Marc Hainaut

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.

Bordetella pertussis Infection in 2-Month-Old Infants Promotes Type 1 T Cell Responses

Neonatal immaturity of the immune system is currently believed to generally limit the induction of immune responses to vaccine Ags and to skew them toward type 2 responses. We demonstrated here that Bordetella pertussis infection in very young infants (median, 2 mo old) as well as the first administration of whole-cell pertussis vaccine induces B. pertussis Ag-specific IFN-γ secretion by the PBMC of these infants. IFN-γ was secreted by both CD4+ and CD8+ T lymphocytes, and the levels of Ag-induced IFN-γ secretion did not correlate with the age of the infants. Appearance of the specific Th-1 cell-mediated immunity was accompanied by a general shift of the cytokine secretion profile of these infants toward a stronger Th1 profile, as evidenced by the response to a polyclonal stimulation. We conclude that the immune system of 2-mo-old infants is developmentally mature enough to develop Th1 responses in vivo upon infection by B. pertussis or vaccination with whole-cell pertussis vaccines.

High incidence of invasive group B streptococcal infections in HIV-exposed uninfected infants.

OBJECTIVES: The occurrence of an unusual number of group B streptococcal (GBS) infections in HIV-exposed uninfected (HEU) infants who were followed in our center prompted this study. The objective of this study was to describe and compare the incidence and clinical presentation of GBS infections in infants who were born to HIV-infected and -uninfected mothers. METHODS: All cases of invasive GBS infections in infants who were born between 2001 and 2008 were identified from the database of HEU infants and from the microbiology laboratory records. The medical charts of all infants with GBS infection were reviewed. RESULTS: GBS invasive infections were described for 5 (1.55%) infants who were born to 322 HIV-infected mothers who delivered in our center. The incidence of GBS infections during the same period was 16 (0.08%) of 20 158 infants who were born to HIV-uninfected mothers. One HEU infant presented a recurrent infection 28 days after completion of treatment for the first episode. Late-onset infection was more frequent in HEU infants (5 of 6 vs 2 of 16 episodes in the control population). The diseases were also more severe in HEU infants with 5 of 6 sepsis or sepsis shock in HEU infants versus 10 of 16 in control subjects, and most HEU infants had leukopenia at onset of infection. CONCLUSIONS: The incidence of GBS infection was significantly higher in HEU infants than in infants who were born to HIV-uninfected mothers. These episodes of GBS sepsis in HEU infants were mostly of late onset and more severe than in the control population, suggesting an increased susceptibility of HEU infants to GBS infection.

Effectiveness of antiretroviral therapy initiated before the age of 2 months in infants vertically infected with human immunodeficiency virus type 1

Abstract The effectiveness and tolerance of antiretroviral therapy with a combination of three reverse transcriptase inhibitors starting at the time of diagnosis (before 2 months of age) was evaluated in four infants with vertically acquired HIV-1 infection. Plasma HIV-1 RNA levels ranged from 230,000 to 1,000,000 copies/ml before onset of triple therapy and fell below 50 copies/ml at 12 to 33 weeks of life in three of the infants. These three children, currently aged 158, 105 and 72 weeks, are asymptomatic, have normal lymphocyte subsets and no hypergammaglobulinaemia. Two children experienced a profound reduction in the amount of proviral DNA detected in blood and have become HIV-1 seronegative, although one of them has had HIV-1 RNA detectable on a single occasion at 114 weeks of life (303 copies/ml). Transient interruption of therapy resulted in a rapid but reversible increase in HIV-1 RNA levels in the third child and was associated with the production of HIV-specific antibodies. The fourth child whose parents were not compliant to treatment and follow-up had a poor virological response. Conclusion Early treatment of vertically acquired human immunodeficiency virus type 1 infection with three reverse transcriptase inhibitors is well tolerated and can result in such suppression of viral replication that specific antibodies are not produced, that proviral DNA falls to the lower limit of quantitation in blood and that all clinical and immunological manifestations of infection are avoided. Parental adhesion is crucial to the effectiveness of 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.

Cytokine and antibody profiles in 1-year-old children vaccinated with either acellular or whole-cell pertussis vaccine during infancy

Two different types of pertussis vaccines are currently available to protect children against whooping cough, the first-generation whole-cell (Pw) vaccines and the more recent acellular (Pa) vaccines. Both types provide good protection, yet induce different types of immune responses in 6-month-old infants, with a strong Th1 response induced by Pw vaccines compared to a mixed Th1/Th2 response and a delay in non-specific IFN-gamma secretions after the administration of Pa vaccines. We show here that at 13 months of age, most Pw- or Pa-vaccinated children display Bordetella pertussis-specific T-cell responses, in addition to significant antibody levels, although a higher Th2/Th1 cytokine ratio remained in Pa recipients compared to Pw recipients. In contrast, the proportion of children with tetanus toxin-specific T-cell responses was lower in Pa than in Pw vaccine recipients, although most children had protective anti-tetanus toxin IgG levels. In addition, the global Th2 bias observed in 6-month-old infants vaccinated with a Pa vaccine was normalized at 13 months.

Effectiveness of early initiation of protease inhibitor-sparing antiretroviral regimen in human immunodeficiency virus-1 vertically infected infants.

Each of the 17 vertically infected infants born to HIV-1-infected mothers in Belgian HIV reference centers since 1996 was treated with a combination of 3 reverse transcription inhibitors as soon as the diagnosis was established. Treatment was initiated in all patients before 66 days of life. Twelve patients, including 11/13 infants treated with the combination of zidovudine, lamivudine and nevirapine, experienced a complete viral suppression (<50 copies/mL) with their first drug regimen. At last follow-up, 12 patients were asymptomatic, 2 were CDC stage A and 3 were stage B; 15 had HIV-1 RNA levels of <50 copies/mL and 14 had ≥25% CD4 lymphocytes. These results suggest that early initiation of treatment with 3 reverse transcription inhibitors is highly effective to inhibit viral replication and to prevent clinical and immunologic progression of HIV infection in vertically infected infants.

Monocyte-Derived Interleukin-10 Depresses the Bordetella pertussis- Specific Gamma Interferon Response in Vaccinated Infants

ABSTRACT Antigen-specific gamma interferon (IFN-γ) has been demonstrated to participate in protection against Bordetella pertussis infection. Circulating mononuclear cells from B. pertussis-infected and from pertussis-vaccinated infants secrete high amounts of IFN-γ after in vitro stimulation by B. pertussis antigens, but with a large variation in the secreted IFN-γ levels between individuals. We show here that the inhibition of the specific IFN-γ response can be at least partially attributed to IL-10 secretion by monocytes. This IL-10 secretion was not associated with polymorphisms at positions −1082, −819, and −592 of the IL-10 gene promoter, suggesting that other genetic or environmental factors affect IL-10 expression and secretion.

Management of vertically HIV-infected children in Europe

Aim: To describe policies for the therapeutic management of vertically HIV‐infected children, and to compare these with practice, using children enrolled in a cohort study in the same setting. Methods: A postal questionnaire survey of clinicians in the paediatric centres of the European Collaborative Study (ECS) was used. Prospective data collected within the ECS on the treatment and clinical status of infected children seen in these centres in 1999–2001 were analysed and compared with the year 2000 policies reported. Results: In 3 of the 10 centres, the policy was routinely to administer antiretroviral therapy (ART) to infants upon confirmation of infection, and in 7 centres initiation of therapy was delayed until specific clinical, virological and immunological criteria were reached. Evidence of disease progression was a reason for treatment modification in all centres; other considerations included adherence problems and side effects. However, practice did not always match policy. For the 84 children with at least 5 y of follow‐up (73 treated and 11 untreated), overall, 69% of the 420 person‐years lived were spent without treatment, and 72% without any HIV‐related symptoms. Untreated children were without symptoms for 94% of these 5 y, whereas treated children spent nearly a third of their time with mild or moderately severe symptoms.

Early vs deferred highly active antiretroviral therapy in HIV infected infants: a European Collaborative Cohort Study

Without antiretroviral therapy (ART), approximately 20% of HIV-1 vertically infected infants develop severe disease manifestations before the age of 1 year [1] and surrogate markers poorly predict infants at higher risk of rapid disease progression. Several small prospective and retrospective studies in developed countries have suggested that ART initiated early in life could prevent this rapid clinical and immunologic deterioration [2-6].