Gender and race do not alter early-life determinants of clinical disease progression in HIV-1 vertically infected children.

Objective: To identify early life predictors of clinical progression before and beyond age 1 year. Design: Prospective follow-up of 161 vertically HIV infected children in the ongoing European Collaborative Study provided data from birth over 16 years. Methods: Kaplan-Meier and Cox regression procedures were used to assess the predictive value of first available laboratory and clinical markers for progression defined as serious disease or death. We investigate gender and race effects on associations and the optimal threshold for longitudinal CD4+ percentage measurements after age 6 months for predicting disease progression. Results: Earliest (during the first 6 months) measurements of CD4+ percentage below 20% [three-fold increased risk (P = 0.041)] and absolute lymphocytes (AL) (reduction of risk of three-quarters for a one log increase (P =0.014)) were independently associated with overall and rapid disease progression during the first year. Persistent lymphadenopathy (or hepatomegaly) in early life was also additionally associated with overall disease progression, and after age 1 year [greater than doubling of risk, (P = 0.040)], but not with rapid progression. Associations were not significantly dependent on gender or race. CD4+ percentage of 10% was the best prognostic cut-off. Conclusions: Early clinical markers are strongly predictive of disease progression after 1 year of age into adolescence. However, rapid progression is less straightforward to predict, probably due largely to early progression during the first few months in such individuals. The independently predictive value of AL measurements suggest they could be used alone in the management of children in resource-poor settings

Increased thymic output after initiation of antiretroviral therapy in human immunodeficiency virus type 1-infected children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial

To investigate the thymic contribution to immune reconstitution during antiretroviral therapy (ART), T cell receptor gene rearrangement excision circles (TRECs) were measured in peripheral blood mononuclear cells (PBMC) and CD4 cells from 33 human immunodeficiency virus (HIV) type 1-infected children monitored for 96 weeks after ART initiation. Baseline TREC levels were associated positively with baseline CD4 cell percentage and inversely with age and HIV-1 RNA load. During therapy, TREC level changes in PBMC and CD4 cells were fairly comparable. TREC level changes were inversely related to baseline CD4 cell percentage and positively associated with CD4 cell percentage increases, the main source being naive CD4 cells. TREC changes were independent of age and baseline HIV-1 RNA load; however, HIV-1 suppression was independently associated with smaller TREC changes. Thymic output appears to be the main source of CD4 cell repopulation in children receiving ART. Recovery of thymic function is independent of age and influenced by the status of peripheral CD4 cell depletion and HIV-1 suppression

Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women

Concerns have been raised over possible adverse effects of prophylactic antiretroviral therapy (ART) on the fetus and newborn. We analyzed data relating to uninfected children enrolled in the European Collaborative Study and investigated the association between ART exposure, perinatal problems, and major adverse health events later in life. Median length of follow-up was 2.2 (0-15.9) years. Of the 2414 uninfected children, 687 (28%) were exposed to ART in all three periods (antenatal, intrapartum, and neonatal). Of the 1008 infants exposed to ART at any time, 906 (90%) were exposed antenatally, 840 (83%) neonatally, and 750 (74%) both antenatally and neonatally. ART exposure was not significantly associated with pattern or prevalence of congenital abnormalities or low birth weight. In multivariate analysis, prematurity was associated with exposure to combination therapy without a protease inhibitor (PI) (OR = 2.66; 95% CI: 1.52-4.67) and with a PI (OR = 4.14; 95% CI: 2.36-7.23). ART exposure was associated with anemia in early life (P < .001). There was no evidence of an association with clinical manifestations suggestive of mitochondrial abnormalities. The absence of serious adverse events in this large cohort of uninfected children exposed to prophylactic ART in the short to medium term is reassurin

Recommendation for drug development for children

No abstrac

Combination antiretroviral therapy and duration of pregnancy

Abstract Objective: To assess the association between type and timing of initiation of antiretroviral therapy in pregnancy and duration of pregnancy. Design: Prospective study. Methods: Data on 3920 mother-child pairs were examined (3075 mother-child pairs from the European Collaborative Study and 905 from the Swiss Mother + Child HIV Cohort Study). Factors examined included gestational age, antiretroviral therapy during pregnancy, maternal CD4 count, viral load, illicit drug use (IDU) and mode of delivery. Deliveries at less than 37 weeks were defined as premature. Results: The prematurity rate was 17% and median gestational age 39 weeks. Twenty-three per cent (896 of 3920) of women received antiretroviral therapy during pregnancy: 64% (573 of 896) zidovudine monotherapy, 24% (215) combination therapy without protease inhibitors (PI) and 12% (108) combination therapy with PI. In multivariate analysis, adjusted for maternal CD4 count and IDU, odds ratio (OR) of prematurity was 2.60 [95% confidence interval (CI), 1.43-4.75] and 1.82 (95% CI, 1.13-2.92) for infants exposed to combination therapy with and without a PI, respectively, compared to no treatment. Exposure to monotherapy was not associated with prematurity, but severe immunosuppression and IDU in pregnancy were. Women on combination therapy from before pregnancy were twice as likely to deliver prematurely as those starting therapy in the third trimester (OR, 2.17; 95% Cl, 1.034.58). Conclusions: Pregnancy issues should be discussed when making decisions about initiation of combination antiretroviral therapy for HIV-infected women. Elective caesarean section to reduce vertical transmission at 36 weeks rather than 38 weeks may be advisable in women on combination therapy with PITo assess the association between type and timing of initiation of antiretroviral therapy in pregnancy and duration of pregnancy

Neurologic signs in young children with human immunodeficiency virus infection

Neurologic and neurodevelopmental problems were investigated in a cohort of 39 human immunodeficiency virus (HIV)-infected children and 164 antibody-negative children born to HIV-positive women. All children were followed from birth for between 1 month and 4 years. Serious neurologic manifestations were present in 5 of 16 children (31%) who developed acquired immunodeficiency syndrome/acquired immunodeficiency syndrome-related complex, although in 2 the neurologic signs were probably not related to HIV. This can be compared with a prevalence of 0 of 23 in children who remained asymptomatic or who had less severe HIV-related symptoms or signs and 2 of 164 (1%) in uninfected children. Neurologic signs in the uninfected group were associated with the presence of drug withdrawal at birth and prematurity. These findings contrast with reports of a high prevalence of neurologic findings in most studies of HIV-infected children