Factors Associated with Mother-to-Child

MAJOR ARTICLE
HIV/AIDS
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,1,2 Jerome Le Chenadec,3,11 Christine Rouzioux,4,5 Laurent Mandelbrot,6,13 Karima Hamrene,7
Catherine Dollfus,8 Albert Faye,9 Constance Delaugerre,4 Stephane Blanche,5,10 and Josiane Warszawski,3,7,11,12
for the ANRS French Perinatal Cohort (ANRS CO1/CO11)a
1
Département des Maladies Infectieuses et Tropicales, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié Salpêtrière, 2Institut
National de la Santé et de la Recherche Médicale (INSERM) U943, 3Institut National Etudes Démographiques, 4Laboratoire de Virologie, AP-HP,
Hopital Necker, 5EA 3620, Université Paris Descartes, 6Université Paris 7, Paris Diderot, 7Service de Santé Publique et Épidémiologie, AP-HP,
Hopital Bicêtre, 8Service d’Hématologie et d’Oncologie Pédiatrique, AP-HP, Hôpital Trousseau, 9Service de Pédiatrie Générale, AP-HP, Hôpital
Robert Debré, and 10Unité d’Immunologie Hématologie Pédiatrique, AP-HP, Hôpital Necker, Paris, 11INSERM U822 and 12Faculté de Médecine
Paris-Sud, Université Paris-Sud, Le Kremlin-Bicêtre, and 13Service de Gynécologie-Obstétrique, AP-HP, Hôpital Louis Mourier, Colombes, France
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 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 p .02),
28 weeks (7.7% vs 62.1%; P p .005), and 32 weeks: (21.4% vs 71.1%; P 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.
A remarkable decrease in the rate of mother-to-child
transmission (MTCT) of human immunodeficiency virus (HIV)–1 has been obtained in industrialized coun-
Received 29 July 2009; accepted 15 October 2009; electronically published 13
January 2010.
Reprints or correspondence: Dr Josiane Warszawski, INSERM, INED U822, 82, rue
du Général Leclerc, 94 276 Le Kremlin Bicêtre cedex, France (josiane.warszawski@
inserm.fr)
Clinical Infectious Diseases 2010; 50:585–96
2010 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2010/5004-0021$15.00
DOI: 10.1086/650005
tries [1–4]. We recently showed [5] that the rate of
MTCT of HIV-1 among mothers who delivered in the
French Perinatal Cohort during the period 1997–2004
was 1.3% (95% confidence interval [CI], 1.0–1.6) and
that the rate of MTCT increased with viral load, very
premature delivery, and short duration of antiretroviral
therapy (ART). However, MTCT of HIV-1 did occur,
even in the context of full-term deliveries and a maternal viral load !400 copies/mL, without breast-feeding.
a
Members of the ANRS French Perinatal Cohort are listed at the end of the text.
Risk Factors for Residual HIV-1 MTCT • CID 2010:50 (15 February) • 585
The duration of antenatal ART was the only factor associated
with such cases, which were referred to as “residual transmissions” [1, 5]. Most publications on the relation between maternal plasma viral load and MTCT considered only the viral
load determined at delivery, and recommendations for initiating ART during pregnancy do not take into account baseline
maternal viral load [3, 6–13]. To better investigate which factors
may explain residual MTCT, we conducted a case-control study
nested in the French Perinatal Cohort (EPF).
SUBJECTS AND METHODS
The ANRS French Perinatal Cohort (CO1/CO11). Since
1986, the French Perinatal Cohort has prospectively enrolled
HIV-infected women delivering in 90 centers throughout
France. The protocol was detailed elsewhere [5]. Mothers and
children were observed according to recommended standards
of care, which are regularly published and updated [14]. No
specific recommendations for immunovirological evaluation,
HIV-1 treatment, and obstetrical care were made for women
included in the cohort. This cohort study was approved, according to French laws, by the Cochin Hospital Institutional
Review Board and the French computer database watchdog
commission (Commission Nationale de l’Informatique et des
Libertés).
Study population. We conducted a case-control survey
among persons in a French Perinatal Cohort subsample who
met the following criteria: (1) the mother was HIV-1 infected
and delivered in French Perinatal Cohort sites in mainland
France during the period from 1 January 1997 through 31
December 2006; (2) ART was administered during pregnancy,
regardless of the type of ART and time of initiation; (3) gestational age at delivery was at least 37 weeks; (4) the last viral
load determined before or at delivery was !500 copies/mL; (5)
there was no evidence of breast-feeding; and (6) the HIV-1
status of the child was established.
An infant was considered to be infected with HIV-1 if the
virus was detected by virological testing (HIV-1 DNA or HIV1 RNA polymerase chain reaction [PCR]) of 2 separate samples
or if anti–HIV-1 antibodies persisted after 18 months of age.
The timing of transmission was considered to be in utero if
the result of the HIV-1 DNA or RNA PCR during the first
week of life was positive or to be intrapartum if the test result
was negative [15, 16].
An infant was considered to be noninfected if virological test
results were negative for 2 separate samples, at least 1 of which
was obtained after termination of neonatal prophylactic treatment or if the serological test result was negative after 18
months. Laboratory tests were performed on site, as described
elsewhere [5, 17–19].
Among the eligible population, as defined above, we selected
all HIV-1–infected children (case patients) and 3 HIV-1–un586 • CID 2010:50 (15 February) • Tubiana et al
infected children (control subjects) born to mothers enrolled
in the French Perinatal Cohort just before or after each case
patient in the same maternity. For 3 control-subject mothers
who participated in a clinical trial [20], we added an extra
mother-child pair. Overall, 19 case patients and 60 control subjects were included. We used the threshold of 500 copies/mL
to define “controlled” plasma HIV-1 RNA level at delivery for
different reasons. First, the sensitivity of PCR assays increased
from 1996 to 2006, and stored samples were not always available
to retest with a 50-copy/mL cutoff. Second, we previously found
no difference in MTCT rates when we considered thresholds
of 50 copies/mL (0.4%; 95% CI, 0.1–0.9) versus 500 copies/
mL (0.6%; 95% CI, 0.3–1.0) [5]. Moreover, recent French
guidelines use the 500-copy/mL cutoff to recommend elective
Cesarean delivery for women who are receiving combination
ART [11].
Data collection. We reviewed medical files for all case patients and control subjects to monitor available data and to
collect supplementary data that were not in the original French
Perinatal Cohort case-report forms. Information available for
analyses were geographical origin, gestational age at booking,
history of HIV-1 infection, all plasma levels of HIV-1 RNA and
CD4+ T cell counts during pregnancy and the last determinations before pregnancy, all types and numbers of ART regimens received during pregnancy, obstetrical and clinical data,
gestational age at delivery, and mode of delivery. Plasma HIV1 RNA and CD4+ T cell counts were not measured at the same
gestational ages for all patients, depending on time at HIV-1
diagnosis, booking, and clinician decision.
First and last ART regimens received during pregnancy were
categorized into 3 classes: monotherapy involving a nucleoside
reverse-transcriptase inhibitor, almost exclusively zidovudine;
dual-drug therapy (ie, 2 nucleoside reverse-transcriptase inhibitors), mostly zidovudine-lamivudine; and highly active antiretroviral therapy (HAART; ⭓3 drugs of any class). Maternal
intrapartum prophylaxis was classified as none versus intravenous zidovudine and/or single-dose nevirapine. Neonatal
prophylaxis initiated by day 3 was classified as none, zidovudine
monotherapy, or combination therapy.
Statistical analysis. Case patients and control subjects were
compared for all of the aforementioned factors using exact
conditional logistic regression [21]. Evolution of the log10 viral
load during pregnancy was described separately in case patients
and in control subjects using locally weighted regression (lowess), overall, and among mothers who initiated ART during
pregnancy [22]. We estimated the proportion of subjects with
a viral load !500 copies/mL and the proportion with a CD4+
T cell count 1200 cell/mm3, the median log10 viral load, and
the median CD4+ T cell count with interquartile ranges at
14 4 weeks, 28 2 weeks and 32 2 weeks. We also esti-
mated median zenith log10 viral load and nadir CD4+ T cell
count during pregnancy.
Viral load and CD4+ T cell count, which were coded as binary
and continuous variables, were compared statistically at each
instance. Multivariate logistic regression was adjusted for noncollinear variables associated with transmission with P values
!.20. Because the immunovirological measures were not performed at the same gestational ages for all patients, as explained
in the “Data collection” subsection above, we used the viral
load and CD4+ T cell count measured at 30 4 weeks to minimize the number of missing immunovirological data. P ! .05
was used to determine statistical significance. Analyses were
conducted using SAS software, version 9.1 (SAS Institute). Lowess curves were estimated with R software (R Foundation for
Statistical Computing).
RESULTS
Study population. Among 7425 mother- infant pairs included
in the French Perinatal Cohort from January 1997 through
December 2006, with an overall MTCT rate of 1.5% (115 of
7425 mother-infant pairs; 95% CI, 1.3%–2.4%), 4281 fulfilled
the study criteria. In this subgroup, 22 children were infected
(0.5%; 95% CI, 0.3%–0.8%). Three of them were excluded
(evidence of breast-feeding for 2 case patients and unclear data
for another). Finally, 19 case and 60 control mother-infant pairs
were included in the study.
Maternal and obstetrical characteristics. Case patients and
control subjects did not significantly differ in term of origin,
marital status, alcohol or drug use during pregnancy, gestational
age at booking, complications during pregnancy, or gestational
age at delivery (Table 1). The rate of premature membrane
rupture and the mode of delivery did not differ between case
patients and control subjects (47% and 48% underwent elective
Cesarean deliveries, respectively).
HIV-1 history. The proportion of women diagnosed with
HIV-1 infection before pregnancy was similar in both groups
(74% of case patients and 68% of control subjects), and 10%
had class C infection before pregnancy in each group (Table
2). Two case patients and 1 control subject were reported to
have primary infection during pregnancy.
ART in pregnancy. Case patients were receiving ART before
conceiving less often than were control subjects (15.8% vs
45.0%; P p .017) (Table 2). Among them, a similar proportion
(10.5% of case patients and 11.7% of control subjects) interrupted therapy during the first trimester. Among the women
who initiated ART during pregnancy (16 case patients and 33
control subjects), there was no difference in median gestational
age at the commencement of ART (29.5 gestational weeks
[range, 6–35 weeks] for case patients and 30.0 weeks [range,
16–34 weeks] for control subjects; P p .47).
Overall, the first ART regimen during pregnancy and the
type of ART at delivery were similar in both groups (Table 2).
Case patients and control subjects had similar rates of intrapartum prophylaxis use (100% vs 98.3%), single-dose nevirapine (5% in both groups), and type of postnatal prophylaxis
for infants. Problems of adherence to ART during pregnancy
were reported significantly more frequently in the medical file
for case patients (7 [37%] of 19) than for control subjects (7
[12%] of 60; P p .005).
HIV-1 RNA levels during pregnancy. As defined by the
selection criteria, the viral load nearest to delivery was !500
copies/mL for all mothers. However, the median zenith viral
load during pregnancy was significantly higher for case patients
than for control subjects (P p .001) (Table 2). It was !500
copies/mL for 0 case patients and for 40% of control subjects
and was 110,000 copies/mL for 63% of case patients and for
36% of control subjects. The viral load was tested with a threshold of 50 copies/mL in 14 case patients (74%) and 45 control
subjects (75%). Among them, 43% of case patients versus 71%
of control subjects presented with a viral load !50 copies/mL
near delivery (P p .07).
Overall, the viral load was initially higher and decreased more
slowly in case patients than in control subjects (Figure 1A).
The proportion of women with a viral load !500 copies/mL at
14 weeks was 0% for case patients versus 38% for control
subjects (P p .02). At 28 weeks, only 7.7% of case patients
versus 62.1% of control subjects had achieved a viral load !500
copies/mL (P p .005). The difference persisted at 32 weeks
(Table 3). The median viral load was also significantly higher
in case patients than in control subjects at weeks 14, 28, and
32 (Table 3).
The pattern was similar in the subgroup of 16 case patients
and 33 control subjects who initiated ART during pregnancy.
Although the gestational age at ART initiation did not differ,
the viral load started to decrease later in case patients than in
control subjects, as shown by the sharper slope of the viral load
curve (Figure 1B). The proportion of women with a viral load
!500 copies/mL at 28 weeks was 10% for case patients and
37.5% for control subjects, and at 32 weeks, the proportions
were 27.3% for case patients and 60.0% for control subjects
(Table 3).
CD4+ T cell counts during pregnancy. Maternal CD4+ T
cell counts did not differ significantly between case patients and
control subjects (Table 3), although more case patients had
CD4+ T cell counts !200 cells/mL at 32 weeks. No significant
difference was found for the nadir CD4+ T cell count during
pregnancy between the groups (Table 2).
Timing of MTCT. HIV-1 RNA PCR or DNA quantification
were performed on samples taken within 7 days of life for 16
of the 19 infected children (Table 4). HIV-1 was detected in 6
infants (37.5%) who were considered to have had in utero
transmission and was not detected in 10 infants (62.5%) who
Risk Factors for Residual HIV-1 MTCT • CID 2010:50 (15 February) • 587
Table 1. Comparison of Maternal and Obstetrical Characteristics between Case Patients
(for Whom There Was Transmission of Human Immunodeficiency Virus) and Control Subjects
(for Whom No Transmission Occurred)
Characteristic
Case patients
Control subjects
Year of delivery
1997–1999
4 (21.1)
14 (23.3)
2000–2002
2003–2006
8 (42.1)
7 (36.8)
26 (43.3)
20 (33.3)
Birth country of mother
France
5 (26.3)
14 (23.7)
Sub-Saharan Africa
North Africa
13 (68.4)
0 (0.0)
38 (64.4)
3 (5.1)
1 (5.3)
4 (6.8)
13 (72.2)
5 (27.8)
36 (63.2)
21 (36.8)
Other region
Marital status
Living in couple
Single
Drug use during pregnancy
Use of drugs, excluding cannabis
Substitutes to drugsb
Tobaccoc
d
Alcohol
Gestational age at booking, median weeks (range)
Complications during pregnancy
Pre-eclampsia
Gestational diabetes
Intrahepatic cholestasis of pregnancy
a
P
.69
.83
.67
0 (0.0)
2 (3.3)
.72
0 (0.0)
1 (1.7)
.63
1 (5.3)
12 (20.0)
.08
0 (0.0)
12 (5–34)
3 (5.0)
13 (6–33)
.31
.39
0 (0.0)
0 (0.0)
1 (5.3)
0 (0.0)
0 (0.0)
0 (0.0)
Hospitalization
Gestational age at delivery, median weeks (range)
Premature rupture of membranes
Yes
5 (26.3)
39 (37–41)
1 (5.9)
5 (8.9)
No
Mode of delivery
16 (94.1)
51 (91.1)
9 (47.4)
3 (15.8)
7 (36.8)
29 (48.3)
6 (10.0)
25 (41.7)
.77
1 (5.9)
7 (11.9)
.51
16 (94.1)
11 (57.9)
52 (88.1)
31 (51.7)
.67
Elective Cesarean delivery
Emergency
Vaginal
Instrumental delivery
Yes
No
Child’s sex (female vs male)
14 (23.3)
38 (37–41)
.13
.89
.95
.52
NOTE. Data are no. (%) of subjects, unless otherwise indicated.
a
b
c
d
Statistical tests are performed using exact conditional logistic regression
Drugs obtained through a maintenance program (eg, methadone or buprenorphine).
Consumption of 110 cigarettes per day.
Consumption of 13 glasses of alcohol per day.
were considered to have had intrapartum transmission, because
none were breast-fed. When comparing the 10 children infected
intrapartum and their control subjects, the pattern was the same
as for the overall population: the proportion of infants with a
viral load !500 copies/mL at 28 and 32 weeks was significantly
lower for case patients than for control subjects. The same trend
was also observed for in utero transmission, although differences did not reach statistical significance, likely because of the
small numbers.
588 • CID 2010:50 (15 February) • Tubiana et al
Multivariate analysis. Multivariate analysis was performed
in the overall study population (Table 5). Plasma HIV-1 load
at 30 4 weeks was found to be significantly associated with
transmission, after adjustment for CD4+ T cell count at same
time and for timing of ART initiation (before pregnancy, during
2 first trimesters, and during the last trimester). The adjusted
odds ratio for transmission associated with a viral load ⭓500
copies/mL versus !500 copies/mL was 23.2 (95% CI, 3.5–553;
P ! .001). The CD4+ T cell count and the timing of ART ini-
Table 2. Comparison of Human Immunodeficieny Virus (HIV)–1 Infection History and Strategies for Prevention of Mother-to-Child
Transmission between Case Patients (for Whom There Was Transmission of HIV-1) and Control Subjects (for Whom No Transmission
Occurred)
Case patients
History of HIV-1 infection
HIV-1 infection diagnosed before pregnancy
14 (73.7)
41 (68.3)
.67
2 (10.5)
0 (0.0)
6 (10.0)
0 (0.0)
1.99
Primary infection during pregnancy
ART received at time of conception
2 (10.5)
3 (15.8)
1 (1.7)
27 (45.0)
.10
.017
ART interruption
Gestational age at commencement of first ART regimen, median weeks (range)
2 (10.5)
7 (11.7)
.83
18.0 (0–34)
30.0 (16–34)
.04
.47
History of CDC stage C disease before pregnancy
CDC stage C disease during pregnancy
Overall
For mothers not treated at conception
Gestational age at commencement of last ART regimen, median weeks (range)
Overall
For mothers not treated at conception
First ART regimen received during pregnancy
NRTI monotherapy
NRTI dual-drug therapy
NRTI triple-drug therapy
PI–containing HAART
Non-NRTI–containing HAART
PI- and non-NRTI–containing HAART
Last ART regimen received during pregnancy
NRTI monotherapy
NRTI dual-drug therapy
NRTI triple-drug therapy
PI-containing HAART
Non-NRTI-containing HAART
PI- and non-NRTI–containing HAART
CD4+ T cell count during pregnancy, median cells/mm3
Nadir
Zenith
CD4+ T cell count at 30 4 weeks, cells/mm3
27.0 (0–35)
29.5 (6–35)
31 (13–37)
30 (13–37)
3 (15.7)
4 (21.1)
1
11
0
0
(5.3)
(57.9)
(0)
(0)
1 (5.3)
6
0
12
0
(31.5)
(0)
(63.2)
(0)
0 (0)
292 (121–744)
4.29 (3.09–4.49)
Control subjects
a
Characteristic
.007
.82
15 (25.0)
13 (21.6)
.66
6
21
4
1
(10.0)
(35.0)
(6.7)
(1.7)
7 (11.7)
20
4
27
1
1 (1.7)
353 (114–1026)
3.52 (1.3–5.21)
3 (15.8)
16 (29.1)
6 (31.6)
20 (36.4)
5 (26.3)
5 (26.3)
14 (25.5)
5 (9.1)
500–9999
2 (10.5)
9 (47.4)
36 (66.7)
12 (22.2)
⭓10,000
8 (42.1)
6 (11.1)
Plasma HIV-1 RNA level nearest to the delivery, copies/mL
⭓50
!50
Less than the threshold of detection but greater than the threshold of 50
copies/mL
Reported poor adherence to treatment
.82
(33.2)
(6.7)
(45.0)
(1.7)
350–499
!500
.84
28 (0–34)
32 (18–34)
⭓500
200–349
!200
Plasma HIV-1 RNA level at 30 4 weeks, copies/mL
P
.184
.007
.20
!.001
8 (57.1)
13 (28.9)
6 (42.9)
32 (71.1)
.07
5 (26.0)
15 (25.0)
7 (36.8)
7 (11.7)
.005
19 (100.0)
59 (98.3)
.60
1 (5.3)
3 (5.0)
.75
3 (15.8)
11 (18.6)
.63
Intrapartum prophylaxis
Zidovudine infusion during per partum
Maternal single-dose viramune
Postnatal prophylaxis (zidovudine plus lamivudine versus zidovudine alone)
NOTE. Data are no. (%) of subjects, unless otherwise indicated. ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; HAART, highly
active antiretroviral therapy; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.
a
Statistical tests are performed using exact conditional logistic regression.
Figure 1. Evolution of median plasma log10 HIV-1 RNA level during pregnancy estimated by lowess curve (bold line) overall (A; 19 case patients and
60 control subjects) and in mothers initiating antiretroviral therapy during pregnancy (B; 16 case patients and 33 control subjects).
tiation did not remain significantly associated with transmission. The results did not change when we excluded the 3 case
patients with primary infection during pregnancy (data not
shown).
DISCUSSION
With progress in multidisciplinary management of HIV-1–
infected pregnant women and their neonates, a low rate of
MTCT has been obtained during the past decade in countries
where such progress could be implemented [1–5]. In recent
studies, the main risk factors of transmission in non–breastfeeding populations are high viral load and premature delivery.
Together, these factors account for most cases of transmission
in our cohort [5], as well as other major cohorts [1, 2, 4].
The rate of “residual” MTCT is as low as 0.5% in term
deliveries in which the maternal viral load was !500 copies/
mL. Nonetheless, residual transmission accounted for 20% of
the HIV-1–infected children in our cohort over the period
1997–2006. Because these cases are considered to be treatment
failures, identifying their causes might allow us to prevent them
altogether.
590 • CID 2010:50 (15 February) • Tubiana et al
In the present study, the only factor that remained independently associated with residual transmission of HIV-1 was early
control of the plasma HIV-1 RNA level. Although the maternal
viral load was !500 copies/mL at delivery in all mothers, it
started to decrease much earlier in control subjects than in case
patients. The viral load was significantly lower at 14, 28, and
32 weeks in control subjects than in case patients. Because the
gestational age at the time of blood sampling varied between
patients, we analyzed measures at 30 4 weeks in the multivariate analysis, using exact conditional logistic regression
adapted for small size matched case-control study: although
the 95% CI for the adjusted odds ratio was wide, viral load
remained significantly and strongly associated with transmission, independent of CD4+ T cell count and of the time at
which ART was initiated during pregnancy (adjusted odds ratio,
23.2; 95% CI, 3.5–553; P ! .001).
Case patients were much less likely to be receiving therapy
before conceiving than were control subjects (16% vs 45%),
which may partly explain why the viral load was controlled
later. None of the case patients had a viral load !500 copies/
mL during the entire pregnancy, compared with 40% of control
14
32 2 weeks
14
32 2 weeks
12
15
28 2 weeks
32 2 weeks
15
32 2 weeks
b
33.3
25.0
9.1
387 (191–472)
370 (190–518)
365 (211–470)
21.4
7.7
0.0
3.6 (3.0–4.2)
4.2 (3.3–4.9)
4.5 (3.9–4.8)
Value
b
Statistical tests were performed using exact conditional logistic regression
Data are median (interquartile range) or percentage of subjects.
12
28 2 weeks
a
11
14 4 weeks
CD4+ T cell count !200 cells/
mm3
11
14 4 weeks
CD4 T cell count, cells/mm
3
13
28 2 weeks
+
10
14 4 weeks
HIV-1 RNA level !500 copies/mL
10
13
14 4 weeks
No. of subjects
28 2 weeks
HIV-1 RNA level, log10 copies/mL
Characteristic, period
Case patients
40
31
40
40
31
40
38
29
42
38
29
42
No. of subjects
b
10.0
3.2
7.5
426 (333–506)
419 (316–504)
399 (320–500)
71.1
62.1
38.1
2.0 (1.4–3.2)
2.4 (2.0–3.4)
3.3 (2.0–4.2)
Value
Control subjects
All women
.02
.22
.81
.20
.08
.14
.004
.005
.02
.005
!.001
.01
P
a
12
9
9
12
9
9
11
10
9
11
10
9
No. of subjects
b
41.7
33.3
11.1
275 (190–469)
276 (169–448)
217 (211–470)
27.3
10.0
0.0
3.5 (2.2–3.9)
4.5 (3.3–4.9)
4.3 (3.9–4.8)
Value
Case patients
23
15
18
23
15
18
20
14
20
20
14
20
No. of subjects
8.7
0.0
5.6
440 (340–527)
410 (320–570)
414 (347–501)
60.0
37.5
15.0
2.4 (2.1–3.7)
3.2 (2.6–3.7)
3.7 (3.0–4.8)
Valueb
Control subjects
Women who initiated ART during pregnancy
.06
.38
.75
.39
.02
.79
.3
.75
.66
.26
.11
.08
Pa
Table 3. Comparison of Evolution of Viral Load and CD4+ T Cell Count during Pregnancy between Case Patients (for Whom There Was Transmission of Human Immunodeficiency
Virus) and Control Subjects (for Whom No Transmission Occurred)
7
8
32 2 weeks
8
6
9
28 2 weeks
32 2 weeks
9
32 2 weeks
d
c
b
22.2
0.0
0.0
467 (200–539)
473 (276–539)
23
17
21
23
17
21
20
15
21
20
15
21
No. (%) of subjects
c
.010
.037
.07
.004
.010
.002
P
d
0.0
0.0
4.8
.031
.62
436 (374–506) .26
419 (332–504) .25
380 (320–459) .45
80.0
73.3
42.9
2.0 (1.4–2.4)
2.2 (1.4–2.9)
3.0 (2.0–4.2)
Value
Control subjects
No HIV-1 detected by HIV-1 RNA polymerase chain reaction or DNA quantification within 7 days of life for case patients.
HIV-1 detected by HIV-1 RNA polymerase chain reaction or DNA quantification within 7 days of life for case patients.
Data are median (interquartile range) or percentage of subjects.
Statistical tests were performed using exact conditional logistic regression.
6
28 2 weeks
a
6
14 4 weeks
CD4+ T cell count, !200 cells/
mm3
6
14 4 weeks
CD4+ T cell count, cells /mm3
304 (211–455)
25.0
7
32 2 weeks
14.3
5
28 2 weeks
0.0
3.7 (2.7–4.3)
4.0 (3.3–4.9)
4.8 (4.8–5.0)
c
Value
14 4 weeks
HIV-1 RNA level !500 copies/mL
5
28 2 weeks
No. (%) of subjects
14 4 weeks
HIV-1 RNA level, log10 copies/mL
Characteristic, period
Case patients
Intrapartum transmission
a
4
3
5
4
3
5
4
3
5
4
3
5
No. (%) of subjects
Value
c
50.0
66.7
20.0
271 (191–369)
169 (138–292)
365 (217–470)
25.0
0.0
0.0
3.3 (2.6–3.6)
4.5 (3.9–4.5)
3.9 (3.5–4.1)
Case patients
10
9
12
10
10
12
11
10
14
11
10
14
No. (%) of subjects
.40
.75
.36
.65
.03
.29
Pd
20.0
0.0
0.0
.42
.06
.07
487 (270–527) .39
439 (360–490) .03
497 (416–617) .07
54.5
50.0
28.6
2.4 (1.4–3.9)
3.0 (2.4–3.5)
3.4 (2.6–4.1)
Valuec
Control subjects
In utero transmissionb
Table 4. Comparison of Evolution of Viral Load and CD4+ T Cell Count during Pregnancy between Case Patients (for Whom There Was Transmission of Human Immunodeficiency Virus
[HIV]–1) and Control Subjects (for Whom No Transmission Occurred), According to Time of HIV-1 Transmission
Table 5. Multivariate Analysis: Independent Factors Associated with Residual Mother-to-Child Transmission of
Human Immunodeficiency Virus
No. (%) of
subjects
Characteristic
Case
patients
Control
subjects
a
Univariate analysis
Crude OR
(95% CI)
P
a
Multivariate analysis
Adjusted OR
(95% CI)
Plasma HIV-1 RNA at 30 4 weeks, copies/mL
⭓500
17 (89.5) 18 (33.3) 22.6 (3.3– 986) !.001 23.2 (3.4–553)
!500
2 (10.5) 36 (66.7)
1
P
!.001
1
CD4+ T cell count at 30 4 weeks, cells/mm3
!200
⭓200
Time of ART initiation
Third trimester (ie, ⭓28 weeks)
First or second trimester (ie, !28 weeks)
Before conception
5 (26.3) 5 (9.1)
14 (73.7) 50 (90.9)
3.7 (0.8–19.1)
1
.085
6.1 (0.6 –182)
1
.09
9 (47.4) 23 (38.3)
3.4 (0.8–17.6)
.034
1.1 (0.2–6.1)
.24
7 (36.8) 10 (16.7)
3 (15.8) 27 (45.0)
6.6 (1.4–39.9)
1
5.1 (0.6–130)
1
NOTE. ART, antiretroviral therapy; CI, confidence interval; OR, odds ratio.
a
Exact conditional logistic regressions were used for univariate and multivariate analysis.
subjects. In mothers who started ART during pregnancy, the
gestational age at initiation of treatment did not differ between
the groups (30 weeks), but the viral load also decreased earlier
for control subjects. This suggests that delayed ART initiation
is not the only reason for late control of the viral load. Poor
adherence to treatment was more often noted in case patients.
Although adherence was not recorded with a standardized
method, it was specified by the physicians during prenatal visits
and thus could not be biased by the HIV-1 status of the child.
Incomplete or delayed adherence may play a role in the delayed
control of the viral load observed in the transmitters.
Ten infants were considered to have been infected intrapartum. Compared with their control subjects, the maternal viral
load was also significantly higher at 14, 28, and 32 gestational
weeks. The role of maternal viral load during pregnancy on
MTCT could be expected for in utero transmissions [23–27],
whereas it was more unexpected for intrapartum transmission
from women with a low viral load at delivery. On one hand,
we cannot exclude that exposure to antenatal HAART may
decrease the sensitivity of PCR in the first days after birth, thus
overestimating intrapartum transmission [28]. On the other
hand, control of the plasma viral load at delivery does not
reflect exactly HIV-1 replication in the compartments involved
in the vertical transmission during delivery. Shedding of HIV1 in the genital tract was described in women with low or
undetectable viral load who were receiving ART [29–31] and
has been identified as a risk factor for vertical transmission
[32]. Recent studies have reported that HIV-1 RNA remained
detectable in genital secretions in 35% of case patients after 28
days of HAART [33] and in 5% after 18 weeks [34]. It might
be speculated that prolonged control of viral replication during
ART may optimize the reduction of HIV-1 genital shedding.
Further investigation is needed to confirm this hypotheses. In
our study, the delayed and sharper slope of plasma viral load
in case patients than in control subjects reflects a higher exposure to HIV-1 during the pregnancy for the mother and could
be associated with a lesser protection against HIV-1 transmission for the infant during delivery.
The cutoff value of 500 copies/mL that we used to define
virological “control” is greater than the currently used threshold. Among women whose delivery samples were tested with
more-sensitive techniques, the proportion with a viral load !50
copies/mL was lower for case patients than for control subjects,
although the trend did not reach statistical significance. In addition, the MTCT rate in mothers with viral load !50 copies/
mL in our cohort was 0.4% [5], confirming that there is no
threshold under which no residual transmission can occur.
Case patients and control subjects did not differ for geographical origin, late booking, complications during the pregnancy, gestational age at HIV-1 diagnosis, or type of first and
last ART. There was no difference in the mode of delivery, use
of intravenous zidovudine during labor or delivery, or postnatal
prophylaxis. Control subjects were matched with case patients
by obstetrical center and date of delivery to limit bias due to
variations in obstetrical and medical management. However,
because of small number of infected children, this case-control
survey has limited power to identify any factors that may have
a weak impact on MTCT and could explain discrepancies with
the results of other studies [2, 9].
Even if our data suggest that control of the maternal viral
load during the entire pregnancy with the lowest viral load
should offer maximum protection from MTCT, we cannot use
our results to define the optimal gestational age at which ART
should be started, the optimal gestational age at which viral
Risk Factors for Residual HIV-1 MTCT • CID 2010:50 (15 February) • 593
load should be controlled, or the threshold of viral load to
reach. In addition, in a context of very low transmission rate,
as achieved in our settings, the benefit of an early ART has to
be balanced with potential risk of toxicity for the mother and
the infant induced by ART during pregnancy [35–38].
The main finding of this study is that a lack of early and
sustained control of maternal HIV-1 load appears strongly associated with residual transmission of HIV-1 to infants born
to mothers with low viral load near delivery, independent of
the timing of ART initiation and the CD4+ T cell count. This
concerns intrapartum as well as in utero transmission. Therefore, to avoid the risk of residual MTCT, the maternal viral
load should be controlled well before delivery. The HIV-1 load
during pregnancy should be monitored closely in order to take
measures soon enough, such as reinforcing adherence, therapeutic dose adjustment, or switching for efficient ART combinations. Guidelines on prevention of HIV-1 MTCT should
take into account not only CD4+ T cell count and risk of
preterm delivery, but also the baseline maternal plasma viral
load for deciding when to start ART during pregnancy.
THE ANRS FRENCH PERINATAL COHORT
Hôpital d’Aix en Provence* (Tadrist B.); Hôpital Nord, Amiens
(Decaux N., Douadi Y., Gondry J., Li Thiao Te V., Schmit J.
L.); Hôpital d’Angers (Fournié A.); Hôpital Victor Dupouy,
Argenteuil (Allisy C., Brault D.); Hôpital Paris La Roseraie*,
Aubervilliers (Rozan M. A.); Hôpital Robert Ballanger, Aulnay
(Questiaux E., Zakaria A., Goldenstein C.); Hôpital Saint
Claude, Basse-Terre* (Sibille G.); Hôpital de Bastia (Pincemaille
O., Rusjan); Hôpital de la Côte Basque, Bayonne (Bonnal F.,
Cayla C.); Clinique du Blanc Mesnil* (Balde P.); Hôpital Saint
Jacques, Besançon (Estavoyer J. M., Maillet R.); Hôpital Avicenne, Bobigny (Bentata M.); Hôpital Jean Verdier, Bondy (Benoist L., Bolie S., Bonier N., Lachassine E., Rodrigues A.); Hôpital Pellegrin, Bordeaux (Douard D., Roux D., Schaeffer V.);
Hôpital Ambroise Paré*, Boulogne Billancourt (Zenaty D.);
Hôpital Clémenceau, Caen (Brouard J., Goubin P.); Hôpital
André Rosemon, Cayenne (Elenga N.); Hôpital Beaujon*, Clichy (De Curtis A.); Hôpital de Creil (Carpentier B., 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., 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, EvryCorbeil (Chevron, Devidas A., Granier M., Guignier M., Lakhdari Y., Marchand C., May A., Nguyen R., Turpault I.); Hôpital
594 • CID 2010:50 (15 February) • Tubiana et al
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 J. P., Esnault J. L., Leautez S., Perré
P., Suaud I.); Hôpital de La Seyne sur Mer (Chamouilli J. M.);
Hôpital Louis Domergue, La Trinité* (Hugon N.); Hôpital André Mignot, Le Chesnay (Hentgen V., Messaoudi F.); Hôpital
de Bicêtre, Le Kremlin-Bicêtre (Fourcade C., Fridman S., Peretti
D.); Hôpital Jeanne de Flandres, Lille (D’angelo S., Hammou
Y., Mazingue F.); Hôpital Dupuytren*, Limoges (De lumley L.);
Hôpital de Longjumeau (Bailly-Salin P., Turpault I., Seaume
H.); Hôpital Hôtel Dieu-Hôpital Debrousse, Lyon (Bertrand
Y., Bertrand S., Brochier C., Cotte L., Kebaı̈li 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 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); Maternité Régionale A. Pinard, Nancy
(Hubert C.); Hôpital de Nanterre* (Karoubi P.); Hôpital de
Nantes (Brunet-François C., Mechinaud, Reliquet V.) Hôpital
de Neuilly sur Seine* (Berterottiere D.); Hôpital l’Archet-Fondation Lenval, Nice (Bongain A., Deville A., Galiba E. Monpoux
F.,); Hôpital Caremeau, Nı̂mes (Dendale-Nguyen J.); Hôpital
Orléans (Arsac P.); Hôpital d’Orsay (Chanzy S., De Gennes C.,
Isart V.); Hôpital Bichat, Paris (Bastian H., Batallan A., Matheron S.); Hôpital Boucicaut*, Paris (Lafay Pillet M. C.); Hôpital
Cochin-Port Royal, Paris (Boudjoudi N., Firtion G., Fouchet
M., Goupil I., Pannier A.); Hôpital Lariboisière, Paris (Ayral
D., Ciraru-Vigneron N., Mouchnino G.); Hôpital des Métallurgistes*, Paris (Rami M.); Institut Mutualiste Montsouris*,
Paris (Carlus Moncomble C.); Hôpital Necker, Paris (Boucly
S., Blanche S., Maignan A., Parat S., Rouzioux C.,Viard J. P.,
Yamgnane A.); Hôpital Notre Dame du Bon Secours, Paris
(Aufrant C.); Hôpital Pitié Salpêtrière, Paris (Bonmarchand M.,
De Montgolfier I., Edeb N., Lemercier D., Marcel S., Pauchard
M., Tubiana R.); Hôpital Robert Debré, Paris (Faye A., Garion
D., Leveille S., Levine M., Ottenwalter A., Recoules A.); Hôpital
Saint-Antoine, Paris (Bui E., Carbonne B., Meyohas, Rodriguez
J.); Hôpital Hôpital Saint Michel, Paris (Aufrant C.); Hôpital
Tenon, Paris (Hervé F., Lebrette M. G.); Hôpital Trousseau,
Paris (Dollfus C., Tabone M. D., Vaudre G., Wallet A.); Hôpital
Marechal Joffre, Perpignan (Bachelard G., Medus M.); Hôpital
Les Abymes, Pointe-à-Pitre (Bataille H.); Hôpital de PoissySaint-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.).
*Closed centers.
Acknowledgments
10.
11.
12.
13.
14.
15.
16.
We thank all mothers who agreed to participate in this study. We also
thank Linda Assoul, Valérie Benhammou, Naı̈ma Bouallag, Leila Boufassa,
Nacima Chernai, Paulette Huynh, Carine Jasseron, Nadia Kessaci, Corinne
Laurent, Jacques Ngondi, Marlène Peres, Elisa Ramos, Thierry Wack, and
Jean-Paul Teglas.
Financial support. Agence Nationale de Recherche sur le SIDA et les
Hépatites virales (ANRS).
Potential conflicts of interest. All authors: no conflicts.
18.
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