Is Intrapartum Intravenous Zidovudine for Prevention of

MAJOR ARTICLE
HIV/AIDS
Is Intrapartum Intravenous Zidovudine for
Prevention of Mother-to-Child HIV-1
Transmission Still Useful in the Combination
Antiretroviral Therapy Era?
Nelly Briand,1,2 Josiane Warszawski,1,2,3 Laurent Mandelbrot,1,4,5 Catherine Dollfus,6 Emmanuelle Pannier,7
Ludovic Cravello,8 Rose Nguyen,9 Isabelle Matheron,10 Norbert Winer,11 Roland Tubiana,12,13 Christine Rouzioux,14,15
Albert Faye,4,16 and Stéphane Blanche;14,17 for the ANRS-EPF CO1-CO11 Study Groupa
1
Downloaded from http://cid.oxfordjournals.org/ by Jules Levin on September 24, 2013
INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, 2Université Paris-Sud, UMRS 1018, and 3AP-HP, Hôpital
Bicêtre, Service d’Epidemiologie et Santé Publique, Le Kremlin-Bicêtre; 4Université Paris Diderot, Paris; 5AP-HP, Hôpital Louis Mourier, HUPNVS, Service
de Gynécologie et d’obstétrique, Colombes; 6AP-HP, Hôpital Trousseau, Service d’Hématologie et d’oncologie pédiatrique, and 7AP-HP, Hôpital CochinPort Royal, Paris; 8Hôpital de la Conception, Service de Gynécologie et d’obstétrique, Marseille; 9Centre Hospitalier Sud Francilien, Service de
Gynécologie et d’obstétrique, Evry Corbeil; 10Centre Hospitalier Intercommunal, Service de Gynécologie et d’obstétrique, Villeneuve Saint Georges;
11
CHU Nantes, Service de Gynécologie et d’obstétrique, Nantes; 12AP-HP, Hôpital Pitié Salpêtrière, Service de maladies infectieuses, 13INSERM, U943,
14
EA 3620, Université Paris Descartes 5, 15AP-HP, Hôpital Necker, Service de Virologie, 16AP-HP, Hôpital Robert Debré, Service de Pédiatrie Générale,
and 17AP-HP, Hôpital Necker, Unité d’Immunologie Hématologie Pédiatrique, Paris, France
Background. Intrapartum intravenous zidovudine (ZDV) prophylaxis is a long-standing component of prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) in high-resource countries.
In some recent guidelines, intravenous ZDV is no longer systematically recommended for mothers receiving combination antiretroviral therapy (cART) with low viral load. We evaluated the impact of intravenous ZDV according to
viral load and obstetrical conditions.
Methods. All HIV-1–infected women delivering between 1 January 1997 and 31 December 2010 in the French
Perinatal Cohort (ANRS-EPF) were analyzed if they received ART during pregnancy and did not breastfeed. We
identified maternal and obstetrical characteristics related to lack of intravenous ZDV and compared its association
with MTCT rate and other infant parameters, according to various risk factors.
Results. Intravenous ZDV was used in 95.2% of the 11 538 deliveries. Older age, multiparity, and preterm and
vaginal delivery were associated with lack of intravenous ZDV (n = 554). In women who delivered with viral load
≥1000 copies/mL, the overall MTCT rate was higher without than with intravenous ZDV (7.5% vs 2.9%; P = .01);
however, there was no such difference when the neonate received postnatal intensification therapy. Among them,
77% of women who had viral load <400 copies/mL, there was no difference in MTCT rate (0% without intravenous
ZDV vs 0.6% with intravenous ZDV; P = .17). Intravenous ZDV was not associated with increased short-term
hematological toxicity or lactate level.
Conclusions. Intravenous ZDV remains an effective tool to reduce transmission in cases of virological failure,
even in cART-treated women. However, for the vast majority of women with low viral loads at delivery, in the
absence of obstetrical risk factors, systematic intravenous ZDV appears to be unnecessary.
Keywords.
mother-to-child HIV transmission; pregnancy; zidovudine; intrapartum prophylaxis; toxicity.
Received 5 February 2013; accepted 22 May 2013; electronically published 31
May 2013.
a
Members of the study group are listed in the Appendix at the end of the text.
Correspondence: Nelly Briand, PhD, Equipe VIH et IST, CESP, INSERM U1018, 82
rue du Général Leclerc, 94276 Le Kremlin Bicêtre cedex, France (nelly.briand@
inserm.fr).
Clinical Infectious Diseases 2013;57(6):903–14
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cit374
A remarkable decrease in mother-to-child transmission
(MTCT) of human immunodeficiency virus type 1
(HIV-1) has been obtained in industrialized countries,
with the widespread use of antiretroviral therapy (ART)
reducing transmission rates to about 1% [1–6]. The
relative contributions of ART during the pregnancy,
HIV/AIDS
•
CID 2013:57 (15 September)
•
903
intrapartum prophylaxis, and postexposure prophylaxis are
somewhat difficult to determine, as all 3 components are
usually implemented. The timing of MTCT, in studies of performed before ART was available, was in the majority of cases
during labor and delivery [7]. Investigators designing the USFrench pivotal trial ACTG076-ANRS024 [8] thus proposed administering intrapartum intravenous zidovudine (ZDV) during
labor or cesarean delivery, as a continuity between the pre- and
postnatal prophylaxis, as well as an “intensification” of the
ZDV monotherapy during this crucial phase [9]. Intravenous
ZDV was then adopted by all guidelines in high-resource countries. With the advent of combination antiretroviral therapy
(cART), the benefit of intravenous ZDV has been questioned.
In a previous report from the French Perinatal Cohort (ANRSEPF CO1-CO11) [5], performed on data collected between
1997 and 2004, we observed that intravenous ZDV was not associated with transmission rate in women who received any
ART during pregnancy and had an HIV RNA <400 copies/mL
near delivery. In contrast, it was strongly associated with a
lower risk of transmission in women whose delivery HIV RNA
was >10 000 copies/mL. Following this report, recent guidelines
suggested that intravenous ZDV could be avoided for HIV-infected women receiving cART with optimal control of HIV-1
RNA near delivery, not defined in the French guidelines in
2010 [10] and defined as <400 copies/mL in the US guidelines
updated in July 2012 [11]. We aim here to evaluate the contribution of intravenous ZDV in the cART era.
METHODS
The ANRS French Perinatal Cohort
Since 1985, the ANRS French Perinatal Cohort (ANRS CO1
and CO11 EPF) has prospectively enrolled HIV-infected
women giving birth at 90 centers throughout France. The
methodology has been described elsewhere [5]. Informed
consent was obtained from all mothers. The EPF study was approved by the institutional review board of Cochin Hospital
and the French computer database watchdog (Commission Nationale de l’Informatique et des Libertés).
No specific recommendation for HIV treatment and obstetric care was made for women included in the cohort. French
national guidelines for prevention of MTCT (PMTCT) are published and updated regularly [10]. Antenatal prophylaxis was
based on ZDV monotherapy since 1994 and on dual nucleoside
analog therapy since 1997, with elective cesarean delivery according to risk/benefit evaluation. Combination of antiretroviral therapies, initially recommended to pregnant women who
had indications for themselves, was extended to all women
during pregnancy in 2004. Elective cesarean delivery for the
purpose of PMTCT was restricted since 2002 to women not
treated by cART whose viral load was >400 copies/mL near
904
•
CID 2013:57 (15 September)
•
HIV/AIDS
Figure 1. Flow chart—ANRS French Perinatal Cohort CO1-CO11, 1997–
2010. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IV, intravenous; NVP, Nevirapine.
delivery. Up to July 2010, intrapartum intravenous ZDV and
neonatal prophylaxis were systematically recommended.
Study Population
HIV-1–infected women delivering between 1 January 1997 and
31 December 2010 in the French national ANRS Perinatal
Cohort were included in this analysis if they received ART
during pregnancy and did not breastfeed; women with multiple
pregnancies were excluded (n = 11 538) (Figure 1).
Analyses of intravenous ZDV tolerance for infants were restricted to HIV-uninfected newborns, that is, after exclusion of
infected children diagnosed either by HIV-1 polymerase chain
reaction done on sites on 2 separate samples or with anti–HIV1 antibodies detected by enzyme-linked immunosorbent assay
and Western blot at 18 months of age.
Variables
Sociodemographic, obstetric, and HIV treatment data recorded
included age, geographic origin (categorized as sub-Saharan
African countries, metropolitan France, or other origins), gestational age at booking in the maternity ward, type of ART and
time of treatment initiation and cessation, gestational age, and
mode of delivery (vaginal, emergency cesarean delivery or elective cesarean delivery) . For this analysis, we used the CD4 cell
counts and percentages and plasma HIV-1 RNA obtained
closest to the time of delivery, not more than 7 days after delivery. Gestational age was determined from the date of the last
menstrual period, corrected when appropriate by the date of
conception as evaluated from the early ultrasound. Baseline
characteristics (including pretherapeutic immunovirological
status) were the first data collected during pregnancy, even if
they were available prior to the booking visit in the maternity.
Maternal ART was categorized into 7 groups according to
the last treatment used during the pregnancy, as follows: nucleoside reverse transcriptase inhibitor (NRTI) monotherapy;
double NRTI therapy; 3 or more NRTIs; protease inhibitor
(PI)–based cART (PI with or without NRTI , or PI plus nonnucleoside reverse transcriptase inhibitor [NNRTI] with or
without NRTI); non-PI-based cART (NNRTI with or without
NRTI); and other cART. Neonatal prophylaxis was categorized
as NRTI monotherapy, or intensification with double NRTI
therapy (usually ZDV plus lamivudine) or triple therapy.
In HIV-uninfected infants, hemoglobin (g/dL), percentage
of neutrophil, and lactate concentrations (mmol/L) were measured at 1, 3, and 6 months, and then every 6 months until 24
months of age. Grades of severity were defined using established grades and thresholds [12].
Statistical Methods
Associations between maternal, obstetrical, and immunovirological characteristics and no intravenous ZDV was studied
using χ2 or Fisher exact tests to compare percentages, and
Student t tests or Wilcoxon rank-sum tests to compare continuous variables in univariate analysis. The propensity score of
receiving intravenous ZDV was calculated after searching for
predictive factors for treatment attribution, which were generated with a logistic regression [13–15].
The MTCT rate was compared between women who received
intravenous ZDV and those who did not. The analysis was conducted separately according to the level of viral load at delivery
(<400, 400–999, or ≥1000 copies/mL), and stratified on the
mode of delivery, term at delivery (<37 or ≥37 gestational
weeks), and type of postnatal prophylaxis. Independent association of MTCT with intravenous ZDV was assessed using multivariate logistic regression, adjusted for other noncollinear risk
factors of MTCT. This analysis was performed only among
women with viral loads ≥1000 copies/mL at or close to delivery
because there was no case of transmission in women who presented with lower viral loads and did not receive intravenous
ZDV.
Hematological parameters and lactate concentrations at 1, 3,
and 6 months of age were also compared between the 2 groups
of women but restricted to the HIV-uninfected infants. Multivariate linear regression was used to study the association adjusted
for the propensity score of receiving intravenous ZDV using restricted cubic spline functions, postnatal prophylaxis, and birth
level of parameters, except for lactates not measured at birth.
Analyses were conducted with SAS statistical software (version
9.3; SAS Institute, Cary, North Carolina) and the %RCS_Reg SAS
macro [16]. Statistical significance was set at P < .05.
RESULTS
Description of Study Population
Among the 11 538 women included between 1997 and 2010,
95.2% (n = 10 984) received intravenous ZDV, and 554 did not
(Figure 1). The last ART regimen prescribed during pregnancy
was PI-based cART in 60.9% of the women, non-PI-based
cART in 7.8%, NRTI multitherapy in 2.6%, NRTI bitherapy in
17.5%, NRTI (ZDV) monotherapy in 10.2%, and integrase inhibitor or CCR5-based multitherapy in 0.9% of women
(Table 1). At delivery, the median CD4 cell count was 461 cells/
mL (interquartile range [IQR], 319–636 cells/mL), and 43.2%
of women had >500 cells/mL. Maternal HIV-1 RNA at delivery
was <400 copies/mL for 77.7% of women. Almost 79% of neonates received monotherapy as neonatal prophylaxis and 21%
received an intensified prophylactic treatment.
Characteristics of Women Who Did Not Receive Intrapartum
Intravenous ZDV
The percentage of women who did not receive intravenous
ZDV decreased from 7.0% in 1997–1998 to about 4% since
2001 (Table 1).
Women who did not receive intravenous ZDV, compared
with women who received intravenous ZDV, were older, more
often multipara, initiated ART earlier during pregnancy, delivered more often preterm and/or vaginally, and had a higher
HIV RNA level at delivery (Table 1).
After adjustment for these factors and for CD4 cell count at
delivery, year of delivery, maternal origin, and last ART regimen,
the absence of intravenous ZDV remained more frequent in
women aged >35 years of age, multipara, delivering preterm and
vaginally, and with high HIV RNA at delivery (Table 1).
Neonates whose mothers did not receive intravenous ZDV
more often received postnatal intensification treatment than
those whose mothers received intravenous ZDV (35% vs 20%,
P < .001).
HIV/AIDS
•
CID 2013:57 (15 September)
•
905
Table 1. Maternal and Neonatal Characteristics at Baseline by Intravenous Zidovudine Use: ANRS French Perinatal Cohort CO1-CO11,
1997–2010 (N = 11 538)
Univariate Analysis
All
Characteristics
Multivariate
Analysis (n = 9202)
No Intravenous ZDV
P Value
ORa
(95% CI)
.0004
(.66–.24)
1
1.33
(.89–1.99)
0.57
(.41–.80)
0.93
(.60–1.44)
0.63
0.60
(.46–.88)
(.44–.83)
0.82
0.71
(.53–1.29)
(.43–1.15)
(76)
0.56
(.41–.78)
0.64
(.38–1.06)
(75)
0.59
(.43–.82)
0.55
(.33–0.91)
3.0
(38)
1
4.7
5.7
(318)
(198)
1.58
1.95
(1.12–2.22)
(1.37–2.77)
(2350)
(7120)
5.0
4.4
(117)
(317)
1
0.89
%
(No.)
%
(no.)
ORc
1997–1998
1999–2000
9.6
12.0
(1111)
(1379)
7.0
6.4
(78)
(88)
1
0.90
2001–2002
14.4
(1666)
4.1
(69)
2003–2004
2005–2006
16.0
16.7
(1846)
(1931)
4.6
4.4
(84)
(84)
2007–2008
16.1
(1853)
4.1
2009–2010
Maternal age, y
15.2
(1752)
4.3
<25
10.9
(1260)
25–35
≥35
59.0
30.1
(6795)
(3467)
France
Sub-Saharan Africa
20.5
62.2
(95% CI)
P Value
Year of delivery
.0006
.008
1
.06
1.23
1.54
(.82–1.87)
(1.00–2.39)
(.72–1.11)
1
0.86
(.65–1.13)
(.86–1.47)
1.15
(.83–1.59)
Geographical origin
.10
Other
17.2
(1972)
5.6
(110)
1.13
Parity
Primipara
35.4
(4086)
3.2
(131)
1
Multipara
64.6
(7444)
5.7
(421)
1.81
45.9
(4637)
4.7
(217)
1
43.5
(4392)
4.9
(216)
1.05
(.87–1.28)
10.6
(1066)
5.3
(57)
1.15
(.85–1.55)
<20
54.8
(6155)
5.4
(335)
1
20–28
≥28
23.2
22.0
(2610)
(2467)
4.6
3.3
(121)
(83)
0.85
0.61
(.68–1.05)
(.47–.77)
10.2
17.5
(1180)
(2012)
4.9
4.8
(58)
(96)
1
0.97
Gestational age at booking, wk
0–13
14–28
≥28
Initiation of antenatal ART,
gestational wk
<.0001
(1.48–2.21)
.10
1
1.96
<.0001
(1.50–2.55)
.64
.0003
1
.10
0.90
0.71
(.69–1.16)
(.52–.97)
(.69–1.35)
1
0.77
(.50–1.18)
Last antenatal ART
NRTI monotherapy
Dual NRTI
≥3 NRTI
.04
.002
2.6
(302)
2.6
(8)
0.53
(.25–1.12)
0.49
(.20–1.22)
59.9
7.8
(6900)
(901)
4.7
5.4
(326)
(49)
0.96
1.11
(.72–1.28)
(.75–1.64)
1.21
1.09
(.79–1.85)
(.64–1.85)
PI + NNRTI +/– NRTI
1.0
(120)
10.8
(13)
2.35
(1.25–4.43)
3.08
(1.46–6.51)
Other
Maternal CD4 cell count at
delivery, cells/mL
0.9
(106)
3.8
(4)
0.76
(.27–2.13)
0.85
(.19–3.79)
<200
200–349
8.7
21.4
(837)
(2063)
5.3
5.3
(44)
(110)
1
1.02
(.71–1.45)
1
1.03
(.70–1.52)
350–499
26.7
(2580)
4.0
(104)
0.76
(.53–1.09)
0.83
(.55–1.23)
43.2
(4175)
5.0
(207)
0.94
(.67–1.31)
1.09
(.75–1.59)
<400
400–999
77.7
5.7
(8470)
(626)
4.3
5.0
(366)
(31)
1
1.15
(.79–1.68)
1
1.22
(.78–1.91)
≥1000
16.5
(1798)
6.5
(117)
1.54
(1.24–1.91)
1.61
(1.21–2.15)
PI +/– NTRI
NNTRI +/– NTRI
≥500
Maternal HIV-1 RNA at delivery,
copies/mL
906
•
CID 2013:57 (15 September)
•
HIV/AIDS
.16
.0004
.21
.006
Table 1 continued.
Univariate Analysis
All
Characteristics
Multivariate
Analysis (n = 9202)
No Intravenous ZDV
P Value
ORa
<.0001
(.27–.60)
1
0.37
(.23–.59)
0.28
(.20–.40)
0.22
(.15–.33)
4.13
(3.19–5.36)
1.13
(.79–1.63)
%
(No.)
%
(no.)
ORc
<33
33–37
2.8
10.0
(319)
(1155)
13.8
6.0
(44)
(70)
1
0.40
≥37
87.2
(10033)
4.3
(436)
(95% CI)
(95% CI)
P Value
Gestational age at delivery, wk
Mode of delivery
Vaginal delivery
40.5
(4289)
7.9
(338)
3.60
(2.86–4.53)
Emergency cesarean delivery
20.1
(2124)
3.0
(63)
1.29
(.93–1.77)
Elective cesarean delivery
Premature rupture of membranesa
39.4
(4177)
2.3
(97)
1
48.6
(5496)
4.6
(238)
1
84.7
(5129)
3.9
(36)
0.83
51.4
(5806)
4.7
(270)
1
48.6
(5496)
4.9
(272)
1.02
No
Yes
Gender of neonates
Boy
Girl
Birth weight Z score
> −2
≤ −2
Birth height Z score
95.7
4.3
> −2
95.0
≤ −2
5.0
(10761)
4.7
(506)
1
(486)
6.4
(31)
1.38
(10427)
4.6
(481)
1
(544)
7.2
(39)
1.60
<.0001
<.0001
<.0001
1
.31
(.58–1.19)
.71
(.92–1.14)
.09
(.95–2.01)
.007
(1.14–2.24)
Abbreviations: ART, antiretroviral treatment; CI, confidence interval; HIV, human immunodeficiency virus; NNRTI, nonnucleoside reverse transcriptase inhibitor;
No., the total number of women with available data for the concerned category; no., the number of women without intravenous ZDV; NRTI, nucleoside reverse
transcriptase inhibitor; ORa, adjusted odds ratio; ORc, crude odds ratio; PI, protease inhibitor; ZDV, zidovudine.
a
Collected in 2005–2010 only.
Association Between Intravenous ZDV and MTCT Transmission
Rate
The overall MTCT rate was 0.9% (95/10 239) with intravenous
ZDV and 1.8% (9/514) without intravenous ZDV (P = .06), but
the pattern was different according to the level of viral load
near delivery and to the type of postnatal prophylaxis (Table 2
and Figure 2).
In women who delivered with viral loads ≥1000 copies/mL,
there was a higher risk of MTCT associated with the lack of intravenous ZDV, but only in neonates who received postnatal
prophylaxis with ZDV monotherapy: 10.2% vs 2.5% in the
presence of intravenous ZDV (P < .01). In neonates who received intensified postnatal prophylaxis, there was no difference
in transmission rate (4.8% vs 4.1%, respectively; P = .83). In
particular, for women who term delivered by elective cesarean
delivery, the transmission rate remained higher without than
with intravenous ZDV (9.5% vs 1.8%; P = .01). In multivariate
analysis, the association between MTCT and lack of intravenous ZDV remained significant after adjustment for known risk
factors of MTCT (adjusted odds ratio, 3.51 [95% confidence interval, 1.29–9.54]; P = .01; Table 3).
Among women who delivered with viral load <1000 copies/
mL, there was no case of HIV transmission in those who did
not receive intravenous ZDV 0% (0/369) vs 0.6% (47/8132) in
the presence of intravenous ZDV, even in women with viral
load <400 copies/mL (Table 2).
Similar results were observed among term births (Table 2),
after including multiple pregnancies, or in the subgroups of
women who received cART (data not shown).
Hematological Parameters and Lactate Concentrations in HIVUninfected Infants
Mean hemoglobin level at 1 month of age was lower in infants
exposed to intravenous ZDV compared with unexposed
infants, but this association was no longer significant after adjustment for propensity score of receiving intrapartum intravenous ZDV, type of neonatal prophylaxis, and value of
hemoglobin at birth in multivariate linear regression (Table 4).
The rates of grade 3/4 anemia and neutropenia did not differ
significantly at 1 month between the 2 groups (4.4% and 3.9%
in infants exposed to intravenous ZDV vs 5.3% and 3.3% in unexposed infants; P = .43 and P = .62, respectively) and at 3
HIV/AIDS
•
CID 2013:57 (15 September)
•
907
908
•
CID 2013:57 (15 September)
Table 2. Mother-to-Child Transmission Rates Among HIV-1–Infected Pregnant Women Receiving Antiretrovirals During Pregnancy, by Use of Intravenous Zidovudine: ANRS French
Perinatal Cohort CO1-CO11, 1997–2010
<400 copies/mL,
% (no./No.)
Alla, % (no./No.)
•
HIV/AIDS
Characteristics
No
Intravenous
ZDV
All births (N = 10 753)
1.8 (9/514) 0.9 (95/10239)
.06
0 (0/341) 0.6 (42/7576)
.17
0
(0/28) 0.9 (5/556)
Mode of delivery
Vaginal
1.6 (5/316) 0.8 (30/3696)
.16
0 (0/243) 0.5 (16/3027)
.26
0
(0/9)
2.0 (1/51)
1.1 (22/194)
.46
0 (0/29)
0.8 (11/1469)
.99
0
(0/4)
2.2 (2/92)
0.8 (30/3809)
.15
0 (0/47)
0.4 (11/2597)
.65
0
(0/13) 0.7 (2/272)
Emergency cesarean
Elective cesarean
Postnatal prophylaxis
Intravenous
ZDV
P Value
No
Intravenous
ZDV
Intravenous
ZDV
≥1000 copies/mL,
% (no./No.)
400–999 copies/mL,
% (no./No.)
P Value
No
Intravenous
ZDV
Intravenous
ZDV
P Value
No
Intravenous
ZDV
Intravenous
ZDV
P Value
.61
7.5 (8/107) 2.9 (45/1561)
.01
1.9 (3/161)
.85
8.2 (4/49)
3.1 (11/365)
.07
0
NA
6.3 (1/16)
3.8 (11/289)
.48
.91
6.9 (2/29)
1.9 (16/825)
.07
(0/95)
ZDV monotherapy
2.1 (6/292) 0.8 (56/7088)
.02
0 (0/201) 0.5 (30/5600)
.30
0
(0/13) 0.6 (2/330)
.93
10.2 (6/59)
2.5 (24/955)
<.01
Any intensificationb
Gestational age, wk
1.9 (3/155) 2.0 (35/1794)
.99
0 (0/93)
1.0 (11/1061)
.32
0
(0/14) 1.1 (2/182)
.86
4.8 (2/42)
4.1 (21/513)
.83
3.0 (3/99)
1.2 (10/842)
<37
2.1 (26/1213)
.48
0 (0/56)
.99
0
(0/6)
.99
7.4 (2/27)
5.1 (11/218)
1.5 (6/413) 0.8 (69/9002)
.13
0 (0/285) 0.5 (32/6721)
.24
0
(0/22) 0.2 (1/493)
.96
7.6 (6/79)
2.5 (34/1341)
Vaginal
0.8 (2/263) 0.7 (23/3373)
Emergency cesarean 3.6 (1/28) 0.9 (13/1460)
.88
.23
0 (0/209) 0.5 (13/2785)
0 (0/16) 0.5 (6/1144)
.32
.99
0
0
(0/7)
(0/2)
.25
NA
5.6 (2/36)
10.0 (1/10)
2.8 (9/319)
3.4 (7/208)
.37
.32
Elective cesarean
0.7 (23/3458)
.04
0 (0/39)
0.4 (10/2364)
.68
0
(0/11) 0
(0/253)
NA
9.5 (2/21)
1.8 (13/743)
.01
1.7 (4/236) 0.7 (42/6313)
.06
0 (0/169) 0.5 (25/5024)
.36
0
(0/10) 0
(0/295)
NA
9.8 (4/41)
2.1 (17/830)
<.01
1.7 (2/121) 1.6 (24/1527)
.95
0 (0/75)
.48
0
(0/11) 0.6 (1/158)
.93
6.1 (2/33)
3.9 (17/436)
.54
≥37
Term births: ≥37 GW
(n = 9415)
6.4 (4/63)
.64
<.01
Mode of delivery
Postnatal prophylaxis
ZDV monotherapy
Any intensificationb
2.7 (2/74)
0.7 (6/900)
0.7 (1/145)
0
(0/69)
Abbreviation: GW, gestational weeks; NA, not applicable; No., the total number of women with available data for the concerned category; no., the number of HIV infection among women; ZDV, zidovudine.
a
Levels of viral load were missing for 584 women.
b
Dual nucleoside reverse transcriptase inhibitor (ZDV + lamivudine) or combination antiretroviral therapy.
Figure 2. Mother-to-child human immunodeficiency virus (HIV) transmission rates among HIV type 1–infected pregnant women receiving antiretrovirals
during pregnancy, by use of intravenous zidovudine, according to level of HIV RNA at delivery. ANRS French Perinatal Cohort CO1-CO11, 1997–2010. Abbreviation: IV, intravenous.
months (2.8% and 3.7% of anemia and neutropenia in exposed
infants vs 3.8% and 4.2% in unexposed infants; P = .27 and
P = .63; data not shown). Moreover, exposed and unexposed
children did not differ for lactate concentrations. Similar levels
were observed for all these parameters at 6 months of age.
DISCUSSION
The main finding of our study is that intrapartum intravenous
ZDV was not significantly associated with a lower risk of transmission for the vast majority of women with well-controlled
viral load at delivery, whereas it remains, in the cART era, an effective measure to reduce transmission in cases of maternal virological failure. According to French guidelines before 2005,
ZDV or dual NRTI could be prescribed as PMTCT prophylaxis
to women with no indication of ART for themselves. But our
results remained unchanged when restricted to women who received cART during pregnancy.
Interestingly, a missed opportunity of intravenous ZDV
could be compensated by an intensified postnatal prophylaxis.
In cases of virological failure (viral load at delivery ≥1000
copies/mL) when the mother did not receive intravenous ZDV,
the MTCT rate was 10.2% in infants who received postnatal
monotherapy exclusively and 4.8% in infants who received any
postnatal intensification (9.8% and 6.1%, respectively, in the
subgroup of term births). The postnatal intensified prophylaxes
used were dual nucleoside therapy (ZDV plus lamivudine) or
PI-based cART.
The main strength of this study is the large number of patients included in the French nationwide prospective cohort. Its
main weakness is the fact that the proportion of HIV-infected
women who did not receive intravenous ZDV was relatively
small (5%) and subject to treatment biases inherent to observational studies. Failure to receive intravenous ZDV was more frequent in older, multiparous women, in women with premature
and vaginal deliveries, and in women who had higher HIV-1
RNA at delivery. It can be hypothesized that many of these
women presented in advanced labor, too late to start intravenous ZDV [17]. Prematurity was shown to be a risk factor for
MTCT of HIV [5, 18]. In the absence of ART or only with ZDV
monotherapy, vaginal delivery was also shown to be associated
with a higher rate of MTCT compared to elective cesarean delivery [19–27]. Nonetheless, even among women with viral
loads ≥1000 copies/mL who had elective cesarean delivery at
term, the lack of intravenous ZDV was associated with a significant 5-fold higher risk of MTCT.
When considering the women who delivered with wellcontrolled viral load (<400 copies/mL), no case of transmission
occurred among those who did not receive intravenous ZDV.
However, the 95% confidence interval upper limit of the transmission rate in women without intravenous ZDV was 1.1%,
higher than the upper limit for the transmission rate among
women with intravenous ZDV (0.6%; 95% confidence interval,
0.4% –0.8%). The only definitive proof would be provided by a
randomized trial, but given the low transmission rate, this
would require approximately 10 000 women to be able to test
equivalence of risk, a figure clearly unrealistic. Moreover,
despite the large size of our cohort, there were few infected
infants; thus, the study lacked power to investigate the safety of
withholding intravenous ZDV in case of obstetrical risk factors,
HIV/AIDS
•
CID 2013:57 (15 September)
•
909
Table 3. Mother-to-Child Transmission Rates Among HIV-1–Infected Pregnant Women Receiving Antiretrovirals During Pregnancy, with
Maternal HIV-1 RNA at Delivery ≥1000 copies/mL and Term Births: ANRS French Perinatal Cohort CO1-CO11, 1997–2010 (n = 1420)
Multivariate Analysis
(n = 1196)
Univariate Analysis
Characteristics
%
no./No.
2.5
7.6
34/1341
6/79
France
Sub-Saharan Africa
1.4
3.8
5/368
28/745
Other
2.4
7/297
Intrapartum intravenous ZDV
P Value
P Value
ORa
(95% CI)
.01
1
3.51
(1.29–9.54)
(1.09–7.40)
1
1.80
(.66–4.88)
(.55–5.58)
1.61
(.49–5.24)
ORc
(95% CI)
1
3.16
(1.29–7.77)
1
2.84
1.75
P Value
.008
Yes
No
.01
Geographical origin
Gestational age at booking, wk
0–13
.07
7/564
3.6
20/553
2.99
(1.25–7.12)
2.73
(1.11–6.68)
4.7
9/193
3.89
(1.43–10.59)
3.31
(1.12–9.82)
<200
5.4
10/187
200–349
350–499
3.3
1.8
11/329
6/333
0.61
0.33
(.26–1.47)
(.12–.91)
≥500
2.4
11/462
0.43
(.18–1.03)
1.8
13/742
3.9
29/667
3.1
11/355
3.7
8/218
1.19
(.47–3.01)
2.0
15/764
0.63
(.29–1.38)
<20
2.7
17/624
20–28
≥28
2.2
3.1
6/271
16/512
NRTI monotherapy
Dual NRTI
2.0
2.5
8/395
10/394
cART
3.5
22/629
≥28
Maternal CD4 cell count at delivery, cells/mL
Sex of neonate
Male
Female
Mode of delivery
Vaginal
Emergency caesarean
Elective caesarean
Initiation of antenatal ART, gestational wk
.11
.01
1
1
.76
1
.05
.12
1
1.22
.27
.02
.51
1.2
14–28
.01
.08
.17
(.92–1.64)
1
1
1.31
.12
(.94–1.83)
.28
1
.76
0.81
1.15
(.32–2.07)
(.58–2.30)
1
1.26
(.49–3.23)
1.75
(.77–3.98)
Last antenatal ART
Postnatal child prophylaxis
NRTI monotherapy
Intensifieda
2.4
21/872
4.1
19/469
.35
.09
.36
1
1.71
.09
(.91–3.22)
Abbreviations: ART, antiretrovial therapy; cART, combination ART; CI, confidence interval; HIV-1, human immunodeficiency virus type 1; No., the total number of
women with available data for the concerned category; no., the number of HIV infection among women; NRTI, nucleoside reverse transcriptase inhibitor; ORa,
adjusted odds ratio; ORc, crude odds ratio; ZDV, zidovudine.
a
Intensification: dual NRTI or cART.
such as premature rupture of membranes, preterm delivery,
fever, or bleeding. While awaiting more data, it may appear reasonable to maintain intravenous ZDV even in women with low
viral load in cases of complicated deliveries.
These results are consistent with our previous study, conducted between 1997 and 2004 in the French Perinatal cohort
on a smaller sample size and with a lower proportion of
women treated with cART during pregnancy [5]. Extending the
910
•
CID 2013:57 (15 September)
•
HIV/AIDS
study to 2010 allowed us to evaluate, with an increased power,
whether intravenous ZDV was still beneficial in the context of
systematic cART recommended since 2004 for all pregnant
women. In the current study, 72% of women received combination antiretroviral therapies, mostly PI-based, the proportion
increasing from 38% in 1997–2004 to 86% in 2005–2010. A
recent European study reported no significant association
between intravenous ZDV and transmission rate (3.1% with vs
Table 4. Hematological Parameters According to Receipt of Intravenous Zidovudine During Delivery—Univariate and Multivariate
Linear Regression: ANRS French Perinatal Cohort CO1–CO11, 1997–2010
Multivariate Linear Regressiona
Univariate Analyis
Parameter
No Intravenous
ZDV, Median (IQR)
Intravenous ZDV,
Median (IQR)
P
Value
Mean Difference (Yes
vs No) (95% CI)
P
Value
Adjusted Mean
Difference (95% CI)
P
Value
All births (N = 11 434)
Hemoglobin, g/dL
1 mo of age
3 mo of age
10.1 (9.2–11.4)
10.0 (9.1–11.0)
.01
−0.27 (−.48 to −.06)
.01
−0.002 (−.24 to .23)
.98
10.8 (10.1–11.6)
10.9 (10.5–11.6)
.06
0.09 (−.02 to .21)
.12
0.12 (−.01 to .25)
.08
% neutrophils
1 mo of age
21 (16–27)
21 (16–25)
.07
−0.92 (−1.91 to −.07)
.07
−1.11 (−2.32 to .11)
.07
3 mo of age
21 (17–28)
21 (16–28)
.79
−0.15 (−1.23 to .94)
.79
−0.67 (−2.01 to .68)
.33
Lactates, mmol/L
1 mo of age
2.8 (2.0–3.8)
2.6 (1.8–3.6)
.30
−0.13 (−.45 to .19)
.42
−0.28 (−.61 to .05)
.09
3 mo of age
2.5 (2.0–3.5)
2.4 (1.7–3.4)
.21
−0.15 (−.44 to .13)
.29
−0.16 (−.47 to .14)
.30
10.2 (9.3–11.5)
10.9 (10.3–11.7)
10.0 (9.2–11.0)
11.0 (10.3–11.6)
.01
.03
−0.30 (−.53 to −.07)
0.06 (−.06 to .19)
.01
.33
−0.07 (−.34 to .19)
0.09 (−.06 to .23)
.57
.24
Term births ≥37 wk
(n = 9958)
Hemoglobin, g/dL
1 mo of age
3 mo of age
% neutrophils
1 mo of age
3 mo of age
21 (16–26)
21 (17–29)
20 (16–25)
21 (16–27)
.22
.66
−0.67 (−1.74 to .41)
−0.05 (−1.12 to 1.02)
.22
.93
−1.07 (−2.38 to .24)
−1.15 (−2.63 to .33)
.11
.13
2.9 (2.0–3.8)
2.6 (1.9–3.7)
2.6 (1.9–3.6)
2.4 (1.7–3.4)
.18
.19
−0.19 (−.51 to .13)
−0.20 (−.52 to .12)
.25
.22
−0.25 (−.60 to .10)
−0.21 (−.56 to .13)
.16
.23
Lactates, mmol/L
1 mo of age
3 mo of age
Abbreviations: CI, confidence interval; IQR, interquartile range; ZDV, zidovudine.
a
Adjusted for value at birth of each parameter concerned (except for lactates not measured at birth), and also neonatal prophylaxis, and the propensity score for
receiving intrapartum intravenous ZDV.
12.5% without; P = .23) [28], which was also the case when we
performed the analysis on the overall study population.
However, the authors did not report results separately for low
and high viral load at delivery.
Toxicity outcomes were evaluated in the first 6 months of
life for uninfected infants, according to the use of intravenous
ZDV. The parameters studied were hemoglobin level, neutrophil
percentage, and lactate concentrations because these were previously described to be influenced by ZDV exposure [29–32].
We used multivariate analysis adjusted for a propensity score of
receiving intravenous ZDV. A propensity score is a conditional
probability of being treated given a subject’s observational
characteristics, an approach designed to detect and remove the
selection bias and estimation risk due to lack of randomization.
Our results suggest that intrapartum intravenous ZDV did
not significantly modify short-term hematological outcomes.
As in the ANRS French Perinatal Cohort, the duration of intravenous ZDV was not recorded, so we could not take this parameter into account in our toxicity analyses. Hematological
parameters did not differ in the subgroups of women who
delivered by elective cesarean section, in which duration of
intravenous ZDV, when administered, was likely to be more
homogenous.
Our findings support recent evolutions in the French and US
guidelines, which no longer recommend systematic intravenous
ZDV during labor and delivery in women with a low plasma
viral load, taking into account obstetrical risk factors. Intravenous ZDV does remain an effective prophylactic measure to
prevent MTCT in women with a high or unknown HIV load
near delivery.
APPENDIX: ANRS-EPF CO1-CO11 STUDY
GROUP
Currently Active Contributors to ANRS-EPF
The asterisks indicate the principal investigator of each clinical
site: APHP Hôpital Louis Mourier, Colombes, France (Laurent
Mandelbrot*, Françoise Meier, Dominique Duro, Marine Joras,
Emmanuel Mortier, Catherine Crenn-Hebert, Corinne FlochTudal*, Fabienne Mazy); APHP Hôpital Beaujon, Clichy,
HIV/AIDS
•
CID 2013:57 (15 September)
•
911
France (Mariam Bensalah, Agnès Villemant-Uludag, Agnès
Lefort, Virginie Zarrouk, Pierre-François Ceccaldi*); Hôpital
Sainte Musse, Toulon, France (Gisèle Philip, Gilles Hittinger*);
CHG Marechal Joffre, Perpignan, France (Martine Malet,
Bruno Bachelard, Marie Medus*); CHU Caremeau, Nîmes,
France ( Joëlle Dendale-Nguyen*); CHD les Oudairies, La
Roche sur Yon, France ( Jean-Pierre Brossier, Olivier Aubry,
Jean-Luc Esnault, Sophie Leautez, Philippe Perré*, Isabelle
Suaud); Centre Hospitalier William Morey, Châlon sur Saone,
France (Sandrine-Anne Martha*); Centre Hospitalier, Vernon,
France (Mahfoud Rouha*); Centre Hospitalier Intercommunal
de Cornouaille, Quimper, France (Pascale Perfezou*, Gilles
Blondin, Charles Bellot); Centre Hospitalier Universitaire,
Brest, France (Séverine Ansart*, Philippe Le Moine, Karine
Bages-Jaffuel, Jean-Charles Duthé, Michel Garré, Sylvain
Jaffuel); Centre Hospitalier, St Brieuc, France (Corinne
Daniel*, Christian Calvez, Claude Beuscart, Emmanuelle Boutaric, Jennifer Rohan, Sylvie Lemoal); Centre Hospitalier Universitaire, Rennes, France (Linda Lassel, Ghislaine Cotten,
Christelle Dupré, Esther Beauville, Cédric Arvieux*); Centre
Hospitalier Bretagne Atlantique, Vannes, France (Anabèle Dos
Santos*, Corinne Cudeville, Yves Poinsignon, Virginie
Mouton-Rioux, Gaétane Mousset, Anne Grellier); Centre Hospitalier de Bretagne Sud, Lorient, France (Philippe Moreau,
Philippe Tillaut, Virginie Mouton-Rioux, Odile Luycx-Vaillant,
Philippe de Morel, Marie-Françoise Le Coz, Isabelle Belzic, Mathilde Niault*); Centre Hospitalier de la région d’Annecy,
Annecy, France (Anne Vandenbergh, Cécile Janssen, Susanne
Braig, Virginie Vitrat*, Jacques Gaillat, Gaëlle Clavere, JeanPierre Bru, Blandine Peyret); Centre Hospitalier Intercommunal, Montfermeil, France (Catherine Mullard, Marie Echard,
Philippe Talon*, Marion Dehlinger); Centre Hospitalier Intercommunal, Montreuil, France (Cécile Winter, Brigitte HellerRoussin*); APHP Hôpital Cochin-Port Royal, Paris, France
(Odile Launay, Maria Fouchet, Ghislaine Firtion*, Isabelle
Goupil, Emmanuelle Pannier*, Nora Boudjoudi); APHP
Hôpital Bichat, Paris, France (Agnès Bourgeois-Moine, Marylène Bodard, Valérie Vivier, Mandovi Rajguru, Virginie Huri,
Elie Azria, Sophie Matheron*, Neila Elaoun, Philippe Faucher);
Centre Hospitalier Intercommunal, Créteil, France (Valérie
Garrait*, Christiane Komme, Isabelle Hau*, Laurent Richier,
Claudine Touboul); Hôpital de la Croix Rousse, Lyon, France
(Valérie Thoirain, Laurent Cotte*, Olivier Tariel, Joseph Koffi,
Jean-Marc Labaune, Corinne Brochier); Centre Hospitalier Pellegrin, Bordeaux, France (Denis Roux*, Christophe Elleau,
Camille Runel*); CHU Les Abymes, Pointe à Pître, France
(Henri Bataille*, Marie-Thérèse Sow, Ketty Samar, Blandine
Muanza); Centre Hospitalier Général, Creil, France (Marc
Duval*, Clarisse Kingue-Ekollo, Bénédicte Carpentier); CHI la
Seyne sur Mer, La Seyne sur Mer, France (Isabelle Ronda, JeanMarc Chamouilli*); Hôpital de Haute Pierre, Strasbourg,
912
•
CID 2013:57 (15 September)
•
HIV/AIDS
France (Natacha Entz-Werle); Centre Hospitalier Général,
Longjumeau, France (Hervé Seaume*, Sarah Ducrocq, Philippe
Bailly-Salin, Yvon Lemercier); Hôpital Paule de Viguier, Toulouse, France ( Joëlle Tricoire*, Alain Berrebi*, Michèle Antras,
Evelyne Armand); Centre Hospitalier de la Côte Basque,
Bayonne, France (Claudine Cayla*, François Bonnal, Catherine
Chabanier); Centre hospitalier intercommunal, Villeneuve St
Georges, France (Isabelle Matheron, Anne Chacé*); Centre Hospitalier Intercommunal, Poissy Saint Germain en Laye, France
(Sophie Couderc, Anne Boutemy*); Centre Hospitalier
Général, Fontainebleau, France (Marie-Christelle Dallot, Alain
Al-Issa, Corinne Routier*); Centre Hospitalier Robert Ballanger, Aulnay, France (Ahmed Zakaria, Véronique Favret, Juliette Gerbe, Elisabeth Questiaux); Hôpital Civil, Strasbourg,
France (MariaLuisa Partisani*, David Rey, Christine Cheneau);
Centre Hospitalier Victor Dupouy, Argenteuil, France (Christine Allisy, Dominique Brault*); APHP Hôpital Tenon, Paris,
France (François Hervé, Marie-Gisèle Lebrette*, Lise Selleret);
Centre Hospitalier Général, Saint-Denis, France (Dieudonné
Ekoukou, Pascal Bolot*, Marie-Aude Khuong-Josses, MarieChristine Allemon, Nelly Ghibaudo); APHP Hôpital Necker,
Paris, France (Pierre Frange, Christine Rouzioux, Florence
Veber, Stéphane Blanche*, Delphine Lemercier*, Marie-Christine Mourey); Centre Hospitalier Sud Francilien, Evry Corbeil,
France (Gilles Blasquez); Centre Hospitalier Sud Francilien,
Evry Corbeil, France (Michèle Granier*, Houda Touahri, Rose
Nguyen, Alain Devidas*); Centre Médico-Chirurgical et Obstétrical, Schiltigheim, France (Israël Nisand, Michèle Weil,
Christophe Vayssière); CHR American Memorial Hospital,
Reims, France ( Jean-Luc Berger, Martine Munzer*, Olivier
Graesslin); APHP Groupe Hospitalier Pitié Salpêtrière, Paris,
France (Anne-Florence Naime-Alix, Roland Tubiana*, Frédérique Quetin, Anne Laubies, Manuela Bonmarchand, Jennifer
Sommer, Patricia Bourse); Centre Hospitalier René Dubos,
Pontoise, France (Anne Coursol*, Michel Youssef, Juliette
Laurent); APHP Hôpital Béclère, Clamart, France (Mariem
Raho, Véronique Chambrin*, Philippe Labrune*, Laure Clech,
Alexandra Benachi); Centre Hospitalier Marc Jacquet, Melun,
France (Bertrand Le Lorier*, Isolde Pauly-Ravelly); Centre Hospitalier Général, Evreux, France (Claude Allouche, Ama
Johnson*); APHP Hôpital Jean Verdier, Bondy, France (Laurence Benoist, Catherine Delannoy, Eric Lachassine, Stéphanie
Bolie, Joël Gaudelus, Vincent Jeantils, Amelie Benabara*);
Centre Hospitalier de Meaux, Meaux, France (Leïla Karaoui*,
Véronique Lefèvre); CHU de l’Archet, Nice, France (André
Bongain*, Eliane Galiba, Anne Deville, Fabrice Monpoux*,
Jacques Durant); Centre Hospitalier Saint Joseph, Paris, France
(Christian Aufrant*); Centre Hospitalier François Quesnay,
Mantes La Jolie, France ( Jean Furioli, Jean-Louis Salomon,
Françoise Granier, Antoine Doumet*); CHU Hôpital Nord,
Amiens, France (Youssef Douadi, Jean Gondry, Jean-Luc
Schmit*, Brigitte Pautard); Hôpital de la Conception, Marseille,
France (Marc Gamerre, Ludovic Cravello*, Isabelle Thuret*);
CHU de Brabois-Hôpital des Adultes, Vandoeuvre les Nancy,
France (Laurence Neimann, Claire Hubert*); APHP Hôpital
Trousseau, Paris, France (Bruno Carbonne*, Geneviève
Vaudre, Marie-Dominique Tabone, Catherine Dollfus*);
Hôpital Charles Nicolle, Rouen, France (Didier Pinquier,
Gaëlle Pinto Cardoso*, Brigitte Clavier, Françoise BorsaLebas); APHP Hôpital Robert Debré, Paris, France (Agathe De
Lauzanne, Constance Borie, Sandrine Leveillé, Albert Faye*,
Erianna Bellaton, Dominique Garion, Martine Levine*); APHP
Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (Claire
Colmant, Cécile Goujard, Marc Tardieu, Florent Fuchs, Ikram
Jrad, Delphine Peretti*, Katia Bourdic, Corinne Fourcade*);
CHRU Hôpital Saint Jacques, Besançon, France (Catherine
Chirouze, Jean-Marie Estavoyer*, Robert Maillet); CHU de
Nantes, Nantes, France (Véronique Reliquet*, Norbert Winer,
Cécile Brunet*); CHRU Hôpital du Bocage, Dijon, France (Isabelle Reynaud*, Claire Briandet); CHRU Hôpital Clemenceau,
Caen, France ( Jacques Brouard*, Gaël Beucher, Pascale
Goubin); Centre Hospitalier de Lagny, Lagny, France (Cécile
Lanty, Eric Froguel, Béatrice Gourdel, Arnaud Chalvon Demersay*, Gilbert Algava); Hôpital André Mignot, Le Chesnay,
France (Véronique Hentgen*, Fabienne Messaoudi); CHRU de
Tours, Tours, France (Pascale Nau, Jean-Marc Besnier*, Jérôme
Potin); Institut d’Hémato-Oncologie Pédiatrique, Lyon, France
(Nadine Taché, Yves Bertrand, Kamila Kebaïli*); Hôpital Nord,
Saint Etienne, France (Véronique Ronat, Anne Fresard, Kareen
Billiemaz*); Centre Hospitalier Général, Bastia, France
(Ramona Abrudan*); Centre Hospitalier Universitaire, Angers,
France (Alain Fournié, Jean-Marie Chennebault*); Centre Hospitalier Régional, Orléans, France (Philippe Arsac*); APHP
Hôpital Lariboisière, Paris, France (Nicole Ciraru-Vigneron*,
Geneviève Mouchnino, Dominique Ayral); CHR Arnaud de
Villeneuve, Montpellier, France (Nelly Guigue, Muriel
Lalande*, Paul Benos*); Centre Hospitalier Général, Orsay,
France (Christiane De Gennes*, Sonia Chanzy, Valérie Isart);
Centre Hospitalier de Saint Martin, St Martin, France (François
Cazassus, Véronique Walter, François Bissuel*); CHR Jeanne
de Flandres, Lille, France (Yamina Hammou*, Sophie
d’Angelo, Faïza Ajana, Françoise Mazingue*); CHU–Maison de
la Femme et de l’Enfant, Fort de France, France (Raymond
Mezin, Yves Hatchuel*, André Cabié); CHG Cayenne,
Cayenne, France (Narcisse Elenga*).
Steering Commitee of ANRS-EPF
Stéphane Blanche, Naïma Bouallag, Nelly Briand, Sandrine
Delmas, Catherine Dollfus, Albert Faye, Jérôme Le Chenadec,
Laurent Mandelbrot, Christine Rouzioux, Jeanne Sibiude, JeanPaul Teglas, Roland Tubiana, Josiane Warszawski.
Notes
Acknowledgments. We thank other members of the coordinating
center of ANRS-EPF, INSERM U1018-CESP, Le Kremlin-Bicetre (Souad
Belaggoun, Leïla Boufassa, Céline Ferey, Lila Hamadou, Paulette Huynh,
Julie Lamarque, Corinne Laurent, Jacques Ngondi, Marlène Pérès, Anaïs
Perilhou, Marine Pytkowski, Rihab Rais, Elisa Ramos, Thierry Wack); Loïc
Desquilbet (Institut de Recherche Clinique Animale) for providing us the
RCS_macro and helping us to perform it; and all of the families who agreed
to participate in this study.
We also thank past contributors to ANRS-EPF: APHP Hôpital Louis
Mourier, Colombes, France (Evelyne Hery); APHP Hôpital Beaujon,
Clichy, France (Dominique Luton); CHG des Feugrais, Elbeuf, France
(Kamel Lahsinat); Hôpital d’Aix en Provence, Aix en Provence, France
(Brahim Tadrist); APHP Hôpital Ambroise Paré, Boulogne Billancourt,
France (Delphine Zenaty); CHI Jean Rostand, Sèvres, France (Liliane
Segard); Centre Hospitalier de Neuilly, Neuilly sur Seine, France (Bertrand
Berterottière); Centre Hospitalier Intercommunal, Montreuil, France
(Déborah Fried, Catherine Riehl); APHP Hôpital Saint-Antoine, Paris,
France ( Jacqueline Rodriguez, Eida Bui-Pha, Marie-Caroline Meyohas);
APHP Hôpital Bichat, Paris, France (Huguette Bastian); Centre Hospitalier
Intercommunal, Créteil, France (Christine Pichon, Sophie Lemerle*);
Centre Hospitalier Pellegrin, Bordeaux, France (Véronique Schaeffer, JeanMarie Ragnaud, Danièle Douard); Hôpital de Haute Pierre, Strasbourg,
France ( Jean-Jacques Favreau); Centre Hospitalier Général, Longjumeau,
France (Aly Abbara); Centre hospitalier intercommunal, Villeneuve St
Georges, France (François Guillot); CHRU, Dourdan, France (Valérie
Ercoli); CMC Foch, Suresnes, France (Anne-Marie Raison Boulley); Hôpital
Esquirol, Saint-Maurice, France (Michel Robin); Institut Mutualiste Montsouris, Paris, France (Carole Carlus Moncomble); APHP Hôpital Necker,
Paris, France (Sophie Parat, Véronique Cayol, Marie-Laure Chaix); CHG,
Gonesse, France ( Jean-Bruno Lobut, Bénédicte Paindaveine, Didier Troisvallets); Centre Hospitalier Sud Francilien, Evry Corbeil, France (Adrien
May, Isabelle Turpault); Clinique du Blanc Mesnil, Blanc Mesnil, France
(Pierre Balde); APHP Groupe Hospitalier Pitié Salpêtrière, Paris, France
(Inès de Montgolfier, Michèle Pauchard); APHP Hôpital Béclère, Clamart,
France (Olivier Picone, Laurence Foix l’Hélias); Hôpital des Métallurgistes,
Paris, France (Michel Rami); APHP Hôpital Avicennes, Bobigny, France
(Michelle Bentata); Hôpital Max Fourestier, Nanterre, France (Benoît De
Sarcus); Centre Hospitalier Général, Evreux, France (Kadidia Toure*);
Centre Hospitalier Victor Jousselin, Dreux, France (Marie-France Denavit);
APHP Hôpital Boucicaut, Paris, France (Marie-Christine Lafay-Pillet);
Centre Hospitalier François Quesnay, Mantes La Jolie, France (Audoun Delanete); Hôpital Saint Michel, Paris, France (Christian Aufrant); APHP
Hôpital Trousseau, Paris, France (Aude Wallet); Hôpital Charles Nicolle,
Rouen, France (Véronique Brossard); APHP Hôpital Robert Debré, Paris,
France (Aude Recoules, Annick Ottenwalter*); APHP Hôpital de Bicêtre,
Le Kremlin-Bicêtre, France (Marie-Thérèse Rannou); APHP Hôpital Hôtel
Dieu, Paris, France ( Jean-Paul Viard); CHU de Nantes, Nantes, France
(Françoise Mechinaud); Hôpital Jean Rostand, Ivry, France (Thierry Jault);
Hôpital Hotel Dieu, Lyon, France (Marie-Christine Roussouly, Jérôme Massardier); Centre Hospitalier Général, Bastia, France (Olivier Pincemaille);
Centre Hospitalier Régional, Orléans, France (Evelyne Werner); Hôpital
Saint Claude, Basse Terre, France (Gérard Sibille); CHU–Maison de la
Femme et de l’Enfant, Fort de France, France (William Cécile); Centre Hospitalier Louis Domergues, La Trinité, France (Nicole Hugon, Elisabeth
Dussaix). The asterisks indicate the principal investigator of each clinical
site.
Financial support. This work was supported by the Agence nationale
de recherche sur le Sida et les hépatites virales (INSERM-ANRS).
Disclaimer. The funding agency was not involved in any part of
studies from EPF, especially design, data collection, statistical analyses, interpretation of the results, or writings.
Potential conflicts of interest. J. W.’s institution has received grants
from Abbott, Iatec, ViiV Healthcare, and Parexel, through a contract with
the ANRS, promoter and main funding support of the ANRS-EPF. L. M.
HIV/AIDS
•
CID 2013:57 (15 September)
•
913
has received lecturing honoraria from Merck Sharp & Dohme, BristolMyers Squibb, Abbott, and Gilead. All other authors report no potential
conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
References
1. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral
strategies for the treatment of pregnant HIV-1-infected women and
prevention of perinatal HIV-1 transmission. J Acquir Immune Defic
Syndr 2002; 29:484–94.
2. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudinezidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001; 285:2083–93.
3. European Collaborative Study. Mother-to-child transmission of HIV
infection in the era of highly active antiretroviral therapy. Clin Infect
Dis 2005; 40:458–65.
4. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of
human immunodeficiency virus type 1 by pregnant women with RNA
virus loads <1000 copies/ml. J Infect Dis 2001; 183:539–45.
5. Warszawski J, Tubiana R, Le Chenadec J, et al. Mother-to-child HIV
transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort. AIDS 2008; 22:289–99.
6. Townsend CL, Cortina-Borja M, Peckham CS, et al. Low rates of
mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000–2006. AIDS
2008; 22:973–81.
7. Rouzioux C, Costagliola D, Burgard M, et al. Estimated timing of
mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission by use of a Markov model. The HIV Infection in Newborns
French Collaborative Study Group. Am J Epidemiol 1995; 142:1330–7.
8. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant
transmission of human immunodeficiency virus type 1 with zidovudine
treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study
Group. N Engl J Med 1994; 331:1173–80.
9. Dormont D. Prise en charge des personnes atteintes par le VIH. Paris:
Secrétariat d’Etat à la santé et à la sécurité sociale, 1996.
10. Yeni P. Prise en charge médicale des personnes infectées par le VIH.
Recommandations du groupe d’experts. Paris: Ministere de la Santé et
des Solidarités, 2010.
11. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of
Perinatal Transmission. Recommendations for use of antiretroviral drugs
in pregnant HIV-1-infected women for maternal health and interventions
to reduce perinatal HIV transmission in the United States, 2012.
12. AIDS Clinical Trials Group. Division of AIDS table for grading the severity of adult and pediatric adverse events. Rockville, MD: National Institutes of Health, National Institute of Allergy and Infectious Diseases,
Division of AIDS, 2004.
13. D’Agostino RB Jr. Propensity score methods for bias reduction in the
comparison of a treatment to a non-randomized control group. Stat
Med 1998; 17:2265–81.
14. Kwiatkowski F, Slim K, Verrelle P, Chamorey E, Kramar A. Propensity
score: interest and limits [in French]. Bulletin du cancer 2007; 94:680–6.
914
•
CID 2013:57 (15 September)
•
HIV/AIDS
15. Sturmer T, Schneeweiss S, Avorn J, Glynn RJ. Adjusting effect estimates
for unmeasured confounding with validation data using propensity
score calibration. Am J Epidemiol 2005; 162:279–89.
16. Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic
spline functions in public health research. Stat Med 2010; 29:1037–57.
17. Mayaux MJ, Teglas JP, Blanche S. Characteristics of HIV-infected
women who do not receive preventive antiretroviral therapy in the
French Perinatal Cohort. J Acquir Immune Defic Syndr 2003; 34:338–43.
18. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Trends in
management and outcome of pregnancies in HIV-infected women in
the UK and Ireland, 1990–2006. BJOG 2008; 115:1078–86.
19. European Mode of Delivery Collaboration. Elective caesarean-section
versus vaginal delivery in prevention of vertical HIV-1 transmission: a
randomised clinical trial. Lancet 1999; 353:1035–9.
20. Mandelbrot L, Le Chenadec J, Berrebi A, et al. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. JAMA 1998; 280:55–60.
21. Newell ML, Parazzini F, Mandelbrot L, et al. A randomised trial of
mode of delivery in women infected with the human immunodeficiency virus. Br J Obstet Gynaecol 1998; 105:281–5.
22. Kuhn L, Stein ZA. Mother-to-infant HIV transmission: timing, risk
factors and prevention. Paediatr Perinat Epidemiol 1995; 9:1–29.
23. Bobat R, Coovadia H, Coutsoudis A, Moodley D. Determinants of
mother-to-child transmission of human immunodeficiency virus type
1 infection in a cohort from Durban, South Africa. Pediatr Infect Dis J
1996; 15:604–10.
24. Mother-to-child transmission of human immunodeficiency virus in Italy:
temporal trends and determinants of infection. The Italian Collaborative
Study on HIV infection in pregnancy. Hum Reprod 1999; 14:242–6.
25. Grosch-Worner I, Schafer A, Obladen M, et al. An effective and safe
protocol involving zidovudine and caesarean section to reduce vertical
transmission of HIV-1 infection. AIDS 2000; 14:2903–11.
26. Italian Register for Human Immunodeficiency Virus Infection in Children. Determinants of mother-to-infant human immunodeficiency
virus 1 transmission before and after the introduction of zidovudine
prophylaxis. Arch Pediatr Adolesc Med 2002; 156:915–21.
27. International Perinatal HIV Group. The mode of delivery and the risk
of vertical transmission of human immunodeficiency virus type 1—a
meta-analysis of 15 prospective cohort studies. N Engl J Med 1999;
340:977–87.
28. Chiappini E, Galli L, Giaquinto C, et al. Use of combination neonatal
prophylaxis for the prevention of mother-to-child transmission of HIV
infection in European high-risk infants. AIDS 2013; 27:911–1000.
29. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S,
Enquete Perinatale Francaise Study G. Perinatal antiretroviral treatment
and hematopoiesis in HIV-uninfected infants. AIDS 2003; 17:2053–61.
30. Giaquinto C, De Romeo A, Giacomet V, et al. Lactic acid levels in children perinatally treated with antiretroviral agents to prevent HIV transmission. AIDS 2001; 15:1074–5.
31. Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to
perinatal antiretroviral therapy. Pediatr Infect Dis J 2003; 22:782–9.
32. Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in
human immunodeficiency virus-uninfected infants who are exposed to
antiretrovirals. Pediatrics 2004; 114:e598–603.