A. De Maria

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.

Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus: European Paediatric Hepatitis C Virus Network

OBJECTIVE To investigate the effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. DESIGN Pooled retrospective analysis of prospectively collected data. SAMPLE Data on hepatitis C virus seropositive mothers and their children identified around delivery were sent from 24 centres of the European Paediatric Hepatitis C Virus Network. MAIN OUTCOME MEASURES Hepatitis C virus infection status of children born to hepatitis C virus infected women. RESULTS A total of 1,474 hepatitis C virus infected women were identified, of whom 503 (35%) were co-infected with HIV. Co-infected women were more than twice as likely to transmit hepatitis C virus to their children than women with hepatitis C virus infection alone. Overall 9.2% (136/1,474) of children were hepatitis C virus infected. Among the women with hepatitis C virus infection-only, multivariate analyses did not show a significant effect of mode of delivery and breastfeeding: caesarean section vs vaginal delivery OR = 1.17, P = 0.66; breastfed versus non-breastfed OR = 1.07, P = 0.83. However, HIV co-infected women delivered by caesarean section were 60% less likely to have an infected child than those delivered vaginally (OR = 0.36, P = 0.01) and those who breastfed were about four times more likely to infect their children than those who did not (OR = 6.41, P = 0.03). HIV infected children were three to four times more likely also to be hepatitis C virus infected than children without HIV infection (crude OR = 3.76, 95% CI 1.89-7.41). CONCLUSIONS These results do not support a recommendation of elective caesarean section or avoidance of breastfeeding for women with hepatitis C virus infection only, but the case for HIV infected women undergoing caesarean section delivery and avoiding breastfeeding is strengthened if they are also hepatitis C virus infected.

Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy The Italian Register for HIV Infection in Children*

OBJECTIVE To investigate the outcome in children perinatally infected with HIV-1 whose mothers received zidovudine (ZDV) monotherapy in pregnancy. DESIGN Observational retrospective study of a prospectively recruited cohort. SETTING Italian Register for HIV Infection in Children. PATIENTS A group of 216 children perinatally infected with HIV-1, born in 1992-1997 and derived prospectively from birth: 38 children had mothers receiving ZDV monotherapy and for 178 children the mothers received no antiretroviral treatment during pregnancy. MAIN OUTCOME MEASURES The estimated probability of developing severe disease or severe immune suppression, survival probability [95% confidence interval (CI)] within 3 years, and the hazard ratio (95% CI), adjusted for year of birth, maternal clinical condition at delivery, birthweight and treatments (Pneumocystis carinii pneumonia chemoprophylaxis and/or antiretroviral therapy before the onset of severe disease, severe immune suppression or death) were compared. RESULTS Comparison of HIV-1-infected children whose mothers were treated with ZDV with children whose mothers were not treated showed that the former group had a higher probability of developing severe disease [57.3% (95% CI 40.9-74.3) versus 37.2% (95% CI 30.0-45.4); log-rank test 7.83, P = 0.005; adjusted hazard ratio 1.8 (95% CI 1.1-3.1)] or severe immune suppression [53.9% (95% CI 36.3-73.5) versus 37.5% (95% CI 30.0-46.2); log-rank test 5.58, P = 0.018; adjusted hazard ratio 2.4, (95% CI: 1.3-4.3)] and a lower survival [72.2% (95% CI 50.4-85.7) versus 81.0% (95% CI 73.7-86.5); log-rank test 4.23, P = 0.039; adjusted hazard ratio of death 1.9 (95% CI 1.1-3.6)]. CONCLUSIONS This epidemiological observation could stimulate virologic studies to elucidate whether this rapid progression depends on in utero infection or transmission of resistant virus. Findings may suggest a need to hasten HIV-1 diagnosis in infants of ZDV-treated mothers and undertake an aggressive antiretroviral therapy in those found to be infected.

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.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

ObjectiveTo determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. MethodsIn a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. ResultsHIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31–41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery;P  = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9–16.8 days). This time was increased by 15% (95% CI, −11 to 48%;P  = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. ConclusionsThe outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

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.

Diagnosis of human immunodeficiency virus 1 infection in infants: in vitro production of virus-specific antibody in lymphocytes

In children born to mothers infected with human immunodeficiency virus 1 (HIV-1), a diagnosis of HIV infection cannot be based on a positive antibody result until at least 18 months of age. There is therefore an urgent need for simple and reliable methods of diagnosing HIV infection in these infants. The sensitivity and specificity of a test using the in vitro antibody production of HIV-specific IgG was assessed in children whose infection status was known and compared with virus and antigen detection. In vitro antibody production sensitivity was 90 to 95%, at least as sensitive as virus culture in antibody-positive infected children. In the first 2 months there is a relatively high proportion of false positive results, possibly a result of contamination by maternal cells. However, after this period in vitro antibody production is a simple, inexpensive and reliable tool for early diagnosis.

Factors associated with HIV RNA levels in pregnant women on non-suppressive highly active antiretroviral therapy at conception

BACKGROUND Little is known about pregnancy patterns and levels of HIV RNA in HIV-infected women conceiving on highly active antiretroviral therapy (HAART) with non-suppressed viral load (VL), nor about their therapeutic management. METHODS Linear mixed models were fitted to study changes in VL and potential associated factors including HAART type or duration and immune status among 127 women receiving HAART at conception with detectable VL enrolled in the prospective European Collaborative Study. RESULTS Median duration of HAART at conception was 10 months. A total of 78 (61%) women conceived while on protease inhibitor (PI)-based HAART. Overall, 72 (57%) women remained on the same HAART regimen throughout pregnancy, 24 (19%) switched regimens and 31 (24%) interrupted HAART during early pregnancy. The intention-to-treat model indicated constant VL up to 10 gestational weeks; thereafter, levels decreased significantly, by 0.06 log(10) copies/ml weekly until delivery. At baseline, immune status was significantly associated with HIV RNA levels. Excluding those with treatment interruption, there was no significant difference in VL slope between women who did and did not modify their HAART regimens (P=0.14); women conceiving on non-nucleoside reverse transcriptase inhibitor-based HAART had consistently lower VL throughout pregnancy than those on PI-based HAART (P=0.02). Most (64/103, 62%) women had detectable VL within 4 weeks of delivery (median 2.40 log(10) copies/ml). The overall mother-to-child transmission rate was 1.72% (95% confidence interval 0.21-6.1). CONCLUSIONS Practices regarding management of women conceiving on HAART with detectable VL vary in Western Europe. The existence of this group of pregnant women highlights the need for improved monitoring of and support for treated women before they become pregnant, as well as during pregnancy.