Retrovirology. 2009 Sep 19;6:85

Retrovirology. 2009 Sep 19;6:85

Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns.

We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing.

Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%): drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available) and in newborn lymphocytes (6/8) suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10) and neonatal lymphocytes (2/8) suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped.

This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%), drug resistance was archived in the cellular reservoir and persisted during infancy, with or without antiretroviral treatment. This finding stresses the need for effective antiretroviral treatment of pregnant women.

We evaluated the prevalence of congenital CMV infection before and after HAART availability in neonates born to HIV-infected mothers. We also identified maternal risk factors associated with in utero CMV transmission.

Routine screening for congenital CMV infection was carried out between 1993 and 2004 in children born to the HIV-infected mothers included in the EPF French Perinatal Cohort (ANRS CO1/10/11). Interpretable tests on urine samples collected within the first ten days of life were available for 4797 of the 7563 liveborn infants. Prevalence was estimated according to different periods. Univariate and multivariate logistic regression analyses were carried out to identify factors associated with transmission in HAART era.

The overall prevalence of CMV infection was 2.3% of live-born children (95% CI:1.9–2.8). It was higher in HIV-infected neonates (10.3%; 95% CI: 5.6-17.0) than in HIVuninfected neonates (2.2%, 95% CI:1.8–2.7), p<0.01. The prevalence of CMV infection decreased over time, from 3.5% (1997-98) to 1.2% (2003-04), in HIV-uninfected neonates. Delivery period, maternal age, time at antiretroviral treatment initiation and maternal CD4+ count <200/mm3 close to delivery were independently associated with CMV infection in logistic regression. The proportion of symptomatic CMV infections was 23.1% in HIVinfected newborns and 6.7% in HIV-uninfected neonates.

The prevalence of congenital CMV infection was high and associated with high morbidity rates in HIV-infected neonates. Conversely, it decreased over time in neonates not infected with HIV, reaching levels similar to those observed in the general population, following the introduction and increasing use of HAART for preventing mother-to-child HIV transmission.

AIDS. 2009 Jun 19;23(10):1235-43.
No relation between in utero exposure to highly active antiretroviral therapy and intrauterine growth retardation.
N Briand, L. Mandelbrot, J. Le Chenadec, R. Tubiana, J.P. Teglas, A. Faye, C. Dollfus, C. Rouzioux, S. Blanche, J. Warszawski; for the ANRS French Perinatal Cohort.
BACKGROUND

The use of highly active antiretroviral therapies (HAART) during pregnancy is now standard care to prevent mother-to-child HIV transmission in developed countries. There is controversy about its impact on low birthweight.

To evaluate the impact of ART during the pregnancy on birthweight, lenght and head circumference.

The study was performed in uninfected infants born to HIV-1-infected mothers, enrolled from 1990 to 2006 in the ANRS French Perinatal Cohort CO1. We excluded mothers who used illicit drugs during pregnancy or had no prenatal care before the third trimester, twins and stillbirths. We used Z-scores adjusted for gestational age and sex.

In 8192 mother-infant pairs, the mean birthweight Z-scores increased between 1990 and 1997 and then remained stable until 2006. There was no significant relation between the type of ART and the proportion of small-for-gestational age (birthweight Z-score < -2 SD), which was 4% overall. Infants exposed to HAART compared with monotherapy had a lower mean birthweight Z-scores (difference: -0.09, 95%CI: -0.15 to -0.02), however there was no difference between HAART exposure in 2005-2006 and monotherapy in 1999-2004 which corresponded to standard care during each period, respectively. Height or head circumference Z-scores were not associated with ART exposure. Among pregnancies with HAART, there was no relation between the duration and type of therapy and the anthropometric parameters.

Our findings in a large cohort suggest that HAART during pregnancy does not increase the incidence of infants who are small for gestational age.

AIDS. 2009 23(5):597-604

Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants.

Goetghebuer T, Haelterman E, Le Chenadec J, Dollfus C, Gibb D, Judd A, Green H, Galli L, Ramos JT, Giaquinto C, Warszawski J, Levy J; for the European Infant Collaboration group.


OBJECTIVE

In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants.

Children born to HIV-infected mothers between 1 September 1996 and 31 December 2004, who were diagnosed with HIV and free of AIDS before 3 months, were eligible. Demographics and pregnancy data, details of antiretroviral therapy, and clinical outcome were collected from 11 European countries

The risk of AIDS or death, by whether or not an infant started treatment before 3 months of age, was estimated by Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: Among 210 children, 21 developed AIDS and three died. Baseline characteristics of the 124 infants treated before 3 months were similar to those of the 86 infants treated later. The risk of developing AIDS/death at 1 year was 1.6 and 11.7% in the two groups, respectively (P < 0.001). Deferring treatment was associated with increased risk of progression [crude hazard ratio 5.0; 95% confidence interval (CI) 2.0-12.6; P = 0.001] that persisted after adjusting for cohort in multivariate models (adjusted hazard ratio 3.0; 95% CI 1.2-7.9; P = 0.021)

In HIV-1 vertically infected infants, starting antiretroviral therapy before the age of 3 months is associated with a significant reduction in progression to AIDS and death.

HIV-1 diagnosis in babies born to seropositive mothers is one of the challenges of HIV epidemics in children. A simple, rapid protocol was developed for quantifying HIV-1 DNA in whole blood samples and was used in the ANRS French pediatric cohort in conditions of prevention of mother-to-child transmission. A quantitative HIV-1 DNA protocol (LTR real-time PCR) requiring small blood volumes was developed. First, analytical reproducibility was evaluated on 172 samples. Results obtained on blood cell pellets and Ficoll-Hypaque separated mononuclear cells were compared in 48 adult HIV-1 samples. Second, the protocol was applied to HIV-1 diagnosis in infants in parallel with plasma HIV-RNA quantitation. This prospective study was performed in children born between May 2005 and April 2007 included in the ANRS cohort. The assay showed good reproducibility. The 95% detection cut-off value was 6 copies/PCR, that is, 40 copies/10(6) leukocytes. HIV-DNA levels in whole blood were highly correlated with those obtained after Ficoll-Hypaque separation (r = 0.900, P < 0.0001). A total of 3,002 specimens from 1,135 infants were tested. The specificity of HIV-DNA and HIV-RNA assays was 100%. HIV-1 infection was diagnosed in nine infants before age 60 days. HIV-DNA levels were low, underlining the need for sensitive assays when highly active antiretroviral therapy (HAART) has been given. The performances of this HIV-DNA assay showed that it is adapted to early diagnosis in children. The results were equivalent to those of HIV-RNA assay. HIV-DNA may be used even in masked primary infection in newborns whose mothers have received-HAART.

The objective of the study was to investigate whether performing an amniocentesis increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 (MTCT).

We studied HIV -1 infected mothers and their children enrolled in the multicenter French Perinatal HIV Cohort from 1985 to 2006.

One hundred sixty-six amniocenteses were performed among 9302 singleton pregnancies, the proportion increasing from 1.0% before 2001 to 4.7% in 2005-2006. Use of highly active antiretroviral therapy (HAART) was more frequent in the amniocentesis group (58.4% vs 33.2%). MTCT tended to be higher in the amniocentesis group, among mothers who received no antiretroviral agents (25.0%; 3/12 vs 16.2%; 343/2113; P = .41) as well as among mothers receiving zidovudine monotherapy or a double-nucleoside reverse transcriptase inhibitor combination (6.1%; 3/49 vs 3.3%; 117/3556; P = .22), but the difference was not significant. Among 81 mothers receiving HAART, there was no case of MTCT.

Our results suggest that amniocentesis is not a major risk factor for mother-to-child transmission in mothers treated with effective antiretroviral therapy.

Long-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules.

To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers.

Cancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population.

Ten cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990-1999 or 2000-2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3-1.5) and 1.0 (0.5-1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0-7.2] P = 0.05 and 2.4 [0.8-5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine-lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5-73.9)].

This study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.