Josiane Warszawski

Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort

Objective:To identify factors associated with mother-to-child HIV-1 transmission (MTCT) from mothers receiving antenatal antiretroviral therapy. Design:The French Perinatal Cohort (EPF), a multicenter prospective cohort of HIV-infected pregnant women and their children. Methods:Univariate analysis and logistic regression, with child HIV status as dependent variable, were conducted among 5271 mothers who received antiretroviral therapy during pregnancy, delivered between 1997 and 2004 and did not breastfeed. Results:The MTCT rate was 1.3% [67/5271; 95% confidence interval (CI), 1.0–1.6]. It was as low as 0.4% (5/1338; 95% CI, 0.1–0.9) in term births with maternal HIV-1 RNA level at delivery below 50 copies/ml. MTCT increased with viral load, short duration of antiretroviral therapy, female gender and severe premature delivery: 6.6% before 33 weeks versus 1.2% at 37 weeks or more (P < 0.001). The type of antiretroviral therapy was not associated with transmission. Intrapartum therapy was associated with four-fold lower MTCT (P = 0.04) in case of virological failure (> 10 000 copies/ml). Elective cesarean section tended to be inversely associated with MTCT in the overall population, but not in mothers who delivered at term with viral load < 400 copies/ml [odds ratio (OR), 0.83; 95% CI, 0.29–2.39; P = 0.37]. Among them, only duration of antenatal therapy was associated with transmission (OR by week, 0.94; 95% CI, 0.90–0.99; P = 0.03). Conclusions:Low maternal plasma viral load is the key factor for preventing MTCT. Benefits in terms of MTCT reduction may be expected from early antiretroviral prophylaxis. The potential toxicity of prolonged antiretroviral use in pregnancy should be evaluated.

Response to combination antiretroviral therapy: variation by age.

Objective:To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons. Design and setting:Multicohort collaboration of 33 European cohorts. Subjects:Forty-nine thousand nine hundred and twenty-one antiretroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006. Outcome measures:Time from combination antiretroviral therapy initiation to HIV RNA less than 50 copies/ml (virological response), CD4 increase of more than 100 cells/μl (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2–5, 6–12, 13–17, 18–29, 30–39 (reference group), 40–49, 50–54, 55–59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. Results:The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2–54.1%) and 59.2% (58.7–59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6–12 (adjusted hazard ratio: 0.87) and 13–17 (0.78) years, but was higher in those aged 50–54 (1.24), 55–59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55–59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. Conclusion:Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance.

Prevalence of Hepatitis B and Hepatitis C Virus Infections in France in 2004: Social Factors Are Important Predictors After Adjusting for Known Risk Factors

To monitor the prevalence of hepatitis B and hepatitis C a cross‐sectional survey was conducted in 2004 among French metropolitan residents. A complex sampling design was used to enroll 14,416 adult participants aged 18–80 years. Data collected included demographic and social characteristics and risk factors. Sera were tested for anti‐HCV, HCV‐RNA, anti‐HBc and HBsAg. Data were analyzed with SUDAAN® software to provide weighted estimates for the French metropolitan resident population. The overall anti‐HCV prevalence was 0.84% (95% CI: 0.65–1.10). Among anti‐HCV positive individuals, 57.4% (95% CI: 43.2–70.5) knew their status. Factors associated independently with positive anti‐HCV were drug use (intravenous and nasal), blood transfusion before 1992, a history of tattoos, low socioeconomic status, being born in a country where anti‐HCV prevalence >2.5%, and age >29 years. The overall anti‐HBc prevalence was 7.3% (95%: 6.5–8.2). Independent risk factors for anti‐HBc were intravenous drug use, being a man who has sex with men, low socioeconomic status, a stay in a psychiatric facility or facility for the mentally disabled, <12 years of education, being born in a country where HBsAg prevalence >2%, age >29 and male sex. The HCV RNA and HBsAg prevalence were 0.53% (95% CI: 0.40–0.70) and 0.65% (95% CI: 0.45–0.93), respectively. Among HBsAg positive individuals, 44.8% (95% CI: 22.8–69.1) knew their status. Anti‐HCV prevalence was close to the 1990s estimates whereas HBsAg prevalence estimate was greater than expected. Screening of hepatitis B and C should be strengthened and should account for social vulnerability. J. Med. Virol. 82:546–555, 2010.

Factors Associated with Mother-to-Child Transmission of HIV-1 Despite a Maternal Viral Load <500 Copies/mL at Delivery: A Case-Control Study Nested in the French Perinatal Cohort (EPF-ANRS CO1)

BACKGROUND The rate of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) type 1 is as low as 0.5% in non-breast-feeding mothers who delivered at term while receiving antiretroviral therapy with a plasma viral load <500 copies/mL. This situation accounted for 20% of the infected children born during the period 1997-2006 in the French Perinatal Cohort. We aimed to identify factors associated with such residual transmission risk. METHODS We performed a case-control study nested in the aforementioned subpopulation of the French Perinatal Cohort. RESULTS Nineteen case patients (transmitters) and 60 control subjects (nontransmitters) were included. Case patients and control subjects did not differ by geographical origin, gestational age at HIV diagnosis, type of antiretroviral therapy received, or elective Cesarean delivery. Case patients were less often receiving treatment at the time that they conceived pregnancy than control subjects (16% vs 45%; P=.017). A lower proportion of case patients had a viral load <500 copies/mL, compared with control subjects, at 14 weeks (0% vs 38.1%; P=.02), 28 weeks (7.7% vs 62.1%; P=.005), and 32 weeks: (21.4% vs 71.1%; P=.004). The difference remained significant when we restricted analysis to the 10 of 16 intrapartum transmission cases. In a multivariate analysis at 30+/-4 weeks adjusted for viral load, CD4(+) T cell count, and time at antiretroviral therapy initiation, viral load was the only factor independently associated with MTCT of HIV (adjusted odds ratio, 23.2; 95% confidence interval, 3.5-553; P<.001). CONCLUSIONS Early and sustained control of viral load is associated with a decreasing residual risk of MTCT of HIV-1. Guidelines should take into account not only CD4(+) T cell count and risk of preterm delivery, but also baseline HIV-1 load for deciding when to start antiretroviral therapy during pregnancy.

Premature Delivery in HIV-Infected Women Starting Protease Inhibitor Therapy During Pregnancy: Role of the Ritonavir Boost?

BACKGROUND The association between combination antiretroviral (cARV) therapy use by human immunodeficiency virus (HIV)-infected women during pregnancy and risk of prematurity is still controversial. We explored this question, focusing on the initiation of ritonavir-boosted protease inhibitors (PIs) during pregnancy, which is now standard care. METHODS Trends in prematurity (<37 gestational weeks) were studied among all singleton pregnancies in the Agence Nationale de Recherche sur le SIDA (ANRS) French Perinatal Cohort from 1990 through 2009 (n = 13 271). In-depth analysis was conducted in a more detailed substudy of the cohort, among women starting PI-based ARV therapy during pregnancy (n = 1253). Multivariable analysis adjusted for immunovirological status and known risk factors for prematurity. RESULTS Prematurity increased from 9.2% during 1990-1993 (no therapy) and 9.6% during 1994-1996 (mostly zidovudine monotherapy) to 12.4% during 1997-1999 (dual-nucleoside analog therapy) and 14.3% during 2005-2009 (routine cARV therapy; P < .01). Prematurity was associated with cARV therapy, compared with zidovudine monotherapy, with an adjusted odds ratio of 1.69 (95% confidence interval [CI], 1.38-2.07; P < .01) when accounting for maternal age, intravenous drug use, geographic origin, and CD4 cell count. During 2005-2009, the prematurity rate was higher with boosted than with nonboosted PI therapy started during pregnancy (14.4% vs 9.1% [P = .05]; adjusted hazard ratio, 2.03 [95% CI, 1.06-3.89; P = .03] in multivariate analysis). The difference concerned mainly induced preterm delivery for maternal or fetal indications (5.6% vs 1.6%; P = .02), CONCLUSIONS The prematurity rate among HIV-infected pregnant women was twice that in the general population in France; this was not entirely explained by sociodemographic characteristics. Prematurity was independently associated with cARV therapy and, particularly, with the initiation of ritonavir-boosted PI therapy during pregnancy.

Changes in sexual behaviours: from secular trends to public health policies.

Objective:To explore the relative contribution of secular trends and public health policies to changes in sexual behaviour. Design:Three random probability surveys of the sexual behaviour of people aged 18–69 years were conducted in 1970, 1992 and 2006 in France. Methods:Data of the 2006 survey (n = 12 364) were compared with those from two surveys carried out in 1970 (n = 2625) and 1992 (n = 20 055). Results:Over the last decades, median age at first intercourse has decreased by 4 years for women (22.0 in the 1930s vs. 17.6 in the 2000s) and 1 year for men (18.1 vs. 17.2). Lifetime number of sexual partners increased for women (1.8 in 1970 vs. 4.4 in 2006), but not for men (11.8 vs. 11.6). At the same time, the proportion of respondents, especially women, who reported nonpenetrative sexual practices and considered sexual intercourse essential to well being was on the increase. These changes are mainly attributed to an increase in womens social status. A marked increase in condom use was observed following the first AIDS/HIV prevention campaigns in the 1980s. Conclusion:Public health interventions that are synergistic with trends in social norms are likely to be more effective than those that run counter to them. In France, sexual health and HIV prevention policies aimed at harm limitation appear to have chimed with secular trends. The evidence of greater diversification of sexual practices offers potential to increase the range of safer sex messages used in public health interventions.

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

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. Design: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. Methods: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). Conclusion: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.

Mitochondrial dysfunction following perinatal exposure to nucleoside analogues.

Antiretroviral drugs given during pregnancy and immediately after birth are extraordinarily effective at preventing mother-to-child transmission of HIV-1: the transmission rate is dramatically decreased from 15–20% to less than 1%, at least for women intensively managed with potent antiretroviral therapy [1,2]. Current recommendations are now based on antiretroviral combinations, mostly including at least two nucleoside analogues (NA). Because NA can cross the placenta and can interact with human DNA, fetal tolerance of these drugs used during pregnancy should be carefully assessed [3,4]. Mitochondrial toxicity in adults has been the subject of substantial attention for some years [5]. There is no obvious reason why the fetus and newborn, often exposed for many months, should escape any such effects.

Performance of HIV-1 DNA or HIV-1 RNA Tests for Early Diagnosis of Perinatal HIV-1 Infection during Anti-Retroviral Prophylaxis

OBJECTIVE To compare performance of testing for human immunodeficiency virus (HIV)-1 DNA and HIV-1 RNA for diagnosis of HIV-1 infection in infants receiving preventive antiretroviral therapy. STUDY DESIGN This substudy of the French multicenter prospective cohort of neonates born to HIV-infected mothers, included 1567 infants tested for HIV with polymerase chain reaction (PCR) in a single laboratory, receiving post-natal prophylaxis, not breastfed, and having simultaneous HIV-1 DNA and RNA results before 45 days. The performance of PCR was assessed in reference to the 6-month HIV-1 RNA result. RESULTS Specificity of both HIV-1 RNA and HIV-1 DNA PCR was 100% at all ages (except 99.8% for DNA at birth); sensitivity was 58% (RNA) and 55% (DNA) at birth, and 89% at 1 month, 100% at 3 months for both, and 100% at 6 months (DNA). Concordance between HIV-1 DNA and RNA results was 0.78 and 0.81 (Kappa) at birth and 1 month and 100% at 3 and 6 months. Type of maternal and neonatal prophylaxis had no effect on sensitivity, but influenced viral load. CONCLUSION The performances of testing for HIV-1 DNA and RNA were similar with 100% sensitivity at 3 months. At 1 month during prophylaxis, 11% of infected children had negative PCR results.

No relation between in-utero exposure to HAART and intrauterine growth retardation.

Background:The use of 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 birth weight. Objective:To evaluate the impact of antiretroviral therapy during the pregnancy on birth weight, length and head circumference. Methods:The study was performed in uninfected infants born to HIV-1-infected mothers, enrolled from 1990 to 2006 in the Agence Nationale de Recherche sur le SIDA 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. Results:In 8192 mother–infant pairs, the mean birth weight Z-scores increased between 1990 and 1997 and then remained stable until 2006. There was no significant relation between the type of antiretroviral therapy and the proportion of small for gestational age (birth weight Z-score ≤ −2SD), which was 4% overall. Infants exposed to HAART compared with monotherapy had a lower mean birth weight Z-scores (difference −0.09, 95% confidence interval −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. Length or head circumference Z-scores were not associated with antiretroviral therapy exposure. Among pregnancies with HAART, there was no relation between the duration and type of therapy and the anthropometric parameters. Conclusion:Our findings in a large cohort suggest that HAART during pregnancy does not increase the incidence of infants who are small for gestational age.