194 8 1089
194 8 1089
194 8 1089
Background. With the increasing use of antiretroviral (ARV) drugs to prevent mother-to-child transmission
of human immunodeficienc virus (HIV), large numbers of infants are exposed, with possible consequent toxicity.
Methods. Hematologic values in 1820 uninfected HIV- and ARV-exposed children were compared with those
in 351 ARV-unexposed children from the Women and Infants Transmission Study. Hemoglobin concentrations
and platelet, neutrophil, lymphocyte, and CD4+ and CD8+ cell counts were analyzed at birth and ages 2, 6, 12,
18, and 24 months. Multivariate analysis was conducted age 02 and 624 months, with adjustment for multiple
cofactors.
Results. Hemoglobin concentrations and neutrophil, lymphocyte, and CD4+ cell counts were significantl lower
at age 02 months in infants exposed to ARV drugs than in those who were not. At 624 months, differences in
hemoglobin concentrations and neutrophil counts were no longer significant whereas differences in platelet,
lymphocyte, and CD4+ cell counts persisted and CD8+ cell counts became significantl lower. In comparison with
ARV monotherapy, combination therapy was associated with larger decreases in neutrophil, lymphocyte, and CD8+
cell counts at age 02 months but with only differences in CD8+ cell counts at age 624 months. Clinically
significan abnormalities were rare and did not differ by exposure to ARV drugs.
Conclusion. Infants exposed to ARV drugs have small but significan differences in several hematologic pa-
rameters for the firs 24 months of life. These results indicate the need for long-term follow-up of uninfected
infants with ARV exposure.
There has been a dramatic decrease in perinatal HIV countries since 1994, when Pediatric AIDS Clinical Tri-
infection in the United States and other resource-rich als Group protocol 076 showed that administration of
zidovudine to the HIV-infected woman during preg-
nancy and labor and to her newborn reduced the risk
of mother-to-child HIV transmission by nearly 70%
Received 2 February 2006; accepted 17 May 2006; electronically published 11
September 2006. [1]. Subsequently, it was recognized that the use of
Presented in part: XV International AIDS Conference, Bangkok, Thailand, 11 combination antiretroviral (ARV) drug regimens dur-
16 July 2004 (abstract ThPeB7024).
Financial support to local Clinical Research Centers: National Institutes of Health ing pregnancy could further reduce transmission [2].
(grants GCRC RR00188 to Baylor College of Medicine, GCRC RR00645 to Columbia Current recommendations for the prevention of moth-
University, and GCRC RR02172 to Childrens Hospital Boston).
Potential conflicts of interest: none reported. er-to-child transmission in the United States include
a
Study group members are listed after the text. the use of ARV combination therapy during pregnancy
Reprints or correspondence: Dr. Kenneth McIntosh, Div. of Infectious Diseases,
Childrens Hospital Boston, 300 Longwood Ave., Boston, MA 02115 (Kenneth for women with HIV RNA loads 11000 copies/mL, with
[email protected]). the use of zidovudine prophylaxis alone restricted to
The Journal of Infectious Diseases 2006; 194:108997
2006 by the Infectious Diseases Society of America. All rights reserved.
women with HIV RNA loads !1000 copies/mL [3].
0022-1899/2006/19408-0009$15.00 Although mother-to-child transmission in the United
NOTE. Missing data were not included for calculation of the percentages. ARV, antiretroviral; CDC, Centers
for Disease Control and Prevention; NA, not available.
a
x2 test; all other comparisons were by t test.
b
Hispanic includes blacks and whites. Other includes Asian/Pacific Islander, American Indian, Alaskan
Native, and others.
c
Cocaine, heroin/opiates, methadone, and/or injection drug use, as ascertained by self-report and/or positive
urine toxicology at prenatal or delivery visits.
maturity (for hemoglobin concentration and platelet and neu- decreases in infants in the ARV monotherapy groups, compared
trophil counts), birth weight (for hemoglobin concentration and with those in the ARV combination therapy group.
CD8+ cell count); mode of delivery (for hemoglobin concentra- We also analyzed the impact of exposure to ARV combinations
tion), maternal CDC clinical classificatio (for neutrophil, lym- with PIs, compared with ARV combinations without PIs. There
phocyte, and CD4+ cell counts), and sex of the infant (for platelet, was remarkably little difference between these groups, with the
lymphocyte, CD4+, and CD8+ cell counts) (data not shown). sole exception of an apparent minor platelet-sparing effect of PI
Further analyses controlled for these variables. exposure that was evident both in infants 02 months old and
Table 3 summarizes the multivariate analysis of various he- those 624 months old (P p .006 and .02, respectively; data not
matologic parameters in infants exposed and not exposed to shown).
ARV drugs, with separate comparisons of any, single, and a The effect of maternal immune status (CD4+ cell count at
combination of ARV drugs with no ARV drugs. Hemoglobin delivery !200, 200500, or 1500 cells/mm3) on infant hema-
concentration and platelet, neutrophil, total lymphocyte, and tologic parameters was also examined. In the multivariate mod-
CD4+ cell counts were significantl lower in the any-ARV group els, a maternal CD4+ cell count !200 cells/mm3 was significantl
than in the no-ARV group during the firs 2 months of life. associated with a lower infant CD4+ cell count in both age groups:
The CD8+ cell count was borderline significantl lower in in- 02 months (169 cells/mm3; P p .03) and 624 months (183
fants exposed to ARV drugs. By age 624 months, there were cells/mm3; P p .02).
no longer significan differences in hemoglobin concentration Progression of hematologic parameters over time. Figure
and neutrophil count between ARV exposure groups, although 1A1F shows the changes in hematologic parameters and lym-
the neutrophil count in infants exposed to ARV drugs remained phocyte subsets between birth and age 24 months. The figu e
lower than that in infants not exposed to ARV drugs (regression illustrates several points. First, the differences in hemoglobin
coefficient 152 cells/mm3; P p .05 ). However, platelet, total concentration and neutrophil count, although statistically sig-
lymphocyte, CD4+, and CD8+ cell counts all remained signif- nificant were minimal. Second, the differences in platelet, total
icantly lower in infants exposed to ARV drugs than in infants lymphocyte, CD4+, and CD8+ cell counts between ARV-unex-
not exposed to ARV drugs through age 24 months. posed and -exposed infants were significan at most visits
In infants through age 2 months, exposure to ARV combi- throughout the period of study.
nation therapy was associated with greater differences in neu- Number of infants with 1 event of clinically relevant he-
trophil, lymphocyte, CD4+, and CD8+ counts than exposure to matologic abnormalities, by ARV exposure status. We eval-
a single ARV drug. For example, the difference in neutrophil uated the incidence of clinically significan laboratory abnor-
count between the no-ARV and ARV monotherapy groups was malities among the various ARV exposure groups. Clinically
321 cells/mm3, whereas the difference between the no-ARV significan abnormalities were define as grade 3 toxicities in
and ARV combination therapy groups was 548 cells/mm3; the Division of AIDS pediatric toxicity tables. These thresholds
the corresponding values for lymphocytes were 418 and 568 included hemoglobin concentration !7 g/dL, platelet count
cells/mm3; those for CD4+ cell counts were 136 and 183 !50,000/mm3, neutrophil count !400 cells/mm3, and CD4+ cell
cells/mm3; and those for CD8+ cell counts were 33 and 115 count !750 cells/mm3 in infants age !12 months or !500 cells/
cells/mm3. However, in infants age 624 months, with the ex- mm3 in infants age 1224 months. Less than 3% of children
ception of CD8+ cell count, there was little difference between had 1 hematologic or lymphocytic value in this abnormal
Any ARV vs. no ARV 0.4 !.0001 21.7 .005 434.3 .01 492.8 !.0001 159.1 .03 73.7 .06
Monotherapy vs. no ARV 0.4 !.0001 18.4 .02 320.6 .07 418.1 .001 135.5 .08 32.7 .4
Combination therapy vs. no ARV 0.4 !.0001 24.7 .004 548.1 .003 567.6 !.0001 182.7 .02 114.7 .007
624 months
Intercept 11.8 463.9 3304.5 8307.9 3697.0 1599.5
Any ARV vs. no ARV 0.03 .6 25.7 !.0001 153.3 .05 530.8 !.0001 224.3 .0002 161.8 !.0001
Monotherapy vs. no ARV 0.07 .2 24.4 !.0001 152.3 .06 490.3 !.0001 204.2 .0008 103.4 .002
Combination therapy vs. no ARV 0.1 .04 27.0 !.0001 154.3 .08 570.2 !.0001 244.4 .0005 220.1 !.0001
NOTE. Use of ARV drugs is as defined in Subjects and Methods. Multivariate analysis was adjusted for maternal antenatal use of hard drugs, maternal CD4+
cell count at delivery (!200 or 200 cells /mm3), infant gestational age (!37 weeks), infant birth weight, race/ethnicity, mode of delivery, maternal Centers for
Disease Control and Prevention clinical classification, and infant sex and age. CE, coefficient; combination therapy, 2 ARVs or highly active antiretroviral therapy
used during pregnancy; monotherapy, 1 ARV used during pregnancy.
range, and the proportion of infants with 1 occurrence of fants with perinatal exposure to ARV drugs had significantl
these values did not differ significantl among the various ARV lower hemoglobin concentrations and platelet, neutrophil, total
exposure groups. lymphocyte, CD4+, and CD8+ cell counts than HIV-exposed
infants without perinatal exposure to ARV drugs [10]. Although
DISCUSSION differences in hemoglobin concentrations resolved by age 2
months, the differences in the other hematologic parameters
These data from WITS, a large cohort study in the United
persisted through age 18 months. Those researchers reported
States, demonstrate that several hematologic parameters are
lower in HIV-exposed, uninfected infants with in utero and/ that exposure to combination ARV drugs was associated with
or neonatal exposure to ARV drugs, although these differences larger decreases than exposure to ARV monotherapy up to age
are small and appear to be clinically insignificant The hema- 15 months. In addition, there was a negative relationship be-
tologic effects of exposure to ARV drugs observed during the tween the duration of treatment and neutrophil and lympho-
firs 2 months of life could be secondary to the ongoing ex- cyte counts, and a lower maternal CD4+ cell count at delivery
posure to ARV drugs given to the infant during the firs 6 was associated with lower infant lymphocyte and CD4+ cell
weeks of life to prevent the transmission of HIV. However, counts.
although the difference in hemoglobin concentration resolved In the European Collaborative Study, perinatal ARV exposure
and that in neutrophil count became insignifican after age 2 of HIV-exposed but uninfected children was associated with a
months, significan differences persisted for platelet, lympho- reduced neutrophil count through age 8 years, regardless of
cyte, CD4+, and CD8+ cell counts through age 24 months. race or sex; maternal immune status was only marginally as-
Although exposure to ARV drugs in WITS was not randomized sociated with infant neutrophil counts in uninfected children
and there were changes over time in certain aspects of the study [14]. In a separate analysis, the total lymphocyte count was
population and in the use of ARV drugs, the finding persisted significantl lower in uninfected infants with perinatal exposure
even after we controlled for a number of parameters that have to ARV drugs than in those without exposure to ARV drugs;
been shown to be associated with hematologic variables in other the CD4+ cell count was lower only during the firs year of life,
studies, such as maternal race/ethnicity, drug use, maternal but the CD8+ count was reduced through age 8 years [15].
CD4+ cell count at delivery, and infant gestational age, birth However, there was no significan difference between infants
weight, sex, and age. Despite some differences in methodology who were exposed to ARV drugs, compared with those who
and considerable differences in race/ethnicity, similar finding were not, in the incidence of lymphopenia, define as CDC
were reported from the French Perinatal Cohort Study Group immune stage 2. A lower maternal CD4+ cell count (!200
and the European Collaborative Study [11, 14, 15]. cells/mm3) was associated with lower CD4+ cell counts but not
In the French Perinatal Cohort Study, HIV-uninfected in- with CD8+ cell counts in infants. Exposure to ARV combination