I Bates

Mother to child transmission of HIV infection in the era of highly active antiretroviral therapy

BACKGROUND Very low rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) are achievable with use of highly active antiretroviral therapy (HAART). We examine risk factors for MTCT in the HAART era and describe infants who were vertically infected, despite exposure to prophylactic MTCT interventions. METHODS Of the 4525 mother-child pairs in this prospective cohort study, 1983 were enrolled during the period of January 1997 through May 2004. Factors examined included use of antiretroviral therapy during pregnancy, maternal CD4 cell count and HIV RNA level, mode of delivery, and gestational age in logistic regression analysis. RESULTS Receipt of antenatal antiretroviral therapy increased from 5% at the start of the HAART era to 92% in 2001-2003. The overall MTCT rate in this period was 2.87% (95% confidence interval [CI], 2.11%-3.81%), but it was 0.99% (95% CI, 0.32%-2.30%) during 2001-2003. In logistic regression analysis that included 885 mother-child pairs, MTCT risk was associated with high maternal viral load (adjusted odds ratio [AOR], 12.1; P=.003) and elective Caesarean section (AOR, 0.33; P=.04). Detection of maternal HIV RNA was significantly associated with antenatal use of antiretroviral therapy, CD4 cell count, and mode of delivery. Among 560 women with undetectable HIV RNA levels, elective Caesarean section was associated with a 90% reduction in MTCT risk (odds ratio, 0.10; 95% CI, 0.03-0.33), compared with vaginal delivery or emergency Caesarean section. CONCLUSIONS Our results suggest that offering an elective Caesarean section delivery to all HIV-infected women, even in areas where HAART is available, is appropriate clinical management, especially for persons with detectable viral loads. Our results also suggest that previously identified risk factors remain important.

Maternal viral load, CD4 cell count and vertical transmission of HIV‐1

HIV load and CD4 cell numbers were measured among 95 HIV infected women during pregnancy in order to determine their value as prognostic markers for transmission of virus from mother to infant. Among the 94 live births, 13 children were infected with HIV, 69 were uninfected and 12 were of unknown infection status. HIV RNA levels, as measured by nucleic acid sequence based amplification, were significantly higher (P < 0.001) in women who transmitted virus than among those who did not transmit and maternal viral load was a stronger predictor of transmission than CD4 cell number. The predicted rate of transmission relative to maternal HIV RNA was 2% at 1,000 copies, 11% at 10,000 copies and 40% at 100,000 copies/ml. Little variation in viral load occurred during pregnancy and there was an association between viral load and prematurity, the mean gestation at delivery decreasing by 1.3 weeks for every 10‐fold increase in maternal HIV RNA (P = 0.007). This study demonstrates that a high level of maternal HIV RNA is a risk factor for transmission of virus to the infant and maternal viral load is of more value as a prognostic marker for transmission risk than CD4 cell number. High viral load is also associated with premature delivery. Maternal viral load is therefore a useful marker on which to base management decisions during pregnancy. J. Med. Virol. 54:113–117, 1998.

Level and pattern of HIV-1-RNA viral load over age: Differences between girls and boys?

Objective To estimate RNA viral load patterns over age in vertically infected children that account for between- and within-individual variation, treatment and assay cut-off detection level. To investigate possible sex-based differences. Design A total of 118 infected children with 894 RNA viral load measurements enrolled in the European Collaborative Study were prospectively followed from birth for up to 15 years. Methods Fractional polynomial and mixed effects models with censored data to assess the non-linear pattern of viral load over age, allowing for repeated measures. Results The RNA viral load peaked at approximately 3 months of age, and gradually declined thereafter. The sex by age interaction was significant (χ2 = 19.7, P < 0.001); viral load peaked higher for girls than boys, but after 4 years the RNA load was consistently 0.25–0.5 log10 lower for girls than boys. The effects of sex and treatment on viral load vary over age (χ2 = 6.31, P = 0.043). Sex differences in RNA viral load relating to measurement without treatment were more pronounced than those under treatment. Disease progression was more rapid for girls than for boys up to the age of 4 years, and less rapid thereafter; the overall difference was not statistically significant. Conclusion Differences in RNA viral load over age between untreated boys and girls may have implications for policies for the initiation of antiretroviral therapy, but do not seem to translate into differences in progression to serious disease. The findings would suggest underlying biological explanations, which need further investigation.

Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus

In children born to immunocompetent women, congenital toxoplasmosis almost always results from primary infection during pregnancy. However, reactivation of latent toxoplasmosis during pregnancy could occur in HIV-infected pregnant women, particularly in those who are severely immunocompromised, and result in maternal-fetal transmission of the parasite. This mode of infection has been described in case reports but the risk of transmission is unknown. Findings on toxoplasmosis are presented from the European Collaborative Study, a prospective study of children born to women known to be HIV-infected at the time of delivery. In 1058 children followed for a mean duration of 35 months, only one child developed clinical toxoplasmosis. This child was HIV-infected, severely immunocompromised, and acquired toxoplasmosis postnatally. Congenital infection was excluded serologically in a subgroup of 167 children, of whom an estimated 71 had been at risk of infection. These clinical and serological findings indicate a low general risk of maternal-fetal transmission of Toxoplasma infection in HIV-infected women. It is not possible to draw conclusions about the risk of transmission for severely immunocompromised HIV-infected women because most women in the study were asymptomatic.

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 children.

Risk factors for mother-to-child transmission of HIV-1

Researchers analyzed data on 721 infants enrolled in the European Collaborative Study during 1985-1991 to examine risk factors of vertical transmission of HIV-1 infection. No differences in transmission rates existed between the collaborative centers. The risk of vertical transmission HIV was lower in women with history of IV drug use than those with no such history (odds ration [OR] for no history of IV drug use=1.45). This was due to a high rate of former IV drug users (8%). Overall vertical transmission rate was 14.4%. Further vertical transmission increased greatly for women with a low CD4 count ( 34 weeks gestation (33% vs. 14%; OR=3.80; p=.002). The mechanism may be insufficient passive or active immunity at <34 weeks gestation and increased transmission during labor or delivery. In addition the vaginal delivery procedures of episiotomy (OR=1.66; p=.02) scalp electrodes (OR=0.91; p=.05) and instrumental vaginal deliveries (OR=1.68; p=.07) were strongly related to vertical transmission but only in those centers where these procedures were not routine. Further cesarean section delivery appeared to have a protective effect against vertical transmission of HIV (OR=0.56). Moreover children who were breast fed were more likely to be HIV positive than those not breast fed (31% vs. 14%; p<.05; OR=2.25). No association existed for duration of breast feeding however. Thus based on immunological finding p24-antigenemia status and low CD4 count counselors should inform HIV infected women who are considering pregnancy of an increased risk of HIV transmission.