enquete perinatale francaise anrs - co1/co10/co11

ENQUETE PERINATALE FRANCAISE
ANRS - CO1/CO10/CO11
PUBLICATIONS 2005 - 2009
ABSTRACTS DES PRINCIPALES PUBLICATIONS
Inserm - Unité de recherche U. 822
Hôpital de Bicêtre - Secteur Bleu "Pierre-Marie" - Porte 10 à 15
82, rue du Général Leclerc
94276 Le Kremlin-Bicêtre
Tél. 01 49 59 53 10 - Fax 01 49 59 53 00
E-mail [email protected]
http://u822.kb.inserm.fr/epf/
1
ENQUETE PERINATALE FRANCAISE
ANRS - CO1/CO10/CO11
•
ANRS CO 01 - Etude prospective multicentrique de la transmission materno-fœtale du VIH1
et/ou du VIH2 et de sa prévention
PROMOTEUR : Agence Nationale de Recherches sur le Sida (ANRS)
INVESTIGATEUR PRINCIPAL
Dr Josiane WARSZAWSKI (épidémiologiste), - INSERM Unité U 822, Hôpital Bicêtre
CO-INVESTIGATEURS
Pr Laurent MANDELBROT (obstétricien), Hôpital Louis Mourier
Dr Roland TUBIANA (infectiologue), Hôpital Pitié Salpétrière
Pr Stéphane BLANCHE (pédiatre), Hôpital Necker Enfants Malades -
•
ANRS CO 10 – Cohorte d’enfants infectés par le VIH
PROMOTEUR : Agence Nationale de Recherches sur le Sida (ANRS)
INVESTIGATEUR PRINCIPAL
Dr Josiane WARSZAWSKI (épidémiologiste), - INSERM Unité U 822, Hôpital Bicêtre
CO-INVESTIGATEURS
Dr Catherine DOLLFUS (pédiatre), Hôpital Trousseau
Pr Albert FAYE (pédiatre), Hôpital Robert Debré
•
ANRS CO 11 – Observatoire des enfants nés de mère séropositive
INVESTIGATEUR PRINCIPAUX
Dr Josiane WARSZAWSKI (épidémiologiste), - INSERM Unité U 822, Hôpital Bicêtre
Professeur Stéphane BLANCHE (pédiatre), - Hôpital Necker Enfants Malades
VIROLOGIE : Pr Christine Rouzioux, Hôpital Necker, Paris
EQUIPE DE COORDINATION des cohortes EPF en mars 2009
„ Coordination / monitorage
Linda Asoul, Karima Hamrène, Valérie Benhammou, Sandrine Delmas, Nacima Chernai,
Naïma Bouallag, Jacques N’Gondi, Nadia Kessaci,
„ Gestion base, logistique, mise à jour et saisie
Leila Boufassa, Paulette Huyhn, Corinne Laurent, Thierry Wack
„ Epidémiologistes, statisticiens, informaticiens
Nelly Briand, Jérôme Le Chenadec, Carine Jasseron, Jean-Paul Téglas, Josiane Warszawski
„ Secrétariat
Marlène Péres, Elisa Ramos
2
ENQUETE PERINATALE FRANCAISE
ANRS - CO1/CO10/CO11
Sites participants
Les investigateurs des sites sont soulignés
* sites fermés
Hôpital d’Aix en Provence* (Tadrist B.); Hôpital Nord, Amiens (Decaux N., Douadi Y., Gondry, J.; Li Thiao
Te V.; Schmit J.L.); Hôpital d’Angers (Fournié A.); Hôpital Victor Dupouy, Argenteuil (Allisy C.. Brault D.);
Hôpital Paris La Roseraie*, Aubervilliers (Rozan M.A.); Hôpital Robert Ballanger, Aulnay (Questiaux, E.,
Zakaria A., Goldenstein, C.); Hôpital Saint Claude, Basse-Terre* (Sibille G.); Hôpital de Bastia (Pincemaille
O., Rusjan); Hôpital de la Côte Basque, Bayonne (Bonnal,F.; Cayla C.); Clinique du Blanc Mesnil* (Balde
P.); Hôpital Saint Jacques, Besançon (Estavoyer J.M.Maillet,R;); Hôpital Avicenne, Bobigny (Bentata M.);
Hôpital Jean Verdier, Bondy (Benoist L.; Bolie S., , Bonier N.; Lachassine, E., Rodrigues, A.,); Hôpital
Pellegrin, Bordeaux (Douard D.; Roux D., Schaeffer V.); Hôpital Ambroise Paré*, Boulogne Billancourt
(Zenaty D.); Hôpital Clémenceau, Caen (Brouard J., Goubin P.); Hôpital André Rosemon, Cayenne (Elenga
N.); Hôpital Beaujon*, Clichy (De Curtis A.); Hôpital de Creil (Carpentier B.; Duval-Arnould M., KingueEkollo C); Hôpital Intercommunal, Créteil (Garrait V., Lemerle S., Pichon C., Richier C. Touboul,C.);
Hôpital Béclère, Clamart (Bornarel D., Chambrin V., Clech L., Foix L’Hélias L., Labrune P., Schoen H);
Hôpital Louis Mourier, Colombes (Crenn-Hebert C., Floch-Tudal C., Mazy, F., Hery E.; Meier C.,); Hôpital
de Compiègne* (Lagrue A.); Hôpital d’enfants, Dijon (Martha S .;Reynaud I.); Hôpital de Dourdan* (Ercoli
V.); Hôpital de Dreux* (Denavit M.F.); Hôpital des Feugrais*, Elbeuf (Lahsinat K.); Hôpital
Intercommunal, Evreux (Allouche, C.; Touré K.,.); Hôpital Francilien Sud, Evry-Corbeil (Chevron; Devidas
A., Granier M., Guignier M., Lakhdari Y.; Marchand C. May A., Nguyen R, Turpault I); Hôpital de
Fontainebleau (Routier C.); Hôpital Victor Fouche, Fort de France (Hatchuel Y. William,C.); Hôpital de
Gonesse* (Balde P.); Hôpital Jean Rostand, Ivry (Jault T., Jrad I); Hôpital de Lagny (Chalvon Demersay A.,
Froguel,E.; Gourdel B.); Hôpital du Lamentin* (Monlouis M.); Hôpital Les Oudairies, La Roche sur Yon
(Aubry O., Brossier JP., Esnault JL,; Leautez S.; Perré P., Suaud I.); Hôpital de La Seyne sur Mer (Chamouilli
J.M.); Hôpital Louis Domergue, La Trinité* (Hugon N.); Hôpital André Mignot, Le Chesnay (Hentgen V.,
Messaoudi F.); Hôpital de Bicêtre, Le Kremlin-Bicêtre (Fourcade C.; Fridman S.; Peretti D.); Hôpital Jeanne
de Flandres, Lille (D’angelo S.; Hammou Y.,Mazingue F.,); Hôpital Dupuytren*, Limoges (De lumley L.);
Hôpital de Longjumeau (Bailly-Salin,P.; Turpault,I.; Seaume H.); Hôpital Hôtel Dieu-Hôpital Debrousse,
Lyon (Bertrand Y., Bertrand S.; Brochier C.; Cotte L., Kebaïli K., Tache N., Roussouly,MJ; Thoirain V.,. );
Hôpital François Quesnay, Mantes La Jolie (Delanete A., Doumet A., Granier F., Salomon JL.); Hôpital la
Conception, Marseille (Cravello L.); Hôpital La Timone Marseille (Thuret I.); Hôpital de Meaux (Karaoui
L., Lefèvre V.); Hôpital de Meulan* (Seguy D.); Hôpital Marc Jacquet, Melun (Le Lorier B.); Hôpital
3
Intercommunal, Montfermeil (Dehlinger M.; Echard M.; Mullard C.;Talon P.); Hôpital Arnaud de
Villeneuve, Montpellier (Benos, P.., Guigue N.; Lalande M.); Hôpital Intercommunal, Montreuil (HellerRoussin B.,Riehl C.,Winter.); Maternité Régionale A. Pinard, Nancy (Hubert C.); Hôpital de Nanterre*
(Karoubi P.); Hôpital de Nantes (Brunet-François C.; Mechinaud,; Reliquet, V.) Hôpital de Neuilly sur Seine*
(Berterottiere D.); Hôpital l’Archet-Fondation Lenval, Nice (Bongain A., Deville A., Galiba E. Monpoux F.,);
Hôpital Caremeau, Nîmes (Dendale-Nguyen J.); Hôpital Orléans (Arsac P.); Hôpital d’Orsay (Chanzy S., De
Gennes C.; Isart V.); Hôpital Bichat, Paris (Bastian H. Batallan A., Matheron S.); Hôpital Boucicaut*, Paris
(Lafay Pillet M.C.); Hôpital Cochin-Port Royal, Paris (Boudjoudi,N.; Firtion G., Fouchet, M.; Goupil, I.,
Pannier A., ); Hôpital Lariboisière, Paris (Ayral D., Ciraru-Vigneron N., Mouchnino G.); Hôpital des
Métallurgistes*, Paris (Rami M.); Institut Mutualiste Montsouris*, Paris (Carlus Moncomble C.); Hôpital
Necker, Paris (Boucly S., Blanche S., Maignan A.; Parat S., Rouzioux C.,Viard,JP.; Yamgnane,A.); Hôpital
Notre Dame du Bon Secours, Paris (Aufrant C.); Hôpital Pitié Salpêtrière, Paris (Bonmarchand,M.; De
Montgolfier I.; Edeb N., Lemercier D., ; Marcel,S. Pauchard, M., Tubiana R.,); Hôpital Robert Debré, Paris
(Faye A., Garion D., Leveille S.; Levine M., Ottenwalter A., Recoules A.,); Hôpital Saint-Antoine, Paris (Bui
E., Carbonne B., Meyohas, Rodriguez J.); Hôpital Hôpital Saint Michel, Paris (Aufrant C.); Hôpital Tenon,
Paris (Hervé,F.; Lebrette M.G.); Hôpital Trousseau, Paris (Dollfus C. Tabone MD, Vaudre G., Wallet A.);
Hôpital Marechal Joffre, Perpignan (Bachelard G.; Medus M.); Hôpital Les Abymes, Pointe-à-Pitre
(Bataille H.); Hôpital de Poissy-Saint-Germain en Laye* (Rousset M.C.); Hôpital René Dubos, Pontoise
(Mouchnino G.); Hôpital Américain, Reims (Munzer M.); Hôpital Charles Nicolle, Rouen (Brossard V.);
Hôpital de Saint-Denis (Allemon M.C., Bolot,P.; Dandris S.; Ekoukou D., Ghibaudo N., Khuong M.A.,);
Hôpital Nord, Saint Etienne (Billiemaz K.); Hôpital de Saint Martin (Bissuel F. Walter,V.); Hôpital
Esquirol*, Saint-Maurice (Robin M.); Hôpital de Sèvres* (Segard L.); Hôpital de Haute Pierre-Hôpital
Civil, Strasbourg (Cheneau, M. ; Entz-Werle N Favreau, J., Partisani M.); C.M.C. Foch, Suresnes* (Botto C.);
Hôpital Chalucet,Toulon (Hittinger G.); Hôpital Paule de Viguier, Toulouse (Antras, M.; Armand E.; Berrebi
A., Tricoire J.) Hôpital Bretonneau, Tours (Besnier J.M., Nau P.); Hôpital Brabois, Vandoeuvre les Nancy
(Neimann L.); Hôpital Paul Brousse*,Villejuif (Dussaix E.); Hôpital de Villeneuve Saint Georges (Chacé A.,
Guillot F. , Matheron, I., Tilouche S.).
4
PUBLICATIONS EPF
2005 - 2009
2009
Guibert G, Warszawski, Le Chenadec J, Blanche S, Benmebarek, Mandelbrot, Tubiana R,
Rouzioux C, Leruez-Ville M; on behalf of the French Perinatal Cohort (EPF). Decreased risk of
congenital cytomegalovirus (CMV) infection in children born to HIV-infected mothers in the era of
highly active antiretroviral therapy (HAART).
CID sous presse
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. No relation between
in utero exposure to highly active antiretroviral therapy and intrauterine growth retardation.
AIDS sous presse
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. Effect
of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants.
AIDS. 2009 Feb 2. [Epub ahead of print]
Avettand-Fènoël V, Chaix ML, Blanche S, Burgard M, Floch C, Toure K, Allemon MC,
Warszawski J, Rouzioux C; French Pediatric Cohort Study ANRS-CO 01 Group. LTR real-time
PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive
mothers treated in HAART area (ANRS CO 01).
J Med Virol. 2009 Feb;81(2):217-23.
Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongaoin A, Pannier E, Blanche S, Tubiana R,
Rouzioux C, Warszawski J; for the ANRS French Perinatal Cohort (EPF). Amniocentesis and
mother-to-child HIV transmission in the ANRS-French Perinatal Cohort.
Am J Obstet Gynecol. 2009 Feb;200 (2):160 e1-9.
2008
Benhammou V, Warszawski J, Bellec S, Doz F, André N, Lacour B, Levine M, Bavoux F, Tubiana
R, Mandelbrot L, Clavel J, Blanche S; on behalf ANRS-Enquête Périnatale Française. Incidence of
cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors.
AIDS. 2008 Oct 18;22(16):2165-2177.
Jasseron C, Mandelbrot L , Tubiana R, Teglas J.P., Faye A, Dollfus C., Le Chenadec J., Rouzioux
C., Blanche S., Warszawski J ; ANRS French Perinatal Cohort. Prevention of mother-to-child HIV
transmission: similar access for sub-Sahara African immigrants and for French women?
AIDS. 2008 Jul 31;22(12):1503-11.
5
Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group.
Response to combination antiretroviral therapy: variation by age.
AIDS. 2008 Jul 31;22(12):1463-73.
Warszawski J, Tubiana R, Le Chenadec J, Teglas JP, Faye A, Dollfus C, Briand N, Jasseron C,
Rouzioux C, Blanche S, Mandelbrot L. Transmission mère-enfant du VIH en France : l’impact
majeur des stratégies de prévention – Résultats de l’Enquête périnatale française ANRS-EPF.
BEH Numéro thématique n° 14-15, 2008, 98-101.
Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, Faye A, Burgard M,
Rouzioux C, Mandelbrot L; ANRS French Perinatal Cohort. Mother-to-child HIV transmission
despite antiretroviral therapy in the ANRS French Perinatal Cohort.
AIDS. 2008 Jan 11;22(2):289-99.
2007
Papaleo A, Warszawski J, Salomon R, Jullien V, Veber F, Dechaux M, Blanche S. Increased beta-2
microglobulinuria in human immunodeficiency virus-1-infected children and adolescents treated
with tenofovir.
Pediatr Infect Dis J. 2007 Oct;26(10):949-51.
Warszawski J, Lechenadec J, Faye A, Dollfus C, Firtion G, Meyer L, Douard D, Monpoux F,
Tricoire J, Benmebarek Y, Rouzioux C, Blanche S. Long-term non progression of HIV-1 infection
in children. Evaluation in the prospective French Pediatric Cohort EPF-ANRS.
Clin Infect Dis. 2007 Sept 15;45(6):785-94
Delaugerre C, Warszawski J, Chaix ML, Veber F, Macassa E, Buseyne F, Rouzioux C, Blanche S.
Prevalence and risk factors associated with antiretroviral resistance in HIV.
J Med Virol. 2007 Sept;79(9):1261-9.
Newell ML, Huang S, Fiore S, Thorne C, Mandelbrot L, Sullivan JL, Maupin R, Delke I, Watts
DH, Gelber RD, Cunningham CK; PACTG 316 Study Team. Characteristics and management of
HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the
USA.
BMC Infect Dis. 2007 Jun 20;7:60.
Scavalli Palladino C, Mandelbrot L, Berrebi A, Batallan A, Cravello L, Pannier E, Hamrene K,
Ciraru-Vigneron N, Faye A, Warszawski J, ANRS EPF. Twin pregnancy as a risk factor for
mother-to-child transmission of HIV-1 : trends over 20 years.
AIDS. 2007 May 11;21(8):993-1002.
Benhammou V, Tardieu M, Warszawski J, Rustin P, Blanche S. Clinical mitochondrial dysfunction
in uninfected children born to HIV-infected mothers following perinatal exposure to nucleoside
analogues.
Environ Mol Mutager. 2007 Apr-May ;48(3-4) :173-8.
6
Delaugerre C, Chaix ML, Warszawski J, Rouzioux C, Blanche S. HIV-1 drug resistance in French
infected-children: from newborn to adolescent.
Arch Pediatr. 2007 Mar;14(3):298-302.
Blanche S. Possible long-term effect of in utero antiretroviral exposure?
Arch Pediatr. 2007, 14(6):610-1
2006
S Blanche, M Tardieu, V Benhammou, J Warszawski and P Rustin. Mitochondrial dysfunction
following perinatal exposure to nucleoside analogues.
AIDS 2006, 20:1685-1690.
2005
F. Buseyne, J. Le Chenadec, M. Burgard, N. Bellal, M. J. Mayaux, C. Rouzioux, Y. Riviere and S.
Blanche. In HIV Type 1-Infected Children Cytotoxic T Lymphocyte Responses Are Associated with
Greater Reduction of Viremia under Antiretroviral Therapy.
AIDS Res Hum Retroviruses, 2005 Aug;21(8):719-27.
M. Tardieu, F. Brunelle, C. Raybaud, W. Ball, B. Barret, B. Pautard, E. Lachassine, M. J. Mayaux
and S. Blanche. Cerebral MR imaging in uninfected children born to HIV-seropositive mothers and
perinatally exposed to zidovudine.
AJNR Am J Neuroradiol. 2005 April 26(4): 695-701.
7
CID (sous presse)
Decreased risk of congenital cytomegalovirus (CMV) infection in children born
to HIVinfected mothers in the era of highly active antiretroviral therapy
(HAART).
Guibert G1, Warszawski J1,2,3, Le Chenadec J1, Blanche S4,5, Benmebarek Y1,3 ,
MandelbrotL6, Tubiana R7, Rouzioux C5,8, Leruez-Ville M5,8* ; on behalf of the French
Perinatal Cohort (EPF).
1. INSERM, INED U822, IFR69, Le Kremlin-Bicêtre
2. Université Paris-Sud, Le Kremlin-Bicêtre
3. AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre
4. Unité d’Hématologie Pédiatrique, AP-HP, Hôpital Necker, Paris
5. Université Paris-Descartes EA 3620
6. Maternité, AP-HP, Hôpital Louis Mourrier, Colombes
7. Service de Maladies Infectieuses, AP-HP Hôpital La Pitié Salpétrière, Paris
8. Laboratoire de Virologie, Centre National de référence du cytomégalovirus . AP-HP
Hôpital Necker, Paris,
ABSTRACT:
Background: 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.
Method: 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.
Results: 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.
Conclusions: 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.
8
AIDS sous presse
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.
Abstract
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.
Objective
To evaluate the impact of ART during the pregnancy on birthweight, lenght and head
circumference.
Methods
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.
Results
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.
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.
9
AIDS. 2009 Feb 2.
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.
aPediatric Department, CHU St Pierre, Brussels, Belgium bInserm, U822, Le Kremlin-Bicêtre, France cAP-HP, Hôpital
Trousseau, Service d'Hématologie et d'oncologie pédiatrique, Paris, France dCollaborative HIV Paediatric Study
(CHIPS), MRC Clinical Trials Unit, London, UK eItalian Register, Department of Paediatrics, University of Florence,
Italy fHospital Universitario de Getafe, Madrid, Spain gDepartment of Pediatrics, University of Padova, Padova, Italy
hUniversité Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre iAP-HP, Hôpital Bicêtre, Epidemiology and
Public Health Service, France. * Members of the European Infant Collaboration group are listed in the
Acknowledgements section on page 8.
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.
10
J Med Virol. 2009 Feb;81(2):217-23.
LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early
diagnosis in infants born to seropositive mothers treated in HAART area (ANRS
CO
01).
Avettand-Fènoël V, Chaix ML, Blanche S, Burgard M, Floch C, Toure K, Allemon MC,
Warszawski J, Rouzioux C; French Pediatric Cohort Study ANRS-CO 01 Group.
Assistance Publique - Hôpitaux de Paris, CHU Necker-Enfants Malades, Service de Virologie, Paris, France.
[email protected]
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 motherto-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.
11
Am J Obstet Gynecol. 2009 Feb;200(2):160.e1-9.
Amniocentesis and mother-to-child human immunodeficiency virus
transmission in the Agence Nationale de Recherches sur le SIDA et les Hépatites
Virales French Perinatal Cohort.
Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongain A, Pannier E, Blanche S,
Tubiana R, Rouzioux C, Warszawski J; ANRS French Perinatal Cohort (EPF).Collaborators
(129)
Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Gynecologie-Obstetrique, Hôpital Louis Mourier,
Colombes, and Université Paris 7-Diderot, Paris, France.
OBJECTIVE: The objective of the study was to investigate whether performing an amniocentesis
increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 (MTCT).
STUDY DESIGN: We studied HIV -1 infected mothers and their children enrolled in the
multicenter French Perinatal HIV Cohort from 1985 to 2006. RESULTS: 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 doublenucleoside 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. CONCLUSION: Our results suggest that amniocentesis is not a major risk factor for
mother-to-child transmission in mothers treated with effective antiretroviral therapy.
12
AIDS. 2008 Oct 18;22(16):2165-77.
Incidence of cancer in children perinatally exposed to nucleoside reverse
transcriptase inhibitors.
Benhammou V, Warszawski J, Bellec S, Doz F, André N, Lacour B, Levine M, Bavoux F,
Tubiana R, Mandelbrot L, Clavel J, Blanche S; ANRS-Enquête Périnatale Française.
Collaborators (533)
Inserm, U822, Le Kremlin-Bicêtre, France.
CONTEXT: 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. OBJECTIVE: To evaluate the incidence of cancers in uninfected children born to HIVinfected mothers. METHOD: 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. RESULTS: 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)]. CONCLUSION: 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.
13
AIDS. 2008 Jul 31;22(12):1503-11.
Prevention of mother-to-child HIV transmission: similar access for sub-Sahara
African immigrants and for French women?
Jasseron C, Mandelbrot L, Tubiana R, Teglas JP, Faye A, Dollfus C, Le Chenadec J,
Rouzioux C, Blanche S, Warszawski J; ANRS French Perinatal Cohort.
Collaborators (127)
INSERM Unit 822, Le Kremlin-Bicêtre, Paris, France.
OBJECTIVE: To investigate whether mother-to-child transmission (MTCT) management and rate
differed between African immigrants and French-born women delivering in France. METHODS:
MTCT strategies were studied among human immunodeficiency virus type 1-infected women
delivering between 1984 and 2007 in the multicenter French Perinatal Cohort, according to
geographical origin. RESULTS: Among 9245 pregnancies (in 7090 women), the proportion of
African mothers increased from 12% in 1984-1986 to 64% in 2003-2004. African women had later
access to care than French women, even in recent years (1997-2004). They more often discovered
their HIV infection during pregnancy (40.6 vs. 11.5%, P < 0.001), started prenatal care in the third
trimester (14.1 vs. 9.8%, P < 0.001) and started antiretroviral therapy after 32 weeks gestation (7.6
vs. 4.1%, P < 0.001). The association with late treatment initiation disappeared when adjusted for
late HIV diagnosis and prenatal care (adjusted odds ratio 1.0, 95% confidence interval 0.7-1.4).
African and French women did not differ in terms of access to highly active antiretroviral therapy,
nor for substandard management such as vaginal delivery with uncontrolled viral load, lack of
intrapartum and postpartum treatment or breastfeeding. The MTCT rate was higher for African than
for French women receiving antiretroviral therapy (1.8 vs. 0.8%, P = 0.02), but the difference was
no longer significant after adjustment for main transmission risk factors (adjusted odds ratio = 1.7,
95% confidence interval 0.8-3.7, P = 0.17). MTCT did not differ among 2110 term deliveries with
maternal viral load less than 400 copies/ml, (0.8 vs. 0.6%, P = 0.5). CONCLUSION: African
immigrants more often had late HIV screening in pregnancy than French-born women, but had
similar access to MTCT prevention, once the infection was diagnosed.
14
AIDS. 2008 Jul 31;22(12):1463-73.
Response to combination antiretroviral therapy: variation by age.
Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study
Group.
Collaborators (52)
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 twentyone 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/microl
(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, 5559 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), 5559 (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.
15
BEH Numéro thématique n° 14-15, 2008, 98-101.
Transmission mère-enfant du VIH en France : l’impact majeur des stratégies de
prévention – Résultats de l’Enquête périnatale française ANRS-EPF.
Warszawski J, Tubiana R, Le Chenadec J, Teglas JP, Faye A, Dollfus C, Briand N, Jasseron
C, Rouzioux C, Blanche S, Mandelbrot L.
Résumé
En France, le taux de transmission du VIH-1 de la mère à l’enfant était de 17 % avant 1994, en
l’absence de prophylaxie antirétrovirale disponible. Il est passé à 1,6 % [IC 95 % : 1,3-2,0] entre
1997 et 2004, à l’ère des multithérapies puissantes et atteignait 0,4 % [0,1-0,9] lorsque la charge
virale proche de l’accouchement était inférieure à 50 cp/mL. Trois facteurs de risque indépendants
sont fortement liés à cette transmission « résiduelle » depuis 1997 : le terme gestationnel à
l’accouchement (risque 6 fois plus élevé pour les grands prématurés que pour les enfants nés à
terme), la charge virale en fin de grossesse (augmentation surtout importante au-delà de 10 000
cp/mL), et la durée des antirétroviraux pendant la grossesse (antepartum). Pour les 10 % de femmes
en échec virologique à l’accouchement (>10 000 cp/mL), une première consultation tardive en
maternité et l’absence de perfusion per partum de zidovudine sont associés à un risque accru de
transmission. Dans la situation heureusement majoritaire des femmes accouchant à terme avec une
charge virale bien contrôlée (<400 cp/mL), le seul facteur significativement associé au risque de
transmission est la durée des antirétroviraux administrés pendant la grossesse, le taux diminuant de
manière linéaire avec l’augmentation de cette durée.
Abstract
In France, the rate of mother-to-child HIV1 transmission (MTCT) was 17% prior to 1994, due to
the absence of antiretroviral prophylaxis. It reached 1.6% (95% CI: 1.3-2.0) between 1997 and
2004, in the HAART era, and was as low as 0.4% (5/1338; 95% CI, 0.1-0.9) with maternal HIV-1
RNA level at delivery below 50 copies/mL. Three risk factors were independently associated with
residual transmission since 1997: gestational age (6 fold increase for severe premature delivery
compared with term births), viral load at delivery (10 times higher when viral load was above rather
than below 10,000 c/mL), and duration of antiretroviral therapy during pregnancy (antepartum). In
case of virological failure (>10 000 copies/mL), which concerned 10% of mothers, late booking at
maternity and lack of intrapartum zidovudine infusion were associated with higher MTCT rate. In
most case, mothers luckily delivered with well controlled viral load, <400 copies/mL, and only
duration of antenatal therapy was associated with transmission, increasing duration being related
with a linear decreasing transmission rate.
16
AIDS. 2008 Jan 11;22(2):289-99.
Mother-to-child HIV transmission despite antiretroviral therapy in the
ANRS French Perinatal Cohort.
Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, Faye A,
Burgard M, Rouzioux C, Mandelbrot L; ANRS French Perinatal Cohort.
Inserm, U822, IFR 60, Le Kremlin-Bicêtre, France. [email protected]
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.
17
Pediatr Infect Dis J. 2007 Oct;26(10):949-51.
Increased beta-2 microglobulinuria in human immunodeficiency virus-1infected
children
and
adolescents
treated
with
tenofovir.
Papaleo A, Warszawski J, Salomon R, Jullien V, Veber F, Dechaux M, Blanche S.
Unité d'Immunologie Hématologie Pédiatriques, Hôpital Necker Enfants Malades Assistance Publique-Hôpitaux
de Paris (APHP) et Faculté de médecine René Descartes, (EA 3620) Université Paris V, Paris, France.
A single-center cross sectional evaluation of beta-2 micro-globinuria as a marker of proximal
renal tubule damage in 92 HIV-infected children showed that tenofovir treatment was
significantly associated with very high abnormal values. In view of the very long duration of
treatments for HIV infection, their possible consequences for the child's growing body should
be carefully evaluated.
18
Clin Infect Dis. 2007 Sep 15;45(6):785-94. Epub 2007 Aug 14.
Long-term nonprogression of HIV infection in children: evaluation of the
ANRS prospective French Pediatric Cohort.
Warszawski J, Lechenadec J, Faye A, Dollfus C, Firtion G, Meyer L, Douard D,
Monpoux F, Tricoire J, Benmebarek Y, Rouzioux C, Blanche S.
Institut National de la Santé et de la Recherche Médicale U822, France.
BACKGROUND: Some children who are infected with human immunodeficiency virus type
1 (HIV-1) during the perinatal period remain asymptomatic for very long periods in the
absence of antiretroviral treatment, as is the case for some adults. Our objective was to
estimate the proportion of children who developed neither symptoms nor major
immunological perturbations to the age of > or = 10 years in a prospective cohort of infected
children who had been observed since birth. METHODS: The ongoing prospective French
Pediatric Cohort includes 568 HIV-1-infected children. Here, we report the follow-up data for
all 348 HIV-1-infected children who were born before 1 January 1994. Children with longterm nonprogression of infection (LTNPs) were defined as HIV-1-infected children who had
been observed for at least 10 years, never received antiretroviral treatment other than
zidovudine monotherapy, never developed symptoms of Centers for Disease Control and
Prevention clinical category C or B, and had a CD4+ cell percentage of < 25% no more than
once during follow-up. Other definitions were compared. RESULTS: The Kaplan-Meier
estimate of long-term nonprogression was 2.4% (95% confidence interval, 1.1%-4.6%) at 10
years of age, and 7 children were classified as LTNPs. The Kaplan-Meier estimates decreased
slightly with age, to 1.8% at 12 years of age and 1.4% at 14 years of age. Plasma HIV-1
replication rates were low (< 1000 copies RNA/mL) for 2 of the 7 LTNPs at the age of 10
years (0.6% of the total denominator). None of the routinely measured maternal or perinatal
markers were significantly linked to long-term nonprogression, with the exception of the
mother's Centers for Disease Control and Prevention clinical category at the time of delivery.
CONCLUSIONS: Approximately 2% of children who were infected during the perinatal
period displayed no immunological or clinical progression by the age of 10 years. This figure
is close to that reported for adults in studies that have used similar definitions.
19
J Med Virol. 2007 Sep;79(9):1261-9.
Prevalence and risk factors associated with antiretroviral resistance in
HIV-1-infected children.
Delaugerre C, Warszawski J, Chaix ML, Veber F, Macassa E, Buseyne F, Rouzioux C,
Blanche S.
Department of Virology, Necker Hospital, Paris, France. [email protected]
In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic
failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are
available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study
were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated
with resistance in this population. Prevalence of genotypic resistance was estimated
retrospectively in treated children who experienced virologic failure (with HIV-1-RNA > 500
copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with
resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from
76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside
reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at
least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%,
respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC
status. In multivariate analysis, resistance to any drug remained associated independently with
current low viral load and high lifetime number of past PI. Triple resistance was
independently associated with the high lifetime number of past PI and with gender,
particularly among children aged 11 years old or more with a prevalence seven times higher
in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1infected children and prevalence was similar with those observed in adult population in the
same year period. However, adolescent boys seem to be at greater risk.
20
BMC Infect Dis. 2007 Jun 20;7:60.
Characteristics and management of HIV-1-infected pregnant women
enrolled in a randomised trial: differences between Europe and the USA.
Newell ML, Huang S, Fiore S, Thorne C, Mandelbrot L, Sullivan JL, Maupin R, Delke
I, Watts DH, Gelber RD, Cunningham CK; PACTG 316 Study Team.
Centre of Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, UK.
[email protected]
BACKGROUND: Rates of mother-to-child transmission of HIV-1 (MTCT) have historically
been lower in European than in American cohort studies, possibly due to differences in
population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316
trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing
MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers
of pregnant HIV-infected women from the US and Western Europe enrolling in the same
clinical trial provided the opportunity to identify and explore differences in their
characteristics and in the use of non-study interventions to reduce MTCT. METHODS: In this
secondary analysis, 1350 women were categorized according to enrollment in centres in the
USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active
antiretroviral therapy and with elective caesarean delivery were identified with logistic
regression. RESULTS: In Europe, women enrolled were more likely to be white and those of
black race were mainly born in Sub-Saharan Africa. Women in the US were younger and
more likely to have previous pregnancies and miscarriages and a history of sexually
transmitted infections.More than 90% of women did not report symptoms of their HIV
infection; however, more women from the US had symptoms (8%), compared to women from
Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at
delivery than women enrolling in Europe, and more likely to receive highly active
antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean
delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall,
1.48% of infants were infected and there was no significant difference in the rate of
transmission between Europe and the US despite the different approaches to treatment and
delivery. CONCLUSION: These findings confirm that there are important historical
differences between the HIV-infected pregnant populations in Western Europe and the USA,
both in terms of the characteristics of the women and their obstetric and therapeutic
management. Although highly active antiretroviral therapy predominates in pregnancy in both
settings now, population differences are likely to remain.
21
AIDS. 2007 May 11;21(8):993-1002.
Twin pregnancy as a risk factor for mother-to-child transmission of HIV-1:
trends over 20 years.
Scavalli Palladino C, Mandelbrot L, Berrebi A, Batallan A, Cravello L, Pannier E,
Hamrene K, Ciraru-Vigneron N, Faye A, Warszawski J; ANRS EPF.
Inserm, U822, IFR69, Le Kremlin-Bicêtre, France.
OBJECTIVE: We investigated whether twin pregnancies were at increased risk of mother-tochild HIV-1 transmission (MTCT), in comparison with singletons. METHODS: Among HIV1 infected women enrolled in the French Perinatal HIV Cohort (n = 9262), we studied the
association between twin deliveries and MTCT rate according to three time periods (pre-1994,
1994-1996, 1997-2004) and the effect of birth order. The mother was considered to have
transmitted if at least one of the twins was infected. Univariate and multivariate analyses of
risk factors for MTCT were performed for deliveries in the periods up to 1996. RESULTS:
Overall, 2.1% (192/9262) of all the deliveries were twins. The rate of prematurity was greater
in twins than in singletons (54% and 13%, respectively). Up to 1996 the rate of MTCT of
HIV-1 was 28.3% (15/53) in twin pregnancies, versus 13.5% (414/3077) in singletons [odds
ratio (OR), 2.5; 95% confidence interval (CI), 1.4-4.7; P = 0.002; adjusted OR, 2.3: 95% CI,
1.1-2.3; P = 0.03). In the period from 1997 to 2003, MTCT was low and did not differ
between twins (1.0%) and singletons (1.8%; P = 1.0). Overall, the transmission rate for the
first-born child was threefold that for the second-born child (14/164, 8.5% versus 4/164,
2.4%; P = 0.008). CONCLUSION: Twin pregnancies were at increased risk of transmission,
but in the era of HAART this risk was reduced for twins, as well as singletons. Management
of multiple pregnancies should take into account the risks of premature rupture of the
membranes and preterm delivery.
22
Environ Mol Mutagen. 2007 Apr-May;48(3-4):173-8.
Clinical mitochondrial dysfunction in uninfected children born to HIVinfected mothers following perinatal exposure to nucleoside analogues.
Benhammou V, Tardieu M, Warszawski J, Rustin P, Blanche S.
INSERM U569 Epidémiologie et Reproduction, Hôpital Bicêtre, Kremlin Bicêtre, France.
Clinical and biological observations of mitochondrial dysfunction in children exposed to
zidovudine (azidothymidine, AZT) during the perinatal period rapidly followed similar
observations in animal experiments. To date, two different disorders have been identified. The
first, asymptomatic hyperlactatemia, is observed during treatment in one third of exposed
newborns, and is reversible with treatment cessation. In rare cases, it is associated with
symptomatic acidosis. Regression may be slow, taking up to several months after the end of
the treatment. The long-term clinical consequences of this biochemical disturbance are
unknown. The second disorder involves severe neurological symptoms, which become
clinically detectable during the first 2 years of life. These symptoms are associated with a
series of biochemical and ultrastructural changes consistent with persistent mitochondrial
dysfunction. This latter phenomenon is rare, and affects only 0.3-0.5% of exposed children in
the French pediatric cohort, in which observations continue. Despite initial controversy,
several similar observations in other cohorts have since confirmed its occurrence. The
pathophysiology of these two mitochondrial dysfunctions may differ. Continued efforts to
identify and understand clinical mitochondrial toxicities are essential, given the intensification
and diversification of perinatal prophylaxis strategies, and the number of pregnant women
potentially involved.
23
Arch Pediatr. 2007 Mar;14(3):298-302. Epub 2007 Feb 6.
[HIV-1 drug resistance in French infected-children: from newborn to
adolescent]
[Article in French]
Delaugerre C, Chaix ML, Warszawski J, Rouzioux C, Blanche S.
Laboratoire de virologie, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France.
[email protected]
Limit of antiretroviral treatment success is the emergence of drug-resistant virus. As reported
in adult population, prevalence of resistance was high in treated HIV-infected children with
detectable HIV viral load. Resistance increased with number of prior antiretroviral treatments,
particularly with protease inhibitors. Adolescent boys seem at greater risk to harbor multiclasses resistant virus. In HIV-infected newborns, prevalence of resistance was 20%. Most of
resistance mutations detected were in accord to perinatal antiretroviral exposition. Principal
mechanism of resistance acquisition in newborns was transmission of resistant viruses from
mother to child with early archive in cellular reservoir and long term persistence with or
without treatment. Consequences of long term therapeutic strategies in children are major.
24
AIDS Res Hum Retroviruses. 2005 Aug;21(8):719-27.
In HIV type 1-infected children cytotoxic T lymphocyte responses are
associated with greater reduction of viremia under antiretroviral therapy.
Buseyne F, Le Chenadec J, Burgard M, Bellal N, Mayaux MJ, Rouzioux C, Rivière Y,
Blanche S.
Unité Postulante d'Immunopathologie Virale, URA CNRS 1930, Institut Pasteur, Bat. Lwoff, 75015 Paris,
France. [email protected]
The evolution of the HIV-specific CD8+ T cell response in patients receiving potent
combination therapy has been well documented in adult patients. However, no study reported
whether baseline HIV-specific CD8+ T cell response is linked to treatment outcome. The
aims of this study were to investigate both the impact of baseline memory cytotoxic T
lymphocytes (CTL) on treatment outcome and the effect of potent therapy on memory HIVspecific CTL in HIV-1-infected pediatric patients. The study group comprised 30 children
who started a first-line combination treatment including at least three drugs from two different
classes and were longitudinally followed during treatment. Their memory HIV-specific
responses were measured at baseline and during treatment, as well as their plasma viremia and
CD4+ levels. The intensity of memory Gag-specific CTL and the breadth of the CTL
response at the beginning of treatment were significantly correlated with lower plasma viral
load during treatment, independently of baseline plasma viral load, CD4+ counts, and age.
Children with partially controlled viral replication had enhanced Gag-specific CTL compared
to their baseline value. This improvement of antiviral responses during treatment was not
observed when viral replication was either fully suppressed or uncontrolled. In conclusion,
our results show that higher baseline HIV-specific CTL are linked to lower viremia under
combination therapy. This result adds further support to the hypothesis that cooperation
between the antiviral immune response and antiviral drugs could be helpful for therapeutic
management of HIV-infected patients.
25
American Journal of Neuroradiology 26:695-701, April 2005
Cerebral MR Imaging in Uninfected Children Born to HIV-Seropositive
Mothers and Perinatally Exposed to Zidovudine
Marc Tardieua, Francis Brunelleb, Charles Raybaudc, William Ballf, Béatrice Barretd,
Brigitte Pautarde, Eric Lachassinef, Marie-Jeanne Mayauxd and Stéphane Blanchee
a
Department of Pediatric Neurology, Hôpital Bicêtre AP-HP, Le Kremlin Bicêtre
Department of Pediatric Radiology, Hôpital Necker AP-HP, Paris
c
Department of Neuroradiology, Hôpital de la Timone, Marseille
d
Department of Epidemiology, Demographics, and Social Sciences, Amiens
e
Department of Pediatrics, Hôpital Nord, Amiens
f
Hôpital Jean Verdier AP-HP, Bondy
g
Department of Pediatric Immunology and Hematology, France
h
Department of Radiology, Cincinnati Children’s Hospital Medical Center, OH
Address reprint requests to Stéphane Blanche, MD, Unité d’Immunologie et d’Hématologie Pédiatrique, Hôpital NeckerEnfants Malades, 149, rue de Sèvres, 75743 Paris cedex 15
b
BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been reported in HIVnegative children perinatally exposed to zidovudine, a drug often used in HIV-seropositive
mothers during pregnancy. The purpose of this study was to determine the incidence of
cerebral MR imaging findings in HIV-uninfected children exposed to zidovudine who present
with unexplained neurologic symptoms.
METHODS: Two expert groups conducted a systematic, retrospective review of all cerebral
MR images available in a multicentric, nationwide French prospective cohort of children born
to HIV-seropositive mothers to identify imaging abnormalities. Experts were blinded to each
others’ interpretations, to the children’s neurologic symptoms, and to laboratory evidence of
mitochondrial dysfunction. The incidence of abnormalities was determined and compared with
the neurologic presentation and laboratory evidence of mitochondrial dysfunction.
RESULTS: MR images from 49 HIV-uninfected children (mean age, 26 months) were
available for study. All children were perinatally exposed to zidovudine. Twenty-two had
probable or established mitochondrial dysfunction according to their symptoms and laboratory
data. Twenty-seven children without mitochondrial dysfunction presented with unexplained
neurologic symptoms (n = 14) or nonneurologic symptoms (n = 7), and six were
asymptomatic. Sixteen of 22 MR images in children with mitochondriopathy were considered
abnormal in both independent analyses. Diffuse hyperintensity in the supratentorial white
matter (n = 9) and in the tegmentum pons (n = 9) were the most frequent anomalies. Imaging
abnormalities were often multifocal (n = 10) and sometimes associated with necrotic areas (n
= 3) and volume loss (n = 8). Although 19 of 27 MR images of children without
mitochondrial dysfunction were mainly normal, abnormal images were observed in five of 14
children with unexplained neurologic symptoms and in three of six asymptomatic children.
CONCLUSION: Images observed in children with antiretroviral-induced mitochondrial
dysfunction are similar to those observed in congenital mitochondrial diseases. These images
were also observed in symptomatic or asymptomatic children without evidence of systemic
mitochondrial dysfunction.
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