CD4 cell response before and after HAART initiation according to viral load and growth indicators in HIV-1-infected children in Abidjan, Côte d'Ivoire.
ABSTRACT To analyze the determinants of CD4 change in children during 3 periods: before highly active antiretroviral therapy (HAART), during the first year after HAART initiation, and past 1 year after HAART initiation.
One hundred seventy-seven children enrolled in a prospective cohort in Abidjan received HAART during a mean follow-up of 30 months. A linear mixed-effects model was used for the first period, a mixed-effects piecewise model for the second period, and an asymptotic mixed-effects model for long-term CD4 dynamics.
Before HAART initiation, CD4 percentage decreased along time [beta = -0.59 (-0.92 to -0.26)] was positively associated with body mass index for age [beta = 0.47 (0.22 to 0.72)] and negatively associated with viral load [beta = -1.01 (-1.90 to -0.13)]. During the first year of treatment, the CD4 decrease reverted to a steep increase that was negatively associated with age at HAART initiation [beta = -0.24 (-0.4 to -0.07)] and with the mean viral load under HAART [beta = -1.51 (-2.21 to -0.81)]. The long-term CD4 percentage was also negatively associated with the mean viral load under HAART [beta = -4.97 (-6.22 to -3.72)] and age at HAART initiation [beta = -0.82 (-1.12 to -0.51)].
Before HAART initiation, the CD4 cell percentage was associated with growth indicators whereas, after HAART, an early increase and a long-term plateau were negatively associated with the viral load and age at HAART initiation.
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ABSTRACT: BACKGROUND: Quantifying pediatric immunologic recovery by highly active antiretroviral therapy (HAART) initiation at different CD4 percentage (CD4%) and age thresholds may inform decisions about timing of treatment initiation. METHODS: HIV-1-infected, HAART-naive children in Europe and the Americas were followed from 2002 through 2009 in PENPACT-1. Data from 162 vertically infected children, with at least World Health Organization "mild" immunosuppression and CD4% <10th percentile, were analyzed for improvement to a normal CD4% (>= 10th percentile) within 4 years after HAART initiation. Data from 209 vertically infected children, regardless of immune status, were analyzed for CD4% outcomes at 4 years and viral failure within 4 years. RESULTS: Seventy-two percent of baseline immunosuppressed children recovered to normal within 4 years. Compared with "severe" immunosuppression, more children with "mild" immunosuppression (difference 36%, 95% confidence interval [CI]: 22% to 49%) or "advanced" immunosuppression (difference 20.8%, 95% CI: 5.8% to 35.9%) recovered a normal CD4%. For each 5-year increase in baseline age, the proportion of children achieving a normal CD4% declined by 19% (95% CI: 11% to 27%). Combining baseline CD4% and age effects resulted in >90% recovery when initiating HAART with "mild" immunosuppression at any age or "advanced" immunosuppression at age <3 years. Baseline CD4% effects became greater with increasing age (P = .02). At 4 years, most immunologic benefits were still significant but diminished. Viral failure was highest in infancy (56%) and adolescence (63%). CONCLUSIONS: Initiating HAART at higher CD4% and younger ages maximizes potential for immunologic recovery. Guidelines should weigh immunologic benefits against long-term risks.Pediatrics 09/2014; 134(4). DOI:10.1542/peds.2014-0527 · 5.30 Impact Factor
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ABSTRACT: Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery. CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4-17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization-recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled. Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development. Please see later in the article for the Editors' Summary.PLoS Medicine 10/2013; 10(10):e1001542. DOI:10.1371/journal.pmed.1001542 · 14.00 Impact Factor
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ABSTRACT: Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in future.Advanced drug delivery reviews 01/2014; 73. DOI:10.1016/j.addr.2014.01.002 · 12.71 Impact Factor