The virologic, immunologic and clinical outcomes of HIV-infected children have improved greatly with the introduction of highly active antiretroviral therapy (HAART).1,2 There are few data in the literature about the effects of the introduction of HAART on growth. In children, growth failure is a multifactorial problem, which includes HIV infection itself, HIV-associated opportunistic infections and the lack of virologic and immunologic control before initiation of HAART. Treatment with HAART has improved the clinical manifestations and outcome of HIV infection.3 Weight and height of HIV-infected children tends to lag behind those of uninfected children of similar age.4 Uninfected children born at term to HIV-infected mothers have a similar weight at birth as children born to uninfected mothers.5
There are reports showing that the introduction of HAART results in a significant catch-up in weight and height without an increase in body mass index (BMI).4,6 A previous report of 192 children showed that an increase in mean weight z-scores to normal values was obtained by week 48 and an increase in mean height z-scores approached normal values by week 96.6 Some studies have observed an association between virologic response, previous antiretroviral treatment and age.4 In this study we assessed the growth improvement in children who received HAART and its association with different variables including Centers for Disease Control and Prevention (CDC) category at baseline, immunologic response, virologic response and lipodystrophy, in a large cohort of HIV-infected children in Madrid, Spain.
PATIENTS AND METHODS
A retrospective study was performed by reviewing the medical histories of 264 HIV-infected children from the Madrid Cohort, which includes the majority of HIV-infected children followed in the 9 public hospitals in Madrid. Annual weight, height and BMI were obtained only from those children who had values determined at baseline (before starting HAART). A total of 212 HIV-infected children who had been started on HAART at any time beginning in 1997 were selected. To simplify the analysis, children younger than 2 years at baseline were excluded.
Weight, height and BMI measurements were converted to z-scores with the Spanish revised reference data. Data were obtained at baseline, 12, 24, 36, 48 and 60 months, and annual increases were calculated. Children were classified according to the CDC clinical and immunologic categories.7 Measurements of absolute CD4+ T-cell count and percentage were obtained by standard flow cytometric methods. Plasma HIV-1 RNA was determined with the Amplicor HIV-1 monitor test version (Roche Diagnostic Systems). Clinical lipodystrophy was evaluated by the same clinician in each hospital at the last clinic visit, and recorded. It was classified as follows: (a) clinical lipoatrophy if there was fat loss in the face (sunken cheeks), arms, legs or buttocks; (b) clinical lipohypertrophy if there was enlargement of the breasts, increased abdominal girth or dorso-cervical fat accumulation; and (c) mixed pattern: if both peripheral atrophy and central accumulation of fat occurred. Lipodystrophy was graded according to the clinician's criteria in 3 categories: mild, moderate and severe.
Virologic responders were defined as those children with viremia below 400 copies/mL in more than 50% of the samples, and optimal responders or suboptimal responders if they had >90% or 50–90%, respectively, of the samples with viremia below 400 copies/mL. Children who had a CD4% above 25% at the final evaluation were considered immunologic responders.
Changes from baseline in weight, height and BMI at 12, 24, 36, 48, and 60 months were determined and associations of z-scores at the last visit with immunologic and virologic responses, CDC clinical category and the presence and type of lipodystrophy were evaluated.
A paired t test was used to compare the changes of the values of the different factors analyzed over time. To compare means of z-scores between 2 groups we used the student's t test for parametric variables or Mann–Whitney U test for nonparametric. The ANOVA test (or its corresponding nonparametric) was used when more than 2 groups were compared. All P values were 2 tailed. Statistical analysis was performed by SPSS version 12.0 software (SPSS INC, Chicago, IL, USA).
Characteristics of the Children and Response to Therapy.
By December 2005, 212 HIV-1 infected children who had started on HAART at any time in 1997 or later were included. Baseline characteristics of these children are presented in Table 1. The median time on HAART was 71 months (range: 4–102 months). Most children were treated with a PI-containing regimen.
At the final evaluation 24% children remained on the first HAART regimen, 39% on the second and 37% on the third or more HAART regimen. At this time-point, 51% (103/201) of the children were classified as virologic responders (more than 50% of samples with viremia below 400 copies/mL), and an immunologic response (CD4% above 25%) was achieved by 75% (158/211) of the patients. Any type of lipodystrophy was observed in 39% of the children: lipoatrophy 23% (48/212), lipohypertrophy 17% (35/212) and mixed pattern 27% (57/212). Median weight, height and BMI z-scores at baseline are shown in Table 1.
Changes in Growth Associated With HAART Use.
HAART was associated with significant increases in z-scores of weight and height but not with BMI z-score at all time-points analyzed. (Table 2) (Fig. 1). One hundred and twenty-two children older than 2 years of age were evaluated. The mean increases of weight and height z-score compared with baseline at 12, 24, 36, 48, and 60 months are shown in Table 2. No statistically significant differences were found with BMI z-scores changes at the different time points compared with baseline.
Association Between Growth and Virologic Responders.
Growth improvement was different according to the virological response (Table. 3). Weight and height z-score mean difference between suboptimal virologic responders (50–90% of samples with undetectable viremia) and nonresponders (<50% of samples with undetectable viremia) were significant, whereas the BMI z-score mean difference was not significant. In addition, when virologic nonresponders were compared with children with an optimal response (>90% of undetectable viremia) at the last evaluation the difference was again significant for weight and height but not for BMI z-score.
Association Between Immune Response and Growth.
There were no significant correlations between weight, height and BMI z scores changes and immunologic stage (at the last visit), immune response or baseline CD4 (percentage).
Association Between CDC Clinical Category and Growth Changes.
Mean increase of height z-scores over time in children with CDC clinical category C was greater than in children with category A or B. When we compared the mean height z-score between children with clinical category A and C at the final time-point the difference between them was 0.86 (95% CI: 0.37–1.35) (P = 0.05). We did not find significant differences between children with category B and C. No significant differences were observed as well in weight and BMI changes in children with different clinical categories.
Association Between Lipodystrophy and Growth.
No significant differences were observed in growth change overtime according to the presence or not of lipoatrophy. When children with or without lipohypertrophy were compared, a significantly higher BMI z-score was observed in those with lipohypertrophy, with a mean difference of 0.57 (95% CI: 0.15–0.99) (P = 0.008). On the other hand, no differences in weight or height z-scores were detected.
In our study, HIV-infected children had an increase in weight and height but not in the BMI after the introduction of HAART. Virologic control was related to sustained growth but the immune response was not. In addition, advanced clinical disease was associated with a lower height at the final evaluation.
HIV-1 infected children have experienced significant clinical improvement since the introduction of HAART with a positive impact on growth. Steiner et al8 have shown an improvement in growth in children less than 3 years of age after the addition of a PI to their antiretroviral therapy. Dreimane et al9 observed a statistically significant improvement in height but not in weight velocity in HIV-1 infected children after adding a PI to the ongoing antiretroviral therapy. This improvement in height and weight velocity did not correlate statistically with an increase in CD4 cell number and the decline in HIV-1 RNA. In other studies PI use was associated with a greater mean increase of 0.1 kg in weight and of 0.7 cm in height per year over the expected growth in children with non-PI-containing regimens.10 In our study a comparison with children without HAART was not done.
Various studies have shown improvements in weight during the first year and in height mostly over the second year, after initiating HAART.4,10 In our study HAART resulted in an improvement of weight and height during the first year as well as during the rest of the time-points analyzed compared with baseline values. Miller et al11 found that there was a significant effect of PI therapy on the increase of in weight and arm muscle circumference, and a trend toward improvement in the height z-score using a repeated-measures regression model.
Verwell et al6 showed a trend toward a significant z-score change during 96 weeks on HAART compared with the z-score change that occurred before HAART initiation, for weight and height but not for BMI. In our study we did not observe a significant increment in BMI with HAART, which is similar to other studies where BMI remained stable.4,6,12 This may be related to the fact that children, in contrast to adults, increase their height parallel to their weight, and therefore, their BMI remains stable. Furthermore, after HAART, the recovery of weight and height was significantly greater in naive than in pretreated children. These differences were not seen when BMI was studied.6 Early ages have been associated with better catch-up in weight and height.4,8,10,12
Similarly, in the above-mentioned studies the increases in weight and height in virologic responders were significantly higher than in nonresponders, and again, no differences were observed in BMI changes.6 Other studies have not observed differences regarding virologic control.4 We observed no relationship between immune response and growth. Nachman et al4 demonstrated that height z-scores at baseline were significantly associated with CDC disease category. Thus, children in category C had worse height growth than those in less advanced disease categories at the final visit. By contrast, Verweel et al6 showed that children with more advanced clinical infection at baseline had lower BMI and weight improvement after HAART. After HAART introduction, we found no significant differences in weight and BMI z-scores at the last visit among the different clinical CDC categories, but C category was associated with lower final height z-score.
We also compared the growth z-scores of HIV-infected children with different types of clinical lipodystrophy and did not find significant differences between lipoatrophy and z-scores at the last visit; however, children with lipohypertrophy had higher BMI z-scores.
This study has some limitations, such as that it is retrospective. However, it has the strength of having analyzed children with long-term follow-up. No previous studies have studied the growth of HIV-infected children during such a long period of time since the introduction of HAART. Another limitation was that we did not compare growth with the CD4 count adjusted by age, which may be important since other studies have shown a correlation.6
The possibility of growth hormone resistance in HIV-1-infected children that improves during therapy with PI-containing regimens has been suggested, with final normalization of the sensitivity to this hormone.13
We conclude that the initiation of HAART in HIV-infected children produces a sustained increase in weight and height but not in BMI z-scores, which may be related to a better virologic control according to our study. In addition, children with more severe disease can attain a better growth catch-up than children with mild or moderate HIV-infection. Although initiation of HAART can be very effective in achieving sustained growth in HIV-infected children future efforts should be made to ensure not only similar growth to noninfected children, but also a normal development of these children, minimizing the possible long-term consequences of treatment.
We are indebted to Jesús Saavedra, MD, and Cynthia McCoy, MD, for carefully reviewing and making appropriate corrections to the manuscript. We also thank all the authors participating in the study listed below.
Participating hospitals of the Madrid cohort of HIV-infected children Hospital de Getafe: José Tomás Ramos, MD, Bárbara Rubio, MD. Hospital 12 de Octubre: María Isabel Gonzalez-Tomé, MD, Sara Guillén, MD, María Rosario Martínez, MD. Hospital Gregorio Marañón: María Angeles Muñoz, PhD, María Dolores Gurbindo, MD, María Luisa Navarro, MD, Rosa Resino, PhD, José María Bellón, MSc. Hospital La Paz: María Isabel de José, MD. Hospital Carlos III: Pablo Martín-Fontelos, MD, María José Mellado, MD. Hospital del Niño Jesús: Luis Ciria, MD, Jorge Martínez-Pérez, MD. Hospital Alcalá de Henares: José Beceiro, MD. Hospital de Mostoles: Miguel Ángel Roa, MD. Hospital de Leganés: Cristina Calvo, MD. Hospital de Fuenlabrada: Jesús Saavedra, MD.
The Madrid cohort of HIV-infected children. The Madrid cohort of HIV-infected children is supported by an investigational grant from FIPSE (Fundación para la Investigación y la Prevención del SIDA en España) (grant number 36405/03).
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