The women previously exposed to ART for PMTCT had received HAART in 52.1% of cases, mostly PI based (93.0%), NRTI bitherapy in 19.2% and NRTI (zidovudine) monotherapy in 28.8% (Table 1).
The women of group 1B (ART naive diagnosed before the pregnancy) had CD4 cell counts at delivery higher than those of the women of group 1A (diagnosed during the pregnancy), but similar to those of the women of group 2 (previously exposed to ART) (Table 2). The women of group 2 and the total ART-naive group (group 1) had similar categorical and median CD4 cell counts and percentages at delivery, with similar trends during pregnancy (Fig. 1A), whenever HIV was diagnosed and whatever the type of previous ART (Fig. 1B).
The proportion of women with an undetectable viral load (below 50 copies/mL) close to delivery was similar for ART-naive women and women previously exposed to PMTCT as follows: 68.7% in group 2 versus 64.6% in group 1, P = 0.26. No differences were observed either for the proportions of women with viral loads below 200 copies per milliliter (85.3% vs. 86.3%, respectively; P = 0.70). The proportion of women with viral loads above 10,000 copies per milliliter was 2.3% for group 2 and 1.0% for group 1. The maternal viral load curves during pregnancy were similar for ART-naive and ART-exposed women (Fig. 2A), whenever HIV was diagnosed and whatever the type of previous ART (Fig. 2B).
The proportion of women with detectable VL (≥50 copies/mL) was similar for women who were ART naive at the time of conception (35.4%; 279 of 788) and those previously exposed to PI-based HAART (27.9%; 29 of 104), previously exposed to non-PI-based HAART (25.0%; 2 of 8) or previously exposed to NRTI monotherapy (33.3%; 21 of 63). This proportion tended to be higher in women previously exposed to NRTI bitherapy (38.1%; 16 of 42), but not significantly so (Table 3). The median time interval between treatment initiation during pregnancy and time of viral load measurement was 12.6 weeks (interquartile range: 8.9-17.1).
Detectable viral load was associated with unknowledge of HIV seropositivity before pregnancy, late gestational age at booking, late time at initiation of the first line of treatment, higher level of viral load before ART initiation, and severe prematurity (gestational age < 33 weeks). After adjustment for these factors and for maternal age and CD4 cell count before ART, previous exposures to ART for PMTCT remained not related to a detectable viral load at delivery (Table 3). Overall adjusted odds ratio for women previously exposed to PMTCT versus ART-naive women was 0.92 (95% confidence interval: 0.59 to 1.44, P = 0.72).
In women previously exposed to PMTCT, viral load at delivery was lower in the current pregnancy than in the previous pregnancy (89.9% vs. 74.8% < 400 copies/mL). However, it was similar in the 2 pregnancies for women who received PI-based HAART in both pregnancies. The median time between the last pregnancy and the current pregnancy was 28.1 months (interquartile range: 16.9-47.3). The time between pregnancies was not associated with the risk of obtaining a detectable viral load in the current pregnancy (Table 3).
The French Perinatal Cohort study (ANRS EPF-CO-01) did not record follow-up after delivery, except during the subsequent pregnancy for women re-enrolled at this occasion. This situation, which concerned one-third of women, provided us with a unique opportunity to investigate, in a large sample, the effects of prior exposure to PMTCT on the immunological and viral response to subsequent PI-based HAART. Increasing numbers of HIV-infected women are having several children, as a consequence of improvements in the prognosis of HIV infection and the reduction of mother-to-child transmission.19-21 Repeat pregnancies now account for one-third of the mother-child pairs enrolled in the EPF, which covers an estimated 70% of HIV-infected mothers giving birth each year in France.
Our findings show that the virological response to PI-based HAART in pregnancy did not differ between women who were ART naive and women previously exposed to ART for PMTCT. Plasma viral load at delivery was below 200 copies per milliliter in almost 86% of women in both groups and was undetectable (<50 copies/mL) in 64.6% of ART-naive women and 68.7% of those previously exposed to ART. Our study had a 80% power with a 2-tailed significance level of 5% to show an odds ratio associated with increasing risk of detectable viral load in women previously treated for PMTCT of 1.6 and 99% power to show an odds ratio of 2.0.
The lack of difference in viral load response between women with and without prior exposure to PMTCT could not be accounted for by any difference in gestational age at ART initiation or duration of ART during pregnancy, type of PI used or proportion of changes in ART during pregnancy. The proportion of women with low viral loads by the time of delivery was similar to those reported in various European studies of women receiving HAART who were ART naive before the pregnancy. In the Swiss HIV Cohort Study, 93% of women had a viral load below 400 copies per milliliter at delivery22; in the European Collaborative Study, 73% reached an undetectable viral load23 and, in an Italian study, 66% of women enrolled between 2005 and 2008 had viral load below 50 copies per milliliter during the third trimester.24
The initial characteristics of the women who were ART naive at the onset of pregnancy differed between those who discovered their HIV-positive status during the pregnancy and those who already knew their HIV status. As expected, women aware of their HIV status but not yet receiving ART had better initial immunovirological markers, as most did not require ART for their own health. This subgroup of women did not differ from women who received ART for PMTCT in a previous pregnancy, with this treatment stopped after delivery. The 3 groups were similar in terms of the gestational age at which ART was started and the type of PI used. Similar proportions of women in each group had undetectable viral loads at delivery. Taking the time at diagnosis into account for these women did not affect our findings for virological response after the initiation of PI-based HAART. Immunological reconstitution was also similar in ART-naive women and women previously exposed to ART.
HAART has been recommended for almost all HIV-1-infected pregnant women since 2005.8 Most previous studies on the impact of PMTCT on subsequent response to ART concerned the response to nevirapine-based regimens after prior exposure to single-dose nevirapine for PMTCT, which is associated with the development of resistance.12,13,16 In France, as in other industrialized countries, single-dose nevirapine at delivery is not recommended, and the standard treatment is PI-based HAART.8 To our knowledge, this is the first study to focus on the response to PI-based HAART after previous exposure to ART exclusively for PMTCT. The PI used was ritonavir-boosted lopinavir in two-thirds of cases. Katz et al25 reported a relationship between virological failure in pregnant women receiving mostly PI-based HAART and a self-reported history of HAART before pregnancy, but the type and duration of previous exposure to HAART was not detailed.
Different types of ART were administered during the previous pregnancy as follows: NRTI monotherapy, NRTI bitherapy, non-PI-based HAART, and PI-based HAART. The proportion of women treated with PI-based HAART during the current pregnancy for whom VL was undetectable did not depend on the previous type of exposure. However, it tended to be lower in mothers exposed to NRTI bitherapy, consisting of zidovudine-lamivudine in all cases (except 1 woman previously treated with zidovudine plus didanosine). Nevertheless, the number of mothers in this subgroup (n = 42) was small and consequently the statistical power to show an odds ratio of 1.6 associated with this subgroup compared with naive women was only 54%. Coffie et al15 reported resistance mutations in 15% of women exposed to lamivudine for PMTCT, tested 4 weeks after delivery, in Abidjan, Ivory Coast. In 50% of these women, viral load was not held below 500 copies per milliliter 12 months after the initiation of lamivudine-containing HAART with nevirapine or efavirenz. Data on resistance mutations were not routinely collected in the EPF cohort. The proportion of patients previously exposed to NRTI bitherapy and treated with PI-based HAART during the current pregnancy for whom virological success was recorded was much higher than in the African study as follows: 87% had a viral load below 500 copies per milliliter after a median of 3 months of treatment. This proportion remained high in women who received PI-based HAART containing lamivudine: 90%.
For patients exposed to PI-based HAART in the last pregnancy, the proportion of viral suppression at delivery under PI-based HAART for the current pregnancy (72% < 50 copies/mL) was as high as that for the ART-naive group. This is consistent with the higher genetic barrier for the development of resistance to PI26-33 than for the development of resistance to nevirapine and lamivudine. In previous reports, the prevalence of nevirapine mutations decreased over time and the proportion of women presenting virological failure decreased with increasing time between PMTCT exposure and HAART initiation.12,13 We found no relationship between the timing of treatment with respect to previous ART exposure and viral load response in women treated with PI-based HAART in the current pregnancy.
One limitation of this study is that it concerned only the short-term response to PI-based HAART, until delivery, a median of 3 months after treatment initiation. In women who start treatment for low CD4 counts, a weaker response to HAART after 3 months than observed here would be expected, even if the response did not differ between women with and without prior exposure. We did not routinely collect resistance data in the EPF cohort, but this seems to be only a minor limitation of this study because the viral response did not differ between the groups compared.
The main strength of our study is that it is the first, as far as we are aware, to evaluate responses to PI-based HAART in women previously exposed to ART exclusively for PMTCT. The sizes of the samples of ART-naive women and women previously exposed for PMTCT in this cohort were large enough to obtain a sufficient statistical power.
In conclusion, our findings strongly suggest that exposure to HAART for PMTCT stopped after delivery has no negative impact on the response to PI-based HAART during subsequent pregnancy. We can infer that such exposure should not reduce the response to PI-based HAART subsequently initiated for maternal health indications.
We thank all mothers who agreed to participate in this study. We thank Linda Assoul, Naïma Bouallag, Leila Boufassa, Nacima Chernai, Sandrine Delmas, Karima Hamrène, Paulette Huynh, Carine Jasseron, Nadia Kessaci, Corinne Laurent, Jacques Ngondi Ekome, Marlène Péres, Elisa Ramos, Jean-Paul Teglas, and Thierry Wack.
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APPENDIX I: PEOPLE AND INSTITUTIONS PARTICIPATED IN ANRS FRENCH PERINATAL COHORT
The following people and institutions participated in the ANRS French Perinatal Cohort:
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 Robert Ballanger, Aulnay (Questiaux E, Zakaria A, Goldenstein C); Hôpital de Bastia (Pincemaille O); Hôpital de la Côte Basque, Bayonne (Bonnal F, Cayla C, Hernandorena X); 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 Clémenceau, Caen (Beucher G, Brouard J, Goubin P); Hôpital André Rosemon, Cayenne (Elenga N); Hôpital de Creil (Carpentier B, Duval-Arnould 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, Meier C); Hôpital d'enfants, Dijon (Martha S, Reynaud I); Hôpital Intercommunal, Evreux (Allouche C, Touré K); Hôpital Francilien Sud, Evry-Corbeil (Chevojon P, Devidas A, Granier M, Marchand C, May A, Nguyen R, Turpault I); Hôpital de Fontainebleau (Alissa K, Routier C); Hôpital Victor Fouche, Fort de France (Hatchuel Y, William C); Hôpital de Lagny (Chalvon Demersay A, Froguel E, Gourdel B, Lanty C); Hôpital Les Oudairies, La Roche sur Yon (Aubry O, Brossier J. P, Esnault J. L, Leautez S, Perré P, Suaud I); Hôpital de La Seyne sur Mer (Chamouilli J. M); 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 de Longjumeau (Bailly-Salin P, Turpault I, Seaume H); Hôpital Hôtel Dieu-Institut d'hématologie-oncologie pédiatrique, Lyon (Bertrand Y, Brochier C; Cotte L, Kebaïli K, Tache N, Roussouly M. J, Thoirain V); Hôpital François Quesnay, Mantes La Jolie (Delanete A, Doumet A, Granier F, Salomon J. L); Hôpital la Conception, Marseille (Cravello L); Hôpital La Timone Marseille (Thuret I); Hôpital de Meaux (Karaoui L, Lefèvre V); 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 Nantes (Brunet-François C, Mechinaud, Reliquet, V), Hôpital l'Archet-Fondation Lenval, Nice (Bongain A, Deville A, Galiba E, Monpoux F); Hôpital Caremeau, Nîmes (Dendale-Nguyen J); Hôpital Orléans (Arsac P, Werner E); Hôpital d'Orsay (Chanzy S, De Gennes C, Isart V); Hôpital Bichat, Paris (Bastian H. Bourgeois-Moine A, Matheron S, Rajguru R); 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 Necker, Paris (Boucly S, Blanche S, Maignan A, Parat S, Rouzioux C, Viard J., Yamgnane A, Cayol V); Hôpital Pitié Salpêtrière, Paris (Bonmarchand M, De Montgolfier I, Quetin F, Edeb N, Lemercier D, Harif M, 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 M. C, Rodriguez J); Hôpital Hôpital Saint Michel, Paris (Aufrant C); Hôpital Tenon, Paris (Hervé F, Lebrette M. G); 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 René Dubos, Pontoise (Coursol A); Hôpital Américain, Reims (Munzer M); Hôpital Charles Nicolle, Rouen (Brossard V); Hôpital de Saint-Denis (Allemon M. C, Bolot P, Ekoukou D, Ghibaudo N, Gyardeau S, Khuong M. A); Hôpital Nord, Saint Etienne (Billiemaz K); Hôpital de Saint Martin (Bissuel F, Walter V); Hôpital de Haute Pierre-Hôpital Civil, Strasbourg (Cheneau M, Entz-Werle N, Favreau J, Partisani M); 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 de Villeneuve Saint Georges (Chacé A, Guillot F, Matheron I).