Response to Highly Active Antiretroviral Therapy Varies With Age
Response to Highly Active Antiretroviral Therapy Varies With Age
Objective: To evaluate the effect of age, CD4 percentage (CD4%) and plasma HIV-1 RNA on response to highly active antiretroviral therapy (HAART) in previously untreated children.
Design: Cohort study.
Methods: We examined the association between age at HAART initiation, and CD4 and HIV-1 RNA response using logistic and Cox regression, adjusting for sex, route of infection and pre-HAART values.
Results: CD4% increases of > 10% at 6 months were more likely in younger children [odds ratio (OR), 0.84 per year, P < 0.001] and those with lower pre-HAART CD4% (OR, 0.67 per 5% higher, P < 0.001), but were not related to pre-HAART HIV-1 RNA (P = 0.6). In contrast, HIV-1 RNA suppression < 400 copies/ml at 6 months was more likely in older children (OR, 1.09 per year, P = 0.03), and was unrelated to pre-HAART HIV-1 RNA or CD4% (P > 0.3). CD4% was still increasing during the second year following HAART initiation (60% followed > 24 months). Longer-term increases in CD4% occurred faster, and decreases in HIV-1 RNA occurred more slowly in younger children. The median time to CD4% ≥ 30% after initiating HAART with CD4% ≤ 25% was under 12 months for children under 2 years irrespective of pre-HAART CD4%, and increased progressively in older children and as CD4% decreased.
Conclusions: Children respond immunologically to HAART irrespective of pre-HAART HIV-1 RNA or clinical status. However, immunological response is better in younger children and those with lowest CD4%, whereas younger children have poorer virological response, increasing the risk of resistance. Differences in response to HAART according to age and underlying risk of disease progression should be considered when initiating HAART in children.
Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis for HIV-1-infected adults and children in the industrialized world. However, the optimal time to initiate HAART remains unclear, and has not been evaluated in randomized controlled trials. In their absence, information about immunological and virological response to HAART across varying CD4 and HIV-1 RNA levels can contribute to the decision about when to start therapy.
In adults, increasing concerns about long-term toxicity of HAART have shifted clinical practice towards delaying initiation of treatment. However, a large meta-analysis of observational studies found previously untreated adults initiating HAART with very low CD4 cell counts (< 200 × 10 cells/l) and/or high HIV-1 RNA (> 100 000 copies/ml) were at higher risk of clinical disease progression. In terms of immunological and virological markers, studies have reported that lower pre-HAART CD4 cell counts may result in larger, smaller or no different CD4 cell count increases, with some also reporting greater CD4 increases in those with higher pre-HAART HIV-1 RNA. Slower virological suppression has generally been associated with higher pre-HAART HIV-1 RNA but no consistent relationship with pre-HAART CD4 has been reported.
In children, immune recovery following HAART may be better than in adults because the thymus is more active during childhood. Conversely, in young infants the immature immune system allows less efficient containment of HIV with resultant high viral replication, and higher risk of developing drug resistance. Few paediatric studies have explored factors predicting immunological and/or virological response to HAART, and thus far all studies of more than 50 children have either included pre-treated children, or concentrated on immunological response, or have not considered confounding between possible predictors such as age and pre-therapy levels. Previous mono or dual therapy would be expected to affect overall response to the first HAART regimen, and may also alter the effect of other cofactors such as pre-HAART CD4, which no longer accurately represent pre-therapy levels.
In order to inform decisions for untreated children initiating HAART in the future, we evaluated the effect of age and pre-HAART CD4 percentage (CD4%) and plasma HIV-1 RNA on subsequent immunological and virological response to HAART in a population of previously untreated children enrolled in the UK and Irish Collaborative HIV Paediatric Study (CHIPS).
Objective: To evaluate the effect of age, CD4 percentage (CD4%) and plasma HIV-1 RNA on response to highly active antiretroviral therapy (HAART) in previously untreated children.
Design: Cohort study.
Methods: We examined the association between age at HAART initiation, and CD4 and HIV-1 RNA response using logistic and Cox regression, adjusting for sex, route of infection and pre-HAART values.
Results: CD4% increases of > 10% at 6 months were more likely in younger children [odds ratio (OR), 0.84 per year, P < 0.001] and those with lower pre-HAART CD4% (OR, 0.67 per 5% higher, P < 0.001), but were not related to pre-HAART HIV-1 RNA (P = 0.6). In contrast, HIV-1 RNA suppression < 400 copies/ml at 6 months was more likely in older children (OR, 1.09 per year, P = 0.03), and was unrelated to pre-HAART HIV-1 RNA or CD4% (P > 0.3). CD4% was still increasing during the second year following HAART initiation (60% followed > 24 months). Longer-term increases in CD4% occurred faster, and decreases in HIV-1 RNA occurred more slowly in younger children. The median time to CD4% ≥ 30% after initiating HAART with CD4% ≤ 25% was under 12 months for children under 2 years irrespective of pre-HAART CD4%, and increased progressively in older children and as CD4% decreased.
Conclusions: Children respond immunologically to HAART irrespective of pre-HAART HIV-1 RNA or clinical status. However, immunological response is better in younger children and those with lowest CD4%, whereas younger children have poorer virological response, increasing the risk of resistance. Differences in response to HAART according to age and underlying risk of disease progression should be considered when initiating HAART in children.
Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis for HIV-1-infected adults and children in the industrialized world. However, the optimal time to initiate HAART remains unclear, and has not been evaluated in randomized controlled trials. In their absence, information about immunological and virological response to HAART across varying CD4 and HIV-1 RNA levels can contribute to the decision about when to start therapy.
In adults, increasing concerns about long-term toxicity of HAART have shifted clinical practice towards delaying initiation of treatment. However, a large meta-analysis of observational studies found previously untreated adults initiating HAART with very low CD4 cell counts (< 200 × 10 cells/l) and/or high HIV-1 RNA (> 100 000 copies/ml) were at higher risk of clinical disease progression. In terms of immunological and virological markers, studies have reported that lower pre-HAART CD4 cell counts may result in larger, smaller or no different CD4 cell count increases, with some also reporting greater CD4 increases in those with higher pre-HAART HIV-1 RNA. Slower virological suppression has generally been associated with higher pre-HAART HIV-1 RNA but no consistent relationship with pre-HAART CD4 has been reported.
In children, immune recovery following HAART may be better than in adults because the thymus is more active during childhood. Conversely, in young infants the immature immune system allows less efficient containment of HIV with resultant high viral replication, and higher risk of developing drug resistance. Few paediatric studies have explored factors predicting immunological and/or virological response to HAART, and thus far all studies of more than 50 children have either included pre-treated children, or concentrated on immunological response, or have not considered confounding between possible predictors such as age and pre-therapy levels. Previous mono or dual therapy would be expected to affect overall response to the first HAART regimen, and may also alter the effect of other cofactors such as pre-HAART CD4, which no longer accurately represent pre-therapy levels.
In order to inform decisions for untreated children initiating HAART in the future, we evaluated the effect of age and pre-HAART CD4 percentage (CD4%) and plasma HIV-1 RNA on subsequent immunological and virological response to HAART in a population of previously untreated children enrolled in the UK and Irish Collaborative HIV Paediatric Study (CHIPS).
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