Prise en charge des femmes enceintes infectées par le VIH en France à l'ère des multithérapies (des recommandations aux pratiques)

L objectif de cette thèse est de décrire la prise en charge en France des femmes enceintesinfectées par le VIH à l ère des multithérapies, de mesurer les écarts par rapport auxrecommandations, d identifier des facteurs liés à des prises en charge non optimales du pointde vue du risque de transmission et d améliorer les recommandations pour certaines situationsminoritaires encore mal étudiées. Ce travail est issu des données de l Enquête PérinataleFrançaise (ANRS-EPF), la seule cohorte nationale et l une des plus larges sur le planinternational, avec 17 491 couples mères-enfants inclus depuis 1986.Actuellement, presque toutes les femmes sont traitées par multithérapie (96,5% en 2009) et letaux de transmission est inférieur à 1% (0,6% ; IC95% : 0,2-1,4). Les prises en charge nonoptimales du point de vue de la prévention de la transmission mère-enfant du VIH (PTME)(dépistage du VIH tardif, absence ou retard à l initiation des traitements antirétrovirauxpendant la grossesse, en perpartum ou en prophylaxie post-natale, échec virologique en fin degrossesse, accouchement par voie basse malgré une charge virale non contrôlée, allaitementmaternel) sont de plus en plus rares en France (0,2% à 5,5% en 2009). Le taux de césariennereste cependant nettement plus élevé qu en population générale, du fait notamment d un tauxélevé de césariennes programmées malgré une charge virale contrôlée, ce qui n est pasconforme aux recommandations. On n observe pas pour autant un taux de transmission plusbas pour les césariennes programmées lorsque la charge virale est contrôlée.L immigration en provenance d un pays d Afrique sub-saharienne est associée à undiagnostic du VIH plus tardif pendant la grossesse, mais l accès à la PTME et l observancesemblent similaires à ceux des Françaises de métropole, une fois le diagnostic établi. La nondivulgation du statut VIH maternel au père de l enfant, plus fréquente chez les africaines, estassociée à une PTME moins optimale, mais sans augmentation de la transmission mère enfant du VIH.Nous avons également évalué les recommandations pour certaines situations minoritaires.Pour les femmes infectées par le VIH-2 (2,6% des femmes de la cohorte EPF), dont le risquede transmission mère-enfant est spontanément faible, nos résultats contribuent à justifier uneprise en charge moins intensive que celles des femmes infectées par le VIH-1. Pour lesfemmes nécessitant une amniocentèse, associée à un risque accru de transmission mère-enfantavant l ère des multithérapies, nos résultats ne montrent pas d augmentation de risque chez lesfemmes traitées par multithérapie.Nos résultats sont globalement encourageants pour un système offrant un accès universel etgratuit aux soins pour le VIH, facilitant ainsi l accès aux soins aux populations en situation deprécarité, qui restent néanmoins les plus à risque de prises en charge non optimales.The objective of this Ph.D thesis is to describe the care received by HIV-infected pregnantwomen in France in the era of multitherapy, to assess how actual practices differ fromrecommendations, to identify factors related to non optimal care for prevention of mother-tochildHIV transmission (PMTCT) and to improve recommendations for some minoritysituations that have not been well evaluated.Work for this thesis was done using data from the French perinatal cohort ANRS-EPF, theonly national multicenter cohort and one of the largest, having included 17 491 mother-childcouples since 1986.Currently, almost all women are treated with multitherapy (96.5% in 2009) and thetransmission rate is below 1% (0.6%; 95%CI: 0.2-1.4). Non optimal care for PMTCT (lateHIV diagnosis, lack or late initiation of antiretroviral treatment during pregnancy, intrapartumand postnatal prophylaxis, virological failure at delivery, vaginal delivery despiteuncontrolled viral load, maternal breastfeeding) has become increasingly rare in France(between 0.2% and 5.5% in 2009). The cesarean section rate is however clearly higher than inthe general population, most notably due to a higher rate of elective cesarean section amongwomen with a controlled viral load, which does not comply with the recommendations. Andyet elective cesarean section performed on women with a controlled viral load does not resultin a lower transmission rate.Migration from a sub-Saharan African country is associated with a later HIV diagnosis duringpregnancy, but access to PMTCT and adherence seem similar once HIV infection isdiagnosed. Failure for a mother to disclose her HIV status to the child s father, which occursmore frequently with African women, is associated with less optimal PMTCT strategies butwithout any increase in MTCT rate.We have also evaluated the recommendations for some minority situations. For HIV-2infected women (2% of EPF cohort), who had a spontaneously lower MTC rate, our resultscontribute to justifying a less intensive PMTCT than for HIV-1 infected women. For womenneeding an amniocentesis, which, before the multitherapy era, was associated with anincreased transmission rate, our results suggest that the transmission risk is no longer greaterfor women being treated by multitherapy.Our findings are encouraging as they demonstrate the effectiveness of a health care systemwhich promoting free universal access to HIV care has succeeded in reaching out the mostunder privileged populations, thereby making it easier for them to receive optimal carealthough they remain at risk for non optimal PMTCT practices.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

The breadth of maternal HIV-1 specific neutralizing antibodies is not associated with a lower risk of mother-to-infant transmission

International audienc

Short- and Long-term Immunological and Virological Outcome in HIV-Infected Infants According to the Age at Antiretroviral Treatment Initiation

The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both group

PLoS One

AIM: Metabolic risk factors are poorly documented for the first generation of young adults who have lived with HIV since childhood. We compared their metabolic profile with that of adults of same age from the general population. METHODS: We conducted a cross-sectional analysis of data from two populations: (1) COVERTE (ANRS-CO19), a French national cohort of 18 to 30-year-old patients HIV-infected since childhood, and (2) ENNS, a national cross-sectional population-based household survey on nutrition. Body mass index (BMI), blood pressure, waist circumference, fasting glucose, triglycerides, and HDL-, LDL- and total cholesterol were measured in both studies. Direct standardization on overweight and education level and logistic regression were used to compare the prevalence of metabolic abnormalities between the two populations. RESULTS: Data from 268 patients from COVERTE and 245 subjects from ENNS were analyzed. Tobacco use was similar in both groups. HIV-infected patients had increased mean waist-to-hip ratio and triglycerides to HDL-cholesterol ratio and decreased mean HDL-cholesterol as compared to their counterparts from the general population in both genders. In HIV-infected patients, metabolic syndrome was identified in 13.2% of men (95% confidence interval [CI]: 7.1-19.2) and 10.4% (95% CI: 5.4-15.3) of women versus 10.6% (95%CI: 1.5-19.7) and 1.7% (95%CI: 0-4.1) in subjects from the general population, respectively. CONCLUSION: Young adults infected with HIV since childhood had a higher prevalence of dyslipidemia and metabolically detrimental fat distribution than adults of same age of the general population, supporting close monitoring for cardiometabolic diseases

Front Public Health

OBJECTIVE: To examine the relationship between young adults' labor force participation and depression in the context of the COVID-19 pandemic. DESIGN SETTING PARTICIPANTS: Data come from the nationally-representative EPICOV cohort study set up in France, and were collected in 2020 and 2021 (3 waves of online or telephone interviews: 02/05/2020-12/06/2020; 26/10/2020-14/12/2020; 24/06/2021-09/08/2021) among 2,217 participants aged 18-30 years. Participants with prior mental health disorder (n = 50) were excluded from the statistical analyses. RESULTS: Using Generalized Estimating Equation (GEE) models controlled for participants' socio-demographic and health characteristics and weighted to be nationally-representative, we found that compared to young adults who were employed, those who were studying or unemployed were significantly more likely to experience depression assessed using the PHQ-9 (multivariable ORs, respectively: OR: 1.29, 95% CI 1.05-1.60 and OR: 1.50, 1.13-1.99). Stratifying the analyses by age, we observed that unemployment was more strongly associated with depression among participants 25-30 years than among those who were 18-24 years (multivariable ORs, respectively, 1.78, 95% CI 1.17-2.71 and 1.41, 95% CI 0.96-2.09). Being out of the labor force was, to the contrary, more significantly associated with depression among participants 18-24 years (multivariable OR: 1.71, 95% CI 1.04-2.82, vs. 1.00, 95% CI 0.53-1.87 among participants 25-30 years). Stratifying the analyses by sex, we found no significant differences in the relationships between labor market characteristics and depression (compared to participants who were employed, multivariable ORs associated with being a student: men: 1.33, 95% CI 1.01-1.76; women: 1.19, 95% CI 0.85-1.67, multivariable ORs associated with being unemployed: men: 1.60, 95% CI 1.04-2.45; women: 1.47, 95% CI 1.01-2.15). CONCLUSIONS AND RELEVANCE: Our study shows that in addition to students, young adults who are unemployed also experience elevated levels of depression in the context of the COVID-19 pandemic. These two groups should be the focus of specific attention in terms of prevention and mental health treatment. Supporting employment could also be a propitious way of reducing the burden of the COVID-19 pandemic on the mental health of young adults.Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic: ORCHESTR

PLoS One

BACKGROUND: Long-term growth in HIV-infected infants treated early in resource-limited settings is poorly documented. Incidence of growth retardation, instantaneous risk of death related to malnutrition and growth parameters evolution during the first five years of life of uninfected and early treated HIV-infected children were compared and associated factors with growth retardation were identified. METHODS: Weight-for-age (WAZ), weight-for-length (WLZ), and length-for-age (LAZ) Z-scores were calculated. The ANRS-PEDIACAM cohort includes four groups of infants with three enrolled during the first week of life: HIV-infected (HI, n = 69), HIV-exposed uninfected (HEU, n = 205) and HIV-unexposed uninfected (HUU, n = 196). The last group included HIV-infected infants diagnosed before 7 months of age (HIL, n = 141). The multi-state Markov model was used to describe the incidence of growth retardation and identified associated factors. RESULTS: During the first 5 years, 27.5% of children experienced underweight (WAZ<-2), 60.4% stunting (LAZ<-2) and 41.1% wasting (WLZ<-2) at least once. The instantaneous risk of death observed from underweight state (35.3 [14.1-88.2], 84.0 [25.5-276.3], and 6.0 [1.5-24.1] per 1000 person-months for 0-6 months, 6-12 months, and 12-60 months respectively) was higher than from non-underweight state (9.6 [5.7-16.1], 20.1 [10.3-39.4] and 0.3 [0.1-0.9] per 1000 person-months). Compared to HEU, HIL and HI children were most at risk of wasting (adjusted HR (aHR) = 4.3 (95%CI: 1.9-9.8), P<0.001 and aHR = 3.3 (95%CI: 1.4-7.9), P = 0.01 respectively) and stunting for HIL (aHR = 8.4 (95%CI: 2.4-29.7). The risk of underweight was higher in HEU compared to HUU children (aHR = 5.0 (CI: 1.4-10.0), P = 0.001). Others associated factors to growth retardation were chronic pathologies, small size at birth, diarrhea and CD4< 25%. CONCLUSIONS: HIV-infected children remained at high risk of wasting and stunting within the first 5 years period of follow-up. There is a need of identifying suitable nutritional support and best ways to integrate it with cART in pediatric HIV infection global care

Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Patients and Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

CD4 recovery following antiretroviral treatment interruptions in children and adolescents with HIV infection in Europe and Thailand

Objectives: The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART). Methods: Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for > 6 months before TI of ≥ 30 days while aged < 18 years were included. CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression. Results: In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged < 3 years at the start of TI. Long-term CD4% was highest in those with a TI lasting 1 to <3 months, those with r-ART after year 2000 and those with a CD4% nadir ≥ 25% (all P < 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir < 15% during TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir ≥ 25%. Conclusions: After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI

Feasibility of Early Infant Diagnosis of HIV in Resource-Limited Settings: The ANRS 12140-PEDIACAM Study in Cameroon

BACKGROUND: Early infant diagnosis (EID) of HIV is a key-point for the implementation of early HAART, associated with lower mortality in HIV-infected infants. We evaluated the EID process of HIV according to national recommendations, in urban areas of Cameroon. METHODS/FINDINGS: The ANRS12140-PEDIACAM study is a multisite cohort in which infants born to HIV-infected mothers were included before the 8(th) day of life and followed. Collection of samples for HIV DNA/RNA-PCR was planned at 6 weeks together with routine vaccination. The HIV test result was expected to be available at 10 weeks. A positive or indeterminate test result was confirmed by a second test on a different sample. Systematic HAART was offered to HIV-infected infants identified. The EID process was considered complete if infants were tested and HIV results provided to mothers/family before 7 months of age. During 2007-2009, 1587 mother-infant pairs were included in three referral hospitals; most infants (n = 1423, 89.7%) were tested for HIV, at a median age of 1.5 months (IQR, 1.4-1.6). Among them, 51 (3.6%) were HIV-infected. Overall, 1331 (83.9%) completed the process by returning for the result before 7 months (median age: 2.5 months (IQR, 2.4-3.0)). Incomplete process, that is test not performed, or result of test not provided or provided late to the family, was independently associated with late HIV diagnosis during pregnancy (adjusted odds ratio (aOR) = 1.8, 95%CI: 1.1 to 2.9, p = 0.01), absence of PMTCT prophylaxis (aOR = 2.4, 95%CI: 1.4 to 4.3, p = 0.002), and emergency caesarean section (aOR = 2.5, 95%CI: 1.5 to 4.3, p = 0.001). CONCLUSIONS: In urban areas of Cameroon, HIV-infected women diagnosed sufficiently early during pregnancy opt to benefit from EID whatever their socio-economic, marital or disclosure status. Reduction of non optimal diagnosis process should focus on women with late HIV diagnosis during pregnancy especially if they did not receive any PMTCT, or if complications occurred at delivery

Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE)

Background: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. Methods and Findings: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm3 or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). Conclusions: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP