadian cohort study investigating HIV-1 reservoirs, chronic inflammation and immune responses in children with perinatally acquired HIV-1 infection . Children and young adults were recruited from eight pediatric HIV care centers in Canada, all members of the Canadian Pediatric AIDS Research Group. The group was established in 1987 as a collaborative network for pediatric HIV research and surveillance in Canada, and is comprised of pediatric HIV care providers and researchers from 12 clinical sites across the 10 Canadian provinces. All major academic sites that provide HIV care to children in Canada were included; clinic sites following less than five children living with HIV did not participate in EPIC4. Study visits occurred every 3 months from December 2014 until December 2018. Patient medical records were reviewed for treatment history and viral load data, entered retrospectively at the baseline study visit, and collected prospectively for the duration of the study.
All children with perinatal HIV infection, engaged in care at one of the eight Canadian Pediatric HIV treatment centers , were eligible for the study. Children received their medical care under a system of universal healthcare coverage, and standard of care for HIV treatment in all centers followed US Department of Health and Human Services guidelines for the treatment of pediatric HIV infection at the time . Voluntary informed consent was provided by the participant or their legal guardian as appropriate. The study was approved by the Research Ethics Boards of all participating institutions.
Outcomes and covariates
The primary outcomes were time to viral suppression, and among those who achieved viral suppression, subsequent SVS. Viral suppression was defined as two consecutive undetectable viral loads (<50 copies/ml) at least 30 days apart, after initiation of cART. SVS was defined as viral suppression maintained for at least 3 years.
Kaplan–Meier survival estimates were used to determine the probability of viral suppression over time after cART initiation. The analysis was restricted to those who received cART (excluding mono or dual therapy treatment initiations, or treatment -naïve patients). A subgroup analysis for time to viral suppression was conducted on those who received uninterrupted cART (excluding all planned treatment interruptions, or treatment interruptions due to disengagement from care, or lack of medication) to better assess the role of specific host and viral factors in time to viral suppression.
The following covariates were considered as potential predictors of viral suppression: sex, immigration status (Canadian vs. foreign born), socioeconomic status (on social assistance/Canadian welfare program at any time or not), family disruption (child protection services ever involved with family or not, child in foster care), child birth year (categorized as birth year <2005, 2005–2009, ≥2010), age at cART initiation (<1 year, 1–5 years, >5 years of age), first cART regimen [integrase inhibitor based (INSTI), protease inhibitor based, nonnucleoside reverse transcriptase inhibitor based (NNRTI)], human leukocyte antigen (HLA) status (presence of any protective allele from among HLA B57, B27, or B81 vs. none) and pretreatment HIV-1 viral loads (<100 000 vs. ≥ 100 000 copies/ml). Medication adherence was determined through a combination of patient self-report, clinical team report, and therapeutic drug monitoring in 88% of cases; in the remaining 12% of cases, this was based only on combination of patient self-report and the clinical care team report. Medication adherence was dichotomized as excellent or not, where excellent adherence was defined as none, or very few missed doses. Comparison of Kaplan–Meier curves between groups defined by covariates was based on log-rank test.
Using Cox regression, the adjusted hazard ratios of viral suppression were assessed among covariates with a P less than 0.1 in the log-rank test. Finally, children who did and did not have viral rebound after viral suppression was achieved were compared, and predictors of viral rebound were determined through logistic regression.
Study population characteristics
By December 2015, 228 patients were enrolled in the EPIC4 cohort. Two withdrew their consent after the baseline visit and were therefore excluded from further analysis in this study. Sociodemographic features of these 226 children are summarized in Table 1. Just over half (56.2%) of the children were born outside of Canada; 53.5% were female, and the majority (68.1%) were born prior to 2005. Nearly two-thirds (64%) of the families required social assistance at some point in time, and just over one third (34.7%) of the children had been in foster care. Median CD4+ cell count at baseline was 34% [interquartile range (IQR) 28–40]; the majority of patients (93.2%) had CD4+ cell counts at least 350 cells/μl, 4.1% between 200 and 350 cells/μl, and only 2.1% had less than 200 cells/μl. At their baseline study visit (December 2014–December 2015), 198 patients (87.6%) were on cART, and 181 (81.5%) had an undetectable viral loads. By the final study visit (October–December 2018), 202 patients (89.3%) were on cART, and 170 (78.3%) had an undetectable viral loads. Overall during the study period, nine patients had initiated cART, five stopped, and 19 patients remained off therapy.
Age at cART initiation was less than 48 h for 6.2% of patients, less than 1 year of age for 25.1%, between 1 and 5 years for 33.6%, and over age 5 years for 35.1%. Factors associated with delayed cART initiation (over 5 years of age), included being foreign born vs. Canadian born (82.4 vs. 39.4%, P < 0.001), birth year prior to 2010 vs. after (98.6 vs. 83.2%), and having a pretreatment viral load less than 100 000 copies/ml (67.4 vs. 32.2%, P < 0.001). Overall, 52.8% of patients were initiated on protease inhibitor-based cART, 41.7% on NNRTI-based cART, 17.9% on INSTI-based cART, and 18% on other regimens (combinations of protease inhibitor and INSTI or protease inhibitor and NNRTI).
Of the 226 children, 131 (58%) had received uninterrupted cART since treatment initiation. Of the remaining 95, nine were treatment naive, four had incomplete treatment history, and the rest had treatment interruptions by their physician due to nonadherence, parental or patient treatment refusal. The characteristics of those with and without treatment interruption since beginning cART are summarized in Table 1. Those who had a treatment interruption were more likely to have been older, initiated cART prior to the year 2000, foreign born, and from families with a history of requiring social assistance. Children who did not have a treatment interruption were significantly more likely to be clinical stage N (asymptomatic) at baseline, with higher median CD4+ percentage and absolute CD4+ T-cell counts, compared with who had a treatment interruption.
Figure 1a shows probability of viral suppression among all children who started cART over time. Overall, the median time to viral suppression was 1.29 years (IQR 0.41–4.21); at 6 months, the probability of viral suppression was 31%. This increased to 44% at 1 year, 62% at 2 years, and 66% by 3 years after initiation of cART. On univariate analysis, there was a significant difference in time to viral suppression according to age at cART initiation. At 6 months, the probability of viral suppression was 21% among infants, 23% among toddlers (1–5 years), and 47% among older children (>5 years); this increased to 39, 37, and 54%, respectively, at 12 months and 63, 52 and 71%, respectively, at 24 months post-cART initiation (P = 0.051). Overall, time to viral suppression was shorter among children more than 5 years of age compared with children 5 years or less of age (median of 0.57 vs. 1.38 years respectively, P = 0.015) (Fig. 1b). Other factors associated with a shorter time to viral suppression included lower pretreatment viral loads (<100 000 copies/ml vs. ≥100 000 copies/ml, median time 0.41 vs. 1.03 years, P = 0.007) (Fig. 1c), type of initial cART regimen (INSTI/other vs. protease inhibitor vs. NNRTI, median: 0.40, 1.21, and 1.77 years respectively, P = 0.036) (Fig. 1d), those without child protection services involvement with the family (median time 1.17 vs. 1.32 years, P = 0.007) (Fig. 1e), and excellent adherence (0.84 vs. 1.70 years, P = 0.002) (Fig. 1f). Factors not associated with shorter time to viral suppression included sex, immigration status, foster care placement, history of family requiring social assistance, and the presence of any protective allele (any from among HLA B57, B27, or B81).
In the adjusted Cox regression model (Table 2), the time to viral suppression was significantly shorter for children born after 2010 vs. prior [adjusted hazard ratio (aHR) 1.71, 95% confidence interval (CI) 1.04–2.79, P = 0.03], those without child protection services involvement (aHR 1.44, 95% CI 1.03–2.01, P = 0.03), and children initiating cART after 5 years of age vs. 5 years or less of age (aHR 1.57, 95% CI: 1.13–2.20, P = 0.008).
Time to viral suppression (uninterrupted combination antiretroviral therapy)
Figure 2a shows probability of viral suppression among children with uninterrupted cART. Overall, the median time to viral suppression was 1.03 years (IQR 0.38–3.20 years); at 6 months, the probability of viral suppression was 34%; this increased to 50% at 1 year, 69% at 2 years, and 73% by 3 years after initiation of cART. There was a significant difference in time to viral suppression according to age at cART initiation. At 6 months the probability of viral suppression was 19% among infants, 20% among toddlers, and 61% among older children; this increased to 43%, 37, and 61%, respectively, at 12 months, and 73, 57, vs. 78%, respectively, at 24 months post cART initiation (P = 0.047). Overall, time to viral suppression was shortest among children more than 5 years of age initiating cART vs. younger children 5 years or less of age (median of 0.43 vs. 1.29 years, respectively, P = 0.015) (Fig. 2b). Other factors associated with a shorter time to viral suppression included being born in Canada vs. foreign born (median time 0.68 vs. 1.38 years, P = 0.045) (Fig. 2c), and lower pretreatment viral loads (viral loads <100 000 copies/ml vs. ≥100 000 copies/ml, median time 0.38 vs. 0.80 years, P = 0.001) (Fig. 2d). Although those with any protective allele (any from among HLA B57, B27, or B81) had a tendency to shorter time to viral suppression than those without (median 0.60 vs. 1.00 years), this was not statistically significant (P = 0.37). Other potential predictive factors of shorter time to viral suppression on univariate analysis included no history of foster care placement (median time 0.57 vs. 1.29 years, P = 0.07), and the type of first cART regimen (INSTI/other vs. protease inhibitor vs. NNRTI, median: 0.40, 1.01, and 1.33 years, respectively, P = 0.116) (Fig. 1d). In this group of children, adherence was not a significant predictor of viral suppression (median time among those with vs. without excellent adherence, 0.91 vs. 1.34 years, P = 0.704). In the adjusted Cox regression model (Table 2), the time to viral suppression was significantly shorter for children born in Canada vs. foreign born (aHR 2.02, 95% CI 1.33–3.05, P < 0.001), and children who initiated cART after 5 years of age vs. 5 years or less of age (aHR 1.87, 95% CI 1.21–2.90, P = 0.005).
Viral rebound at 3 and 5 years
Among all those who initiated cART (n = 213), complete 1, 3, and 5-year follow-up data after viral suppression achieved was available for 198, 175, and 144 children respectively. Overall, 12.1% had their first viral rebound within 1 year after viral suppression was first achieved; this increased to 27% at 3 years and 41.7% at 5 years. Table 3 compares those who did and did not have viral rebound by 3 years after viral suppression was achieved. The risk of viral rebound at 3 years was significantly lower among those classified as having excellent adherence [odds ratio (OR) 0.20 95% CI 0.09, 0.44, P < 0.001], those who were foreign vs. Canadian born (OR: 0.36, 95% CI 0.18, 0.73, P = 0.005), females vs. males (OR 0.51, 95% CI 0.26, 0.99, P = 0.047), family not recipient of social assistance (OR 0.16, 95% CI 0.06, 0.46, P > 0.001), and no history of child protection services involvement (OR 0.49, 95% CI 0.25, 0.98, P = 0.043). Sex, family recipient of social assistance, and age at cART initiation remained significant predictors of viral rebound at 3 years in a multivariate model including immigration, sex, social assistance, child protection services involvement, HLA alleles, and age at cART initiation.
In this study, we report on rates of viral suppression and the time to viral suppression among children living with HIV in Canada who initiated cART, and the factors associated with viral suppression and shorter time to viral suppression, and subsequent viral rebound. Our results highlight that despite living within a well structured resource-rich health system with universal healthcare coverage, Canadian children living with HIV face ongoing challenges with respect to attaining and maintaining viral suppression.
Both our cross-sectional and longitudinal results demonstrate that Canadian children in EPIC4 currently fall short of the third 90–90–90 UNAIDS target of achieving 90% viral suppression among those on cART. While at their last study visit in 2018, 89.3% of children were on cART, only 78.3% had viral suppression. This is confirmed in our longitudinal results which are similar to those reported from a meta-analysis of children and adolescents in low and middle-income countries . Overall, 73% of children in our cohort had maintained SVS at 3 years, decreasing to 58.3% by 5 years, similar to a reported 72.5% of children from low and middle-income countries who were suppressed at 3 years after their first line cART was initiated, and a reported 69.2% suppressed 3 years after cART initiation in the TREAT Asia pediatric HIV Observational Database (TApHOD), a regional study including multiple pediatric cohorts in South and Southeast Asia . Although the follow-up and assessment criteria in EPIC4 cohort were stricter (viral loads measures every 3 months) than the majority of the studies reported from low and middle-income countries, these results suggest that the remaining barriers to viral suppression may be universal and not necessarily associated with heath systems and income level .
Our study further highlights that the time to viral suppression after initiation of cART is much longer in children than in comparable adults from the same country, and differs in children according to age at cART initiation. At 12 and 24 months after cART initiation, only 44 and 62% of all children had achieved viral suppression; this is in marked contrast to a comparable group of Canadian adults living with HIV initiating cART after year 2000, which found that at 12 and 24 months after cART initiation, 83 and 91% had, respectively, achieved viral suppression . We further identified differences in time to viral control, and the probability of SVS, across the different age strata that were assessed. While early treatment with SVS in infants is a promising strategy for reservoir control, among the 36 infants in our cohort who initiated cART in the first year of life (including 4 at <48 h of age), less than half (39%) were suppressed a year after cART initiation, and only 69% were suppressed 3 years after cART initiation. While nearly a third of children initiated cART after 5 years of age, time to viral suppression was shorter in this age group vs. infants and toddlers. We suspect that this reflects the higher pretreatment viral loads among the younger children, difficulties with the palatability of the only available oral suspensions for infants and toddlers unable to swallow pills, and the burden of twice-daily drug administration .
Older children (above age 5 years), while quicker to achieve viral suppression than infants, were also more likely to rebound. Although overall, 27% of children had viral rebound after 3 years, toddlers (age 1–5 years) were less likely to have viral rebound at as compared with children over age 5 years (13.1 vs. 32.7%, P = 0.016). These results are similar to data previously reported from the TApHOD study , which found that while children over 18 months age were more likely to be suppressed at one year post cART than those younger than 18 months, older children (>3 years) were more likely to have a virological failure as compared with younger children. This is also similar to the risk of viral rebound reported in the European CHIPS cohort, where overall 23.6% of children had a viral rebound within two years of cART, the risk being greatest for older children (10 years) as compared with younger children .
We suspect that our results reflect the epidemiology of perinatal HIV infection in Canada, which in our very low prevalence setting, disproportionally affects new immigrants to Canada and those who are more marginalized . The children in the EPIC4 cohort are more vulnerable than the general population of Canadian children , with just over half foreign-born, nearly two thirds of families ever dependent on social assistance, just over one third of children ever having been in foster care, and nearly a third with a history of child protection services involvement. These factors played a role in the likelihood of these children having had a treatment interruption, as this was more likely for children whose families had ever required social assistance, and those who had immigrated to Canada. Among those who did not have a treatment interruption, the only significant predictor of shorter time to viral suppression, other than age at cART initiation, was being Canadian vs. foreign born, with Canadian born children twice as likely to achieve viral suppression than those who immigrated (aHR: 2.02, 95% CI 1.33–3.05).
These social vulnerabilities are also reflected in identified risk factors associated with viral rebound at 3 years post cART. The risk of viral rebound was significantly lower in children of families with no history of needing social assistance (7.4 vs. 35.4%, P < 0.001), suggesting that despite living in a resource-rich setting, caregivers in our cohort face similar challenges to supporting adherence in their children to those documented elsewhere , namely socioeconomic fragility, and family structure and stability. Significantly, while the risk of viral rebound was higher among those with child protection services involved (36.1 vs. 21.6%, P = 0.043), this was not the case among those children in foster care vs. not (23.1 vs. 29.4%, P = 0.386), suggesting that the stability of the home environment, whether through foster care or the biological family, played a role in viral rebound.
Our study has a number of limitations. First, EPIC4 was a heterogeneous, retrospective cohort representing different years of birth and practice changes across different time periods, and eight different centers in Canada. Though enrolment was open to all patients across study sites, those who participated may represent those most willing to engage in care, with a resulting over-estimate of rates of viral suppression and SVS. Moreover, the complex relationship between the different covariates assessed makes it difficult to assess the roles played by each specific variable for time to viral suppression and likelihood of viral rebound. Although we excluded adherence from the multivariate models, given its role on the causal path for the other covariates, there were likely other overlapping factors which we were unable to assess. We were unable to adjust for baseline viral loads in the multivariate models (due to missing data); as a result it is not clear whether the longer time to viral suppression is a result of age, or a reflection of higher baseline viral loads, in the infant and toddler group. Those born in the earlier period (<2000) were likely treated with less potent and more complex regimens consisting of less palatable formulations, and were therefore potentially more likely to rebound that those in the current era. We did not collect data on parental health, adherence, knowledge of and engagement in care, which may be important predictors of viral control in children. Finally, our findings are also not necessarily generalizable across all settings, specifically in areas of high HIV prevalence, where access to treatment and systemic barriers to care remain one of the primary issues facing pediatric HIV care providers.
In conclusion, despite living in a well structured health system in a resource-rich country with universal healthcare coverage, Canadian children fall short of the UNAIDS target of 90% viral suppression on cART . Our study identified a specific subset of children at highest risk of viral rebound; notably those who were foreign-born, in unstable family environments, and whose families required social assistance. Identifying these high-risk children will allow clinical care teams to proactively implement interventions to improve adherence and viral control. In our setting these may include more frequent clinic visits for adherence support, home visits by social and community workers, and additional financial support for those on social assistance to cover transportation, food, child-care costs associated with health visits. Clinicians may further choose to use therapeutic drug monitoring more frequently in high-risk children to identify adherence problems prior to viral rebound, and select antiretroviral regimens with the highest barrier to resistance and greatest tolerability.
In summary, the findings from our study suggest that factors independent of health system resources are at play, and that improving clinical outcomes for children living with HIV in resource-rich settings requires proactive identification of those at risk of poor health outcomes, and implementation of interventions designed to mitigate the barriers to effective care for these children.
The authors wish to thank all study participants as well as the following individuals for expert and technical assistance: Cheryl Arneson, Christine Bon, Jennifer Bowes, Martine Caty, Anika Gerois, Zoe Hassall, Cathy den Hollander, Gillian Morantz, Audrée Janelle-Montcalm, Danny Dong Hyun Kim, Mbaye Ndiaye, Barb Neufeld, Laura Puri, Annie Qiu, Suzanne Taillefer, Silvie Valois.
Author contributions: F.K., A.B., J.B. M.H., L.S., S.R., and H.S. designed the study. F.K., A.B. and T.L. analyzed the data. S.S, B.T, W.V., V.L., C.K., J.S. critically reviewed the data. F.K., A.B., and T.L. drafted the article. All authors contributed to interpreting the data, critically revising the article, and approved the final version.
Author contributors: Doris Ransy, Marie-Astrid Lefebvre.
EPIC4 is a study of the Canadian HIV Trials Network (CTN-281), and was supported by the Canadian Institutes of Health Research (CIHR), the International AIDS Society (IAS), and the Canadian Foundation for AIDS Research (CANFAR) (grant no. HIG-133051). F.K. was the recipient of a Junior 1 Career Scholarship from the FRQS.
Conflicts of interest
There are no conflicts of interest.
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