ASSEMBLEE GENERALE 21 JANVIER 2011

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), CESP - INSERM U1018, 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), CESP - INSERM U1018, 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), CESP - INSERM U1018, Hôpital Bicêtre
Pr Stéphane BLANCHE (pédiatre), Hôpital Necker Enfants Malades

ANRS CO 19 – Coverte (Cohorte d’Enfants Infectés par voie verticale et dans l’enfance)
PROMOTEUR : Agence Nationale de Recherches sur le Sida (ANRS)
INVESTIGATEUR PRINCIPAL
Dr Josiane WARSZAWSKI (épidémiologiste), CESP - INSERM U1018, Hôpital Bicêtre
CO-INVESTIGATEUR
Dr Jean-Paul VIARD, Hôpital Hôtel Dieu

ANRS 145 – Primeva
PROMOTEUR : Agence Nationale de Recherches sur le Sida (ANRS)
INVESTIGATEUR PRINCIPAL
Dr Roland TUBIANA (infectiologue), Hôpital Pitié Salpétrière
RESPONSABLE METHODOLOGIQUE
Dr Josiane WARSZAWSKI (épidémiologiste), CESP - INSERM U1018, Hôpital Bicêtre

ANRS EP38 – Immip
PROMOTEUR : Agence Nationale de Recherches sur le Sida (ANRS)
INVESTIGATEUR PRINCIPAL
Pr Stéphane BLANCHE (pédiatre), Hôpital Necker Enfants Malades
RESPONSABLE SCIENTIFIQUE
Florence BUSEYNE (Immunologiste), Institut Pasteur
RESPONSABLE METHODOLOGIQUE
Dr Josiane WARSZAWSKI (épidémiologiste), CESP - INSERM U1018, Hôpital Bicêtre
VIROLOGIE : Pr Christine Rouzioux, Hôpital Necker, Paris
CESP Inserm U 1018
Hôpital de Bicêtre - Secteur "Lasjaunias" - Porte 76
82, rue du Général Leclerc
94276 Le Kremlin-Bicêtre
Tél. 01 49 59 53 10 - Fax 01 49 59 53 00
E-mail epf.u822@inserm.fr
http://u822.kb.inserm.fr/epf
EQUIPE DE COORDINATION
CESP 1018 / Equipe 4
Hôpital Bicêtre
 Coordination
Naïma Bouallag (EPF, Immip), Sandrine Delmas (Primeva), Nelly Briand (Coverte)
 Monitorage, codage
Linda Assoul, Florie Chrétien, Stéphane Couao-Zotti, Parfait Kouadio, Jacques N’Gondi
 Datamanagement et organisation logistique des études
Céline Ferey, Corinne Laurent, Elisa Ramos, Thierry Wack
 Saisie, mise à jour, archivage
Leila Boufassa, Paulette Huyhn
 Epidémiologistes, statisticiens, informaticiens
Nelly Briand, Carine Jasseron, Jérôme Le Chenadec, Jean-Paul Teglas, Josiane Warszawski,
 Secrétariat
Marlène Péres
2
ENQUETE PERINATALE FRANCAISE
ANRS - CO1/CO10/CO11
Sites participants
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., Jeantils V., 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
(Ceccaldi-Carp P., Fantin B., Luton D., Pejoan H.), Clichy (De Curtis A.); Hôpital de Creil (Carpentier B.; DuvalArnould M., Kingue-Ekollo 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., Mandelbrot L., 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 ( Bourdic K., Colmant C., Fourcade C., Fridman S., Peretti D.); Hôpital Jeanne de Flandres, Lille
(D’angelo S.; Hammou Y.,Mazingue F., Yazdanpanah Y.); Hôpital Dupuytren*, Limoges (De lumley L.); Hôpital
de Longjumeau (Bailly-Salin P., Turpault I., Seaume H.); Hôpital de la Croix Rousse, Lyon (Brochier C., Cotte L.,
Labaune J.M., Le Thi T., Roussouly M.J., Tariel O., Thoirain V.); IHOP, Lyon (Bertrand Y., Kebaïli K., Tache N.) ;
Centre Hospitalier Lyon Sud, Lyon (Massardier J.); 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 Intercommunal, Montfermeil (Dehlinger M., Echard M., Mullard C., Talon
P.); Hôpital Arnaud de Villeneuve, Montpellier (Benos, P., Guigue N., Lalande M.); Hôpital Intercommunal,
Montreuil (Heller-Roussin B., Riehl C., Winter C.); Maternité Régionale A. Pinard, Nancy (Hubert C.); Hôpital de
Nanterre* (Karoubi P.); Hôpital de Nantes (Brunet-François C., Mechinaud F., 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
3
Gennes C., Isart V.); Hôpital Bichat, Paris (Bastian H., Batallan A., Bodard M., Elaoun N., Matheron S., Rajguru M.);
Hôpital Boucicaut*, Paris (Lafay Pillet M.C.); Hôpital Cochin-Port Royal, Paris (Boudjoudi N., Firtion G., Fouchet
M., Goupil I., Pannier A., Salmon D.); 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., Cayol V., Frange P., Mourey M.C., Parat S., Rouzioux C.); Hôpital
Pitié Salpêtrière, Paris (Bonmarchand M., Bourse P., Edeb N., Harif M., Marcel S., Naime-Alix A., Quetin F.,
Pauchard M., Tubiana R.,); Hôpital Robert Debré, Paris (De Lauzanne A., Faye A., Garion D., Leveille S., Levine
M., Ottenwalter A., Recoules A.); Hôpital Saint-Antoine, Paris (Bui E., Carbonne B., Meyohas M.C., Rodriguez J.);
Hôpital Notre-Dame du Bon-Secours, Paris (Aufrant C.); Hôpital Tenon, Paris (Duvivier C., Hervé,F., Lebrette
M.G., Maignan A., Viard J.P.); Hôpital Trousseau, Paris (Dollfus C., Tabone M.D., 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.).
(* sites fermés)
4
PUBLICATIONS EPF
2005 - 2010
2010
Burgard M, Jasseron C, Matheron S, Damond F, Hamrene K, Blanche S, Faye A, Rouzioux C,
Warszawski J, Mandelbrot L; ANRS French Perinatal Cohort EPF-CO1. Mother-to-child transmission of
HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1.
Clin Infect Dis. 2010 Oct 1;51(7):833-43.
Dollfus C, Lechenadec J, Faye A, Blanche S, N Briand, Rouzioux C, Warszawski J. Long-term outcomes
of adolescents perinatally infected with HIV-1 and followed since birth in the French Pediatric Cohort
EPF –ANRS C010.
Clin Infect Dis. 2010 Jul 15;51(2):214-24
Tubiana R, Lechenadec J, Rouzioux C, Mandelbrot L, Hamrene K, Dollfus C, Faye A, Delaugerre C,
Blanche S, Warszawski J; for the ANRS French Perinatal Cohort (ANRS CO1/CO11). Factors
associated with HIV-1 mother to child transmission despite a maternal viral Load < 500 copies/ml at
delivery. Case control study nested in the French Perinatal Cohort (EPF- ANRS CO1).
Clin Infect Dis. 2010 ;50(4): 585-96
Frange P, Burgard M, Lachassinne E, le Chenadec J, Chaix ML, Chaplain C, Warszawski J, Dollfus C,
Faye A, Rouzioux C, Blanche S; ANRS French Perinatal Cohort Study Group. Late postnatal HIV
infection in children born to HIV-1-infected mothers in a high-income country.
AIDS. 2010 Jul 17;24(11):1771-6
The PLATO II Project Team for the Collaboration of Observational HIV Epidemiological Research
Europe (COHERE) Group. Triple class virologic failure in HIV-infected patients on antiretroviral
therapy for up to 10 years.
Arch Intern Med. 2010 Mar 8;170(5):410-9.
2009
Delaugerre C, Chaix ML, Blanche S, Warszawski J, Cornet D, Dollfus C, Schneider V, Burgard M, Faye
A, Mandelbrot L, Tubiana R, Rouzioux C; ANRS French Perinatal Cohort. Perinatal acquisition of drugresistant HIV-1 infection: mechanisms and long-term outcome.
Retrovirology. 2009 Sep 19;6:85.
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. 2009 Jun 19;23(10):1235-43.
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 23(5):597-604
5
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-tochild 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
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.
6
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-1infected 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, CiraruVigneron 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
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.
7
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.
8
Abstracts
9
10
Clin Infect Dis. 2010 Oct 1;51(7):833-43.
Mother-to-Child Transmission of HIV-2 Infection from 1986 to 2007 in the
ANRS French Perinatal Cohort EPF-CO1
M. Burgard, C. Jasseron, S. Matheron, F. Damond, K. Hamrene, S. Blanche, A. Faye, C.
Rouzioux, J. Warszawski, L. Mandelbrot, and the ANRS French Perinatal Cohort EPF-CO1
Background
Management of pregnant women with human immunodeficiency virus (HIV) type 2 infection
remains unclear because of its low prevalence and important differences from HIV-1.
Methods
Pregnant women monoinfected with HIV-2 or HIV-1 and their infants enrolled in the prospective,
national, multicenter French Perinatal Cohort between 1986 and 2007.
Results
Overall, 2.6% (223/8660) of mothers were infected with HIV-2, and they accounted for 3.1%
(367/11841) of the total births. Most were born in sub-Saharan Africa. A higher proportion of
HIV-2-infected mothers than HIV-1-infected mothers had no symptoms, had received no
antiretroviral threrapy at conception (85.9% vs 66.7%), and had received no antiretroviral
therapy during pregnancy (42.8% vs 19.9%), particularly highly active antiretroviral therapy
(HAART) (79.7% vs 46.1%), and they had higher CD4 cell counts near delivery (median, 574 vs
452 cells/mm3; P < .01). If antiretroviral therapy was used, it was started at a later gestational
age for HIV-2-infected mothers (median, 28 vs 25 weeks; P < .01). HIV-2-infected mothers were
more likely to deliver vaginally (67.9% vs 49.3%) and to breastfeed (3.6% vs 0.6%; P < .01),
and their infants less frequently received postexposure prophylaxis. In the period 2000–2007,
the proportion with viral load <100 copies/mL at delivery was 90.5% of HIV-2-infected mothers,
compared with 76.2% of HIV-1-infected mothers (P = .1). There were 2 cases of transmission: 1
case in 1993 occurred following maternal primary infection, and the other case occurred
postnatally in 2002 and involved a mother with severe immune deficiency. The mother-to-child
transmission rate for HIV-2 was 0.6% (95% confidence interval, 0.07%–2.2%).
Conclusions
Care for HIV-2-infected pregnant women rests on expert opinion. The mother-to-child
transmission residual rate (0.07%–2.2%) argues for systematic treatment: protease inhibitorbased HAART for women requiring antiretroviral therapy or for primary infection and simplified
prevention of mother-to-child transmission in other instances.
11
Clin Infect Dis. 2010 Jul 15;51(2):214-24
Long-Term Outcomes in Adolescents Perinatally Infected with HIV-1 and
Followed Up since Birth in the French Perinatal Cohort (EPF/ANRS CO10)
C. Dollfus, J. Le Chenadec, A. Faye, S. Blanche, N. Briand, C. Rouzioux, and J.
Warszawski
Background
Increasing numbers of children perinatally infected with human immunodeficiency virus (HIV)
are reaching adolescence, largely because of advances in treatment over the past 10 years, but
little is known about their current health status. We describe here the living conditions and
clinical and immunovirologic outcomes at last evaluation among this pioneering generation of
adolescents who were born before the introduction of prophylaxis for vertical transmission and
whose infections were diagnosed at a time when treatment options were limited.
Methods
The eligible population consisted of HIV-1—infected children who were born before December
1993 and who were included at birth in the prospective national French Perinatal Cohort
(EPF/ANRS CO10).
Results
Of the 348 eligible children, 210 (60%; median age, 15 years) were still alive and regularly
followed up. Current treatment was highly active antiretroviral therapy (HAART) in 77% and 2
nucleoside analogues in 5.0%; 16% had stopped treatment, and 2% had never been treated.
The median CD4 cell count was 557 cells/µL, and 200 cells/µL was exceeded in 94% of
patients. The median viral load was 200 copies/mL. Viral load was undetectable in 43% of the
adolescents and in 54.5% of those receiving HAART. Median height, weight, and body mass
index were similar to French reference values for age, and school achievement was similar to
nationwide statistics. Better immunologic status was associated with being younger and with
having begun HAART earlier. Undetectable viral load was associated with maternal geographic
origin and current HAART.
Conclusions
Given the limited therapeutic options available during the early years of these patients' lives and
the challenge presented by treatment adherence during adolescence, the long-termoutcomes
among this population are encouraging.
12
Clin Infect Dis. 2010 ;50(4): 585-96
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)
Roland Tubiana, Jerome Le Chenadec, Christine Rouzioux, Laurent Mandelbrot, Karima
Hamrene, Catherine Dollfus, Albert Faye, Constance Delaugerre, Stephane Blanche,
Josiane Warszawski, and ANRS French Perinatal Cohort (ANRS CO1/CO11)
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.
13
AIDS. 2010 Jul 17;24(11):1771-6
Late postnatal HIV infection in children born to HIV-1-infected mothers in a
high-income country.
Frange, Pierre; Burgard, Marianne; Lachassinne, Eric; le Chenadec, Jerome; Chaix,
Marie-Laure; Chaplain, Chantal; Warszawski, Josiane; Dollfus, Catherine; Faye, Albert;
Rouzioux, Christine; Blanche, Stephane; for the ANRS French Perinatal Cohort Study
Group
Objective
To evaluate the risk of late postnatal HIV-1 infection in nonbreastfed children enrolled in the French
ANRS Cohort CO01 (EPF).
Methods
The EPF cohort has prospectively enrolled HIV-infected mother/child pairs with a low proportion of
known breastfeeding (<0.2%). Children were followed until they were 24 months old, with HIV-1
DNA/RNA PCR tests performed at birth, M1, M3 and M6 and a late serology at 18-24 months. This
substudy included 4539 children who were uninfected at the age of 6 months in 1984-2005.
Results
Five children were late diagnosed with HIV-1 infection despite negative PCR tests until 6 months. In
three cases, the infection was diagnosed between 14 and 18 months. The other infections were
diagnosed at 10 and 12 years of age because of AIDS-defining symptoms; their last (negative)
serologies were performed at 19 and 9 months, respectively. A phylogenetic study performed in the
latest case revealed a strong homology between the mother and child strains. No known mode of viral
transmission (including breastfeeding or use of premasticated food) could be found. However, we
observed previously reported risk factors for intrafamilial HIV-1 transmission: poor socioeconomic
backgrounds and sustained HIV-1 viremia in the mothers during the follow-up of their children.
Conclusion
Late postnatal HIV-1 infection can rarely be diagnosed in the absence of known breastfeeding in highincome countries. Our results highlight the need for a maintained close follow-up of the noninfected
children even after 6 months, especially when there are risk factors for intrafamilial viral transmission.
14
Arch Intern Med. 2010 Mar 8;170(5):410-9
Triple-Class Virologic Failure in HIV-Infected Patients Undergoing
Antiretroviral Therapy for Up to 10 Years.
The PLATO II Project Team for the Collaboration of Observational HIV Epidemiological
Research Europe (COHERE) Group
Background
Life expectancy of people with human immunodeficiency virus (HIV) is now estimated to
approach that of the general population in some successfully treated subgroups. However, to
attain these life expectancies, viral suppression must be maintained for decades.
Methods
We studied the rate of triple-class virologic failure (TCVF) in patients within the Collaboration of
Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral
therapy (ART) that included a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a
ritonavir-boosted protease inhibitor (PI/r) from 1998 onwards. We also focused on TCVF in
patients who started a PI/r-containing regimen after a first-line NNRTI-containing regimen failed.
Results
Of 45 937 patients followed up for a median (interquartile range) of 3.0 (1.5-5.0) years, 980
developed TCVF (2.1%). By 5 and 9 years after starting ART, an estimated 3.4% (95%
confidence interval [CI], 3.1%-3.6%) and 8.6% (95% CI, 7.5%-9.8%) of patients, respectively,
had developed TCVF. The incidence of TCVF rose during the first 3 to 4 years on ART but
plateaued thereafter. There was no significant difference in the risk of TCVF according to
whether the initial regimen was NNRTI or PI/r based (P = .11). By 5 years after starting a PI/r
regimen as second-line therapy, 46% of patients had developed TCVF.
Conclusions
The rate of virologic failure of the 3 original drug classes is low, but not negligible, and does not
appear to diminish over time from starting ART. If this trend continues, many patients are likely
to need newer drugs to maintain viral suppression. The rate of TCVF from the start of a PI/r
regimen after NNRTI failure provides a comparator for studies of response to second-line
regimens in resource-limited settings.
15
Retrovirology. 2009 Sep 19;6:85
Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and
long-term outcome.
Constance Delaugerre, Marie-Laure Chaix, Stephane Blanche, Josiane Warszawski,
Dorine Cornet, Catherine Dollfus, Veronique Schneider, Marianne Burgard, Albert Faye,
Laurent Mandelbrot, Roland Tubiana, Christine Rouzioux, and the ANRS French Perinatal
Cohort
Background
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.
Patients and Methods
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.
Results
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-tochild 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 longterm persistence of resistance when suboptimal prophylaxis was stopped.
Conclusion
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.
16
CID. 2009 Jun 1;48(11):1516-25.
Decreased risk of congenital cytomegalovirus (CMV) infection in children
born to HIVinfected mothers in the era of highly active antiretroviral therapy
(HAART).
Guibert G, Warszawski J, Le Chenadec J, Blanche S, Benmebarek Y, Mandelbrot L,
Tubiana R, Rouzioux C, Leruez-Ville M; on behalf of the French Perinatal Cohort (EPF).
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.
17
AIDS. 2009 Jun 19;23(10):1235-43.
No relation between in utero exposure to highly active antiretroviral therapy
and intrauterine growth retardation.
N Briand, L. Mandelbrot, J. Le Chenadec, R. Tubiana, J.P. Teglas, A. Faye, C. Dollfus, C.
Rouzioux, S. Blanche, J. Warszawski; for the ANRS French Perinatal Cohort.
Background
The use of highly active antiretroviral therapies (HAART) during pregnancy is now standard
care to prevent mother-to-child HIV transmission in developed countries. There is controversy
about its impact on low birthweight.
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.
18
AIDS. 2009 23(5):597-604
Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected
infants.
Goetghebuer T, Haelterman E, Le Chenadec J, Dollfus C, Gibb D, Judd A, Green H, Galli
L, Ramos JT, Giaquinto C, Warszawski J, Levy J; for the European Infant Collaboration
group.
Objective
In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1infected 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.
19
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.
HIV-1 diagnosis in babies born to seropositive mothers is one of the challenges of HIV
epidemics in children. A simple, rapid protocol was developed for quantifying HIV-1 DNA in
whole blood samples and was used in the ANRS French pediatric cohort in conditions of
prevention of mother-to-child transmission. A quantitative HIV-1 DNA protocol (LTR real-time
PCR) requiring small blood volumes was developed. First, analytical reproducibility was
evaluated on 172 samples. Results obtained on blood cell pellets and Ficoll-Hypaque separated
mononuclear cells were compared in 48 adult HIV-1 samples. Second, the protocol was applied
to HIV-1 diagnosis in infants in parallel with plasma HIV-RNA quantitation. This prospective
study was performed in children born between May 2005 and April 2007 included in the ANRS
cohort. The assay showed good reproducibility. The 95% detection cut-off value was 6
copies/PCR, that is, 40 copies/10(6) leukocytes. HIV-DNA levels in whole blood were highly
correlated with those obtained after Ficoll-Hypaque separation (r = 0.900, P < 0.0001). A total of
3,002 specimens from 1,135 infants were tested. The specificity of HIV-DNA and HIV-RNA
assays was 100%. HIV-1 infection was diagnosed in nine infants before age 60 days. HIV-DNA
levels were low, underlining the need for sensitive assays when highly active antiretroviral
therapy (HAART) has been given. The performances of this HIV-DNA assay showed that it is
adapted to early diagnosis in children. The results were equivalent to those of HIV-RNA assay.
HIV-DNA may be used even in masked primary infection in newborns whose mothers have
received HAART.
20
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)
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 double-nucleoside reverse transcriptase inhibitor
combination (6.1%; 3/49 vs 3.3%; 117/3556; P = .22), but the difference was not significant.
Among 81 mothers receiving HAART, there was no case of MTCT.
Conclusion
Our results suggest that amniocentesis is not a major risk factor for mother-to-child transmission
in mothers treated with effective antiretroviral therapy.
21
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.
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 HIV-infected 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 didanosinelamivudine 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.
22
AIDS. 2008 Jul 31;22(12):1503-11.
Prevention of mother-to-child HIV transmission: similar access for subSahara 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.
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.
23
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.
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/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, 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.
24
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.
25
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.
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.
26
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.
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.
27
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.
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 long-term nonprogression of infection (LTNPs) were defined as HIV-1infected 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.
28
J Med Virol. 2007 Sep;79(9):1261-9.
Prevalence and risk factors associated with antiretroviral resistance in HIV1-infected children.
Delaugerre C, Warszawski J, Chaix ML, Veber F, Macassa E, Buseyne F, Rouzioux C,
Blanche S.
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-1-infected 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.
29
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.
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.
30
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.
Objective
We investigated whether twin pregnancies were at increased risk of mother-to-child HIV-1
transmission (MTCT), in comparison with singletons.
Methods
Among HIV-1 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.
31
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.
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.
32
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.
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.
33
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.
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 HIV-specific CTL in HIV-1infected 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.
34
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 Tardieu, Francis Brunelle, Charles Raybaud, William Ball, Béatrice Barret, Brigitte
Pautard, Eric Lachassine, Marie-Jeanne Mayaux and Stéphane Blanche
Background and Purpose
Mitochondrial dysfunction has been reported in HIV-negative 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 HIVseropositive 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.
35