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

<p>Objective: To identify early life predictors of clinical progression before and beyond age 1 year.</p> <p>Design: Prospective follow-up of 161 vertically HIV infected children in the ongoing European Collaborative Study provided data from birth over 16 years.</p> <p>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.</p> <p>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.</p> <p>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.</p&gt

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

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

CD4 cell response to antiretroviral therapy in children with vertically acquired HIV infection: Is it associated with age at initiation?

Background. Considerable uncertainty remains as to whether early initiation of antiretroviral therapy (ART) in children with vertically acquired human immunodeficiency virus (HIV) infection increases the benefit in terms of immunological response. Methods. The association between immunological outcome and early initiation of and/or more-potent ART was investigated, using age-standardized z scores for CD4 cell counts (hereafter, "CD4 z scores"), in 131 HIV-infected children enrolled in the European Collaborative Study, a birth cohort study. Results. Median age at initiation of the most-potent ART was 4 years (range, 0.1-15.5 years). Initiation of treatment after 5 months of age resulted in nonsignificantly lower CD4 z scores 6 months after initiation. Time to a 20% increase in CD4 z score was associated with age at initiation of the most-potent ART (adjusted hazard ratios [AHRs], 0.37 [P&lt;.01] and 0.43 [P = .05] for 5 months-5 years of age and &gt;5 years of age, respectively, compared with &lt;5 months of age), ethnicity (AHR, 0.48 [P = .01], for black vs. white), and highly active ART (HAART) with or without prior ART (AHRs, 3.16 [P&lt;.01] and 3.95 [P&lt;.001], vs. mono or dual ART, respectively). The risk of subsequent deterioration of CD4 z score was similar for children who initiated ART in different age groups (\u3c72 = 0.824; P = .82). Conclusions. We confirm the effectiveness of HAART with respect to the recovery of CD4 cell count and suggest a benefit of initiating ART before the age of 5 months. Age at initiation of the most-potent ART was not associated with the likelihood of sustaining the recovery of CD4 cell count

Levels and patterns of neutrophil cell counts over the first 8 years of life in children of HIV-1-infected mothers

Background: Antiretroviral drugs (ARV) as prophylaxis to prevent mother-to-child transmission of HIV results in decreased haematological parameters during and shortly after exposure, with recent data suggesting a more prolonged inhibition of haematopoiesis until at least 18 months. Design: Data on 156 HIV-infected and 1533 uninfected children in the European Collaborative Study followed from birth until at least 8 years of age. Methods: Smoothers and splines were used to elucidate patterns over age; linear mixed effects allowed for repeated measurements. Covariates included the child's HIV-1 infection status, prematurity, gender, race, drug withdrawal symptoms at birth and ARV exposure; effects on neutrophil count were quantified in regression analyses using z-scores (SD from mean) of neutrophil counts obtained after modelling untransformed values using the LMS method. For HIV-infected children, progression to AIDS and ARV therapy were also included. Results: After approximately 4 months of age, neutrophil counts were consistently and substantially lower in HIV-infected children than in uninfected children; in both groups, black children had significantly lower counts than white children across the whole age range. In uninfected children, male gender and ARV exposure were associated with reduced neutrophil count until at least 8 years of age. In HIV-infected children, advanced disease and ARV treatment were significantly associated with neutrophil count. Conclusion: A considerably longer effect of exposure to ARV was shown in uninfected children than previously thought and significant associations were shown between race and gender and neutrophil count, as previously observed for lymphocyte counts. The clinical relevance of these reduced levels of neutrophils requires further investigation. (C) 2004 Lippincott Williams Wilkins

Age-related standards for total lymphocyte, CD4(+) and CD8(+) T cell counts in children born in Europe

Objective: Currently used reference values for immunologic markers in children are largely derived from cross-sectional data from historic, small sample size studies in predominantly white children. There is a lack of reliable age-related standards for immunologic markers, such as CD4(+) cell counts, in particular in black children whose values according to recent reports may differ from those in white children. Standards are essential for diagnosing and monitoring childhood diseases such as pediatric human immunodeficiency virus (HIV) infection. Design: Prospective cohort study with data on 1781 uninfected children born to HIV-infected mothers in the European Collaborative Study. Methods: Age-related standards (centiles) for immunologic markers (CD4(+) and CD8(+) cell counts and total lymphocyte counts) up to 5 years in black and up to 10 years in white children were constructed using Generalized Additive Models for Location, Scale and Shape method, which allows for variability and skewness of the data. The optimal model was chosen according to the Akaike Information Criterion. Results: Patterns and values of total lymphocyte, CD4(+) and CD8(+) cell counts varied with age, especially in the first 3 years of life, but less so thereafter. Values of all 3 immunologic markers were substantially and significantly lower in black than in white children of the same age. Conclusions: We present age-related standards separately for black and white children to aid clinicians in the monitoring of childhood diseases. These standards may also contribute to the decision on an accurate cutoff for CD4(+) cell counts for initiating treatment of HIV-infected childre