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Two-Dose Intrapartum/Newborn Nevirapine and Standard Antiretroviral Therapy to Reduce Perinatal HIV Transmission
A Randomized Trial
Alejandro Dorenbaum, MD;
Coleen K. Cunningham, MD;
Richard D. Gelber, PhD;
Mary Culnane, MS, CRNP;
Lynne Mofenson, MD;
Paula Britto, MS;
Claire Rekacewicz, MD;
Marie-Louise Newell, PhD;
Jean Francois Delfraissy, MD;
Bethann Cunningham-Schrader, MS;
Mark Mirochnick, MD;
John L. Sullivan, MD;
for the International PACTG 316 Team
JAMA. 2002;288:189-198.
ABSTRACT
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Context A 2-dose intrapartum/newborn nevirapine regimen reduced perinatal human
immunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatal
antiretroviral therapy (ART). However, it is unknown whether the addition
of the 2-dose nevirapine regimen to standard ART would further reduce perinatal
HIV transmission.
Objective To determine whether a 2-dose nevirapine regimen can decrease perinatal
transmission of HIV in nonbreastfeeding women receiving standard ART.
Design and Setting International, blinded, placebo-controlled, phase 3 trial enrolling
women between May 1997 and June 2000 at clinical sites providing care for
HIV infection throughout the United States, Europe, Brazil, and the Bahamas.
Participants A total of 1270 women received nevirapine (n = 642) or placebo (n =
628). Infants were followed up for 6 months to determine HIV-infection status,
which was available for 1248 deliveries.
Intervention A 200-mg dose of oral nevirapine to women after onset of labor and a
2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours after
birth.
Main Outcome Measures Detection of HIV infection in infants and grade 3 and 4 toxic effects
in women and newborns.
Results After review by the data and safety monitoring board, the trial was
stopped early because the overall transmission rates were significantly lower
than assumed for the study design. Antenatal ART included zidovudine alone
in 23%; combinations without protease inhibitors in 36%; and combinations
with protease inhibitors in 41%. Thirty-four percent of women had elective
cesarean delivery. No significant safety concerns were identified for women
or infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidence
interval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%;
95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the difference
in transmission rate (-0.2) between the 2 study arms ranged from -1.5%
in favor of nevirapine to 1.2% in favor of placebo (P
= .82, Fisher exact test). The transmission rate was higher in women with
lower baseline CD4 cell counts and higher delivery HIV RNA levels, but there
was no significant difference between treatment arms in any subgroup.
Conclusion Risk of perinatal HIV transmission was low and no benefit from additional
intrapartum/newborn nevirapine was demonstrated when women received prenatal
care and antenatal ART, and elective cesarean section was made available.
INTRODUCTION
Transmission of human immunodeficiency virus (HIV) from mother to child
can occur in utero and during or after delivery.1
Most transmission occurs late in pregnancy or at the time of delivery.2 The results of the Pediatric AIDS [acquired immunodeficiency
syndrome] Clinical Trials Group (PACTG) 076, published in 1994, offered proof
of the concept that a zidovudine regimen given antepartum, intrapartum, and
to the newborn for 6 weeks could significantly reduce HIV transmission.3 Implementation of this regimen in the developed world
has reduced transmission rates of perinatal HIV to between 5% and 8%.4-6 About two thirds of
the remaining transmission occurs intrapartum,3-4
and therefore has the potential to be further reduced by additional intrapartum
interventions.
Nevirapine is a potent nonnucleoside reverse transcriptase inhibitor
that rapidly reduces viral load, is well absorbed orally, and readily crosses
the placenta. The safety and pharmacokinetics of nevirapine administered to
pregnant women during labor and to their newborns were previously evaluated.7-8 Administration of a 200-mg oral dose
to women during active labor with a 2-mg/kg oral dose to their newborns between
48 and 72 hours after birth maintained newborn nevirapine concentrations above
100 ng/mL (10 times the in vitro inhibitory concentration) through the first
7 days of life.
Recommendations have been developed, which reflect studies occurring
subsequent to the PACTG 076, regarding the potential benefit of combination
therapy in reducing perinatal transmission as well as for maternal disease
during pregnancy (http://hivatis.org/trtgdlns.html). During the
time the PACTG 316 trial was being conducted, investigators showed that the
2-dose maternal/newborn nevirapine regimen produced a decrease in maternal
to newborn HIV transmission compared with an ultrashort course of zidovudine
in predominantly breastfeeding women in Uganda who were not receiving antiretroviral
therapy (ART) (13.1% vs 25.1%, respectively, at 14-16 weeks).9
It remained unknown if this simple nevirapine regimen would provide additional
benefit in the interruption of mother to newborn transmission of HIV in nonbreastfeeding
women receiving standard ART. To test the hypothesis that a 2-dose intrapartum/newborn
nevirapine regimen in addition to standard ART could further reduce perinatal
HIV transmission, the following randomized, placebo-controlled trial was conducted.
METHODS
Trial Design
The PACTG 316 study was a phase 3, international, multicenter, randomized,
double-blind study of intrapartum and newborn nevirapine regimens in addition
to standard ART (Figure 1). In addition
to US PACTG sites, international collaborating sites were added to obtain
sufficient numbers of subjects to address the primary study question, and
subjects in Europe, Brazil, and the Bahamas were enrolled. In Europe, 2 study
groups participated (Agence Nationale de Recherches sur le SIDA [ANRS] and
the European Collaborative Study [ECS]).10-11
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Figure. Enrollment and Accessibility for the
Primary Analysis in PACTG 316
Asterisk indicates newborns who received study drug indirectly through
maternal dosing; 98% received an additional dose directly to the newborn.
PACTG 316 indicates Pediatric AIDS Clinical Trials Group 316; HIV, human immunodeficiency
virus.
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The study protocol and informed consent were reviewed by the institutional
review board at each study site. After written informed consent was obtained,
HIV-infected pregnant women were randomized to either nevirapine (200 mg of
oral nevirapine at onset of labor and 2 mg/kg of oral nevirapine for newborns
between 48 and 72 hours after birth) or the corresponding placebo doses. Study
drug remained at the hospital where delivery was planned and was directly
administered by medical staff when delivery was determined to be likely within
24 hours. An additional dose of nevirapine or placebo could be dispensed to
the mother if labor continued more than 48 hours after the initial dose or
to the newborn immediately after delivery if the mother did not receive study
drug or received her dose less than a hour prior to delivery.
In addition to study medication, participating women were receiving
standard ART, as determined by their health care clinician, which could include
any licensed antiretroviral agent except a nonnucleoside reverse transcriptase
inhibitor. Women were encouraged to receive the PACTG 076 zidovudine regimen
as a minimum therapy.3
Study Population
Eligible subjects were HIV-infected women who were 13 years or older
(or of legal age to give consent) and at least 28 weeks' gestation. Following
closure of another study (PACTG 185), which had enrolled patients at 20 weeks'
or more gestation,4 PACTG 316 lowered the gestational
age to 20 weeks. Gestational age was estimated using either reliable menstrual
history that corresponded with uterine size, or physical examination, and/or
sonogram performed at less than 20 weeks gestation. Women were excluded from
the study if enrolled in other perinatal treatment trials; previously received
nonnucleoside reverse transcriptase inhibitors; hypersensitive to benzodiazepines;
or had elevated serum alanine aminotransferase (>10 times upper limit of normal).
Women who intended to breastfeed and those pregnancies identified with a fetal
anomaly incompatible with life were also excluded.
Evaluations
Evaluations that included safety assessments were conducted for women
throughout follow-up to 6 weeks postpartum and for infants throughout follow-up
to age 6 months. Safety assessments consisted of obtaining medical history,
physical examination, and laboratory testing. Women underwent clinical and
laboratory evaluation at enrollment, during labor, and between 48 and 72 hours
postpartum and 4 and 6 weeks postpartum. Evaluations included history and
physical examination, complete blood count, CD4 cell count, blood chemistry
levels, and HIV RNA quantification.
Newborns had a complete birth history recorded. Additional study visits
occurred between 48 and 72 hours after birth; between days 6 and 9; between
weeks 4 and 6; and at months 3 and 6. History and physical examination were
obtained at each visit through the end of the 6-month follow-up. The safety
laboratory tests to obtain complete blood count and alanine aminotransferase
were performed after birth, between days 6 and 9 of life, and again between
weeks 4 and 6. If laboratory results were significantly abnormal, testing
was repeated until the abnormalities resolved. A HIV DNA polymerase chain
reaction (PCR) assay was performed at birth, between weeks 4 and 6, at month
3, and at month 6. If any DNA PCR assay was positive, the infant returned
to the study site for another DNA PCR assay and a peripheral blood mononuclear
cell culture. Women or infants discontinued from the study prior to receiving
study medication continued to be followed up for a prespecified duration.
Virological Methods
The HIV DNA PCR assays were performed in laboratories certified by the
ACTG or another regional quality-assurance program. At all PACTG sites, and
at most international sites, DNA PCR assay was performed using Amplicor Detect
kits (Roche Diagnostic Systems, Branchburg, NJ) as outlined in the PACTG virology
manual.12 Although the commercial Amplicor
Detect assay is sensitive for HIV clade B subtypes, sensitivity is reduced
for non–clade B. Therefore, the international sites used the DNA PCR
method with optimal sensitivity in their patient populations. The HIV peripheral
blood mononuclear cell culture was required for infants with HIV-positive
DNA PCR assay results. The HIV culture was performed using fresh cells with
standard techniques.13
The HIV RNA quantitation was performed in laboratories certified by
the ACTG14 or other regional quality-assurance
program. Plasma was separated and frozen at -70°C within 30 hours
of collection. Analysis was done using either reverse transcriptase PCR (Amplicor
HIV Monitor, Roche Diagnostic Systems), nucleic acid sequence-based amplification
(Nuclisens, Organon Teknika Corp, Durham, NC) or branched-chain DNA signal
amplification (Quantiplex HIV RNA, Bayer Diagnostics, East Walpole, Mass)
per manufacturers' instructions.
Definition of HIV Infection in Infants
An infant was considered HIV-infected if specimens obtained at 2 different
time points tested positive for the virus (with HIV DNA PCR assay and/or culture).
Infants were considered uninfected if they had 2 HIV-negative DNA PCR assays,
one at or after age 1 month and the other after age 2 months. If infection
status could not be determined based on protocol-specified virological studies,
a subgroup of the study team, who were blinded to study treatment assignment,
reviewed clinical and virological data to determine HIV status. Infection
status was considered "indeterminate" if an infant had a positive assay, but
did not meet the definition of infected, or did not have a DNA PCR assay beyond
age 1 month. Twin births were assessed as a single HIV transmission if either
infant was infected with HIV, and as a single nonoccurrence of transmission
if both twins were uninfected. Twins were considered indeterminate if they
did not meet either of the above criteria.
Statistical Considerations
The study was designed to achieve an 80% power to detect a reduction
in HIV transmission from 5% in the control group to 2.5% in the nevirapine
group using a 1-sided .05-level test. Target accrual was 2009 patients to
obtain 1808 cases assessable for the primary analysis. Randomization was stratified
according to use of ART during pregnancy (none, monotherapy only, or multiagent
therapy) and CD4 cell count at randomization (<200, 200-399, or  400
cells/mm3).
The primary end point was incidence of HIV transmission from mother
to infant. Because the study was blinded and study treatment commenced at
labor and delivery, the independent data and safety monitoring board endorsed
an unbiased maximally powerful primary analysis that included only women who
were dispensed the study drug during labor.
The primary treatment comparison was based on a Fisher exact test, stratifying
by participating group.15 Fisher exact tests
were also used in all univariate analyses, including comparison of infection
rates between treatments within subgroups of patients, and comparison of infection
rates for different levels of a potential risk factor. P<.05 was considered significant. Logistic regression models were
used to assess the association between multiple risk factors and transmission.
Maternal and neonatal clinical and laboratory toxic effects were monitored
and reported according to the National Institutes of Health Division of AIDS
standardized grading system (grades extended from mild [grade 1] to serious
[grade 4]). Data analysis was performed by the Statistical and Data Management
Center of the Pediatric AIDS Clinical Trials Group at Harvard School of Public
Health.
Administrative and safety data were reviewed at least once per year
by an independent data and safety monitoring board composed of members from
the Division of AIDS in the National Institutes of Health. Four interim analyses
and 1 final efficacy analysis of the primary treatment comparison were planned.
At the third interim analysis in June 2000, the transmission rate in both
groups was significantly less than the 5% assumed for the study design. Because
a substantial increase in sample size would have been required to meet the
original study objectives, the data and safety monitoring board recommended
discontinuing new patient enrollment, continuing blinded follow-up for those
who had delivered, and removing women from the study who had not yet delivered.
Therefore, study enrollment was discontinued June 8, 2000. Sample size calculations
and interim stopping boundaries were based on the binomial data design module
of the program EaSt (Cytel Software Corp, Cambridge, Mass). Statistical analyses
were performed using SAS software (version 6.12, SAS Institute Inc, Cary,
NC).
RESULTS
Baseline Characteristics
Between May 13, 1997, and June 8, 2000, a total of 1506 women were enrolled.
The PACTG accrued patients during the entire period and enrolled 1052 women
from 67 sites distributed throughout mainland United States and Puerto Rico.
International groups began enrolling at the following times: ANRS, December
1998 (287 subjects at 21 sites); ECS, February 1999 (118 subjects at 14 sites);
the Bahamas, September 1999 (18 subjects at 1 site); and Brazil, December
1999 (31 subjects at 2 sites).
Of the 1506 women enrolled, 1270 received study drug and delivered a
newborn (Figure 1). These 1270 deliveries
resulted in 1245 singleton births and 25 sets of twins (total of 1295 newborns).
Study drug was not administered for 236 women primarily per data and safety
monitoring board study closure recommendation, precipitous delivery, or logistical
problems (Figure 1). The number
of women who did not receive intrapartum study drug had a similar distribution
between the nevirapine (n = 112) and placebo arms (n = 124) and between PACTG
and international groups. Ninety-eight percent of women (1245/1270) had a
final study visit at least 4 weeks postpartum and 98% of infants (1222/1248)
had a final study visit at least 5 months after birth.
The study drug was dispensed at the hospital. Among the 1270 women,
92% received the study drug at least 1 hour prior to delivery and 98% of their
1295 newborns received study medication. Median time between the last study
dose and delivery was 5.3 hours (18 women received 2 doses). Eleven newborns
received a second dose of nevirapine. Proportions of patients receiving study
drug were similar between the 2 treatment arms (C.K.C., unpublished data,
December 2001).
As shown in Table 1, women
who received intrapartum nevirapine (n = 642) were similar to those who received
placebo (n = 628) with respect to baseline and delivery characteristics. Only
12% of women enrolled had a CD4 cell count below 200 cells/mm3
at baseline. Eleven percent had HIV RNA above 10 000 copies/mL at the
time of delivery, with over half below 400 copies/mL. Fifty percent of women
from PACTG had a delivery HIV RNA below 400 copies/mL compared with 62% from
ANRS, 62% from ECS, 47% from Brazil, and 13% from the Bahamas.
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Table 1. Characteristics of Women and Infants
in Pediatric AIDS Clinical Trials Group 316*
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Only 4 women refused standard ART or prophylaxis. Of the remaining 1266
women, 291 started therapy before pregnancy and 975 started treatment at a
median gestational age of 22 weeks. Twenty-three percent of the women received
zidovudine alone; 28%, zidovudine plus lamivudine; 8%, other combinations
without a protease inhibitor (PI); and 41%, combinations including a PI. The
most commonly used PI was nelfinavir (60%), followed by indinavir (21%), saquinavir
(6%), and ritonavir (1%). Twelve percent received treatment with 2 PIs. The
proportion of women from PACTG sites who received PIs increased during the
study period from 32% during the first year of recruitment to 45% during the
second year and 53% during the third year. Thirty percent of women from ANRS
and 39% from ECS received PIs. Seventeen percent of PACTG patients received
zidovudine alone compared with 30% of patients from ANRS, 36% from ECS, 42%
from Brazil, and 100% from the Bahamas.
Thirty-four percent of women delivered by elective cesarean section
(before onset of labor and before rupture of membranes). Twenty-four percent
of PACTG patients delivered by elective cesarean section compared with 58%
of patients from ANRS, 81% from ECS, 26% from Brazil, and 0% from the Bahamas.
Nineteen percent of infants were preterm (<37 weeks' gestation); 1.5%,
very preterm (<32 weeks' gestation); 12%, low birth weight (<2500 g);
and 3%, very low birth weight (<2000 g). The frequency of preterm delivery
(<37 weeks) was the same (19%) for all women regardless of PI treatment
(P>.99, Fisher exact test).
HIV Transmission
Infant HIV infection status was determined for 1248 of 1270 deliveries
based on the protocol-specified definition (1200 cases) or on sufficient data
to allow classification by the study virological review subgroup (48 cases).
Twenty-two deliveries (11 in each treatment group) were classified as indeterminate.
All newborns classified as indeterminate had either no DNA PCR results or
negative results, and no samples available after age 4 weeks. No newborns
in this group had any positive DNA PCR assay results. Detection of HIV infection
occurred in 19 newborns, 9 (1.4%) of 631 deliveries in the nevirapine arm
and 10 (1.6%) of 617 deliveries in the placebo arm (Table 2). The 95% confidence interval for difference in transmission
rate (-0.2%) between nevirapine and placebo arms ranged from –1.5%
in favor of nevirapine to 1.2% in favor of placebo (P
= .82, Fisher exact test). Ten (53%) of the 19 transmissions occurred in utero
as defined by a positive DNA PCR assay within 72 hours of birth; 1 infected
infant did not have a birth sample obtained; and the remaining 8 (42%) had
negative samples at birth with subsequent positive results and would be considered
to be infected intrapartum16 (Table 2).
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Table 2. Incidence of Human Immunodeficiency
Virus (HIV) Transmission*
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Rates of transmission according to randomized treatment assignment based
on study group, maternal characteristics (including type of antepartum ART),
and infant characteristics are shown in Table 3. Differences according to randomized treatment assignment
were not statistically significant for any subgroup, even for women with baseline
CD4 cell counts below 200 cells/mm3 (P
= .37), delivery HIV RNA above 10 000 copies/mL (P = .40), or antenatal zidovudine monotherapy (P
= .69). All P values were calculated using the Fisher
exact test.
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Table 3. Patient Characteristics and Perinatal
Human Immunodeficiency Virus (HIV) Transmission*
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Overall, women with low baseline CD4 cell counts (<200 cells/mm3) had a higher risk of HIV transmission (3.4%) than those with CD4
cell counts of 400 cells/mm3 or higher (0.8%) (P = .03, Fisher exact test). Transmission risk was also higher among
women with HIV RNA levels of 400 copies/mL or higher (2.9%) compared with
those with HIV RNA below 400 copies/mL (0.3%) (P<.001,
Fisher exact test). In univariate analyses, risk for HIV transmission did
not differ significantly according to type of antepartum ART or mode of delivery.
Treatment arm, study group (PACTG compared with other groups), type
of antenatal ART, mode of delivery, and maternal HIV RNA level were included
in multiple logistic regression models. Maternal viral load at delivery (85
were missing data) was the only significant predictor of HIV transmission
(C.K.C., unpublished data, December 2001).
Table 4 shows the frequency
of HIV transmission according to maternal viral load at delivery, type of
antepartum ART, and mode of delivery. Although maternal viral load is an important
risk factor for perinatal transmission, the relative merit of specific maternal
ART regimens cannot be ascertained due to confounding. For example, women
who received zidovudine monotherapy were more likely to undergo elective cesarean
section (43% vs 30% receiving other treatment regimens) and have an HIV RNA
level of 400 copies/mL or more (62% vs 43% receiving other treatment regimens).
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Table 4. Perinatal HIV Transmission According
to Maternal Viral Load at Delivery, Type of Antepartum Antiretroviral Therapy,
and Mode of Delivery*
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Of the 236 women excluded from the primary analysis because they did
not receive study drug, 152 delivered during the study and infection status
was determined for 139 (71 in the nevirapine arm and 68 in the placebo arm).
Transmission of HIV occurred in 2 deliveries (1.4%), both assigned to the
placebo group.
Toxicity
All posttreatment infant and maternal rash events of grade 2 or higher
were reported. Nonrash toxic events were reported for events of grade 3 or
higher. Overall, severe toxicity was rare in both women and infants and did
not differ significantly between nevirapine and placebo groups (Table 5). For all maternal and infant toxic events, there was no
statistically significant difference identified between the nevirapine and
the placebo group. In all cases, the comparisons were by Fisher exact test.
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Table 5. Maternal and Infant Toxicity*
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Maternal rashes of grade 2 or higher were uncommon, occurring in only
15 women (7 in the nevirapine and 8 in the placebo group). Of these, 10 had
defined alternative etiologies for the skin changes, including surgical site
infection and contact dermatitis. Seventy-eight women (6.1%) had grade 3 or
higher nonrash toxicity. The most frequent events reported were anemia (2.5%)
and delivery/postpartum complications (1.1%). Grade 3 or higher hepatic toxicity
(elevated aminotransaminases or bilirubin) was reported in 10 women (5 in
each treatment group). Underlying liver disease was identified in 4 of these
women (2 in each treatment group: cholestasis, hepatitis B, and 2 cases of
hepatitis C). Three women died during the postpartum follow-up period (2 in
the nevirapine arm and 1 in the placebo arm); all had received study treatment.
Deaths were attributed to ischemic cardiomyopathy, sickle cell disease, and
disseminated histoplasmosis. All were considered unrelated to study treatment.
Toxicity evaluation included all newborns with exposure to study drug
(n = 1413) through transplacental passage of maternal drug and/or through
receipt of study drug directly to the newborn (Table 5). Grade 2 or higher rash was reported in 76 newborns (5.4%)
(31 in the nevirapine arm and 45 in the placebo arm). Most rashes were attributed
to typical newborn findings (16, diaper dermatitis; 15, seborrhea; 11, fungal
skin lesions; 5, atopic dermatitis; and 1, impetigo). Of 4 infants with grade
3 rashes, 2 occurred between birth and age 3 days and 2 at age 4 days or older.
No rash was attributed to nevirapine, which was determined by assessing factors
such as timing and whether there was another obvious etiology, such as Candida dermatitis. No grade 4 rashes were reported.
Nonrash toxicity of grade 3 or higher was reported in 430 newborns (30.4%).
Most events were judged to be unrelated to study drug, which was determined
by assessing factors such as timing and whether there was another obvious
etiology such as cytomegalovirus hepatitis (see below). The most frequent
events included anemia (13.1%) and neutropenia (12.6%). More than 90% of events
resolved during follow-up. As physiological hyperbilirubinemia is a common
event in newborns, elevated bilirubin without elevated alanine aminotransferase
was not considered a hepatic toxicity. Three newborns (1 in the nevirapine
arm and 2 in the placebo arm) had grade 3 or higher hepatic events; all events
occurred after study day 4. All 3 cases were attributed to cytomegalovirus
hepatitis.
Eight infants died, 3 in the nevirapine and 5 in the placebo group.
At the time of death, 4 infants were uninfected, 3 were classified as indeterminate,
and 1 was HIV-positive. Deaths occurred between birth and age 24 weeks and
were attributed to sudden infant death syndrome (3 cases), bacterial infection
(2 cases), gastric hemorrhage (1 case after open-heart surgery for congenital
heart disease), trauma (1 case), and cause of death undetermined (1 case).
COMMENT
The observed transmission rate of 1.5% in PACTG 316 was much lower than
anticipated. Additionally, in the presence of standard therapy, most (53%)
of the few remaining perinatal transmissions occurred in utero (as defined
by a positive HIV DNA PCR assay at birth) and hence would be unaffected by
an intervention targeted at the intrapartum period. The risk of transmission
was the same for nevirapine and placebo arms and the tight confidence interval
for difference in transmission risk indicates that any benefit of adding the
intrapartum/newborn nevirapine regimen to standard ART is likely to be small.
Even among women with characteristics known to increase the risk of
perinatal transmission (eg, delivery HIV RNA >10 000 copies/mL or CD4
cell count <200/mm3), transmission rates were below 5%. These
low transmission rates may be due to the frequent use of antenatal treatment
with highly active ART (HAART) and/or elective cesarean delivery in these
high-risk populations.
Consistent with the low transmission rate observed in this study, several
recent studies have demonstrated that antenatal treatment with ART regimens,
including PIs in some women and/or combining ART with elective cesarean delivery,
can decrease perinatal HIV transmission to less than 2%.11, 17-20
Use of elective cesarean delivery and combination ART with PIs varied among
groups involved in this study. Elective cesarean section was used frequently
in European subjects. Elective cesarean section was performed less frequently
in US subjects, while use of combination therapy including a PI was more frequent.
Despite these differences, overall transmission rates did not vary by subject
location (United States vs other). This suggests that the end result of these
different standards of care related to the use of elective cesarean delivery
and HAART is the same low transmission rate overall of 1.5% or less.
The 2-dose nevirapine regimen was safe and well tolerated by mothers
and newborns, as has been reported in 2 other perinatal trials of the nevirapine
regimen conducted in Africa in women who did not receive antenatal ART.9, 21-22 Although there were
grade 3 and 4 events, these were evenly distributed between the 2 treatment
groups. This demonstrates that the events were related to the underlying diagnosis
(perinatal events or HIV infection) or other medications received by the women
and newborns. Furthermore, there were no additive adverse effects when nevirapine
was combined with other ART.
While the risk of maternal and newborn toxicity with intrapartum/newborn
nevirapine appears minimal, data from a Ugandan trial of the 2-dose nevirapine
regimen (HIV Network for Prevention Trials [HIVNET] 012) indicate the potential
for development of nevirapine-resistance mutations in women with active viral
replication at the time they receive single-dose nevirapine.23
In HIVNET 012, the resistance mutations detected during the early postpartum
period were not apparent when the women were tested at later time points.24 In a substudy of women participating in PACTG 316
who had active viral replication, new nevirapine-resistance mutations were
demonstrated in 15% (95% confidence interval, 8%-23%), suggesting that risk
of new nevirapine-resistance mutations may occur even in women receiving other
ART.25-26 The long-term impact
of these mutations on subsequent maternal treatment is not yet known.
The PACTG 316 does not address use of the intrapartum/newborn nevirapine
regimen in women not receiving other ART, for whom the risk of perinatal HIV
transmission is high (25%).3 Two African
trials have shown that the 2-dose nevirapine regimen is effective in reducing
transmission in women who have not received antenatal ART. In HIVNET 012,
the 2-dose nevirapine regimen significantly reduced perinatal HIV transmission
compared with an ultra-short intrapartum/newborn regimen of zidovudine in
breastfeeding Ugandan women who did not receive antenatal treatment.9 An additional trial in South Africa demonstrated that
the 2-dose nevirapine regimen is comparable with an effective intrapartum/newborn
combined regimen of zidovudine and lamivudine in reducing perinatal HIV transmission
in breastfeeding and formula-feeding women who had not received antepartum
therapy.21 Although such a study has not been
done in a developed nation, the intrapartum/newborn nevirapine regimen may
still be a treatment option in developed countries for women who have received
no ART prior to labor and delivery.
Thus, in situations in which antenatal ART has not been received and
the risk of perinatal HIV transmission is therefore high, use of the 2-dose
nevirapine regimen appears safe and offers significant benefit in reducing
perinatal transmission. In developing countries, implementation of this regimen
could potentially prevent HIV infections in many children each year, with
the benefits of nevirapine clearly outweighing potential risks. However, in
circumstances in which women are receiving prenatal care including antenatal
ART and can safely undergo elective cesarean delivery, there is no demonstrable
benefit of intrapartum/newborn nevirapine therapy.
AUTHOR INFORMATION
Author Contributions: Drs Dorenbaum and Cunningham
contributed equally to the study. Dr Cunningham, as principal author, had
full access to all of the data and takes full responsibility for the integrity
of the data and the accuracy of the data analyses.
Study concept and design: Dorenbaum, Cunningham,
Gelber, Culnane, Mofenson, Britto, Newell, Mirochnick, Sullivan.
Acquisition of data: Dorenbaum, Cunningham,
Gelber, Britto, Rekacewicz, Newell, Delfraissy, Cunningham-Schrader, Mirochnick,
Sullivan.
Analysis and interpretation of data: Dorenbaum,
Cunningham, Gelber, Culnane, Mofenson, Britto, Newell, Cunningham-Schrader,
Mirochnick, Sullivan.
Drafting of the manuscript: Dorenbaum, Cunningham,
Gelber, Culnane, Mofenson, Britto, Newell, Cunningham-Schrader, Mirochnick,
Sullivan.
Critical revision of the manuscript for important
intellectual content: Dorenbaum, Cunningham, Gelber, Culnane, Mofenson,
Britto, Rekacewicz, Newell, Delfraissy, Mirochnick, Sullivan.
Statistical expertise: Gelber, Britto.
Obtained funding: Gelber, Mofenson.
Administrative, technical, or material support:
Culnane, Mofenson, Rekacewicz, Cunningham-Schrader, Mirochnick, Sullivan.
Study supervision: Dorenbaum, Cunningham, Gelber,
Culnane, Rekacewicz, Newell, Sullivan.
International PACTG 316 Team: Brigitte Bazin
(ANRS France), Yvonne Bryson (University of California School of Medicine,
Los Angeles), Nina Sublette (Regional Medical Center, Memphis, Tenn), Isaac
Delke and Mobeen Rathore (University of Florida, Jacksonville), Scharla Estep
(National Institute of Allergy and Infectious Diseases, Bethesda, Md), Simona
Fiore (ECS Institute of Child Health, London, England), Maria Gigliotti (Boehringer
Ingelheim), Robert Maupin (Louisiana State University Health Sciences Center,
New Orleans), Heather Watts (National Institute of Child Health and Human
Development, Bethesda, Md), Adolfo Gonzalez-Garcia (University of Miami, Miami,
Fla), and Maureen Shannon (San Francisco General Hospital, San Francisco,
Calif).
European Collaborative Study: I. Grosch-Wörner
and K. Seel (Charite Virchow-Klinikum, Berlin, Germany), J. Jimenez (Hospital
12 De Octubre, Madrid, Spain), A. B. Bohlin and S. Lindgren (Huddinge and
Karolinska Hospitals, Sweden), A. Mûr and A. Paya (Hospital del Mar,
Barcelona, Spain), O. Coll and C. Fortuny (Hospital Clinic, Barcelona, Spain),
M. Casellas Caro (Hospital Vall D'Hebron, Barcelona, Spain), M. Leyes and
L. Ciria (Hospital Son Dureta, Mallorca), P. Martinelli, W. Buffolano, and
M. Sansone (II Policlinico, Naples, Italy), C. Tibaldi and N. Ziarati (St
Anna Hospital, Torino, Italy), S. Alberico and C. Salvatore (Burlo Garofolo
Hospital, Trieste, Italy), M. Temmerman (University of Ghent), I. Hoesli and
C. Rudin (University of Basel, Basel, Switzerland), X. Carnet and J. Pich
(University of Barcelona, Barcelona, Spain), M. Ravizza, G. Pardi and L. Mangiarotti
(San Paolo Hospital, Milan, Italy), V. Savasi, A. E. Semprini and E. Ferrazzi
(Sacco Hospital, Milan, Italy), M. Sharland and T. Chester (St George's Hospital,
London, England), A. Fakoya (Newham General Hospital, London, England), G.
Scaravelli (PUI, Rome, Italy), W. Coroleou and Cavalle Gelabret (H Universitari
Germans Trials I Pujol, Badalona, Spain), C. Loveday (University College,
London, England). France: Scientific Committee: Annie
Metro (Agence Nationale de Recherches sur le SIDA), Marie-Jeanne Mayaux, Stephane
Blanche, Christine Rouzioux, and Marc Tardieu (Enquete Pediatrique Francaise),
Jean-Pierre Aboulker (Service Commun 10), Bertrand Baumelou (Boehringer Ingelheim,
France); Clinicians: Veronique Chambrin and Hassina Razafimahefa (Hopital
Antoine Beclere, Clamart), Laurent Mandelbrot and Guislaine Firtion (Hopital
Cochin-Port Royal, Paris), Nicole Ciraru-Vigneron and Claudine Bruner (Hopital
Lariboisiere, Paris), Alain Berrebi and Joelle Tricoire (Hopital Purpan, Toulouse),
Claude Hocke and Daniele Douard (Hopital Pellegrin, Bordeaux), Catherine Crenn-Hebert
and Corinne Floch-Tulal (Hopital Louis-Mourier, Colombes), Etienne Wilmer
and Annick Ottenvalter (Hopital Robert Debre, Paris), Marie-Aude Khuong and
Jean-Marc Retbi (Hopital Delafontaine, Saint-Denis), Vincent Jeantils and
Eric Lachassine (Hopital Jean-Verdier, Bondy), Sophie Matheron and Jean-Louis
Benifla (Hopital Bichat-Claude-Bernard, Paris), Cristianne Huraux-Rendu and
Joelle Teboul (Hopital Henri-Mondor, Creteil), Deborah Fried and Brigitte
Heller-Roussin (Hopital Intercommunal Montreuil), Brigitte Clavier and Veronique
Brossard (Hopital Charles Nicolle, Rouen), Andre Bongain and Fabrice Monpoux
(Hopital de l'Archet, Nice), Michel Levardon and Fabienne Mazy (Hopital Beaujon,
Clichy), Veronique Cayol and Catherine Dolfus (Hopital Saint-Antoine-Trousseau,
Paris), Paul Benos and Joelle Nicolas (Hopital Arnaud De Villeneuve, Montpellier),
Daniel Raudrant and Laurent Cotte (Hopital de l'Hotel Dieu, Lyon), Cecile
Francois and Francoise Mechinaud (Hopital de l'Hotel-Dieu, Nantes), Rose Nguyen
and Adrien May (Hopital Louise Michel, Evry), Benedicte Mougeon and Alain
Devidas (Hopital Gilles de Corbeil, Corbeil). Brazil:
Susie Andries Nogueira and Marcia Bondarowisky (Federal University of Rio
de Janeiro, Brazil), Esaú Custódio João Filho and Marcos
Machado D'Ippolito (Hospital dos Servidores in Rio de Janiero, Brazil). Bahamas: M. Perry Gomez and P. McNeil (Princess Margaret
Hospital, the Bahamas).
PACTG: Mobeen Rathore and Isaac Delke (University
of Florida Health Science Center), Charles D. Mitchell and Patricia Bryan
(University of Miami), Edwin Thorpe and Nina Sublette (Regional Medical Center),
Robert Maupin and Thomas Alchediak (Tulane University Hospital), Eleanor Jimenez
and Jorge Gandia (San Juan City Hospital), William Borkowsky and Maryam Minter
(Bellevue Hospital), Janet Squires and George Wendel (Children's Medical Center,
Dallas, Tex), William T. Shearer and Hunter A. Hammill (Baylor College of
Medicine), Ellen Moore and Theodore Jones (Children's Hospital of Michigan),
Ana M. Puga and Winston O. Bliss (Children's Diagnostic and Treatment Center),
Jane Pitt and Gina Brown (Columbia University), I. Heyer and L. Lugo (University
of Puerto Rico), Diane Wara and Karen P. Beckerman (San Francisco General),
Andrew D. Hull and Stephen A. Spector (University of California Medical Center,
San Diego), Sohail Rana and Marilyn Dennis (Howard University Hospital), Gregory
J. Wilson and Peggy Bender (Vanderbilt University Medical Center), Ram Yogev
and Donna Stanislawski (Children's Memorial and Prentice Women's Hospital),
Arlene Bardeguez and Jocelyn Grandchamp (New Jersey Medical School), Gary
Kaufman and Laureen Kay (Boston Medical Center), Jaime Deville and Maryanne
Dillon (University of California Medical Center, Los Angeles), Ruth Tuomala
(Brigham and Women's Hospital), Sandra Burchett (Children's Hospital, Boston),
John Farley and Barbara Davis (University of Maryland, Baltimore), Kenneth
C. Rich and Mark Vajaranant (University of Illinois, Chicago), Indu Pathak
and Hamida Khakoo (Metropolitan Hospital Center New York), Nancy Wade and
Renee Samuelson (Children's Hospital at Albany Medical Center), Deb Goldman
and Jane Hitti (Children's Hospital and Medical Center), Audra Deveikis and
Lisa Melton (Long Beach Memorial), Elizabeth Livingston and Lori Ferguson
(Duke University), Emily Barr and John Nosovitch (State University of New
York Upstate Medical University), Alice Stek and Andrea Kovacs (University
of Southern California), Susanne R. Lavoie and Tima Y. Smith (Medical College
of Virginia), Pam Daniel and Patricia Kohler (University of Cincinnati), Margaret
Keller and Marie Beall (Harbor University of California Medical Center, Los
Angeles), Elizabeth J. McFarland and Carol Salbenblatt (Children's Hospital),
Angela Ranzini and Marian Lake (St Peters Medical Center), Juan C. Salazar
and Winston Campbell (University of Connecticut), Robert F. Pass and Marilyn
J. Crain (University of Alabama, Birmingham), Katherine Luzuriaga and Sheila
Noone (University of Massachusetts Medical School), Geoffrey A. Weinberg and
Susan Laverty (University of Rochester), Wilma Lim and Elizabeth Pitkin (University
of North Carolina, Chapel Hill), Dan Lancaster and Debra Terry (Methodist
Hospital Central), Valerie E. Whiteman and Ellen M. Tedaldi (Temple University
School of Medicine), Carla Duff and John Sleasman (University of Florida Gainesville),
Hannah Gay and Netta Boudreaux (University of Mississippi Medical Center),
Beverly E. Sha and Ruth M. Davis (Rush-Presbyterian-St Luke's, Chicago, Ill),
Hector Cintron, Wanda Figueroa, Ramon Ruiz Arnau, George Johnson, and Moya
Clarken (Medical University of South Carolina), Diane Wara and Maureen Shannon
(University of California, San Francisco, and Moffitt Hospital), Savita Pahwa
(North Shore LIJ Research Institute), Sunanda Gaur and Whitley Williams (Robert
Wood Johnson), Myron J. Levin and Adriana Weinberg (Denver Medical Center),
Harold W. Lischner and Kelly R. Hassey (St Christopher's Hospital for Children),
Andrew Wiznia (Jacobi Medical Center), Heather Watts and Lynne Mofenson (National
Institute of Child Health and Human Development).
Pharmaceutical Company Contribution: Boehringer
Ingelheim (BI) had representatives on the study team who participated in discussion
of trial design and implementation, but had no leadership role. The trial
design was primarily developed by the Pediatric AIDS Clinical Trials Group
(PACTG) investigators with assistance by international investigators when
international sites were added. Study drug was provided by BI for all domestic
and international sites. When international sites were added, BI provided
limited support such as for data entry and quality assurance to allow implementation
at European sites (European Collaborative Study [ECS] and France). Additional
support was provided by the National Institute of Allergy and Infectious Diseases
(NIAID)–funded PACTG. Although BI had access to the database after completion
of the study, they did not hold or maintain the data, or perform data analysis.
The Statistical and Data Analysis Center at Harvard University, in conjunction
with Frontier Science, was responsible for the statistical and data analysis,
which was funded by the NIAID. Although a BI representative reviewed the manuscript
and provided constructive suggestions, BI had no authority to require changes
or prevent publication, and did not suggest significant alterations in the
presentation of the material.
Financial Disclosures: Dr Dorenbaum is employed
by and owns stock and has stock options in Chiron Corp; Dr Cunningham was
a consultant to Boehringer Ingelheim previously; Dr Gelber has NIH grants
and is a consultant on a protocol review committee of the Ludwig Institute
for Cancer Research, Orion Pharmaceuticals regarding an oncologic drug; Dr
Rekacewicz has research grants or funding from Boehringer Ingelheim France
and government grants or research funding through ANRS sponsorship in France;
Dr Delfraissy received honoraria for clinical studies and international trials,
government grants or research funding, or lecture sponsorships from, or is
a consultant for ANRS, Bristol-Myers Squibb, GlaxoSmithKline, and Roche; Ms
Cunningham-Schrader owns stock and has stock options in Millennium Pharmaceuticals;
Dr Mirochnick has received honoraria and support for travel to scientific
meetings from Boehringer Ingelheim; and Dr Sullivan has stock options in,
or research grants or funding, honoraria, lecture sponsorships, assay kits
or reagents, honoraria for continuing medical education programs from, or
was a consultant or advisor to, or gave expert testimony for, Boehringer Ingelheim
Pharmaceuticals Inc, or Therion Biologics Corp.
Funding/Support: This work was supported by
the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy
and Infectious Diseases and the Pediatric/Perinatal HIV Clinical Trials Network
of the National Institute of Child Health and Human Development, National
Institutes of Health; the Agence Nationale de Recherches sur le SIDA (ANRS
083) and Boehringer Ingelheim (France); and the European Commission (grants
PL 962005 and QLRT-1999-30002); and the Medical Research Council.
Corresponding Author: Coleen K. Cunningham,
MD, Department of Pediatrics, State University of New York Upstate Medical
University, 750 E Adams St, Syracuse, NY 13210 (e-mail: cunningc{at}upstate.edu).
Author Affiliations: Department of Pediatrics,
University of California, San Francisco (Dr Dorenbaum); Department of Pediatrics,
State University of New York Upstate Medical University, Syracuse (Dr Cunningham);
Statistical and Data Analysis Center, Harvard School of Public Health, Boston,
Mass (Dr Gelber and Ms Britto); National Institute of Allergy and Infectious
Diseases, Rockville, Md (Ms Culnane); National Institute of Child Health and
Human Development, Bethesda, Md (Dr Mofenson); Agence Nationale de Recherches
sur le SIDA, Villejuif, France (Drs Rekacewicz and Delfraissy); INSERM SC10,
Villejuif, France (Dr Rekacewicz); Centre for Paediatric Epidemiology and
Biostatistics, Institute of Child Health, London, England (Dr Newell); Enquete
Perinatale Francaise, CHU BICETRE, Paris, France (Dr Delfraissy); Frontier
Science, Buffalo, NY (Ms Cunningham-Schrader); Department of Pediatrics, Boston
University School of Medicine, Boston, Mass (Dr Mirochnick); and Department
of Pediatrics and Molecular Medicine, University of Massachusetts Medical
School, Worcester (Dr Sullivan). Dr Dorenbaum is now at Chiron Corp, Emeryville,
Calif.
Dr Newell represents the European Collaborative Study.
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