Lars Navér

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.

Children born to HIV-1-infected women in Sweden in 1982-2003: trends in epidemiology and vertical transmission.

Summary: To describe the HIV-1 epidemic among childbearing women and their children in Sweden, a population-based analysis of data on all known mother-child pairs in Sweden with perinatal exposure to HIV-1 1982-2003 was conducted. The mother-to-child transmission (MTCT) rate in children prospectively followed from birth decreased from 24.7% in 1985-1993 to 5.7% in 1994-1998 and 0.6% in 1999-2003. The use of antiretroviral treatment of the mother during pregnancy and/or prophylactic antiretroviral intervention increased from 2.3% to 91.6% during the same period, and the elective cesarean delivery rate increased from 8.0% to 80.3%. No MTCT of HIV-1 occurred in Sweden after 1999. Fifty-one vertically HIV-1-infected children aged 2.7 to 17.6 years were living in Sweden by 31 December 2003, 71% being treated with antiretroviral agents. No HIV-1-related child death has been reported in Sweden after 1996. The conclusion is that MTCT of HIV-1 can be almost eliminated when appropriate resources are available. A national pregnancy screening program for HIV-1 running since 1987 with a high acceptance rate and the implementation of measures to prevent MTCT since 1994 have resulted in a significant decrease in the number of infected children. Inasmuch as knowledge of the infection status of the mother is crucial for reduction in MTCT of HIV-1, continued antenatal screening is important even in a low-prevalence country such as Sweden.

Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes

Change of HIV-1 coreceptor use has been connected to progression of disease in children infected with HIV-1, presumably subtype B. It has not been possible to discern whether the appearance of new viral phenotypes precedes disease development or comes as a consequence of it. We studied the evolution of coreceptor use in HIV-1 isolates from 24 vertically infected children. Their clinical, virological, and immunological status was recorded and the env V3 subtype was determined by DNA sequencing. Coreceptor use was tested on human cell lines, expressing CD4 together with CCR5, CXCR4, and other chemokine receptors. The children carried five different env subtypes (nine A, five B, four C, three D, and one G) and one circulating recombinant form, CRF01_AE (n = 2). Of the 143 isolates, 86 originated from peripheral blood mononuclear cells (PBMCs) and 57 originated from plasma, received at 90 time points. In 52 of 54 paired plasma and PBMC isolates the coreceptor use was concordant. All 74 isolates obtained at 41 time points during the first year of life used CCR5. A change from use of CCR5 to use of CXCR4 occurred in four children infected with subtype A, D, or CRF01_AE after they had reached 1.5 to 5.8 years of age. There was a significant association with decreased CD4+ cell levels and severity of disease but, interestingly, the coreceptor change appeared months or even years after the beginning of the immunological deterioration. Thus CXCR4-using virus may emerge as a possible consequence of immune deficiency. The results provide new insights into AIDS development in children.

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.

Link between the X4 phenotype in human immunodeficiency virus type 1-infected mothers and their children, despite the early presence of R5 in the child

Coreceptor use was determined for human immunodeficiency virus type 1 (HIV-1) isolates of various subtypes from 11 women during pregnancy and their infected children. Isolates from peripheral blood mononuclear cells (n=79) and from plasma (n=59) were available. The clinical and immunological stages of HIV-1 infection were recorded. Coreceptor use was tested on human cell lines expressing CD4 and different chemokine receptors. The R5 virus predominated, and only 9 isolates from 2 mothers used CXC chemokine receptor 4. All children carried the R5 virus at the time of diagnosis of HIV-1 infection. In 2 children of mothers carrying the X4 virus, the virus switched from R5 to X4 or to R5X4 by age 18 months (child no. 9) and age 48 months (child no. 10), whereas no children followed up to a similar age whose mothers were carrying the R5 virus experienced such a switch (P=.048). This points to a link between the presence of X4 virus in the mother and the emergence of X4 virus in her child.

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.

The selection and evolution of viral quasispecies in HIV-1 infected children

Objectives To analyse the diversity and divergence of the viral populations in three mother–child pairs in longitudinally obtained samples for up to 7 years.

Antiretroviral treatment of HIV infection: Swedish recommendations 2007

On 3 previous occasions, in 2002, 2003 and 2005, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. An expert group, under the guidance of RAV, has now revised the text again. Since the publication of the previous treatment recommendations, 1 new drug for the treatment of HIV has been approved – the protease inhibitor (PI) darunavir (Prezista®). Furthermore, 3 new drugs have become available: the integrase inhibitor raltegravir (MK-0518), the CCR5-inhibitor maraviroc (Celsentri®), both of which have novel mechanisms of action, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC-125). The new guidelines differ from the previous ones in several respects. The most important of these are that abacavir is now preferred to tenofovir and zidovudine, as a first line drug in treatment-naïve patients, and that initiation of antiretroviral treatment is now recommended before the CD4 cell count falls below 250/µl, rather than 200/µl. Furthermore, recommendations on the treatment of HIV infection in children have been added to the document. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).

Palivizumab prophylaxis and hospitalization for respiratory syncytial virus disease in the Stockholm infant population, 1999 through 2002.

Background. There are few independent, population-based reports that estimate the risk of hospitalization of respiratory syncytial virus (RSV)-infected infants before and during the palivizumab era. We present figures from the greater Stockholm area during the three seasons after the introduction of palivizumab and relate them to data based on 1400 hospitalizations for RSV disease in the same population area during 1987 through 1998. Methods. The number of births, neonatal complications and palivizumab prescriptions was obtained. We retrieved information about all infant hospitalizations for confirmed RSV infections with risk factors and complications. Chronic lung disease (CLD) in preterm infants was defined as oxygen dependency beyond 36 weeks of postconceptional age. Results. Eight hundred eighteen infants (1.3% of the population) were hospitalized for confirmed RSV infection. The hospitalization rates were 3.7% (24 of 642) among preterm infants with gestational age <33 weeks without CLD and 7.2% (14 of 195) in those with CLD. Palivizumab had been given to 235 infants, usually those with CLD and in need of continuous oxygen or steroid treatment or the <6 month-old infants with extremely preterm birth (gestational age <26 weeks). The risk of hospitalization for RSV disease was low, but this was the case also before the introduction of palivizumab. Conclusions. In countries with a low baseline risk of hospitalization for RSV infection, the benefit of palivizumab might not justify the cost of its widespread use. We advocate defining more rigorous prescription criteria.

Appropriate prophylaxis with restrictive palivizumab regimen in preterm children in Sweden

Aim: Palivizumab (Synagis®) was registered in Sweden in 1999 for prophylaxis against respiratory syncytial virus (RSV) in premature infants. The high costs and the limited knowledge of the efficacy of this substance have led to debate about how and when it should be used. National guidelines for the use of palivizumab in Sweden were constructed in the year 2000. The aim of this study was to evaluate the guidelines. Methods: A nation‐wide prospective study was conducted during the two RSV seasons of the years 2000–2002. The paediatric departments in Sweden reported the use of palivizumab, the indication for its use, and the number of infants born preterm before 36 wk of gestation and less than 2 y old who were admitted to hospital for RSV infection. Results: During the two seasons, 218 (3.8%) children who were born before 36 wk of gestation, and 97 (5.4%) who were born before 33 wk, were hospitalized because of RSV infection. Five children were treated with mechanical ventilation. No death caused by RSV was reported. A total of 390 children were treated with palivizumab, and 16 (4.1%) of those who received prophylactic treatment were admitted to hospital with RSV infection.