Introduction
In the absence of antiretroviral therapy (ART), HIV infection in children cause retardation in height and weight [
1,
2]. Early diagnosis and effective treatment result in major improvement in previously growth retarded children [
3,
4] and only children severely stunted before treatment initiation end up with final height growth retardation [
5‐
8]. On the other hand, risk for increased weight gain during ART has been observed without conclusive evidence of a causative effect related to specific antiretroviral drugs. The mechanisms by which different antiretroviral agents would contribute to weight gain are unknown and the background to the observed weight gain seems to be multifactorial. Demographic factors, HIV status and composition of the ART regimen may contribute [
9].
Specific concerns have been raised for excessive weight gain during treatment with integrase inhibitors (INSTI) and especially dolutegravir (DTG) [
10‐
12]. However, data is conflicting and both absence of as well as increase in weight associated to DTG have been reported [
3,
12]. Specific concerns have been raised about the combination of DTG and tenofovir alafenamide fumarate (TAF) [
11]. Switch from TDF to TAF has been associated with weight gain irrespective of core antiretroviral agent [
13]. Knowledge about children and adolescents, DTG, TAF and weight gain is limited. To date, a few published studies have reported an increase in body mass index (BMI) in children and adolescents living with HIV after switching to DTG-based ART [
14‐
16]. No randomized controlled trial of excessive weight gain related to certain antiretrovirals (ARV) has been performed.
WHO recommend DTG as first line therapy in HIV infection in adults and children from six years of age in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) [
17]. INSTIs are generally well tolerated compared to protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) and has a high barrier towards development of antiretroviral resistance. Overweight and obesity is an emerging global problem, in low-, middle- and high-income countries [
18,
19], which make interpretation of weight gain during certain treatment regimens difficult.
The aim of this study was to present demographic data and growth parameters for all children born 1996- 2015 from a single center cohort representing more than 50% of children living with HIV in Sweden and especially to study if switch to DTG affected BMI and to describe final adult height in the cohort.
Discussion
We present a study about weight, height and BMI from a cohort of children and adolescents living with HIV, representing half of them living with HIV in Sweden, a high-income country with available resources for optimal pediatric HIV care. The cohort is representative for children/adolescents living with HIV in Sweden but differs from the general population and from cohorts of other chronic diseases since almost all are immigrants, mainly from Africa. In addition, only 2/3 lived with a biological parent and one fourth were internationally adopted (Table
1). The general adherence to ART was good and the degree of viral suppression was high throughout the study period.
The children recovered height after arrival in Sweden. The background to this is probably multi factorial and might be attributed to HIV diagnosis and treatment for those previously undiagnosed, effective treatment and follow-up for those previously not well treated in addition to better nutritional supply. A similar pattern has been observed in HIV negative internationally adopted children. The growth spurt occurred within the normal age span compared to the WHO growth charts and final height was within the normal range apart from a few children who were stunted already at arrival before ART initiation. This is similar to patterns described in HIV negative internationally adopted children [
26,
27]. Reduced height in HIV-infected children was reported in studies from the pre-ART era [
1,
2]. Final height in our cohort was almost within normal range compared to the WHO growth charts. This is similar to what was found in the large EPPICC cohort, where a recovery was seen after ART initiation, at least for those not severely stunted [
8,
28] and children with height SDS ≥ -1 at ART initiation gained height similarly to HIV negative children at comparable age [
8]. In the pre-ART era, a study of HIV-infected hemophilic boys in the UK showed normal growth the first 4.5 years after seroconversion [
29], indicating that normal growth is expected if the child is not malnourished or severely affected by the HIV infection. The short final height in a few children in our cohort could be explained by factors like severe disease, malnutrition before immigration or genetic factors. Without knowledge of parental height, no certain interpretation is possible.
At last documented visit, 14 out of 50 (28%) of the girls and 5 out of 44 (12%) of the boys were overweight or obese defined as ISO-BMI ≥ 25. Thiscould be related to overweight and obesity in 14- 21% among girls and 10- 25% of boys aged 4- 18 years in the general Swedish adolescent population [
30,
31]. A recent Swedish study shows that overweight is common already from 4 years of age (14- 18% in girls and 10–13% in boys) and increase to the numbers reported above in adolescents 13–19 years [
31]. The referred studies used IOTF BMI cut-offs for overweight and obesity [
25]. Boys were initially less prone to overweight than girls, but the opposite condition was seen among adolescents [
30,
31]. In our study, obesity defined as BMI SDS ≥ 2 was observed in 9 out of 50 (18%) of all girls and in 4 out of 44 (9%) of all boys at last visit, while obesity defined according to IOTF (ISO-BMI ≥ 30) was observed in 5 out of 50 (10%) of the girls and 2 out of 44 (5%) of the boys (Table
3), which could be compared to 3- 4% (girls) and 2.7- 6% (boys) in the general population [
30]. Thus, the degree of overweight and obesity may be higher among girls in our study than in the general population but as expected in boys [
30,
31]. However, with a small cohort, the estimated proportions of overweight and obesity are uncertain making comparisons with.
There is concern in adults about possible excessive weight gain related to INSTIs and particularly DTG [
11]. Especially women and none-whites have been reported to be at risk [
10,
11]. However, a recent study suggested the difference in weight gain between DTG and EFV based regimens to be mainly related to impaired weight gain in slow metabolisers of EFV, due to possible side effects. Quick EFV metabolisers gained weight at similar rates as patients on DTG [
32].
Little is published about a possible relation between DTG and weight gain in children and adolescents, but recently two studies have addressed excessive weight gain in relation to DTG switch [
14,
15]. Transition to DTG in in 460 virally suppressed adolescents in Swaziland was associated with an increase in BMI change. Female adolescents experienced a larger change than males [
15]. Notably, the conclusions were made without correction for puberty. In addition, boys and girls were analysed together in a cohort > 10 years of age, when age, puberty and sex are important parameters in analyses of BMI changes in children and adolescents. A smaller retrospective study of 38 children and youth (aged 0- 19 years) in the United States reported an increase in BMI change after switch to DTG. The median follow-up time was 527 days [
14]. Neither did this study take puberty into account. In addition, the Odyssey study, not designed to study outcome of growth, compared DTG based therapy to standard of care in children and adolescents starting first- or second-line ART. BMI–for–age z score increased slightly more in the DTG group than in the standard of care group, but from low baseline levels. The weight gain occurred early and alongside a small increase in height, which was interpretated as improvement in normal growth [
16].
We found no difference in weight gain between children and adolescents treated with DTG compared to other regimens. Among 50 children who switched to DTG, 22 kept their BMI position, compared to 13 and 15 with decrease or increase in BMI SDS respectively, suggesting absence of systematic increase in BMI after DTG switch. No change in BMI SDS could be seen 13 months after switch to DTG regardless of age and sex. We considered an observational time of 13 months as optimal to evaluate if a drug per se constitutes a risk factor for excessive weight gain. With longer observational time, other factors like environmental factors and changes in lifestyle will complicate the analysis.
Despite an increased number of adolescent girls with BMI SDS ≥ 2 between first (0/38) and last visit (8/38), there was no difference related to ART regimen. Eighteen individuals were on DTG at last visit and their BMI SDS did not differ from the 20 with an NNRTI or PI as core agent. Weight gain seen in HIV-infected individuals starting effective ART might be a normalization or adaption of BMI to levels seen in the general population rather than an excessive BMI increase caused by the different drugs. However, case reports of children and adolescents with excessive weight gain after shift to DTG [
33] and reversion after change back to the initial ART combination might indicate the occurrence of certain individual factors predisposing for DTG related effects on weight. RCTs comparing the relationship between certain antiretrovirals and weight gain to healthy controls with similar socioeconomic background are lacking.
One strength of our study is the well-controlled, thoroughly monitored study cohort consisting of a considerable part of all available children and adolescents living with HIV in Sweden and another is taking puberty in account. To our knowledge it is the first study analysing DTG-related weight and BMI change to age adjusted growth charts and to the condition in the general population. We consider it a strength to have analyses of age adjusted change in BMI SDS with observations one year before, at switch and one year after switch to DTG. As a complement we also present the occurrence of overweight and obesity. Several studies define cut-off for suspected DTG-related weight gain as more than 7% increase in BMI from pre-ART BMI [
11], which could represent unwanted weight gain but also reflect a desirable increase due to positive treatment effects. In addition, the 7% BMI increase does not take puberty in account. Thorough follow-up and repeated height and weight measurements guarantee good data quality. Despite representing half of the pediatric HIV population in Sweden, the cohort is small which limits definite conclusions regarding DTG and weight gain. Another limitation is the retrospective design.
In conclusion DTG was the dominating core agent at the last documented visit in this well treated pediatric cohort and we found no evidence of DTG and/or TAF causing excessive weight gain. The children and adolescents gained height and weight significantly between their first and last visit which might be an expected return to health effect caused by efficient ART. For those followed from prepubertal age, timing of pubertal growth and final height was within the normal range compared to the WHO growth standards. Short adult stature was seen only in those severely stunted before arrival in Sweden. Overweight and obesity in children and adolescents are growing problems in the general population as well as in this cohort. Adolescent girls gained weight to a greater extent than expected regardless of ART regimen but children/adolescents living with HIV and on effective ART essentially had a weight and height development like their Swedish peers.
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