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Efficacy of Zidovudine and Human Immunodeficiency Virus (HIV)
Hyperimmune Immunoglobulin for Reducing Perinatal HIV Transmission
from HIV-Infected Women with Advanced Disease: Results of Pediatric
AIDS Clinical Trials Group Protocol 185
E. Richard Stiehm, John S. Lambert,
Lynne M. Mofenson, James Bethel, Jean Whitehouse,
Robert Nugent, John Moye, Jr., Mary Glenn Fowler,
Bonnie J. Mathieson,
1
Patricia Reichelderfer,
1
George J. Nemo, James Korelitz, William A. Meyer III,
Christine V. Sapan, Eleanor Jimenez, Jorge Gandia,
Gwendolyn Scott, Mary Jo O’Sullivan, Andrea Kovacs,
Alice Stek, William T. Shearer, and Hunter Hammill,
for the Pediatric AIDS Clinical Trials Group
Protocol 185 Team
2
University of California at Los Angeles Medical Center, and
University of Southern California Medical Center, Los Angeles;
Institute of Human Virology, University of Maryland, and Quest
Diagnostics, Baltimore, Pediatric, Adolescent, and Maternal AIDS
Branch, National Institute of Child Health and Human Development,
Division of AIDS, National Institute of Allergy and Infectious
Diseases, and Division of Blood Diseases and Resources, National
Heart, Lung and Blood Institute, National Institutes of Health,
Bethesda, and Westat, Rockville, Maryland; North American
Biologicals, Boca Raton, and University of Miami School of
Medicine, Miami, Florida; San Juan City Hospital, San Juan,
Puerto Rico; and Baylor College of Medicine, Houston, Texas
Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether zidovudine combined
with human immunodeficiency virus (HIV) hyperimmune immunoglobulin (HIVIG) infusions
administered monthly during pregnancy and to the neonate at birth would significantly lower
perinatal HIV transmission compared with treatment with zidovudine and intravenous im-
munoglobulin (IVIG) without HIV antibody. Subjects had baseline CD4 cell counts <500/
mL (22% had counts
!200/mL) and required zidovudine for maternal health (24% received
zidovudine before pregnancy). Transmission was associated with lower maternal baseline CD4
cell count (odds ratio, 1.58 per 100-cell decrement; ; 10.0% vs. 3.6% transmission forP 5 .005
count
!200 vs. >200/mL) but not with time of zidovudine initiation (5.6% vs. 4.8% if started
before vs. during pregnancy; ). The Kaplan-Meier transmission rate for HIVIG re-P 5 .75
cipients was 4.1% (95% confidence interval, 1.5%–6.7%) and for IVIG recipients was 6.0%
(2.8%–9.1%) ( ). The unexpectedly low transmission confirmed that zidovudine pro-P 5 .36
phylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine
therapy, although it limited the study’s ability to address whether passive immunization di-
minishes perinatal transmission.
In 1994, Pediatric AIDS Clinical Trials Group (PACTG) pro-
tocol 076 demonstrated that zidovudine administered to the
mother during pregnancy and labor and to the newborn re-
duced the risk of perinatal human immunodeficiency virus
Received 16 July 1998; revised 19 October 1998.
Presented in part: 37th Interscience Conference on Antimicrobial Agents
and Chemotherapy, Toronto, September 1997 (abstract I-117).
The Pediatric AIDS Clinical Trials Group protocol 185 was reviewed and
approved by the institutional review boards at each participating center.
Each woman (and the father of the child, when available) gave written
informed consent for her participation and that of her child. Human ex-
perimentation guidelines of the US Department of Health and Human Serv-
ices were followed in the conduct of this research.
Financial support: NIH (contracts HD-33162 [J.B., J.W., J.K., W.A.M.,
E.J., J.G., A.K., A.S.] and HL-57128 [C.V.S.] and cooperative agreements
AI-27565 [Johns Hopkins, J.S.L.], AI-27550 [UCLA, E.R.S.], AI-27551
[Baylor, W.T.S., H.H.], AI-27560 [University of Miami, G.S., M.J.O.]).
C.V.S. is an employee of North American Biologicals, manufacturer of
HIV-IG.
The Journal of Infectious Diseases 1999;179:567–75
q 1999 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/99/7903-0005$02.00
(HIV) transmission by two-thirds; infection rates were 25.5%
in placebo compared with 8.3% in zidovudine recipients [1].
However, enrollment into PACTG 076 was restricted to HIV-
infected pregnant women with CD4 lymphocyte counts >200/
mL not receiving or requiring antiretroviral therapy during the
current pregnancy. The trial did not address the efficacy of
zidovudine prophylaxis in women with more advanced disease
or prior zidovudine therapy.
We sought to determine whether infusions of human HIV
hyperimmune immunoglobulin (HIVIG) added to zidovudine
prophylaxis would further reduce the rate of transmission from
women with these characteristics. PACTG protocol 185 en-
1
Current affiliations: Office of AIDS Research (B.J.M.) and Contracep-
tive and Reproductive Health Branch, National Institute of Child Health
and Human Development (P.R.), National Institutes of Health, Bethesda,
Maryland.
2
Contributors are listed after text.
Reprints or correspondence: Dr. Lynne M. Mofenson, Pediatric, Ado-
lescent, and Maternal AIDS Branch, National Institute of Child Health and
Human Development, 6100 Executive Blvd., Room 4B11, Rockville, MD
20852 (LM65D@nih.gov).
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568 Stiehm et al. JID 1999;179 (March)
rolled HIV-infected pregnant women with baseline CD4 cell
counts <500/mL and HIV-related symptoms requiring antire-
troviral therapy, who were receiving zidovudine during the cur-
rent pregnancy for maternal health indications. At the time the
study was designed, we estimated that the perinatal transmis-
sion rate in the women enrolled in PACTG 185 might be as
high as 15%, despite zidovudine prophylaxis, and that addi-
tional interventions would be needed to further decrease HIV
transmission. This estimate was based on epidemiologic studies
in infected pregnant women not receiving antiretroviral therapy,
which demonstrated that clinically symptomatic HIV disease,
low CD4 lymphocyte count, and high virus load (at that time
measured by p24 antigen levels) were associated with an ele-
vated risk of perinatal HIV transmission [2–6]. Additionally,
zidovudine prophylaxis was less effective in women who had
received zidovudine before pregnancy in a study in France [7].
Passive immunoprophylaxis with polyclonal and monoclonal
virus-specific antibodies successfully prevented transmission of
simian, feline, and human immunodeficiency viruses in some
animal studies [8–12] but not in others [13–15]. PACTG 185
evaluated whether HIVIG infusions administered to the mother
monthly during pregnancy and to the neonate at birth com-
bined with zidovudine prophylaxis would significantly lower
perinatal HIV transmission compared with infusions of intra-
venous immunoglobulin (IVIG) without HIV antibody com-
bined with zidovudine prophylaxis.
Methods
Study design. PACTG 185 was a multicenter, randomized, con-
trolled phase III clinical trial conducted between October 1993 and
March 1997 at 53 clinical sites in the mainland United States and
Puerto Rico. Results from an initial pharmacokinetic and safety
substudy of the first 28 mother-infant pairs have been published
[16]. Eligibility criteria included laboratory documentation of ma-
ternal HIV infection, current receipt of zidovudine, baseline CD4
cell count <500/mL, gestational age between 20 and 30 weeks,
hemoglobin level >8 g/dL, serum creatinine level <1.5 mg/dL, and
urine protein grade
!21 by dipstick or level !4 g in 24 h of urine
collection.
Exclusion criteria included evidence of preexisting fetal anom-
alies with high probability that the fetus or infant would not survive
the study period (e.g., anencephaly), chorionic villous or percu-
taneous umbilical blood sampling during the current pregnancy,
illnesses associated with extensive protein loss, preexisting condi-
tions that required IVIG treatment, receipt of HIV vaccine or pas-
sive immunotherapy during the current pregnancy, and severe
preeclampsia.
Receipt of nucleoside analogues other than zidovudine and/or
nonnucleoside reverse transcriptase inhibitor antiretroviral drugs
during the current pregnancy was permitted with protocol chair
approval. Protease inhibitor antiretroviral drugs became available
only during the last year of the study; because there were no avail-
able safety data on use of these drugs during pregnancy during the
time PACTG 185 was conducted (late 1993 through early 1997),
women receiving protease inhibitors during the current pregnancy
were excluded from the study.
Before randomization, subjects were stratified by baseline ma-
ternal antenatal CD4 cell count (
!200/mL or >200/mL), whether
zidovudine therapy was initiated before or during the current preg-
nancy, and the geographic region where the study center was
located.
Detailed description of the preparation and content of HIVIG
(manufactured as HIV-IG by North American Biologicals, Boca
Raton, FL) have been provided elsewhere [16, 17]. Study treatment
consisted of HIVIG, 200 mg/kg by intravenous infusion every 4
weeks beginning at 20–30 weeks of gestation through delivery, or
standard polyvalent, HIV antibody–negative IVIG (Gamimune N;
Bayer, West Haven, CT) at the same dose and regimen. The new-
born infant received an intravenous infusion of HIVIG or IVIG
(200 mg/kg) within 12 h of birth; the infant received the same
randomized study treatment (HIVIG or IVIG) as the mother.
Women continued receiving their physician-prescribed antepartum
antiretroviral regimen and received intrapartum zidovudine (intra-
venous loading dose of 2 mg/kg followed by a continuous infusion
of 1.0 mg/kg/h until the umbilical cord was clamped); infants re-
ceived the standard 6-week course of zidovudine prophylaxis (2
mg/kg zidovudine syrup orally every 6 h) starting within 8–12 h
of birth [1].
Women were seen monthly for infusions and monitoring during
pregnancy and at 6 weeks and 3, 6, 12, and 18 months postpartum.
Women were followed for 18 months postpartum to evaluate
whether HIVIG infusions had any long-term positive or negative
effect on maternal virus load and/or disease progression. HIV quan-
titative peripheral blood mononuclear cell (PBMC) culture was
done at baseline, just before the third infusion, at delivery, and 6
months postpartum; CD4 lymphocyte percentage and absolute
number were assessed at baseline, just before the third infusion,
and 6, 12, and 18 months postpartum; and blood specimens were
obtained for storage at baseline, just before the third infusion, at
delivery, and 3, 6, 12, and 18 months postpartum.
Infants were seen at weeks 1, 2, 6, and 12; every 4 weeks from
week 16 through week 24; every 12 weeks from week 36 through
week 60; and for a final evaluation at week 78 (18 months). HIV
quantitative PBMC culture was done at birth, 6 weeks, 24 weeks,
and 48 weeks on study; a second, confirmatory culture was done
on all children who had an initial positive culture.
Laboratory assays. HIV quantitative PBMC microculture and
lymphocyte phenotyping were done in laboratories certified by the
ACTG according to published standard methods [18, 19]. HIV
antibody EIA and Western blot were done by use of US Food and
Drug Administration–approved, commercially available methods.
HIV-1 RNA concentration was measured in stored maternal
plasma by use of the nucleic acid sequence–based amplification
assay according to the manufacturer’s instructions (Organon Tek-
nika, Durham, NC). The lower limit of quantitation was 500 cop-
ies/mL. Whenever possible, all specimens for an individual patient
were assayed in a batched fashion, and all HIV-1 RNA assays were
done by a single laboratory.
Statistical methods. The targeted sample size was 400 women
per arm, which provided 80% power to detect a 50% reduction in
perinatal HIV transmission with HIVIG, assuming transmission in
the IVIG arm was >15%; noncompliance and loss to follow-up
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JID 1999;179 (March) Perinatal HIV Transmission Prophylaxis 569
Table 1. Status of women and infants in study of HIV hyperimmune
immunoglobulin (HIVIG) as of 25 March 1997.
Patient status HIVIG IVIG Total
Women enrolled 254 247 501
Still pregnant 22 17 39
Lost to follow-up 1 2 3
Eligible women who gave birth 231 228
a
459
a
Women who died during postpartum period
b
4 2 6
Live-born infants
Total 237 230 467
Singletons 225 224 449
Twins 12 6 18
Eligible mother-infant pairs
c
231 227
a
458
a
HIV culture data unavailable 1 3 4
Included in Kaplan-Meier analysis 230 224 454
NOTE. IVIG, intravenous immunoglobulin. Data are no. of patients.
a
1 women delivered stillborn infant.
b
Infants born to these women are included in efficacy analysis.
c
Twins are counted as single pregnancy outcome.
were together assumed to be ∼10%. Data analysis was undertaken
on an intent-to-treat basis.
Three interim efficacy analyses were planned, each occurring
after ∼200 infants achieved 6 months of follow-up; stopping rules
were based on O’Brien-Fleming boundaries [20]. HIV infection
status for the purpose of the primary efficacy analyses was assessed
on the basis of HIV culture data for all children by 6 months of
age. Infants with one or more confirmed HIV culture results were
designated as HIV-infected; infants without such positive culture
results were designated as uninfected. Results of all virologic assays
were reviewed in a blinded fashion by a subgroup of the study
team. Pregnancies that yielded multiple births were assessed as a
single HIV transmission event if any of the infants were HIV-
infected and as a single nonoccurrence of transmission if none were
HIV-infected.
The transmission rate was estimated by the Kaplan-Meier
method [21, 22], with the end point of time to first positive HIV
culture. Infants with indeterminate infection status were treated as
censored in the efficacy analysis, with their follow-up times set to
the latest negative culture. Variances were calculated by Green-
wood’s formula, with significance tests based on the normal dis-
tribution. Alternative analyses based on the restricted subset of
infants with definitive HIV status were also done. Prognostic fac-
tors for the risk of transmission were evaluated with logistic re-
gression and x
2
analysis. Stratified analysis of risk factors used the
Mantel-Haenszel method.
Results
Enrollment. Enrollment into the initial pharmacokinetic
substudy in PACTG 185 began in October 1993. The first ef-
ficacy analysis by the independent Data and Safety Monitoring
Board was 21 March 1997 and used data entered through 23
December 1996. The current report includes data from all births
through the termination of study enrollment on 25 March 1997.
As of 25 March 1997, 501 women had enrolled and 459 had
given birth to a total of 467 live-born infants and 1 stillborn
infant; there were 9 sets of twins and 449 singleton births (table
1). Three women (
!1%) were lost to follow-up and 39 (8%)
were still pregnant at the time of the efficacy analysis. There
were no significant differences between patients by study arm
in terms of these parameters.
Characteristics of women and infants. There were no sig-
nificant differences between study groups in characteristics of
women or infants (table 2). Median maternal age was 26 years,
and 87% of women were of minority race/ethnicity; median
length of gestation at baseline was 26 weeks. Median baseline
CD4 cell count was 306/mL; 22% of women had a baseline CD4
cell count
!200/mL and 76% had a baseline CD4 cell count
between 200 and 500/mL (5 women were granted exemptions
to enter with counts slightly higher than 500/mL). Median base-
line HIV-1 RNA level was 9150 copies/mL (range,
!500–
740,000); 19% of women had
150,000 RNA copies/mL.
Twenty-four percent of women had initiated zidovudine ther-
apy before the current pregnancy. Only a minority of women
(54/459, 12%; 27 in the HIVIG arm and 27 in the IVIG arm)
received antenatal antiretroviral therapy with drugs other than
zidovudine monotherapy during the current pregnancy. Of
these, 1 received lamivudine, 2 received zalcitabine, and 3 re-
ceived didanosine alone; 44 received combination therapy with
lamivudine plus zidovudine (28), zalcitabine plus zidovudine
(10), stavudine plus zidovudine (3), didanosine plus zidovudine
(1), lamivudine plus stavudine (1), or delaviridine plus dida-
nosine (1); and 4 received more than one dual nucleoside an-
alogue combination regimen during the study. Eighty-eight per-
cent of women who delivered had received three or more study
drug infusions; the median number of infusions received during
pregnancy was four.
Elective cesarean delivery was done for 8% and nonelective
cesarean delivery was done for 19% of patients (table 2). The
median gestational age of delivered infants was 38 weeks. Eigh-
teen percent of infants were born preterm (gestational age
!37
weeks), although only 4% were very preterm (
!32 weeks). Me-
dian birth weight was 3143 g; 15% of infants were of low birth
weight (
!2500 g). There were no differences between study arms
in these parameters.
Safety and toxicities. The few reported toxicities related to
study drug infusions were side effects commonly associated with
receipt of IVIG infusions, such as chills, headache, and back
pain. Seven women experienced 12 episodes of moderate (grade
2) toxicity, and 2 women experienced 5 episodes of serious
(grade 3) toxicity related to study drug infusions. No moderate
or serious (grade 2 or higher) toxicities related to study drug
infusions were reported in infants; 2 infants experienced 3 ep-
isodes of mild (grade 1) toxicity. Only 6 women (1%) required
discontinuation of study drug infusions, 4 in the HIVIG and
2 in the IVIG arm; no infant required discontinuation of study
drug infusions.
Intrapartum and newborn zidovudine were provided as part
of the trial. Serious (grade 3 or higher) zidovudine-related he-
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570 Stiehm et al. JID 1999;179 (March)
Table 2. Characteristics of women and infants in study of HIV hyperimmune globulin (HIVIG) versus
intravenus immunoglobulin (IVIG).
Population, characteristic HIVIG IVIG Total
Women
Age at baseline (years), median 5 SD 27 5 6.0 26 5 5.8 26 5 5.9
Race/ethnicity, no. (%)
Black, not Hispanic 123 (53) 112 (49) 235 (51)
Hispanic 81 (35) 80 (35) 161 (35)
White, not Hispanic 25 (11) 35 (15) 60 (13)
Other 2 (1) 1 (1) 3 (1)
Hard drug use
a
26 (11) 36 (16) 62 (14)
Maternal gestation length at baseline (weeks), median 5 SD 25 5 3.5 26 5 3.2 26 5 3.4
Baseline CD4 cell count/mL, no. (%)
!200 54 (23) 49 (21) 103 (22)
200–500 174 (75) 177 (78) 351 (76)
1500 3 (1) 2 (1) 5 (1)
Baseline CD4 cell count/mL, median 5 SD 298 5 120.9 321 5 127.3 306 5 124.1
Baseline HIV-1 RNA (copies/mL)
b
Median 5 SD 9,750 5 84,576 7,450 5 90,153 9,150 5 87,301
Range
!500–720,000 !500–740,000 !500–740,000
No. (%) with
150,000 46 (20) 40 (18) 86 (19)
Zidovudine initiation, no. (%)
Before pregnancy 55 (24) 57 (25) 112 (24)
During pregnancy 176 (76) 171 (75) 347 (76)
Number of maternal study drug infusions, median 5 SD 4 5 1.1 4 5 1.1 4 5 1.1
Type of delivery, no. (%)
Vaginal 167 (72) 170 (75) 337 (73)
Non-elective cesarean 44 (19) 43 (19) 87 (19)
Elective cesarean 20 (9) 15 (7) 35 (8)
Duration of membrane rupture (h), median 5 SD 1 5 13.1 2 5 8.4 2 5 11.0
No. (%) with premature rupture (>24 h) 15 (6) 9 (4) 24 (5)
No. (%) with abruptio placentae 1 (1) 1 (1) 2 (1)
Infants
Gestational age at delivery (weeks), median 5 SD 38 5 2.6 38 5 2.8 38 5 2.7
Preterm (
!37 weeks), no. (%) 44 (19) 38 (16) 82 (18)
Very preterm (
!32 weeks), no. (%) 9 (4) 10 (4) 19 (4)
Birth weight (g) median 5 SD 3150 5 648 3133 5 638 3143 5 643
Birth weight
!2500 g, no. (%) 37 (16) 32 (14) 69 (15)
NOTE. Maternal baseline characteristics refer to all women enrolled and delivered by 25 March 1997; infant baseline
characteristics refer to all delivered infants.
a
Use of cocaine, heroin, and/or injection drugs.
b
HIV-1 RNA copy number was available for 458 women (230 HIVIG and 228 IVIG recipients).
matologic toxicities included anemia in 7 infants (1.5%) and
leukopenia in 48 infants (10.3%).
There were 6 maternal deaths in the postpartum period, 4
in the HIVIG and 2 in the IVIG study arm. Deaths were due
to HIV encephalopathy with aspiration pneumonia, Pneumo-
cystis carinii pneumonia, end-stage renal disease with compli-
cating pneumonia, drug addiction and asthma, sepsis, and un-
specified HIV disease progression; none were treatment-related.
There were 7 infant deaths during the study, 3 in the HIVIG
and 4 in the IVIG study arm. Deaths in the HIVIG study arm
were due to perinatal asphyxia with severe hypoxic ischemia,
pneumonia, and renal dysgenesis with multiorgan failure.
Deaths in the IVIG study arm were due to sudden infant death
syndrome, prematurity, necrotizing enterocolitis and prematu-
rity, and a single stillbirth (maternal diabetes mellitus). None
of the deaths were treatment-related, and in 2 of the deaths,
no study HIVIG/IVIG or zidovudine had been administered
to the infant.
Analysis of transmission and treatment efficacy. Four hun-
dred fifty-nine women gave birth to 468 infants, 1 of whom
was stillborn, resulting in 467 live-born infants and 458 mother-
infant pairs (9 women gave birth to twins) eligible for analysis
(table 1). Four infants did not have an HIV culture available,
leaving 454 mother-infant pairs with at least one viral culture
result available (table 3). Twenty-two infants were determined
to be HIV-infected. The overall Kaplan-Meier transmission rate
was 5.0% (95% confidence interval [CI], 3.0%–7.1%). Thirteen
infants (6 in HIVIG, 7 in IVIG) were unable to have infection
status classified definitively because of loss to follow-up after
an HIV culture was obtained but before definitive infection
status could be determined at age 6 months. Restricting analysis
to the 441 mother-infant pairs with definitive infant infection
status determined, the overall transmission rate was similar:
5.1% (95% CI, 3.0%–7.2%).
Maternal baseline CD4 cell count was significantly associated
with transmission risk (logistic regression analysis; ).P 5 .005
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JID 1999;179 (March) Perinatal HIV Transmission Prophylaxis 571
Table 3. Perinatal HIV transmission in study of HIV hyperimmune globulin (HIVIG) versus intravenous
immunoglobulin (IVIG).
Characteristic HIVIG IVIG Total
Total no. of infants 230 224 454
No. of infected infants 9 13 22
Positive HIV culture at birth 0 5 5
Negative HIV culture at birth 9 8 17
Kaplan-Meier transmission rate
a
(95% confidence interval) 4.1% (1.5%–6.7%) 6.0% (2.8%–9.1%) 5.0% (3.0%–7.1%)
a
P for HIVIG treatment ; required cutoff for significance for first efficacy analysis was .effect 5 .36 P ! .005
The Kaplan-Meier estimated transmission rate for women with
baseline CD4 cell count
!200/mL was 10.0% (95% CI, 4.1%–
15.8%) compared with 3.6% (95% CI, 1.6%–5.6%) for women
with baseline CD4 cell count >200/mL. In contrast, the Kaplan-
Meier estimated transmission rates were similar regardless of
time of initiation of zidovudine: 5.6% (95% CI, 1.2%–10.0%)
for women who started zidovudine before pregnancy compared
with 4.8% (95% CI, 2.5%–7.1%) for those who first initiated
zidovudine during the current pregnancy ( ).P 5 .75
The estimated transmission rate by Kaplan-Meier analysis
by treatment arm was 4.1% (95% CI, 1.5%–6.7%) in HIVIG
and 6.0% (95% CI, 2.8%–9.1%) in IVIG recipients ( )P 5 .36
(table 3). In an alternative analysis restricted to infants who
had definitive infection status, transmission rates were 4.1%
(95% CI, 1.5%–6.8%) in HIVIG recipients and 6.1% (95% CI,
2.9%–9.3%) in IVIG recipients ( ).P 5 .35
There was a difference between treatment arms in the dis-
tribution of infants who had a positive HIV culture at birth
(none in HIVIG vs. 5 in IVIG recipients; ). HIV DNAP 5 .05
polymerase chain reaction (PCR) testing was done on stored
cell pellet specimens, and HIV RNA testing (nucleic acid se-
quence–based amplification; Organon Teknika) was done on
stored plasma specimens obtained at birth, for all infected in-
fants with negative birth cultures who had an available stored
specimen. Seven of the 9 infected infants in the HIVIG group
had a stored birth cell pellet available, 6 of whom also had a
stored birth plasma specimen. All infants except 1 were negative
by DNA PCR, and all infants, including the DNA PCR–
positive infant, had RNA levels that were below the level of
assay quantification. Six of the 8 infected infants in the IVIG
group with a negative HIV birth culture had a stored birth cell
pellet specimen; none of these were positive on DNA PCR
testing, and the 2 with available plasma specimens also had
HIV RNA levels below quantification limits of the assay.
Most infected infants were identified by 6 weeks of age, and
all infected infants except 1 were identified by 6 months of age.
One child in the IVIG arm had negative HIV cultures during
the study but a persistently positive HIV Western blot antibody
assay at age 18 months; at 92 weeks of age, the child was HIV
culture–negative but positive by a CD8-depleted DNA PCR
and an HIV RNA assay (at a very low number of copies per
milliliter). The association between birth culture positivity and
gestational age at baseline, mother’s HIV culture titer at base-
line and delivery, mother’s CD4 cell count at baseline, and
number of days of antiretroviral use before entry were evalu-
ated. None of these covariates showed significant associations
with culture positivity at birth (data not shown).
Table 4 provides transmission rates stratified by risk factors
for HIV transmission. No statistically significant association
between treatment arms and transmission was observed in these
analyses. However, there was a trend toward lower transmission
among women receiving HIVIG who started zidovudine before
pregnancy (transmission, 1.9% in HIVIG vs. 9.2% in IVIG
recipients; ) or who had baseline CD4 cell count
!200P 5 .09
mL (transmission, 5.6% in HIVIG vs. 14.9% in IVIG recipients;
). Among the 182 women who had either baseline CD4P 5 .12
cell count
!200/mL or started zidovudine before pregnancy, the
transmission rate in HIVIG recipients was 3.2% (95% CI, 0%–
6.8%) and in IVIG recipients was 10.3% (95% CI, 3.9%–
16.6%) ( ). In contrast, for women with baseline CD4P 5 .06
cell count >200/mL or who started zidovudine during preg-
nancy, transmission was 4.7% in HIVIG compared with 3.1%
in IVIG recipients ( ).P 5 .53
Discussion
The overall transmission rate (5.0%) in this study was well
below the figure on which the initial power and sample size
calculations were based. Given the unexpectedly low overall
transmission rate, a conditional power analysis indicated that
the ability to detect a 50% treatment effect with 400 women
per arm was only 29%. The increased sample size required to
address the original hypothesis was deemed too large to enroll
in a timely fashion, and on the basis of the first efficacy analysis,
the estimated treatment effect appeared to be much less than
50%. On the basis of these considerations, the PACTG 185
Data and Safety Monitoring Board recommended discontin-
uing enrollment into PACTG 185, unblinding the study par-
ticipants, and discontinuing HIVIG and IVIG study infusions
for all currently enrolled women and infants.
Although PACTG 185 does not answer whether passive im-
munization can diminish perinatal HIV transmission, the study
confirms the efficacy of zidovudine prophylaxis originally dem-
onstrated in PACTG 076 and extends this observation to
women with more-advanced disease and prior zidovudine use.
The overall low rate of perinatal transmission (5.0%) cannot
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572 Stiehm et al. JID 1999;179 (March)
Table 4. Transmission rates stratified by potential risk factors in study of HIV hyperimmune
globulin (HIVIG) versus intravenous immunoglobulin (IVIG).
Risk factor, stratum
HIVIG
IVIG
Comparison
P
a
Stratified
P
b
No. % infected No. % infected
Baseline maternal CD4 cell count/mL
!200 54 5.6 47 14.9 .12 .29
>200 176 3.6 177 3.6 .99
Maternal zidovudine use
Begun before pregnancy 54 1.9 55 9.2 .09 .34
Begun during pregnancy 176 4.7 169 4.9 .95
Duration of membrane rupture
c
!4 h 135 3.2 129 5.7 .33 .26
>4 h 81 5.0 84 7.2 .56
Mode of delivery
Vaginal 167 4.4 167 6.8 .36 ND
d
Nonelective cesarean 44 4.7 42 5.1 .93
Elective cesarean 19 — 15 — ND
d
Gestational age at birth
!37 weeks 41 5.0 35 9.1 .50 .33
>37 weeks 189 3.9 189 5.4 .48
No. of maternal infusions received
<3 110 3.9 103 5.1 .69 .35
4 71 2.8 73 7.0 .25
>5 49 6.4 48 6.3 .99
Birthweight
e
!2500 g 35 6.4 29 14.2 .33 .31
>2500 g 195 3.7 195 4.8 .59
Hard drug use
f
during pregnancy
Yes 26 — 34 12.2 .03 .36
No 204 4.6 190 4.9 .89
a
Comparison P tests for differences between treatment arms at each level of given risk factor; tests are based
on Kaplan-Meier method. All pregnancy outcomes with culture data are included.
b
Stratified P tests for association between treatment arm and HIV transmission, controlling for given risk
factor; tests are based on Mantel-Haenszel method. This analysis is restricted to 441 infants with definitive
infection status.
c
Data are missing for membrane rupture duration for 25 women.
d
Not calculated because of zero transmission events for elective cesarean delivery.
e
For twin births, minimum weight was used.
f
Defined as use of cocaine, heroin, and/or injection drugs.
be attributed to use of combination antiretroviral therapy dur-
ing the study, since only 10% of women had received combi-
nation antiretroviral therapy. A transmission rate this low was
not anticipated in women with advanced HIV disease receiving
zidovudine prophylaxis, although it is within the 95% confi-
dence interval (4.3%–12.3%) for the zidovudine arm in PACTG
076 [1].
We expected that the IVIG control group transmission rate
in this study would be higher than observed in the zidovudine-
treated women in PACTG 076, because the women enrolled in
PACTG 185 had more-advanced HIV disease. However, the
relatively low overall transmission rate observed in PACTG
185 is in accordance with epidemiologic data from other recent
studies, in which significant effectiveness of zidovudine was ob-
served in women with advanced disease [7, 23]. For example,
in a study in Connecticut, 4% of 23 women with CD4 cell counts
!200/mL who received zidovudine during pregnancy transmit-
ted HIV to their infants, compared with 39% of 23 infected
women with similar CD4 cell counts who did not receive an-
tenatal zidovudine therapy [23].
Consistent with other studies [6, 24–26], a low maternal CD4
cell count was associated with increased risk of transmission
in PACTG 185. However, in contrast to data reported from
France [7], use of zidovudine before pregnancy did not increase
the risk of perinatal transmission in PACTG 185. Additionally,
transmission was unrelated to length of zidovudine use during
pregnancy. In-depth evaluation of risk factors associated with
perinatal HIV transmission in PACTG 185, particularly the
relationship between virus load and transmission, will be re-
ported elsewhere.
Could the low rate of perinatal transmission observed in
PACTG 185 be due to a nonspecific effect of immunoglobulin
on HIV transmission? Several investigators have hypothesized
that in utero perinatal HIV transmission might result from
transport of virus-antibody complexes across the placental bar-
rier via Fc receptors found on trophoblastic cells [27–29]. Thus,
IgG administration could nonspecifically block placental Fc
receptors, thereby lowering transplacental transmission. Alter-
natively, exogenous immunoglobulin could modulate cytokine
production by the mother. Inflammatory cytokines, such as
interleukin-1b, interleukin-6, and tumor necrosis factor-a, are
synthesized in larger quantities in placental cells of HIV-infected
at NIH Library on July 25, 2011jid.oxfordjournals.orgDownloaded from
JID 1999;179 (March) Perinatal HIV Transmission Prophylaxis 573
than uninfected women and may play a role in transmission
[30]. IVIG down-regulates proinflammatory cytokine produc-
tion, particularly interleukin-6, and this could be associated
with a decrease in transplacental transmission [31]. However,
these potential mechanisms would only affect in utero trans-
mission, and most transmission occurs near or during delivery
[32].
Additionally, the use of zidovudine prophylaxis during preg-
nancy in women not receiving IVIG has resulted in low trans-
mission rates consistent with those observed in this study. The
French Perinatal HIV Cohort Study evaluated perinatal trans-
mission rates during 1994 and 1995; transmission decreased
from 14% in women who did not receive zidovudine to 5% with
zidovudine prophylaxis ( ) [7]. In North Carolina, trans-
P
! .01
mission has declined over time from 21% in 1993 (before use
of zidovudine prophylaxis) to 6.2% in early 1996; in women
who received all three components of the PACTG 076 zido-
vudine regimen, transmission was only 3.2% [33]. Data from
surveillance between August 1995 and January 1997 in New
York State indicates a similarly low 6.1% rate of transmission
in women and infants receiving the full three-part zidovudine
regimen [34].
The intriguing finding that none of the 9 infected infants in
the HIVIG group had a positive HIV culture at birth, whereas
5 (38%) of 13 infected infants in the IVIG group did, suggests
that, if HIVIG had a biologic effect, it was primarily on re-
ducing in utero but not intrapartum perinatal transmission.
However, the majority of perinatal transmission occurs near or
during the intrapartum period [32], and the number of infected
infants was small. A passive immunoprophylaxis perinatal trial
underway in Uganda, in which HIVIG (from Ugandan donors)
is given once in late pregnancy to the mother and at birth to
her infant, may provide more information regarding HIVIG
efficacy in the future. One infected infant in the HIVIG group
was HIV DNA PCR–positive at birth but had undetectable
virus by culture and HIV RNA assay. Although in utero HIV
transmission may not have been prevented in this patient, it is
possible that HIVIG might have significantly decreased repli-
cating virus. High-dose simian immunodeficiency virus hyper-
immune globulin administered at days 1 and 14 to macaques
after inoculation with simian immunodeficiency virus did not
protect against infection but was associated with lower virus
loads and slower disease progression in infected animals [35].
Evaluation of disease progression in the infected infants in
PACTG 185 will be needed to determine whether there is prog-
nostic significance related to the timing of initial HIV culture
positivity in HIVIG-treated infants.
The unexpectedly low overall transmission rate limited the
power of PACTG 185 to detect a treatment effect, and the
clinical trial was not able to determine whether passive im-
munization with HIVIG lowers perinatal transmission. How-
ever, although not statistically significant, there was an intrigu-
ing trend toward lower transmission with HIVIG among
women who would be expected to have more-advanced HIV
disease and theoretically higher viral load and higher baseline
risk of transmission—those with baseline CD4 cell count
!200/
mL or who started zidovudine before pregnancy. Thus, it should
not be concluded that PACTG 185 demonstrated that passive
immunization is an ineffective intervention for reducing peri-
natal transmission. Further study is warranted; the perinatal
HIVIG trial in Uganda will provide more-definitive data on
the efficacy of HIVIG to reduce transmission.
PACTG Study Group Participants
The following are PACTG 185 participating sites, principal inves-
tigators, and protocol team members. Case Western University Hos-
pital, Cleveland: P. Toltzis and S. Gillinou; University of Medicine and
Dentistry of New Jersey, Newark: J. Oleske, A. Bardequez; Children’s
Hospital and Brigham and Women’s Hospital, Boston: S. Burchett, K.
McIntosh, and R. Tuomala; Boston Medical Center, Boston: S. Pelton
and M. Mirochnick; University of California at Los Angeles Medical
Center: E. R. Stiehm, Y. Bryson, and P. Boyer; Harbor University of
California Medical Center, Los Angeles: M. Keller and M. Beall; Johns
Hopkins University School of Medicine, Baltimore: J. Lambert, A.
Ruff, and J. Anderson; University of Maryland, Baltimore: P. Vink
and L. Alger; Baylor College of Medicine and University of Texas
Medical School, Houston: W. Shearer and H. Hammill: Columbia Pres-
byterian Medical Center, New York: A. Gershon, J. Pitt, and G. Brown;
University of Miami School of Medicine: G. Scott and M. J. O’Sullivan;
Mount Sinai School of Medicine, New York: H. Sacks and R. Sperling;
New York University Medical Center: W. Borkowsky and M. Allen;
University of California, San Francisco, and San Francisco General
Hospital: D. Wara, S. Kilpatrick, and D. Landers; University of Cal-
ifornia, San Diego, La Jolla: S. Spector, M. Besser, and M. Caffery;
University of North Carolina, Chapel Hill: W. Lim and M. McMahon;
University of Illinois, Chicago: K. Rich and M. Vajaranant; San Juan
City Hospital, San Juan, Puerto Rico: E. Jimenez and J. Gandia; Ra-
mon Ruiz Arnau University Hospital, Bayamon, Puerto Rico: R.
Aguayo and H. Cintron-Principe; State University of New York at
Stony Brook: S. Nachman and D. Baker; Children’s Hospital Michigan
and Hutzel Hospital, Detroit: E. Moore and T. Jones; Albany Medical
Center, Albany, NY: M. Lepow, N. Wade, and R. Samelson; University
of Texas Southwestern Medical Center, Dallas: J. Squires and G. Wen-
del; Howard University Hospital, Washington, DC: S. Rana and B.
Wesley; University of Southern California/Los Angeles County Med-
ical Center, Los Angeles: A. Kovacs and A. Stek; University of Florida
Health Science Center, Jacksonville: M. Rathore and I. Delke; Uni-
versity of Colorado Health Science Center, Denver: M. Levin, E.
McFarland, and J. McGregor; Virginia Commonwealth University,
Richmond: S. Lavoie and M. Dinsmoor; St. Jude Children’s Research
Hospital, Regional Medical Center of Memphis, Methodist Hospital,
Memphis: P. Flynn and R. Lewis; University of Puerto Rico School
of Medicine, San Juan, Puerto Rico: C. Diaz and C. Zorrilla; Children’s
Hospital of Philadelphia and Hospital of University of Pennsylvania,
Philadelphia: S. Starr, J. Merrill, and N. Rose; Thomas Jefferson Uni-
versity Hospital, Philadelphia: S. Adeniyi-Jones and N. Silverman; St.
Christopher’s Hospital for Children and Temple University, Philadel-
phia: H. Lischner and V. Whiteman; Children’s Hospital and Medical
Center, Seattle: L. Frankel and D. H. Watts; Bronx Lebanon Hospital,
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574 Stiehm et al. JID 1999;179 (March)
Bronx, NY: A. Wiznia and L. Solomon; Children’s National Medical
Center and Washington Hospital Center, Washington, DC: T. Rakusan
and P. Goldstein; Children’s Hospital of the King’s Daughter and Sen-
tara Norfolk General, Norfolk, Virginia: T. Rubio and B. Dattel; Tu-
lane University and Louisiana State University, New Orleans: M. Silio
and R. Maupin; Medical Center of Central Massachusetts, Worcester:
W. Durbin and K. Green; Baystate Medical Center, Springfield, Mas-
sachusetts: B. Stechenberg and L. Bayer-Zwerillo; University of Con-
necticut Health Center and Connecticut Children’s Medical Center,
Farmington: P. Krause and W. Campbell; University of Alabama at
Birmingham: R. Pass and J. Hauth; State University of New York
Health Science Center, Brooklyn: H. Minkoff; George Washington Uni-
versity Medical Center, Washington, DC: H. Fox; University of Min-
nesota, Minneapolis: C. Fletcher; Community Representatives: B. Fin-
ley, J. Davids; PACTG Statistical and Data Analysis Center, Harvard
University School of Public Health, Boston: D. Shapiro; National In-
stitutes of Health, Bethesda, Maryland: G. Nemo, L. Barbosa, E.
Sloand, N. L. Geller, D. Follman (National Heart, Lung and Blood
Institute); L. Mofenson, J. Moye, R. Nugent, A. Willoughby (National
Institute of Child Health and Human Development); M. G. Fowler,
P. Reichelderfer, L. Purdue, B. Mathieson (National Institute of Allergy
and Infectious Diseases); Westat, Rockville, Maryland: J. Whitehouse,
J. Bethel, J. Korelitz, D. R. Harris, M. Martin, R. Mitchell, C. Larson
Chebili, D. Butler; North American Biologicals, Boca Raton, Florida:
C. V. Sapan, F. Malinoski; Glaxo Wellcome, Research Triangle Park,
North Carolina: S. Hetherington; Quest Diagnostics, Baltimore: W. A.
Meyer III, H. Suter.
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