A national registry of all HIV-infected patients residing in the Netherlands was initiated in 1996. Their clinical, immunological, virological and survival state (www.hiv-monitoring.nl) was continuously monitored from this moment onwards. Similar to other industrialized countries, this was the time that HIV-infected children in the Netherlands gained access to combination antiretroviral therapy (cART). In total, 19 985 HIV-infected patients have now been registered in the Netherlands, which is 0.1% of the total Dutch population; 282 of them were children at the time of HIV diagnosis .
Combination antiretroviral therapy has dramatically decreased morbidity and mortality in HIV-infected children and adults worldwide [2–5]. Early initiation of cART in vertically HIV-infected children has proven to be beneficial for their survival [6–10]. The WHO currently adviseds starting cART in all children under 2 years of age, regardless of their CD4+ T-cell count or clinical status , based on studies that showed a clear decrease in mortality and disease progression after early cART initiation in infants from sub-Saharan Africa (SSA) [8,12,13].
In the industrialized world, paediatricians are mainly led by CD4+ cell counts in deciding whether to start treatment in children above 2 years of age. Several studies have investigated the influence of age and CD4+ cell count prior to the start of any ART on (long-term) immune reconstitution. Results from 127 therapy-naive children starting cART showed a less complete T-cell recovery in the oldest group of children (with a median age at cART initiation of 10 years) . This age-dependent T-cell recovery was shown repeatedly [15,16]. Uncertainty remains on when to start cART, which is illustrated by other studies showing no correlation with age and especially long-term T-cell reconstitution in children [10,17,18]. The consequences of early cART initiation, such as an increasing risk of (long-term) adverse effects and development of viral resistance, should be carefully considered as long as literature on this subject is not clear.
In this study, we describe the Dutch paediatric vertically HIV-infected population, their long-term response to cART (with emphasis on the age-dependency of this response) and the outcome in terms of mortality.
Patients and methods
The Dutch vertically HIV-infected paediatric population as registered by the Dutch HIV Monitoring Foundation (SHM) from 1 January 1996 to 1 March 2012 was studied.
Data collection and study parameters
Designated data collectors from the SHM collected information from all four paediatric HIV clinics in the Netherlands. The study parameters used for this analysis were clinical and treatment characteristics, immunological and virological parameters and mortality, collected for each child at regular outpatient clinic intervals of approximately 3 months.
The follow-up time for all patients was the number of years from the start of registration until the date at which patients became 18 years old, the date of the last visit before lost to follow-up, death or database closure.
HIV viral load follow-up was done by the Nasba HIV-1 RNA QT with a lower limit of detection (LLD) of less than 1000 copies/ml (1996), the NucliSens HIV-1 RNA with a LLD of less than 400 copies/ml (1997–2001), Cap/CA v1.5 (1996–2009), the Versant HIV-1 RNA 3.0 with a LLD of less than 50 copies/ml (2001–2007) and ultimately the Abbott Real Time HIV-1 with a LLD of less than 40 copies/ml and CAP/CTM v 2.0 (2009 till current). HIV infection was confirmed by several similar tests with decreasing detection limits from 1000 copies/ml in 1996 to 150 copies/ml in 2012.
Time of HIV diagnosis was defined as the first positive HIV test. Infants were regarded as infected if HIV-1 antibodies persisted after the age of 18 months, or if two consecutive HIV-1 virus detection tests (RNA PCR/DNA PCR) were positive below 18 months of age. CD4+ and HIV viral load at diagnosis were the first measurements after HIV diagnosis. CD4+ and HIV viral load before cART initiation were defined as closest measurements prior to the start of cART. An undetectable viral load was defined as a HIV viral load below the LLD of the assay used at that time.
Adverse effects, virological failure and therapy adherence problems (as reported by clinicians) were regarded as switch reasons from first to secondary cART regimen. Weight-related dose changes were not regarded as treatment switches. Alterations in backbone [nucleoside reverse transcriptase inhibitors (NRTIs)] or base [non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs)] were regarded as regimen switches.
Patients were stratified by age at cART initiation (group 1: 0–2 years; group 2: 2–5 years; group 3: 5–18 years of age). Descriptive statistics were performed on the demographic characteristics. The Kruskal–Wallis test for non-parametric numerical data and the Chi-square test for categorical data were used to compare variables between groups.
Incidences of the different stop reasons were calculated per 1000 person-years on treatment amongst children. Person-years were calculated from the start of cART until the date of treatment cessation, the date of the last visit or closure of the database on 1 March 2012. Mortality rate was calculated as the number of deaths per 100 person-years of follow-up in the Dutch HIV registry.
Z-scores were calculated for CD4+ cell counts to correct for age-related differences. These Z-scores were used to express the SD from the reference values for the HIV-negative population. All absolute CD4++ T-cell counts were transformed into Z-scores by subtracting the age-related reference value for the age at the time of the CD4+ measurement  and dividing this by the age-related SD. A Z-score of 0 represents the age-appropriate median. A CD4+Z-score of −1 indicates that a child's CD4+ cell count is 1 SD below the age-specific median of the HIV-negative population.
We compared the changes in mean Z-scores from the start of cART onwards between the three age categories. To analyse changes in long-term CD4+ response from the start of cART, mixed-effect models were used. All Z-scores between the start of cART and the following 10 years were included.
Mean changes in Z-scores were calculated separately for the following time periods: 0 to less than 6 months, 6 to less than 12 months, 1 to less than 2 years, 2 to less than 3 years, 3 to less than 5 years, 5 to less than 8 years and 8 to less than 10 years. The model included random slopes for these time periods for each patient. A first-order autoregressive covariance was used to correlate intra-individual serial measurements. The other covariates in the model (sex and being cART-naive) were allowed to have one effect on the slopes between the start of cART and 10 years thereafter.
HIV viral load
HIV viral load measurements were transformed into log copies/ml and changes in HIV RNA levels from cART initiation onwards were compared between the three age groups using mixed-effect modelling with similar time periods as described for the CD4+Z-scores. The longitudinal analyses for HIV viral load were based on a LLD of 500 copies/ml for all HIV RNA measurements and were adjusted for sex, being cART-naive and calendar time period of starting cART (prior to or after January 2000). In addition, for every consecutive year after 1996, the first HIV viral load measurement in that year per child was used to determine the percentage of children with an undetectable HIV viral load; here the LLD of the HIV viral load test per year was taken into account. Data were analysed in SPSS version 19 (SPSS Inc. Chicago, Illinois, USA) and SAS version 9.2 (SAS Institute, Cary, North Carolina, USA).
In total, 282 HIV-infected children were included between January 1996 and March 2012. Modes of HIV transmission were blood contact (4%), sexual contact (4%) or unknown (10%), but most children (82%) were infected through mother-to-child transmission. We included these 229 vertically HIV-infected children in the further analyses of our study. Their characteristics are shown in Table 1.
The median follow-up time was 8.7 years (range 0.1–21.1). During the study period, registration of 15 patients was stopped before they became 18 years old; 12 moved abroad and 3 were lost to follow-up. The majority were born in the Netherlands (46%) or SSA (43%). Most children were born to mothers originating from SSA (64%). Since 2004 (the introduction of HIV-screening in the first trimester of pregnancy in the Netherlands), only eight HIV-infected infants have been born in the Netherlands.
The median age at HIV diagnosis was 2.1 years [interquartile range (IQR) 0.5–4.9]. The median age at the time of study analysis was 12.7 years (IQR 9.7–17.7, range 1.8–28.0). Children originating from SSA (n = 99) were diagnosed at a median age of 2.9 years (IQR 1.0–6.2) and commenced cART at a median age of 3.8 years (IQR 1.8–9.0). Children of Dutch origin were diagnosed at an age of 1.1 years (IQR 0.3–2.7) and initiated cART at 2.4 years of age (IQR 0.5–5.6). Diagnosis and cART initiation were significantly delayed for children originating from SSA compared to Dutch children (P < 0.001). By March 2012, 49 (21.4%) vertically HIV-infected patients had reached adulthood (range 18–27 years).
By March 2012, 210 out of 229 (90%) children had been started on cART. The median age of all children at cART initiation was 3.2 years (IQR 0.9–6.7). The median time from HIV diagnosis until cART initiation was 3.6 months (IQR 0.9–20.7). Of all patients treated, 175 (84%) were therapy-naive at cART initiation; 33 (16%) were pre-treated with mono or dual therapy. Two patients had an unknown pre-cART treatment status. Of the pre-treated children, 27 commenced cART before 1999. The remaining 6 children originated from SSA and had received mono or dual therapy in their country of origin.
The time from HIV diagnosis until cART initiation was investigated stratifying the children by age at HIV diagnosis. This time differed significantly between the three age groups (P < 0.001); children being 0–2 years old at HIV diagnosis had the shortest time period between diagnosis and cART initiation (median of 1.6 months, IQR 0.5–11.2). Children being between 2 and 5 years at HIV diagnosis had the longest period of 10.0 months (IQR 2.5–30.2) between diagnosis and therapy initiation, and children being older than 5 years at diagnosis had a median period of 2.6 months (IQR 1.3–17.4) before they were started on cART. More children in the youngest age group were diagnosed with Centres for Disease Control and Prevention (CDC) category C (34%) as compared to the 2–5 years age group (12%) and the oldest age group (9%) (P < 0.001). Of the youngest group, 48% were categorized as CDC A, whereas 71% of both the 2–5-year-old children and the oldest group were in that category at HIV diagnosis.
The median number of cART regimens per patient was 3 (IQR 2–5; range 1–11). Of the 210 patients on cART, 39 (19%) were still on their first-line regimen in March 2012 for a median duration of 2.8 years (IQR 1.5–5.4; range 0.5–9.9). Seventeen percentage had been treated with a first-line regimen only and ceased before March 2012 without a registered reason; 64% had been switched to a second cART regimen. This last group was on their first-line cART regimen for a median duration of 1.5 years (IQR 0.5–2.9; range 0.0–8.3).
Of the 134 children who were treated with a second-line regimen, 86% had also experienced a third regimen. This group was on their second-line regimen for a median of 1.2 years (IQR 0.2–2.7). Fourteen percent was still on their second-line regimen in March 2012, for a median duration of 5.3 years (IQR 2.0–8.0).
The most commonly prescribed first-line drugs (alongside the backbone of two NRTIs) are shown in Fig. 1. From 1996 to 2001, nelfinavir and indinavir were most commonly used, whereas lopinavir has been the predominantly prescribed protease inhibitor since 2000. Efavirenz has been the most frequently prescribed NNRTI since 2000. Alterations in cART regimens were made for five main reasons for which incidence rates (per 1000 person-years) were calculated: adverse effects: 124 [95% confidence interval (CI) 102–148], virological failure: 94 (74–118), therapy adherence problems: 101 (80–126), regimen simplification/improvement: 215 (190–240) and patient/parent(s) decision: 56 (40–76). There was no significant difference in cART switch-incidence rates between the three age groups.
Long-term immunologic and virologic response to combination antiretroviral therapy
The youngest children (0–2 years at cART initiation) had the highest absolute CD4+ cell counts at cART initiation (P < 0.001), but age adjusted CD4+Z-scores did not differ significantly between groups (Table 1). In the first year after cART initiation, CD4+Z-scores increased in all children, but a significant increase was only seen in the two youngest groups. The increase was largest among children aged 0–2 years (P < 0.001). After 3 up to 10 years of cART, there was no significant difference in CD4+Z-scores between all three groups (Fig. 2a). When stratifying children by the median of the initial CD4+Z-score (−1.1), the group with the lowest initial CD4+Z-score (<1.1) had a steeper increase in the first year after cART initiation (P < 0.001). The CD4+Z-score after 10 years of cART appeared to be higher in the group that started out with the best CD4+Z-score, but this difference was not statistically significant (Fig. 2b).
At cART initiation, children aged 0–2 years at time of cART initiation had a higher HIV viral load (P < 0.001) in comparison to the other age groups (see Table 1). During the first 6 months of treatment, a significant decline in HIV viral load was seen in all three age groups. HIV viral load tended to decrease over the first 10 years after cART initiation. In addition, we found that children who started cART after 2000 had a significantly more rapid HIV viral load decline than children who commenced cART before 2000 (P = 0.028) (Fig. 3).
The percentage of children on cART with an undetectable HIV viral load from 1996 to 2012 (excluding children previously treated with mono or dual ART) is shown in Fig. 4. A clear increase is shown from 1996 to 2006, whereas after 2006, the percentage stabilized at around 80%. Ultimately, 89% of all children had an undetectable HIV viral load in 2012.
From 1996 to 2012, four HIV-infected children died (0.3 per 100 person-years). The first was a 10-year-old child with CDC category C who died 5 months after HIV diagnosis (in 1998) due to a Mycobacterium avium meningitis.
In 2002, a 10-year-old child died of liver failure due to interaction of her protease inhibitor-based cART regimen and voriconazole . In the same year, a 6-month-old infant died due to a sepsis with a generalized cytomegalovirus infection and a Pneumocystis jirovecii pneumonia. The last case was a 6-year-old boy who died of a status epilepticus in 2003.
In this study, we evaluated the epidemiologic and treatment characteristics, immunological and virological response to cART, and mortality in the Dutch paediatric vertically HIV-infected population, registered since 1996.
The drastic decline in vertically HIV-infected infants born in the Netherlands from 2004 onwards can be explained by the successful introduction of a HIV screening programme in the first trimester of pregnancy . This decline is comparable to results from other western European studies [22–24].
Similar to other western European countries, most of the Dutch paediatric HIV-infected population either originate from SSA or are first-generation immigrants from that region [20,24–28]. These HIV-infected children were diagnosed with HIV and commenced cART at an older age than children born in the Netherlands, as was also reported in studies from France and Denmark [22,27].
Almost every HIV-infected child in the Netherlands (92%) is currently treated with cART, which is higher compared to the UK (72%) and Sweden (80%) [3,26,29]. The reason for these differences within Europe is unknown, as similar guidelines for treatment of HIV-infected children are used.
In our study, the time until cART initiation was shortest for children between 0 and 2 years at HIV diagnosis. For recent years, this can be explained by a proper execution of the WHO recommendations, stating that all HIV-infected children under 1 year of age, and later under 2 years of age, are to be started on cART . Also, the youngest age group had the highest initial HIV viral load and was most often classified as CDC category C. The latter is not very surprising, since children in the older groups were diagnosed after a median age of 2.4 years, and their episodes of illness before the HIV diagnosis would not have been classified according to the CDC guidelines. The generally poor clinical and virological state of young children has been described previously [30,38–40].
Preferred treatment regimens have changed over time based on research on simplification of regimens, reduction and prevention of adverse effects, or expected improvement of virological response rates [31–33]. In the Netherlands, the protease inhibitors nelfinavir and (boosted) indinavir were used in the early years of cART , but are currently no longer prescribed, and have been replaced by (boosted) lopinavir and the most frequently used NNRTI, efavirenz [35,36] (Fig. 1). No entry or integrase inhibitors were prescribed in the Dutch paediatric population.
There was no difference in CD4+Z-scores at cART initiation between the three age groups. The youngest children showed the most rapid short-term immune reconstitution, which was described previously , and might be due to their higher thymic T-cell production  and more voluminous thymus . After 3 up to 10 years of cART, no difference in Z-scores for CD4+ cell counts was observed between the three age groups, indicating that longer-term immune responses might be independent of age at cART initiation, as described in previous studies of HIV-infected children in Europe [10,17,18]. These studies all had shorter follow-up periods in comparison to this analysis. In addition, children with a lower median CD4+Z-score had a more rapid CD4+ increase in the first year after cART initiation, as has been described previously [15,39,40]. However, the initial CD4+Z-score had no influence on immunological reconstitution after 3 up to 10 years of cART, which was in agreement with other European studies [18,39,41]. This was in contrast with some studies from Europe [15,40,42] and the USA , stating that a lower pre-cART CD4+ percentage was a predictor for a worse immunological outcome after 3–5 years of cART. As has been said by Walker et al., it may take longer than this to reach a normal CD4+Z-score when the pre-cART Z-score is very low.
We showed in Fig. 3 that earlier (in calendar time) cART initiation was related to a slower decline of HIV viral load. Children who commenced cART after 2000 had the fastest decline of their HIV viral load compared to children who initiated cART between 1996 and 2000. This may be explained by the fact that in 2000, therapeutical options for Dutch children were extended with more potent cART, such as the addition of nevirapine, efavirenz and lopinavir to only indinavir and nelfinavir [35,43].
The percentage of children with an undetectable HIV viral load rose over time from 27 to 89%, which is higher than in other industrialized countries [29,44]. This substantial rise was even more remarkable because the LLD of the HIV viral load test decreased from less than 1000 copies/ml to less than 40 copies/ml. It must be noted that in 2012, data from only 19 patients were available.
In contrast to other studies [45,46], mortality was not increased in the youngest age group and was overall very low in our population (0.3 per 100 person-years). As compared to reports from other industrialized countries [3,27,29,41,47] the mortality rate in the Netherlands was lower, and equal to reports from Sweden and Spain [26,48]. These reports were based on data collected until 2009; current data from these countries may contain mortality rates approaching results from this analysis.
There are several possible explanations for the positive achievements in Dutch paediatric HIV care. An important characteristic of the care for HIV-infected children in the Netherlands is that it is centred within four academic hospitals with multidisciplinary HIV-specialized teams. This allows for up-to-date knowledge, evidence-based treatment and strict follow-up of all HIV-infected children. Secondly, therapeutic drug monitoring (TDM) is routinely used by Dutch paediatric HIV clinicians , allowing optimal personal dosing and leading to fewer adverse reactions and more sustainable viral suppression . Lastly, simultaneously with the introduction of cART, treatment adherence programmes have been initiated in various paediatric HIV centres in the Netherlands, contributing to reducing treatment failures and improved long-term outcomes .
Despite the relatively large size of our patient population, the wide range of ages and the long-term follow-up period as compared to other overview articles [14,16,29,52], our study has its limitations. Virological and immunological values, especially CD4+ percentages, were not always registered from HIV infection onwards for every child; this mostly happened in immigrant children of whom consequent registration only started when their treatment at one of the paediatric HIV clinics commenced.
In conclusion, our results offer a broad overview of a long-term registered vertically HIV-infected population in an industrialized country. The majority of paediatric patients in the Netherlands originate from SSA or are first-generation immigrants from that region. Short-term CD4+ reconstitution was fastest in children who were between 0 and 2 years old at cART initiation, as well as in children with the lowest initial CD4+Z-score. However, a longer-term immunological response was independent of age at cART initiation or pre-cART CD4+Z-score, despite a higher initial HIV viral load in the youngest children. The percentage of children with an undetectable HIV viral load rose significantly over the years and the HIV-associated mortality rate was among the lowest reported.
We thank Professor Dr T.W. Kuijpers and Professor Dr P. Reiss for their comments. We are grateful to the data collectors from the HIV monitoring foundation for gathering the data from the different paediatric HIV centres.
Members of the Dutch Paediatric HIV Study Group: S. Cohen, D. Pajkrt, T.W. Kuijpers, A. van der Plas, H.J. Scherpbier, A. Weijsenfeld (Amsterdam); R.A. Doedens, H.de Groot-de Jonge, E.H. Schölvinck (Groningen); D.M. Burger, M. van der Flier, R. Strik-Albers, A. Warris (Nijmegen); G.J.A. Driessen, P.L.A. Fraaij, R. de Groot, N.G. Hartwig, P. van Jaarsveld, L. van der Knaap, A.M.C. van Rossum (Rotterdam) and L. Bont, S.P.M. Geelen, N. Nauta, T.F.W. Wolfs (Utrecht).
Author contributions: S.C. wrote the manuscript and performed the statistical analysis in cooperation with C.S. D.P., H.S., Av.R., P.F., T.W., S.G., E.S. and A.W. provided the data and revised and edited the manuscript. All the authors have read and approved the text as submitted to AIDS.
Conflicts of interest
There are no conflicts of interest.
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