AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 24, Number 12, 2008 © Mary Ann Liebert, Inc. DOI: 10.1089/aid.2008.0037
Immunological Recovery and Metabolic Disorders in Severe Immunodeficiency HIV Type 1-Infected Children on Highly Active Antiretroviral Therapy Salvador Resino,1,2 Dariela Micheloud,2 Beatriz Larrú,1 Jose M. Bellón,1 Juan Antonio Léon,3 Rosa Resino,1 M. Isabel De José,4 M. Dolores Gurbindo Gutiérrez,5 M. José Mellado,6 Sara Guillen,7 José Tomas Ramos,7 and M. Ángeles Muñoz-Fernández1 on Behalf of the Spanish Group of Paediatric HIV Infection
Abstract
Little is known about immunologic reconstitution in children on highly active antiretroviral treatment (HAART) during very long-term periods. A retrospective study was carried out to assess the effectiveness and development of metabolic disorders after very long-term periods on HAART in HIV-infected children with severe immunodeficiency. We included 55 children who were stratified into three groups according to %CD4 preHAART and rate of immunologic recovery: (1) S1-Rec: CD4 5% at baseline and slow immunologic recovery; (2) S2-Rec: CD4 5–15% at baseline and slow immunologic recovery; (3) R-Rec: CD4 15% at baseline and rapid immunologic recovery (reference group). An adequate immune recovery after 8 years on HAART was achieved by only 25% of children. S1-Rec never achieved a mean of CD4 25% after 8 years on HAART. All children had a significant increase in plasma cholesterol levels during the first 2 years. Afterward, cholesterol levels reached a plateau and remained stable until year 8 of follow-up. Higher rates of lipodystrophy were found in the R-Rec group [14 (100%)] than in the S1-Rec group [9/19 (47.4%)] or the S2-Rec group [13/20 (65%)] at the end of the study (p 0.006). Overall, having a low nadir of CD4 hindered immune reconstitution; however, children with rapid immunologic recovery showed a higher prevalence of the lipodystrophy syndrome. ders such as hypercholesterolemia or insulin resistance.9–11 The rate of metabolic disorders found in different studies varies widely and the etiology of the lipodystrophy remains unclear. To address those issues, we carried out a retrospective study to define the very long-term impact of HAART in %CD4, viral load (VL), and lipodystrophy syndrome in pretreated vertically HIV-infected children with severe immunodeficiency, followed-up for 8 years.
Introduction
A
is widely recommended for patients with severe immunodeficiency, regardless of plasma HIV RNA levels or absence of symptoms.1 Several studies have shown the relationship between CD4 increases and baseline CD4 counts in children with HIV infection on highly active antiretroviral therapy (HAART).2–4 It has been suggested that when HAART is started before severe immunologic deficiency occurred, it might produce a more effective and sustained immune recovery.4 However, the appearance of several side effects after HAART use has also been described, including a group of conditions characterized by dyslipidemia and lipodystrophy syndrome.5–8 This syndrome is characterized by peripheral fat wasting, central fat accumulation, and metabolic disorNTIRETROVIRAL THERAPY
Materials and Methods Population and study design A retrospective study was carried out on 55 vertically HIVinfected children recruited from November 1996 and fol-
1Laboratorio
de Inmuno-Biología Molecular, Hospital General Universitario “Gregorio Marañón,” Madrid, Spain. de Salud Carlos III, Majadahonda, Madrid, Spain. 3Pediatría-Infecciosas, Hospital Universitario “Virgen de Rocío,” Seville, Spain. 4Inmuno-Pediatría, Hospital Universitario “La Paz,” Madrid, Spain. 5Inmuno-Pediatría, Hospital General Universitario “Gregorio Marañón,” Madrid, Spain. 6Pediatría-Infecciosas, Hospital Universitario “Carlos III,” Madrid, Spain. 7Pediatría, Hospital Universitario de Getáfe, Madrid, Spain. 2Instituto
1
2 lowed-up until September 2006. All the children included belonged to a cohort that we have been previously studying among six large Spanish pediatric referral hospitals. All infants were diagnosed as HIV-1 infected on the basis of positive results in both DNA-polymerase chain reaction (PCR) and virus culture assays.12 The inclusion criteria in our study were (1) starting HAART with a protease inhibitor (PI) and CD4 15% at baseline, (2) having at least 6 years of follow-up, and (3) having CD4 or VL values recorded 1 year before HAART initiation. All children had received mono or dual nucleoside therapy before starting HAART. We included only children with prior antiretroviral therapy (ART) when starting HAART in the analysis so that the study groups were more homogeneous in terms of previous exposure to antiretroviral drugs and possible accumulation of HIV resistance mutations. We collected data from 305 children belonging to our cohort from 1996 to 2001. This cohort included 125 pretreated and 48 naive children who started HAART, 85 children who had not started HAART (1996 to 2001), and 47 children lost to follow-up or death after 1996. In addition, 35 out of 47 children who were lost to follow-up never used HAART and 12 died between 1996 and 2001; those children were not included in our study due to not having at least 6 years of follow-up. The study was approved by the Ethical Committees of all hospitals involved. Clinical classification was based on the 1994 revised guidelines from the Centers for Disease Control (CDC).13 Children were monitored at least every 3 months with repeated interviews, physical examinations according to published guidelines,14 and blood sample collection for serial %CD4, %CD8, and VL measurements.15 There was no uniform approach regarding ART. Instead, each pediatrician administered the appropriate ART regimen and changed the drugs according to his or her interpretation of the children’s data and following international CDC14 and European guidelines.1,16,17 Not all the hospitals involved had access to resistance tests to guide treatment decisions during the entire period of follow-up. Lipodystrophy Lipodystrophy diagnosis was based on clinical examination at the last visit. The pediatricians recorded any sign of lipoatrophy or lipohypertrophy following the criteria of Hartman et al.18 The degree of lipoatrophy or lipohypertrophy in every part of the body was measured as absent (score of 0), mild (noticeable on close inspection, score 1), moderate (readily noticeable by the patient and physician, score 2), or severe (readily noticeable to a casual observer, score 3). Only patients with mild, moderate, or severe features of lipodystrophy (score 1) were classified as cases. Statistical analysis Initiation of HAART was considered as the first time children received three or more antiretroviral drugs that include at least one PI. Subsequent changes of HAART were ignored in terms of statistical analysis. We determined the mean of CD4 and log10 VL per year before and after HAART as each patient’s representative measures. Baseline CD4 cell count was the mean CD4 count in the year prior to HAART (mean of three to four re-
RESINO ET AL. sults of CD4 for each child). The values of %CD4 and log10 VL of children were plotted by year of follow-up and stratified by %CD4 pre-HAART (5%; 5–15%) and rate in %CD4 recovery (slow or rapid recovery). HIV-infected children were stratified according to %CD4 pre-HAART (5%; 5–15%) and rate in %CD4 recovery (slow recovery if they did not reach CD4 25% by the second year of follow-up or rapid recovery if they achieved CD4 25% by the second year of follow-up). Therefore, HIV-infected children were classified into three study groups: (1) S1-Rec: CD4 5% at baseline and slow immunologic recovery, (2) S2-Rec: CD4 5–15% at baseline and slow immunologic recovery, and (3) R-Rec: CD4 15% at baseline (seven children with CD4 5% and seven with CD4 5–15%) and rapid immunologic recovery (reference group). All statistical analyses were performed with SPSS (version 12). All p values were two-tailed. Statistical significance was defined as p 0.05. For categorical variables, the Pearson chi-square test and Spearman’s correlation coefficient were applied. We carried out a multivariate analysis by UNINOVA (univariate analysis of variance) in the GLM (general liniear model) procedure to determine the long-term response to HAART. Dependent variables were mean differences (increase or decrease) of %CD4, log10 VL, cholesterol, and triglycerides per year from pre-HAART year (1 year) to the second year on HAART (first period), from second year to the year 6 on HAART (second period), and from years 6 to 8 on HAART (third period). Afterward, we made a subsequent data analysis at 2, 6, and 8 years, with CD4 or VL stratum an independent variables. We compared stratum by the Bonferroni test (post-hoc tests of “multiple comparisons”) with the R-Rec group as the reference category. These multivariate analyses was adjusted by baseline characteristics [previous diagnosis of AIDS, time with ART (nucleoside analogue HIV reverse transcriptase inhibitor; NRTI), number of new drugs (NRTI), age at baseline, and mean of VL during each period of follow-up]. Because resistance data to antiretroviral drugs and reliable data on adherence were not available during the entire follow-up period we considered VL during each period of follow-up as an indirect measure of the effect of lack of adherence and subsequent development of antiretroviral drug resistance. We also analyzed the progression of hyperlipidemia; we calculated the percentage of children with a mean per year of plasma triglycerides and cholesterol levels above 170 and 200 mg/dl, respectively. We performed a logistic regression analysis to determinate the odds ratio (OR) to achieve hyperlipidemia values per year, with CD4 as an independent variable. Results Characteristics of the HIV-infected children Table 1 summarizes baseline characteristics of pretreated vertically HIV-infected children. In the R-Rec group, seven (50%) children had values of CD4 5% at baseline. The mean age of HIV-infected children when they were first enrolled in the cohort was approximately 7 years old with a follow-up of nearly 10 years. During the follow-up, one child progressed to AIDS and two children died. In the R-Rec
IMMUNE RECOVERY AND METABOLIC DISORDERS TABLE 1.
DEMOGRAPHIC
AND
CLINICAL CHARACTERISTICS S1-Rec
Number of HIV children Age (years)b Malec Diagnosis of AIDS (CDC)c Antiretroviral treatment (ART) prior to HAART Monotherapy Combined therapy Monotherapy combined therapy Time (months) with ART previousb ART protocol switches previousb First HAART regimen at baselinec Number of new drugs in HAARTd 0 NRTI 1 NRTI 2 NRTI 1 NNRTI Nucleoside analogue (NRTI) AZT ddl D4T 3TC Abacavir Protease inhibitor (PI) Ritonavir Saquinavir Indinavir Nelfinavir Amprenavir Nonnucleoside analogue (NNRTI) Efavirenz HAART protocols 2 NRTI 1 PI 2 NRTI 1 NNRTI 3 NRTI 1 PI 1 NRTI 1 PI 1 NNRTI Others 2 years on HAART initiation Same regimen as the HAART initiation (%)c Number of line therapyb 6 years on HAART initiation Same regimen as the HAART initiation (%)c Number of line therapyb 8 years on HAART initiation Same regimen as the HAART initiation (%)c Number of line therapyb
3
19 7.9 (5.1; 9.9) 14 (73.7) 16 (84.2) 3 5 11 10.6 1
(15.8) (26.3) (57.9) (7.6; 21) (0;2)
OF
VERTICALLY HIV-INFECTED CHILDRENa S2-Rec 22 9.3 (6.2; 12.3) 10 (45.5) 13 (59.1) 5 6 11 15.6 1
(22.7) (27.3) (50) (10.7; 28) (0; 2)
R-Rec 14 6.6 (5.1; 8.6) 7 (50) 7 (50) 5 0 9 10.6 1
(35.7) (0) (64.3) (4; 16.5) (0; 2)
p 0.080 0.165 0.089 0.224
0.034 0.904
9 5 5 3
(47.4) (26.3) (26.3) (15.8)
8 8 6 2
(36.4) (36.4) (27.3) (9.1)
7 4 3 0
(50) (28.6) (21.4) (0)
0.918
3 5 15 12 0
(15.8) (26.3) (78.9) (63.2) (0)
4 5 17 16 1
(18.2) (22.7) (77.3) (72.7) (4.5)
2 3 12 10 0
(14.3) (21.4) (85.7) (71.4) (0)
0.95 0.94 0.818 0.785 0.466
6 3 6 3 0
(31.6) (15.8) (31.6) (15.8) (0)
1 4 11 4 2
(4.5) (18.2) (50) (18.2) (9.1)
3 4 6 1 0
(21.4) (28.6) (42.9) (7.1) (0)
0.076 0.638 0.489 0.646 0.211
3 (15.89) 12 1 1 2 3
(63.2) (5.3) (5.3) (10.5) (15.8)
2 (9.1) 17 1 1 1 2
(77.3) (4.5) (4.5) (4.5) (9.1)
0 (0) 11 0 1 0 2
0.296
(78.6) (0) (7.1) (0) (14.3)
0.917
8/19 (42.1)
10/22 (45.5)
4/14 (28.6)
0.650
1 (0; 1)
1 (0; 1)
1 (0; 1)
0.763
2/17 (11.8) 2 (1; 3) 1/15 (6.7) 3 (1; 4)
1/22 (4.5) 2 (1; 3) 0/16 (0) 2 (1; 3)
1/14 (7.1) 2 (1; 2) 0/12 (0) 2 (2; 4)
0.812 0.725 0.628 0.349
aVL, viral load; CDC, Centers for Disease Control; HAART, highly active antiretroviral therapy; NRTI, nucleoside analogue HIV reverse transcriptase inhibitor; NNRTI, nonnucleoside analogue HIV reverse transcriptase inhibitor. b,cValues are expressed as (b) median (P25; P75) and (c) absolute (percentage). dPI was not included. p-value, level of statistical significance. S1-Rec, children with CD4 5% at baseline and slow recovery of CD4 T cells. S2-Rec, Children with CD4 5–15% at baseline and slow recovery of CD4 T cells. R-Rec, children with CD4 15% at baseline and rapid recovery of CD4 T cells (reference group). p-values were calculated to determine differences equally among the three groups of children.
group, children had a mean age of 6.6 years old and they had a better evolution in spite of the greater immaturity of their immunologic system. Only 13 (23.6%) children initiated HAART with prior monotherapy, whereas the rest of the children had received combined therapy prior to starting
HAART, with the exception of the R-Rec group in which no children had received combined therapy. In addition, 17 (30.9%) children included a new NRTI in their HAART regimen, 14 (25.5%) included two new NRTI in their HAART, and 5 (9.1%) included one nonnucleoside analogue HIV re-
4
RESINO ET AL.
verse transcriptase inhibitor (NNRTI). More frequently antiretroviral drugs used in the first-line HAART were similar within the groups. We did not find differences in changes in antiretroviral therapy during follow-up among groups. Evolution of CD4 T cells and viral load We observed that S1-Rec did not achieve a mean of CD4 25% after 8 years on HAART while S2-Rec reached a mean of CD4 25% at year 5 on HAART (Fig. 1A). S1-Rec had lower CD4 values than S2-Rec in the first year pre-HAART (1 year) and the first year on HAART (p 0.05). Furthermore, S1-Rec had lower CD4 values than R-Rec from the first year pre-HAART (1 year) until year 7 on HAART (p 0.05). When we analyzed whether children reached CD4 30% in every year of follow-up, we found similar percentages of children between S1-Rec and S2-Rec until year 4 on HAART (Fig. 1B). After the second year, R-Rec had a higher percentage of children reaching CD4 30% than other groups. When we considered VL (Fig. 1C), S1-Rec had higher
S1-Rec
A
VL values than S2-Rec in the 2 and 1 year pre-HAART and year 4 on HAART (p 0.05). S2-Rec had lower VL values than R-Rec in the 2 and 1 year pre-HAART (p 0.05). We did not find statistical differences among groups in achieving VL 400 copies/ml in every year of follow-up (Fig. 1D). Table 2 summarizes the mean changes %CD4 and log10 VL (copies/ml) from the first year pre-HAART (1 year) to years 2, 6, and 8 on HAART. R-Rec showed a great increase of CD4, and after the second year on HAART %CD4 reached a plateau and remained stable until year 8 of followup. We also found a decrease of VL after the second year on HAART in this group. When we analyzed children with slow CD4 recovery during the first 2 years on HAART (S1-Rec and S2-Rec), we found a significant increase of %CD4 and a decrease of VL (p 0.05). However, these changes were less significant than those observed for the R-Rec group. During the following 4 years of follow-up in children with slow recovery (from year 2 to 6) we found a significant increase only of %CD4 in the S2-Rec group. Moreover, when we an-
B
40
R-Rec
S2-Rec 100 Percentage of children with CD4 30%
CD4 T-cells (%)
35 30 25 20 15 10
80 60 40 20
5 0
0 2 1
C
1
2 3 4 5 Follow-up (years)
6
7
8
D
5,0 4,0 3,0 2,0 1,0 0,0
1
2 3 4 5 Follow-up (years)
6
7
8
2 1
1
2 3 4 5 Follow-up (years)
6
7
8
100 Percentage of children with VL 400 cp/mL
Viral load (copies/mL)
6,0
2 1
80 60 40 20 0
2 1
1
2 3 4 5 Follow-up (years)
6
7
8
FIG. 1. Evolution of CD4 T cell percentage and log10 VL (copies/ml) during follow-up of pretreated vertically HIV-infected children on HAART. (A, B) Values of CD4 T cells (%) as mean standard error of mean and percentage of HIVinfected children with a mean of CD4 per year 30%. (C, D) Log10 VL (copies/ml) as mean standard error of mean and percentage of HIV-infected children a mean of VL per year 400 copies/ml. S1-Rec: children with CD4 5% at baseline and slow recovery of CD4 T cells. S2-Rec: children with CD4 5–15% at baseline and slow recovery of CD4 T cells. RRec: children with CD4 15% at baseline and rapid recovery of CD4 T cells (reference group).
IMMUNE RECOVERY AND METABOLIC DISORDERS
5
TABLE 2. SUMMARY OF ESTIMATED MARGINAL MEANS OF CHANGE IN CD4 T CELLS (%) AND LOG10 VL (COPIES/ml) OF HIV CHILDREN FROM BASELINE TO YEAR 2, 6, OR 8 ON HAARTa,b From baseline to year 2
From year 2 to year 6
From year 6 to year 8
No.
Mean (CI 95%)
No.
Mean (CI 95%)
No.
Mean (CI 95%)
CD4 T cells (%) S1-Rec S2-Rec R-Rec
19 22 14
14.3 (10.3; 18.3)* 8.7 (5.9; 11.6)* 23 (19.5; 26.6)
17 22 14
5.3 (0.2; 10.3) 6.6 (3.2; 10)* 0.7 (5; 3.6)
13 16 12
0.9 (3.8; 5.7) 1.3 (1.9; 4.6) 0.2 (3.5; 3.9)
log10 VL (copies/ml) S1-Rec S2-Rec R-Rec
19 21 12
17 21 14
0.56 (1.12; 0) 0.82 (1.2; 0.43) 0.31 (0.8; 0.17)
11 14 12
0.13 (0.69; 0.44) 0.16 (0.47; 0.15) 0.03 (0.03; 0.36)
0.71 (1.19; 0.24)* 0.6 (0.95; 0.25)* 1.63 (2.1; 1.16)
aCI 95%, confidence interval of 95%; values are expressed as mean (CI 95%). VL, viral load. Statistical significance (*p 0.05) with R-Rec group. S1-Rec, children with CD4 5% at baseline and slow recovery of CD4 T cells. S2-Rec, children with CD4 5–15% at baseline and slow recovery of CD4 T cells. R-Rec, children with CD4 15% at baseline and rapid recovery of CD4 T cells (reference group). bMultivariate analysis was adjusted by previous diagnosis of AIDS, time with ART (nucleoside analogue HIV reverse transcriptase inhibitor; NRTI), number of new drugs (NRTI) in baseline HAART, age at baseline, and mean of viral load among year 2 and 8 of follow-up.
alyzed the last 2 years of follow-up (from year 6 to 8) we did not find a significant increase of %CD4 and decrease of VL in all groups.
covery and lipoatrophy (r 0.382; p 0.005). However, we did not find statistically significant values among groups and lipohypertrophy (Fig. 2F).
Lipids and lipodystrophy
Discussion
When we analyzed the appearance of dyslipidemia, we did not find a significant increase of plasma triglyceride levels during the entire period of follow-up in the three groups (p 0.05) (Fig. 2A). However, all of them had a significant increase in plasma cholesterol levels during the first 2 years of follow-up (Fig. 2C): S1-Rec [55.6 (CI95%: 23; 88.3) mg/dl], S2-Rec [40.7 (CI95%: 17.5; 63.9) mg/dl], and R-Rec [67.2 (CI95%: 39.2; 95.2) mg/dl]. After the second year on HAART, plasma cholesterol levels reached a plateau and remained stable until year 8 of follow-up. Overall, all groups had a significant increase in plasma cholesterol during the entire period of follow-up (p 0.05). Regarding hyperlipidemia (Fig. 2B and D), 12% of all children at the beginning of the study, 24% at year 2 on HAART, 29% at year 6 on HAART, and 36% at the end of study had triglycerides 170 mg/dl. We did not find a statistically significant increase in percentage of children with triglycerides levels 170 mg/dl. Furthermore, 0% of children at the entry of the study, 35% at the second year on HAART, 31% at year 6 on HAART, and 18% at the end of study had hypercholesterolemia. We found a significant increase of HIV-infected children with hypercholesterolemia at the second year on HAART (p 0.001). Afterward, this percentage was 15% in all groups during follow-up. The percentage of children with hypercholesterolemia was higher at the end of the study than at baseline (p 0.016). Higher values of prevalence of lipodystrophy were found in the R-Rec group [14 (100%)] than in the S1-Rec group [9/19 (47.4%)] and S2-Rec group [13/20 (65%)] at the end of the study (p 0.006). Moreover, we found statistically significant values of the Spearman correlation coefficient between rate of CD4 recovery and lipodystrophy (r 0.429; p 0.001). We also found statistical differences (p 0.05) among groups in prevalence of lipoatrophy (Fig. 2E) with a positive Spearman correlation coefficient between rate of CD4 re-
Our study suggests that HIV-infected children with slow recovery and CD4 5% at baseline (S1-Rec) never achieve complete CD4 recovery after 8 years on HAART, in spite of an acceptable control of VL. Thus, a very low CD4 count at baseline may be associated with less effective immune recovery or maintenance of normal CD4 values. Only 25% of children in our study achieved an excellent CD4 recovery (R-Rec). Children in the S2-Rec group had slower immunologic recovery but still demonstrated significant CD4% increases after a prolonged period on HAART (6 year followup point). This might reflect the inhibitory effect of HIV on thymic function.19 In addition, when CD4 counts remain very low, it is associated with immune system activation,20 which can be used as a predictive marker of virologic failure21–23 and increase of CD4.24–26 We also found that the R-Rec group achieved CD4 values close to 25% in year 2 on HAART, and then reached a plateau in CD4, as has been described in adults.4,27,28 In this group the CD4 nadir did not influence immune recovery since 50% of children had CD4 5% and the other 50% had CD4 between 5 and 15%. This could be explained by the fact that the R-Rec group was slightly younger when they started HAART compared to the other groups. The role of age on immunologic recovery in our study was difficult to assess because it was not a randomized clinical trial and the independent effect of baseline CD4 level cannot be controlled completely by adjustment for age in multivariate regression. Furthermore, children who died were not included in this study. They had a smooth CD4 increase and VL decrease. Obviously, a slight overestimation of immunologic recovery might have occurred because CD4 recovery was lower among the children who died than in those with CD4 15% who were included in the study. The best control of VL and sustained immune recovery reduced the occurrence of opportunistic infections and im-
6
RESINO ET AL. S1-Rec
A
B
250 Tryglicerides (mg/dL)
50% Children with trygliclerides 170 mg/dL
300
200 150 100 50
2 1
1
2 3 4 5 Follow-up (years)
6
7
D
150 100 50
2 1
1
2 3 4 5 Follow-up (years)
6
7
1
2 6 Follow-up (years)
8
1
2 6 Follow-up (years)
8
50% 40% 30% 20% 10%
8
S1-Rec
S2-Rec
60% 50% 40% 30% 20% 10%
0%
R-Rec
lipohypertrophy
F
lipoatrophy
50% Children with llpowrophy(%)
Children with llpowrophy(%)
10%
0%
0
ED1
20%
60%
Children with cholesterol 200 mg/dL
Cholesterol (mg/dL)
200
70%
30%
8
250
E
40%
0
0
C
R-Rec
S2-Rec
45% 40% 35% 30% 25% 20% 15% 10% 5% 0%
Mild
Moderate
Severe
Mild
Moderate
Severe
FIG. 2. Evolution of triglycerides (mg/dl) and cholesterol (mg/dl) levels during follow-up of pretreated vertically HIVinfected children on HAART. (A, B) Values of triglycerides (mg/dl) as mean standard error of mean and percentage of HIV-infected children with a mean of triglycerides 170 mg/dl. (C, D) Values of cholesterol (mg/dl) as mean standard error of mean and percentage of HIV-infected children with a mean of cholesterol 200 mg/dl. (E, F) Percentage standard error of percentage of children with lipoatrophy and lipohypertrophy. S1-Rec: children with CD4 5% at baseline and slow recovery of CD4 T cells. S2-Rec: children with CD4 5–15% at baseline and slow recovery of CD4 T cells. RRec: children with CD4 15% at baseline and rapid recovery of CD4 T cells (reference group).
proved the survival in HIV-infected children.29 However, metabolic disorders and lipodystrophy syndrome are common side effects in HIV-infected patients receiving HAART.9,30,31 In our study, children who achieved a good
CD4 recovery showed a higher prevalence of lipodistrophy, which could increase their future risk of cardiovascular disease.32,33 We found a significant increase in cholesterol levels among the three groups; however, only a small per-
IMMUNE RECOVERY AND METABOLIC DISORDERS centage of children in our study had significant hyperlipidemia during follow-up. It is possible that cholesterol and triglyceride levels on peripheral blood did not have a good correlation with metabolic disorders and endothelial disease, and an exhaustive analysis of the lipoprotein profiles should be recommended. During the first years of the study none of the children received any treatment for lipid disorders and plasmatic lipids were increased after several years on HAART. Current guidelines on pediatric HIV treatment recommend improvements in diet and exercise as the first intervention and pharmacologic agents (statins) are not considered for routine use in children and adolescents.34 In our study the prevalence of lipodystrophy was higher than in other reports.7,8,31,35,36 This could be explained by the fact that children included in our study had previous longterm ART. In addition, the entire history of CD4 counts during the course of HIV infection in children, particularly in the period pre-HAART, was not considered in other reports. Lower rates of lipodystrophy syndrome are also reported when patients enrolled in studies had higher median CD4 counts, which potentially could exclude those individuals who may have been more likely to develop lipodystrophy. Our findings suggest that lipodystrophy syndrome is associated with a better immune reconstitution. It is possible that apoptotic changes were more pronounced in patients with higher increases in CD4 and CD8 counts and in those with a large decrease in VL.37 The number of treatment changes might not be considered as a limitation of this study. Treatment changes take place frequently in routine practice and, thus, our study provides a more accurate description of the development of lipodystrophy in clinical practice. In addition, none of the children changed ART due to the development of signs or symptoms lipodystrophy. The major limitation of our study was that it was a retrospective study with a small number of patients. Another important limitation was the lack of a uniform approach to treatment decisions and changes in treatment. In addition, all the children included had some prior ART with NRTI before they received HAART. Prior therapy and new drugs in the HAART regimen may also play an important role in response to HAART, but we did not find any association of these variables with long-term response to HAART. Other possible limitations might be the previous HIV resistance mutations that obviously could influence the outcome of therapy; however, ART (monotherapy and combined therapy), length of ART, ART protocol switches, and numbers of new drugs in HAART were similar among the three groups of children. In conclusion, our study shows that having a low nadir CD4 (15%) hinders the immune reconstitution in the majority of children included at least during the 8 years of follow-up. On the other hand, children with rapid immunologic recovery experienced higher rates of lipodystrophy. Acknowledgments This work has supported by grants from Fundación para la Investigación Sanitaria (FIS) del Ministerio de Sanidad y Consumo (PI052411; PI07/90201) and Fundación para la Investigación y la Prevención del SIDA en España (FIPSE) to S.R. and from FIS (PI052476, PI061479), Red RIS RD06-00060035, FIPSE (36514/05, 24534/05), Fundación Caja Navarra,
7 and Comunidad de Madrid (S-SAL-0159-2006) to M.A.M.F. Dariela Micheloud is supported by a grant from Fundación Lair (Grant 020907). Spanish Group of Paediatric HIV Infection: Participating hospitals and personnel staff in this paper: Madrid: Hospital Universitario “12 Octubre”: P. Carreño, J. Ruiz, J. Clemente. Hospital Universitario de Getáfe: J.T. Ramos, Sara Guillen. Hospital General Universitario “Gregorio Marañón”: S. Resino, D. Micheloud, B. Larrú, R. Resino, J.M. Bellón, M.D. Gurbindo, M.L. Navarro, M.A. Muñoz-Fernández. Hospital Universitario “La Paz”: M.I. Isabel de José. Hospital Universitario “Carlos III”: P. Martín-Fontelos, M.J. Mellado, J. Villota. Seville: Hospital Universitario “Virgen del Rocio”: J.A. León Leal. Disclosure Statement No competing financial interests exist. REFERENCES 1. Sharland M, Blanche S, Castelli G, Ramos J, and Gibb DM: PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Med 2004;5(Suppl. 2):61–86. 2. Resino S, Resino R, Micheloud D, et al.: Long-term effects of highly active antiretroviral therapy in pretreated, vertically HIV type 1-infected children: 6 years of follow-up. Clin Infect Dis 2006;42:862–869. 3. Nikolic-Djokic D, Essajee S, Rigaud M, et al.: Immunoreconstitution in children receiving highly active antiretroviral therapy depends on the CD4 cell percentage at baseline. J Infect Dis 2002;185:290–298. 4. Soh CH, Oleske JM, Brady MT, et al.: Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents. Lancet 2003;362:2045–2051. 5. Group EPL: Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS 2004;18:1443–1451. 6. Beregszaszi M, Dollfus C, Levine M, et al.: Longitudinal evaluation and risk factors of lipodystrophy and associated metabolic changes in HIV-infected children. J Acquir Immune Defic Syndr 2005;40:161–168. 7. Guillen S, Ramos JT, Resino R, Bellon JM, and Munoz MA: Impact on weight and height with the use of HAART in HIVinfected children. Pediatr Infect Dis J 2007;26:334–338. 8. Dzwonek AB, Lawson MS, Cole TJ, and Novelli V: Body fat changes and lipodystrophy in HIV-infected children: Impact of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2006;43:121–123. 9. Taylor P, Worrell C, Steinberg SM, et al.: Natural history of lipid abnormalities and fat redistribution among human immunodeficiency virus-infected children receiving long-term, protease inhibitor-containing, highly active antiretroviral therapy regimens. Pediatrics 2004;114:e235–242. 10. Wohl DA, McComsey G, Tebas P, et al.: Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006;43:645–653. 11. Amaya RA, Kozinetz CA, McMeans A, Schwarzwald H, and Kline MW: Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002;21:405–410. 12. Resino S, Gurbindo M, Bellón J, Sanchez-Ramón S, and Muñoz-Fernández M: Predictive markers of clinical outcome in vertically HIV-1 infected infants. A prospective longitudinal study. Pediatr Res 2000;47:509–515.
8 13. CDCP: 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR CDC Surveill Summ 1994;43:1–10. 14. CDC: Guidelines for use of antiretroviral agents in pediatric HIV infection. MMWR Morb Mortal Wkly Rep 1998;47:1–43. 15. Resino S, Bellón J, Gurbindo D, et al.: Viral load and CD4 T-cells response to HAART in HIV-infected children: An observational study. Clin Infect Dis 2003;37:1216–1225. 16. Sharland M, Gibb D, and Giaquinto C: Current evidence for the use of paediatric antiretroviral therapy—a PENTA analysis. Paediatric European Network for the Treatment of AIDS Steering Committee. Eur J Pediatr 2000;159:649–656. 17. Sharland M, di Zub GC, Ramos JT, Blanche S, and Gibb DM: PENTA guidelines for the use of antiretroviral therapy in paediatric HIV infection. Pediatric European Network for Treatment of AIDS. HIV Med 2002;3:215–226. 18. Hartman K, Verweel G, de Groot R, and Hartwig NG: Detection of lipoatrophy in human immunodeficiency virus-1infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J 2006;25:427–431. 19. Haynes BF, Markert ML, Sempowski GD, Patel DD, and Hale LP: The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 2000;18:529–560. 20. Resino S, Seoane E, Gutierrez MD, Leon JA, and Munoz-Fernandez MA: CD4() T-cell immunodeficiency is more dependent on immune activation than viral load in HIV-infected children on highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2006;42:269–276. 21. Resino S, Bellón J, Gurbindo D, and Muñoz-Fernández MA: CD38 in CD8 T cells predict virological failure in HIV-infected children receiving antiretroviral therapy. Clin Infect Dis 2004;38:412–417. 22. Paul ME, Mao C, Charurat M, et al.: Predictors of immunologic long-term nonprogression in HIV-infected children: Implications for initiating therapy. J Allergy Clin Immunol 2005;115:848–855. 23. Resino S, Galan I, Perez A, et al.: Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children. AIDS Res Hum Retroviruses 2005;21:398–406. 24. Koletar SL, Williams PL, Wu J, et al.: Long-term follow-up of HIV-infected individuals who have significant increases in CD4 cell counts during antiretroviral therapy. Clin Infect Dis 2004;39:1500–1506. 25. Deeks SG, Barbour JD, Grant RM, and Martin JN: Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002;16:201–207. 26. Le Moing V, Thiebaut R, Chene G, et al.: Predictors of longterm increase in CD4() cell counts in human immunode-
RESINO ET AL.
27.
28.
29.
30.
31.
32.
33. 34. 35.
36.
37.
ficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis 2002;185: 471–480. Kaufmann GR, Bloch M, Finlayson R, Zaunders J, Smith D, and Cooper DA: The extent of HIV-1-related immunodeficiency and age predict the long-term CD4 T lymphocyte response to potent antiretroviral therapy. AIDS 2002;16: 359–367. Tarwater PM, Margolick JB, Jin J, et al.: Increase and plateau of CD4 T-cell counts in the 3(1/2) years after initiation of potent antiretroviral therapy. J Acquir Immune Defic Syndr 2001;27:168–175. Resino S, Resino R, Maria Bellon J, et al.: Clinical outcomes improve with highly active antiretroviral therapy in vertically HIV type-1-infected children. Clin Infect Dis 2006;43: 243–252. Jones SP, Qazi N, Morelese J, et al.: Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens. J Acquir Immune Defic Syndr 2005;40:565–572. Carter RJ, Wiener J, Abrams EJ, et al.: Dyslipidemia among perinatally HIV-infected children enrolled in the PACTSHOPE cohort, 1999–2004: A longitudinal analysis. J Acquir Immune Defic Syndr 2006;41:453–460. Farley J, Gona P, Crain M, et al.: Prevalence of elevated cholesterol and associated risk factors among perinatally HIVinfected children (4–19 years old) in Pediatric AIDS Clinical Trials Group 219C. J Acquir Immune Defic Syndr 2005;38: 480–487. Tershakovec AM, Frank I, and Rader D: HIV-related lipodystrophy and related factors. Atherosclerosis 2004;174:1–10. American Academy of Pediatrics, Committee on Nutrition: Cholesterol in childhood. Pediatrics 1998;101:141–147. Ene L, Goetghebuer T, Hainaut M, Peltier A, Toppet V, and Levy J: Prevalence of lipodystrophy in HIV-infected children: A cross-sectional study. Eur J Pediatr 2007;166:13–21. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, and Kuijpers TW: Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics 2006;117:e528–536. Domingo P, Matias-Guiu X, Pujol RM, et al.: Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 1999;13:2261–2267.
Address reprint requests to: Salvador Resino Instituto de Salud Carlos III (Campus Majadahonda) Carretera Majadahonda-Pozuelo, Km 2.2 28220 Majadahonda (Madrid), Spain E-mail:
[email protected]
RESINO ED1 Spelling OK? art msp unclear.
