Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group

Article (PDF Available)inNew England Journal of Medicine 343(11):759-66 · October 2000with27 Reads
DOI: 10.1056/NEJM200009143431102 · Source: PubMed
Abstract
Perinatal exposure to zidovudine may cause cardiac abnormalities in infants. We prospectively studied left ventricular structure and function in infants born to mothers infected with the human immunodeficiency virus (HIV) in order to determine whether there was evidence of zidovudine cardiac toxicity after perinatal exposure. We followed a group of infants born to HIV-infected women from birth to five years of age with echocardiographic studies every four to six months. Serial echocardiograms were obtained for 382 infants without HIV infection (36 with zidovudine exposure) and HIV-58 infected infants (12 with zidovudine exposure). Repeated-measures analysis was used to examine four measures of left ventricular structure and function during the first 14 months of life in relation to zidovudine exposure. Zidovudine exposure was not associated with significant abnormalities in mean left ventricular fractional shortening, end-diastolic dimension, contractility, or mass in either non-HIV-infected or HIV-infected infants. Among infants without HIV infection, the mean fractional shortening at 10 to 14 months was 38.1 percent for those never exposed to zidovudine and 39.0 percent for those exposed to zidovudine (mean difference, -0.9 percent; 95 percent confidence interval, -3.1 percent to 1.3 percent; P=0.43). Among HIV-infected infants, the mean fractional shortening at 10 to 14 months was similar in those never exposed to zidovudine (35.4 percent) and those exposed to the drug (35.3 percent) (mean difference, 0.1 percent; 95 percent confidence interval, -3.7 percent to 3.9 percent; P=0.95). Zidovudine exposure was not significantly related to depressed fractional shortening (shortening of 25 percent or loss) during the first 14 months of life. No child over the age of 10 months had depressed fractional shortening. Zidovudine was not associated with acute or chronic abnormalities in left ventricular structure or function in infants exposed to the drug in the perinatal period.
Volume 343 Number 11
·
759
ABSENCE OF CARDIAC TOXICITY OF ZIDOVUDINE IN INFANTS
ABSENCE OF CARDIAC TOXICITY OF ZIDOVUDINE IN INFANTS
S
TEVEN
E. L
IPSHULTZ
, M.D., K
IRK
A. E
ASLEY
, M.S., E. J
OHN
O
RAV
, P
H
.D., S
AMUEL
K
APLAN
, M.D.,
T
HOMAS
J. S
TARC
, M.D., J. T
IMOTHY
B
RICKER
, M.D., W
YMAN
W. L
AI
, M.D., M.P.H., D
OUGLAS
S. M
OODIE
, M.D.,
G
EORGE
S
OPKO
, M.D., M.P.H., K
ENNETH
M
C
I
NTOSH
, M.D.,
AND
S
TEVEN
D. C
OLAN
, M.D.,
FOR
THE
P
EDIATRIC
P
ULMONARY
AND
C
ARDIAC
C
OMPLICATIONS
OF
V
ERTICALLY
T
RANSMITTED
HIV I
NFECTION
S
TUDY
G
ROUP
*
A
BSTRACT
Background
Some evidence suggests that perina-
tal exposure to zidovudine may cause cardiac abnor-
malities in infants. We prospectively studied left ven-
tricular structure and function in infants born to
mothers infected with the human immunodeficiency
virus (HIV) in order to determine whether there was
evidence of zidovudine cardiac toxicity after perina-
tal exposure.
Methods
We followed a group of infants born to HIV-
infected women from birth to five years of age with
echocardiographic studies every four to six months.
Serial echocardiograms were obtained for 382 infants
without HIV infection (36 with zidovudine exposure)
and 58 HIV-infected infants (12 with zidovudine ex-
posure). Repeated-measures analysis was used to
examine four measures of left ventricular structure
and function during the first 14 months of life in re-
lation to zidovudine exposure.
Results
Zidovudine exposure was not associated
with significant abnormalities in mean left ventricular
fractional shortening, end-diastolic dimension, con-
tractility, or mass in either non–HIV-infected or HIV-
infected infants. Among infants without HIV infection,
the mean fractional shortening at 10 to 14 months was
38.1 percent for those never exposed to zidovudine
and 39.0 percent for those exposed to zidovudine
(mean difference, ¡0.9 percentage point; 95 percent
confidence interval, ¡3.1 to 1.3 percentage points; P=
0.43). Among HIV-infected infants, the mean frac-
tional shortening at 10 to 14 months was similar in
those never exposed to zidovudine (35.4 percent) and
those exposed to the drug (35.3 percent) (mean dif-
ference, 0.1 percentage point; 95 percent confidence
interval, ¡3.7 to 3.9 percentage points; P=0.95). Zi-
dovudine exposure was not significantly related to
depressed fractional shortening (shortening of 25
percent or less) during the first 14 months of life. No
child over the age of 10 months had depressed frac-
tional shortening.
Conclusions
Zidovudine was not associated with
acute or chronic abnormalities in left ventricular struc-
ture or function in infants exposed to the drug in the
perinatal period. (N Engl J Med 2000;343:759-66.)
©2000, Massachusetts Medical Society.
From the Division of Pediatric Cardiology, University of Rochester
Medical Center and Children’s Hospital at Strong, and the Department of
Pediatrics, University of Rochester School of Medicine and Dentistry
both in Rochester, N.Y. (S.E.L.); the Department of Cardiology (S.E.L.,
S.D.C.) and the Division of Infectious Diseases (K.M.), Childrens Hospi-
tal, Boston; the Department of Pediatrics, Harvard Medical School, Boston
(S.E.L., K.M., S.D.C.); the Department of Pediatrics, Boston Medical Cen-
ter and Boston University School of Medicine, Boston (S.E.L.); the De-
partment of Biostatistics and Epidemiology (K.A.E.) and the Department
of Pediatrics, Division of Pediatric Cardiology (D.S.M.), Cleveland Clinic
Foundation, Cleveland; the Department of Medicine, Brigham and Wom-
ens Hospital, Boston (E.J.O.); the Department of Pediatrics, Division of
Pediatric Cardiology, University of California, Los Angeles, Medical Cen-
ter and School of Medicine, Los Angeles (S.K.); the Department of Pedi-
atrics, Division of Pediatric Cardiology, Presbyterian Hospital and Colum-
bia University School of Medicine, New York (T.J.S.); the Department of
Pediatrics, Division of Pediatric Cardiology, Baylor College of Medicine,
Houston (J.T.B.); the Department of Pediatrics, Division of Pediatric Car-
diology, Mount Sinai School of Medicine, New York (W.W.L.); and the Na-
tional Heart, Lung, and Blood Institute, Bethesda, Md. (G.S.). Address re-
print requests to Dr. Lipshultz at the Division of Pediatric Cardiology,
University of Rochester Medical Center, 601 Elmwood Ave., Box 631,
Rochester, NY 14642, or at steve_lipshultz@urmc.rochester.edu.
*Participants in the study are listed in the Appendix.
ONCERN that zidovudine may be associ-
ated with cardiac mitochondrial dysfunction
has been aroused by several studies in ani-
mals and by limited clinical data. In studies
in monkeys, zidovudine at 21 percent and 86 per-
cent of the human daily dose was administered to fe-
males in the second half of pregnancy, and the effects
on fetal cardiomyocytes were observed. The cardio-
myocytes were found to have abnormal and disrupt-
ed sarcomeres with myofibrillar loss; dose-related ab-
normalities of mitochondrial structure and function
were also found. These changes were consistent with
the presence of zidovudine-induced mitochondrial
cardiomyopathy in fetal monkeys.
1-3
Zidovudine has toxic effects on cardiac mitochon-
dria in animals and adult humans.
4
In addition, zido-
vudine and its metabolites can cross the placenta and
have been found in the fetal heart in animals.
5,6
A re-
cent report suggested that mitochondrial dysfunction
in 8 of 1754 children, including 1 child with sympto-
matic hypokinetic hypertrophic cardiomyopathy, may
have been caused by zidovudine alone or in combina-
tion with lamivudine.
7
These children were exposed
to the drug or drugs both in utero and after birth. Car-
diomyopathy in children can be associated with mi-
tochondrial deletions or mutations or abnormal mi-
tochondrial-enzyme function.
8,9
At least one study
10
found evidence to suggest that zidovudine may cause
cardiomyopathy in children, and the investigators
C
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760
·
September 14, 2000
The New England Journal of Medicine
recommended withholding zidovudine from patients
with left ventricular dysfunction.
Other studies, however, have not found detrimen-
tal clinical effects on the heart. Studies of ventricular
dysfunction conducted by members of our group
11
and others
12
have found no evidence of zidovudine-
related cardiomyopathy in children. Studies in adults
have not found effects of zidovudine on left ventricular
end-diastolic dimension, mass, or fractional shorten-
ing.
13
Similarly, administration of zidovudine to preg-
nant baboons did not affect the fetal heart rate or the
variability of the rate.
14
Short-term and long-term fol-
low-up of uninfected children born to women infect-
ed with the human immunodeficiency virus (HIV)
has not identified detrimental effects of perinatal zi-
dovudine exposure or clinically important cardiovas-
cular disease.
15,16
The progressively more severe manifestations of
drug-induced mitochondrial damage in cardiomyo-
cytes are cardiomyopathy, congestive heart failure, and
death due to pump failure, or sudden cardiac death.
On echocardiographic evaluation, infants with mito-
chondrial cardiomyopathy frequently have reduced left
ventricular contractility, depressed left ventricular sys-
tolic performance as indicated by fractional shortening,
left ventricular dilatation, and increased left ventricular
mass.
17
Whereas children with HIV infection have a
two-year cumulative incidence of chronic congestive
heart failure of 5.1 percent, subclinical echocardio-
graphic abnormalities of left ventricular structure and
function are found in more than 90 percent of seri-
ally monitored HIV-infected children.
18-20
These ab-
normalities are independent risk factors for death in
HIV-infected children.
21
Subclinical manifestations of
cardiac toxicity and cardiomyopathy, indicated by ab-
normalities in left ventricular structure and function,
were used as surrogates for adverse outcomes in this
study.
21
We used longitudinal assessment by means of sen-
sitive noninvasive echocardiographic measurements to
compare four measures of left ventricular structure
and function during the first year of life between in-
fants exposed to zidovudine and those not so exposed.
Our objective was to assess whether zidovudine has
acute or chronic effects on left ventricular structure
and function.
METHODS
Study Design
The Pediatric Pulmonary and Cardiac Complications of Verti-
cally Transmitted HIV Infection Study was a large, prospective,
longitudinal study designed to monitor heart disease and the pro-
gression of cardiac abnormalities in children born to HIV-infected
women.
19,20,22
The current study was limited to the cohort of the
611 infants enrolled during fetal life (443 infants) or after delivery
but before 28 days of age (168 infants). Eleven of these infants were
stillborn and 600 were born alive; of those born alive, 93 were sub-
sequently found to have HIV infection, 463 were found not to have
HIV infection, and 44 were of unknown HIV status. The HIV
status of the 600 live-born infants was unknown at enrollment.
Cultures for HIV were performed for the infants at birth and at
three and six months of age. HIV infection was diagnosed if an in-
fant had two cultures that were positive for HIV, had a positive test
for HIV antibodies at 15 or more months of age, died of an HIV-
associated condition, or had the acquired immunodeficiency syn-
drome (AIDS). Infants with two negative cultures for HIV (at least
one at 5 or more months of age) or negative results on serologic
tests for HIV at 15 or more months of age were considered to be
uninfected with HIV. The status of all others was considered to
be indeterminate with respect to HIV. The cohort included in the
current analysis entered the study between May 1990 and January
1994 and were followed through January 1997.
The study subjects were treated at five major clinical centers in
different parts of the United States. Multiple cardiac and pulmonary
tests were performed, and antiretroviral and antimicrobial therapies
(e.g., intravenous immune globulin) were administered as clinically
warranted. The original study protocol was not designed to gather
complete data about antiretroviral therapy. We began collecting
postnatal data on the infants prospectively in 1994. Data were ret-
rospectively retrieved for patients enrolled before 1994. Data on
whether the mothers had used zidovudine during pregnancy were
collected prospectively throughout the study by reviewing medical
records. Data on the length of in utero exposure to zidovudine were
later collected retrospectively. The study was approved by the insti-
tutional review board at each center, and written informed consent
was obtained from the parents or guardians of the infants.
According to the protocol, all children underwent echocardio-
graphic testing at four-to-six-month intervals, regardless of their
clinical status. For each echocardiographic study, sedation was used
as necessary, primarily in children less than three years of age. Two-
dimensional echocardiography and Doppler studies with stress–
velocity analysis of left ventricular contractility
19
were performed
for each child. All echocardiograms were examined at a central lab-
oratory by technicians unaware of the child’s clinical status or med-
ications. Measurements of left ventricular end-diastolic dimension
and fractional shortening were excluded from the analysis if wall-
motion abnormalities or septal-motion abnormalities were identi-
fied. Data on left ventricular function in three children with congen-
ital heart abnormalities were also excluded.
Statistical Analysis
Repeated-measures analyses were performed separately for HIV-
infected infants and for those without HIV infection. For each
measurement of left ventricular function, data from birth to 14
months of age were used. For each left ventricular outcome, we fit-
ted a linear model using restricted maximum-likelihood estimation
and either an unstructured variance–covariance form or a hetero-
geneous compound symmetry form among repeated measurements.
This method allowed us to make separate estimates of the mean ac-
cording to the presence or absence of postpartum zidovudine expo-
sure and according to age (birth to 1.5 months, >1.5 to 6 months,
>6 to 10 months, and >10 to 14 months). The analyses of left
ventricular end-diastolic dimension and mass were also adjusted
for body-surface area. For each age category, the adjusted mean
for a subgroup (exposed or not exposed to zidovudine) was de-
fined as the mean response obtained by evaluating the statistical
model at the mean body-surface area of the two subgroups. The
results were summarized with adjusted means and 95 percent con-
fidence intervals. The proportions of infants with and without zi-
dovudine exposure in the first six weeks of life who had depressed
fractional shortening (shortening of 25 percent or less) were ana-
lyzed separately for HIV-infected and non–HIV-infected infants by
Fisher’s exact test. The reported P values are two-sided, and a P val-
ue of 0.05 or less was considered to indicate statistical significance.
More complete longitudinal data on children without HIV in-
fection were available for the first 14 months of life than for the
period from 14 months to 5 years, for two reasons. First, as would
be expected, loss to follow-up was high for non–HIV-infected
children. Second, approximately half the children without HIV in-
fection were randomly selected to remain in the study as a control
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ABSENCE OF CARDIAC TOXICITY OF ZIDOVUDINE IN INFANTS
Volume 343 Number 11
·
761
group, and the remainder were randomly selected to leave the
study.
22
Regardless of the childrens HIV status, approximately 55
to 60 percent of all possible echocardiograms obtained during the
first 14 months of life were available for analysis. Approximately 22
percent of the scheduled echocardiograms were not obtained be-
cause of missed visits. Fewer than 10 percent of the HIV-infected
children were lost to follow-up by 14 months of age.
22
We con-
ducted separate qualitative analyses of the data obtained between 14
months and 5 years, using all available echocardiograms, but we do
not report P values, because of the scientific rigor they imply.
RESULTS
The characteristics of the infected and uninfected
infants are shown in Table 1. Most were black (51.6
percent) or Hispanic (31.4 percent); 52.3 percent
were male.
Of the 93 HIV-infected infants, 35 were not includ-
ed in the 14-month analyses. Twelve of the remain-
ing 58 were exposed to zidovudine at the time every
echocardiogram was obtained during the first 14
months of life. The remaining 46 infants did not re-
ceive zidovudine before any of the echocardiograph-
ic studies performed in the first 14 months of life.
Of the 35 infants not included in the analysis, 31 re-
ceived zidovudine at some point but not throughout
the initial 14 months, and 4 did not undergo echocar-
diographic measurements of systolic function. None
of the 58 infants included in the analysis had conges-
tive heart failure at the initial cardiac evaluation or dur-
ing follow-up.
Of the 463 non–HIV-infected infants, 382 were
included in the analysis at 14 months. Of the 81 in-
fants not included in the analysis, no echocardiograph-
ic data before 14 months of age were available for 39
and no data on zidovudine exposure were available for
42. Thirty-six of the 382 infants included were given
zidovudine after birth, before their uninfected status
was confirmed, and 346 were not given zidovudine af-
ter birth. The median length of postnatal zidovudine
treatment for 35 of the 36 infants was 42 days (range,
35 to 48). Data on length of treatment were not avail-
able for the remaining infant. All 36 were also exposed
to zidovudine in utero. The median length of prena-
tal exposure for 33 of the 36 fetuses was 66 days
(range, 8 to 273).
None of the 382 non–HIV-infected infants includ-
ed in our study had congestive heart failure at enroll-
ment or during follow-up.
Other Therapy
Among the 382 non–HIV-infected infants, none
received therapies for HIV infection other than zi-
dovudine. Forty of the 58 HIV-infected infants re-
ceived one or more therapies for HIV infection other
than zidovudine during the first 14 months of follow-
up (Table 2). The most common were didanosine and
intravenous immune globulin. Because of the num-
ber of different therapies and the sporadic nature of
their use, we did not adjust for the use of other ther-
apies in the analyses.
Initial Measures of Left Ventricular Structure and Function
The median length of in utero exposure to zido-
vudine was 103 days (data on length of exposure were
available for 85 of 107 fetuses with any exposure [79
percent]). The infants who were found after birth not
to have HIV infection had a median length of in
utero exposure to zidovudine of 105 days; those who
were found after birth to be infected with HIV were
exposed to zidovudine in utero for a median of 68
days. Among the infants for whom a first echocardio-
gram was available that was obtained between birth
and three months of age, in utero zidovudine exposure
had no significant effect on any of the four measures
of left ventricular structure or function (Table 3).
Longitudinal Measures of Left Ventricular Structure
and Function
Zidovudine had no significant effect on mean left
ventricular fractional shortening, contractility, end-
diastolic dimension, or mass in the first 14 months
after birth in either HIV-infected or non–HIV-infect-
*ACTG denotes AIDS Clinical Trials Group, and NA not applicable.
†Percentages are based on 90 HIV-infected infants and 445 non–HIV-
infected infants for whom data on in utero zidovudine exposure were available.
‡Percentages are based on the 62 HIV-infected infants who were con-
tinuously exposed to zidovudine postnatally or who were never exposed
and on the 421 non–HIV-infected infants who were never exposed to zi-
dovudine postnatally or who were only exposed up to six weeks of age.
§Percentages are based on 58 HIV-infected infants and 382 non–HIV-
infected infants who had at least one echocardiogram.
T
ABLE
1.
C
HARACTERISTICS
OF
556 I
NFANTS
WITH
K
NOWN
HIV S
TATUS
B
ORN
A
LIVE
TO
HIV-I
NFECTED
W
OMEN
.*
C
HARACTERISTIC
HIV-I
NFECTED
I
NFANTS
(N=93)
N
ON
–HIV-I
NFECTED
I
NFANTS
(N=463)
number (percent)
Lost to follow-up 15 (16.1) 156 (33.7)
Exposed to zidovudine in utero† 27 (30.0) 158 (35.5)
Zidovudine use according to ACTG
076 protocol
3 (3.2) 29 (6.3)
Postnatal medications from 0 to 14 mo
Continuous zidovudine use
No zidovudine use
Zidovudine up to 6 wk
No medications
Zidovudine sometimes
Data not available
12 (12.9)
50 (53.8)
NA
NA
31 (33.3)
0
NA
NA
41 (8.9)
380 (82.1)
0
42 (9.1)
No. of echocardiograms up to 14 mo‡
0
1
2
3
4
4 (6.5)
17 (27.4)
16 (25.8)
17 (27.4)
8 (12.9)
39 (9.3)
72 (17.1)
162 (38.5)
106 (25.2)
42 (10.0)
Died§
0–14 mo
>14 mo to 5 yr
4 (6.9)
9 (15.5)
0
1 (0.2)
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762
·
September 14, 2000
The New England Journal of Medicine
ed infants after adjustment for age and body-surface
area (Table 4). Figures 1 and 2 illustrate the similar-
ity of the changes in infants exposed to zidovudine
and those not exposed (additional data are available
elsewhere*). At 10 to 14 months of age, the mean dif-
ference in fractional shortening between non–HIV-
infected infants never exposed to zidovudine and
non–HIV-infected infants exposed to zidovudine in
utero or up to six weeks after birth was ¡0.9 per-
centage point (95 percent confidence interval, ¡3.1
to 1.3 percentage points; P=0.43). For HIV-infected
infants, the mean difference in fractional shortening at
10 to 14 months between those never exposed to zi-
dovudine in the first year of life and those exposed
throughout the year was also small (mean difference,
0.1 percentage point; 95 percent confidence interval,
¡3.7 to 3.9 percentage points; P=0.95).
*Thirty-one children received zidovudine before the age of five years (median duration of therapy,
16.2 months).
†The median duration of zidovudine therapy was 27.2 months.
T
ABLE
2.
T
REATMENTS
FOR
HIV I
NFECTION
O
THER
T
HAN
Z
IDOVUDINE
A
DMINISTERED
TO
58 HIV-I
NFECTED
I
NFANTS
, A
CCORDING
TO
Z
IDOVUDINE
E
XPOSURE
UP
TO
14 M
ONTHS
OF
A
GE
.
T
HERAPY
N
O
Z
IDOVUDINE
E
XPOSURE
(N=46)*
C
ONTINUOUS
Z
IDOVUDINE
E
XPOSURE
(N=12)†
ANY
USE AGE
AT
FIRST
USE
MEDIAN
DURATION
OF
THERAPY
ANY
USE AGE
AT FIRST USE
MEDIAN
DURATION
OF THERAPY
«1
mo
>1–14
mo
>14
mo
«1
mo
>1–14
mo
>14
mo
number mo number mo
Didanosine 29 0 12 17 16.5 10 1 5 4 15.7
Zalcitabine 2 0 0 2 2.3 0 0 0 0
Lamivudine 11 0 0 11 5.2 3 0 0 3 10.6
Interferon 1 0 0 1 5.3 0 0 0 0
Nevirapine 3 0 1 2 9.5 0 0 0 0
Stavudine 12 0 4 8 14.9 2 0 0 2 5.6
Intravenous
immune
globulin
10 0 8 2 4.5 5 0 2 3 9.9
Any anti-
retroviral
drug
42 0 28 14 34.9 12 5 7 0 40.8
*The P values are for the comparisons between zidovudine-exposed and unexposed infants, by
two-sample t-test.
†Among HIV-infected infants, the median age at the first echocardiogram was 38 days for those
exposed to zidovudine in utero and 29 days for those not exposed.
‡Among non–HIV-infected infants, the median age at first echocardiogram was 21 days for those
exposed to zidovudine in utero and 25 days for those not exposed.
TABLE 3. INITIAL ECHOCARDIOGRAPHIC MEASURES ACCORDING TO HIV STATUS
AND EXPOSURE TO ZIDOVUDINE IN UTERO.*
MEASURE
ZIDOVUDINE
EXPOSURE HIV-INFECTED INFANTS†NON–HIV-INFECTED INFANTS
NO. OF
INFANTS MEAN ±SD P VALUE
NO
. OF
INFANTS MEAN ±SD P VALUE
Fractional shortening
(%)
Yes
No
16
40
34.1±3.7
34.3±5.8
0.87 91
162
34.4±6.2
34.5±4.9
0.86
Contractility Yes
No
15
39
¡0.53±1.04
¡0.63±1.71
0.80 84
156
¡0.66±1.73
¡0.75±1.44
0.68
End-diastolic dimen-
sion (cm)
Yes
No
16
40
1.99±0.30
1.96±0.24
0.70 91
162
1.90±0.25
1.92±0.23
0.47
Left ventricular mass
(g)
Yes
No
16
40
14.6±6.0
12.7±3.5
0.25 88
159
13.1±4.0
13.1±3.7
0.98
*See NAPS document no. 05568 for 9 pages of supplementary materi-
al. To order, contact NAPS, c/o Microfiche Publications, 248 Hempstead
Tpke., West Hempstead, NY 11552.
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
ABSENCE OF CARDIAC TOXICITY OF ZIDOVUDINE IN INFANTS
Volume 343 Number 11 · 763
*CI denotes confidence interval, and BSA body-surface area.
†The P value for zidovudine indicates whether differences between means due to postnatal zidovudine exposure were detected. The P value for the statistical interaction of zidovudine with age indicates whether
age-related changes were similar for infants exposed and not exposed to zidovudine postnatally.
TABLE 4. ECHOCARDIOGRAPHIC MEASURES ACCORDING TO HIV STATUS AND ZIDOVUDINE EXPOSURE FROM BIRTH TO 14 MONTHS OF AGE.*
MEASURE AND AGE (MO) HIV-INFECTED INFANTS NON–HIV-INFECTED INFANTS
NO
ZIDOVUDINE EXPOSURE
(N=46)
CONTINUOUS ZIDOVUDINE
EXPOSURE
(N=12) P VALUE
NO ZIDOVUDINE EXPOSURE
(N=346)
ZIDOVUDINE
ONLY
UP TO SIX WEEKS
(N=36) P VALUE
no. mean (95% CI) no. mean (95% CI)
zido-
vudine
zidovudine
by age no. mean (95% CI) no. mean (95% CI)
zido-
vudine
zidovudine
by age
Fractional shortening (%)
0–1.5
>1.5–6
>6–10
>10–14
22
33
28
22
31.9 (30.0 to 33.9)
34.5 (32.7 to 36.3)
35.1 (33.3 to 37.0)
35.4 (33.5 to 37.4)
3
7
7
10
35.7 (30.5 to 40.9)
33.6 (30.0 to 37.2)
36.1 (32.0 to 40.2)
35.3 (32.1 to 38.6)
0.53 0.51
170
283
157
193
34.3 (33.5 to 35.1)
36.7 (36.2 to 37.3)
39.2 (38.5 to 39.8)
38.1 (37.5 to 38.7)
25
25
15
14
33.9 (31.8 to 35.9)
36.0 (34.2 to 37.7)
39.0 (36.9 to 41.0)
39.0 (36.9 to 41.1)
0.85 0.65
Contractility
0–1.5
>1.5–6
>6–10
>10–14
22
31
28
21
¡0.87 (¡1.59 to ¡0.16)
¡0.99 (¡1.50 to ¡0.49)
¡1.24 (¡1.74 to ¡0.74)
¡1.41 (¡1.89 to ¡0.93)
3
7
6
10
0.14 (¡1.78 to 2.06)
¡0.81 (¡1.99 to 0.37)
¡1.14 (¡2.18 to ¡0.09)
¡1.34 (¡2.18 to ¡0.50)
0.43 0.86
163
275
148
191
¡0.81 (¡1.03 to ¡0.58)
¡0.71 (¡0.87 to ¡0.55)
¡0.58 (¡0.77 to ¡0.39)
¡1.02 (¡1.18 to ¡0.85)
23
23
15
14
¡0.31 (¡0.92 to 0.30)
¡0.63 (¡1.15 to ¡0.10)
¡0.63 (¡1.23 to ¡0.04)
¡1.02 (¡1.63 to ¡0.40)
0.49 0.58
BSA-adjusted end-diastolic
dimension (cm)
0–1.5
>1.5–6
>6–10
>10–14
22
33
27
21
1.94 (1.87 to 2.01)
2.30 (2.23 to 2.36)
2.53 (2.46 to 2.60)
2.69 (2.61 to 2.77)
3
7
7
10
1.90 (1.71 to 2.10)
2.45 (2.32 to 2.58)
2.63 (2.48 to 2.77)
2.63 (2.71 to 2.95)
0.12 0.38
169
281
155
190
1.86 (1.83 to 1.88)
2.26 (2.24 to 2.28)
2.50 (2.47 to 2.53)
2.64 (2.62 to 2.67)
25
24
15
14
1.92 (1.84 to 1.99)
2.28 (2.22 to 2.35)
2.47 (2.39 to 2.56)
2.66 (2.56 to 2.75)
0.58 0.49
BSA-adjusted left ventricu-
lar mass (g)
0–1.5
>1.5–6
>6–10
>10–14
22
33
27
21
11.9 (10.1 to 13.6)
20.1 (18.5 to 21.7)
25.3 (23.5 to 27.0)
28.3 (26.6 to 30.1)
3
7
7
10
12.1 (7.4 to 16.8)
21.6 (18.4 to 24.8)
27.1 (23.7 to 30.6)
30.3 (27.2 to 33.3)
0.27 0.94
165
279
151
190
12.3 (11.7 to 12.8)
19.6 (19.1 to 20.0)
23.9 (23.3 to 24.6)
27.4 (26.8 to 28.0)
25
24
15
14
13.0 (11.6 to 14.5)
18.7 (17.2 to 20.2)
22.4 (20.3 to 24.4)
28.9 (26.6 to 31.2)
0.93 0.04
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764 · September 14, 2000
The New England Journal of Medicine
We did find a significant interaction between the
effects of zidovudine and age on left ventricular mass
in infants without HIV infection (Table 4). The mean
left ventricular mass in infants exposed to zidovudine
was higher at the first echocardiogram than in those
never exposed (13.0 g vs. 12.3 g), lower at 4 months
(18.7 g vs. 19.6 g) and 8 months (22.4 g vs. 23.9 g),
and higher at 12 months (28.9 g vs. 27.4 g). There-
fore, there was no consistent effect of zidovudine ex-
posure on left ventricular mass.
Long-Term Effects on Left Ventricular Structure
and Function
An effect of zidovudine on echocardiographic meas-
ures was not identified among either HIV-infected or
non–HIV-infected children. No clinically important
differences were found between zidovudine-exposed
and unexposed children for any of the four echocar-
diographic measures between 14 months and 5 years
of age (data available elsewhere*).
Depressed Fractional Shortening
To address the possibility that zidovudine expo-
sure may have an extreme effect on a vulnerable sub-
group of infants, rather than a consistent effect among
all infants, we tested whether the proportion of chil-
dren with fractional shortening of 25 percent or less
(defined as depressed fractional shortening) differed
according to postnatal zidovudine exposure. No sig-
nificant differences were found between exposed and
unexposed infants, either in the HIV-infected or the
non–HIV-infected group, in the first 14 months of
life. None of the 12 HIV-infected infants who were
continuously exposed to zidovudine for 14 months
had fractional shortening of 25 percent or less by 10
months of age. Among the 46 HIV-infected infants
without zidovudine exposure, 9 percent (2 of 22 test-
ed) had depressed fractional shortening at 0 to 1.5
months, as did 6 percent (2 of 33) at >1.5 to
6 months, and 7 percent (2 of 28) at >6 to 10
months. By six weeks of age, 12 percent (3 of 25 test-
ed) of the 36 non–HIV-infected infants who had
been exposed to zidovudine for six weeks or less had
fractional shortening of 25 percent or less. Depressed
fractional shortening was not identified in these 36
infants after 6 weeks of age (0 of 25 tested at >1.5 to
6 months and 0 of 15 at >6 to 10 months). Among
the 346 non–HIV-infected infants never exposed to
zidovudine after birth, 4 percent (7 of 170 tested) had
depressed fractional shortening at 0 to 1.5 months
Figure 1. Left Ventricular Fractional Shortening during the First 14 Months of Life in 382 Infants without HIV Infection,
According to Zidovudine Exposure.
The vertical bars indicate the 95 percent confidence intervals for the means.
15
55
Birth 14
20
25
30
35
40
45
50
1 2 3 4 5 6 7 8 9 10 11 12 13
Age (months)
Fractional Shortening (%)
Zidovudine exposure only in first 6 wk of life
No postnatal zidovudine exposure
*See NAPS document no. 05568 for 9 pages of supplementary materi-
al. To order, contact NAPS, c/o Microfiche Publications, 248 Hempstead
Tpke., West Hempstead, NY 11552.
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
ABSENCE OF CARDIAC TOXICITY OF ZIDOVUDINE IN INFANTS
Volume 343 Number 11 · 765
and 1 percent (3 of 283) had depressed fractional
shortening at >1.5 to 6 months. None of the non–
HIV-infected infants without postnatal zidovudine ex-
posure had depressed fractional shortening between
6 and 10 months of age. After 10 months of age, no
infants had depressed fractional shortening, regard-
less of zidovudine exposure or HIV status.
DISCUSSION
In our study, infants born to HIV-infected wom-
en and exposed to zidovudine were no more likely to
have abnormal left ventricular structure and function
than were infants who did not have zidovudine treat-
ment throughout the first 14 months of life. These
results support the findings of a previous retrospec-
tive study that used longitudinal cardiac data in older
children to compare those who had been exposed to
zidovudine with those who had not been exposed to
zidovudine,
11
as well as recent studies by the Nation-
al Institutes of Health AIDS Clinical Trials Group.
16
However, a recent study from France
7
suggested that
a negative cardiac effect may persist over a consider-
able period after exposure to zidovudine in infants
without HIV infection and infants born to HIV-
infected mothers. That study, however, did not have a
control group, whereas our study had an uninfected
cohort. Similarly, persistent cardiotoxicity was ob-
served in neonatal monkeys exposed to zidovudine in
utero.
1-3
Both our study and the French study
7
pro-
vide evidence that cardiotoxicity is not a common
complication of zidovudine treatment in children.
In looking at the percentage of children with de-
pressed fractional shortening as an indication of a
detrimental effect of zidovudine within a vulnerable
subgroup, we are limited by our small sample. The
samples in our study are too small to provide an accu-
rate estimate of the frequency of an uncommon toxic
effect. Also, the small number of infants exposed to
zidovudine who were followed after 14 months of age
is likely to be inadequate for us to detect late-emerging
events. We may also have missed instances of depressed
fractional shortening in longer-term follow-up, be-
cause the sickest children may not have been able to
attend follow-up visits. In addition, during longer-
term follow-up of the HIV-infected subgroup, the
effect of zidovudine becomes more ambiguous, be-
cause these children are exposed to many other drugs,
and it is hard to ascribe changes specifically to zido-
vudine. Finally, the effects of dosage were not assessed
in this study.
Gerschenson et al.
1-3
found profound changes in
the structure and function of cardiac-muscle mito-
Figure 2. Left Ventricular Fractional Shortening during the First 14 Months of Life in 58 Infants with HIV Infection, Ac-
cording to Zidovudine Exposure.
The vertical bars indicate the 95 percent confidence intervals for the means.
15
55
Birth 14
20
25
30
35
40
45
50
1 2 3 4 5 6 7 8 9 10 11 12 13
Age (months)
Fractional Shortening (%)
Continuous zidovudine exposure
No zidovudine exposure
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766 · September 14, 2000
The New England Journal of Medicine
chondria in neonatal monkeys exposed to zidovudine
at the end of gestation. In contrast, we found no clear
association between zidovudine and left ventricular
structure or function, as assessed by echocardiogra-
phy, in neonates without HIV infection who received
zidovudine as part of postnatal prophylaxis, even when
echocardiograms were obtained at the time the chil-
dren were taking the drug. Although our intensive
follow-up included children only up to the age of 14
months, the data of Gerschenson et al.
1-3
indicate
that subclinical dysfunction, if present, should be
seen at birth or soon after. However, no such mani-
festations were observed in our cohort.
We found no evidence of acute or chronic adverse
cardiac effects in non–HIV-infected infants exposed
to zidovudine in the perinatal period. This absence
of evidence of toxicity is reassuring, given the reports
of Gerschenson et al.
1-3
and Blanche et al.
7
Our
echocardiographic data suggest that the benefits of
zidovudine during pregnancy in reducing vertical
transmission of HIV outweigh the reported cardiac
risks a conclusion similar to that of other stud-
ies.
7, 2 3
Any decision not to initiate zidovudine thera-
py, or to stop it, should be made with great caution.
Supported by grants from the National Heart, Lung, and Blood Insti-
tute (NO1-HR-96037, NO1-HR-96038, NO1-HR-96039, NO1-HR-
96040, NO1-HR-96041, NO1-HR-96042, and NO1-HR-96043) and in
part by grants from the National Institutes of Health (RR-00865, RR-
00188, RR-02172, RR-00533, RR-00071, RR-00645, RR-00685, and
RR-00043).
APPENDIX
The following is a partial list of participants in the study group, with
principal investigators identified by asterisks (a complete list of study par-
ticipants can be found in an earlier report
22
):
National Heart, Lung, and Blood Institute: H. Peavy (project offi-
cer), A. Kalica, E. Sloand, G. Sopko, and M. Wu; Steering Committee
Chair: R. Mellins; Clinical Centers: Baylor College of Medicine, Houston
W. Shearer,* N. Ayres, J.T. Bricker, A. Garson, L. Davis, P. Feinman, and
M.B. Mauer; University of Texas, Houston — D. Mooneyham and T. Tons-
berg; Children’s Hospital and Harvard Medical School, Boston S. Lip-
shultz,* S. Colan, L. Hornberger, S. Sanders, M. Schwartz, H. Donovan,
J. Hunter, E. McAuliffe, N. Moorthy, P. Ray, and S. Sharma; Boston Medical
Center, Boston K. Lewis; Mount Sinai School of Medicine, New York
M. Kattan,* W. Lai, D. Carp, D. Lewis, and S. Mone; Beth Israel Medical
Center, New York — M.A. Worth; Presbyterian Hospital and Columbia Uni-
versity, New York R. Mellins,* F. Bierman* (through May 1991), T.
Starc, A. Brown, M. Challenger, and K. Geromanos; University of Califor-
nia, Los Angeles, School of Medicine, Los Angeles S. Kaplan,* Y. Al-Khatib,
R. Doroshow, J. Isabel-Jones, R. Williams, H. Cohen, S. Golden, K. Si-
mandle, and A.-L. Wong; Children’s Hospital, Los Angeles A. Hohn, B.
Marcus, A. Gardner, and T. Ziolkowski; Los Angeles County Hospital, Los
Angeles L. Fukushima; Clinical Coordinating Center: The Cleveland
Clinic Foundation, ClevelandK.A. Easley,* M. Kutner* (through De-
cember 1999), M. Schluchter* (through April 1998), J. Goldfarb, D.
Moodie, C. Chen, S. Husak, V. Konig, S. Rao, A. Shah, S. Sunkle, and W.
Zhang; Policy, Data, and Safety Monitoring Board: H. Rigatto (chair-
man), E.B. Clark, R.B. Cotton, V.V. Joshi, P.S. Levy, N.S. Talner, P. Taylor,
R. Tepper, J. Wittes, R.H. Yolken, and P.E. Vink.
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The New England Journal of Medicine
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
    • "Long-term use of nucleoside reverse transcriptase inhibitors (NRTIs) has been associated with mitochondrial toxicity that includes skeletal muscle and cardiac wasting (Beach, 1998; Dalakas et al., 1990; Lewis and Dalakas, 1995), elevated serum lactic acid (Brinkman, 2001; Gerard et al., 2000), abnormal oxidative phosphorylation (OXPHOS) enzyme activity (Mhiri et al., 1991; Tomelleri et al., 1992), and abnormal alterations in the quantity of mitochondrial (mt) DNA (Dagan et al., 2002; Lewis and Dalakas, 1995 ). In HIV-1–uninfected NRTIexposed infants, because few abnormal clinical findings were reported at birth or during the early years of life (Brogly et al., 2007; Caselli et al., 2000; Culnane et al., 1999; Hanson et al., 1999; Lipshultz et al., 2000; Mofenson and Munderi, 2002; Newschaffer et al., 2000; Tuomala et al., 2002), it was generally assumed that in utero exposures were of insufficient duration to compromise the mitochondrial integrity of the fetus. However, that premise was reconsidered when two children born to mothers receiving Zidovudine (AZT) and Lamivudine (3TC) during pregnancy (Blanche et al., 1999) died at about 1 year of age from severe mitochondrial toxicity. "
    [Show abstract] [Hide abstract] ABSTRACT: Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function.
    Article · Nov 2010
    • "Most of these cases have been associated with d4T therapy. However, the experience with AZT and mitochondrial myopathy (Simpson et al, 1993) urges caution in accepting such theories until well-controlled trials with adequate control groups clearly separate the effects of the presumed toxic drug from that of HIV or other confounds, which may result in similar clinical syndromes (Lipshultz et al, 2000). The author is investigating these issues further in prospective studies. "
    [Show abstract] [Hide abstract] ABSTRACT: A variety of peripheral neuropathies are associated with human immunodeficiency virus (HIV) infection. Although the incidence of certain forms of neuropathy is increased in HIV infection, in other cases, the association may be fortuitous. Different forms of peripheral neuropathy occur with increased frequency at particular stages of HIV disease. For example, inflammatory demyelinating neuropathy (IDP) is often the first manifestation of HIV disease, when CD4 lymphocyte counts are relatively high. As immunosuppression progresses and HIV viral load becomes uncontrolled, the incidence of distal symmetrical polyneuropathy (DSP) increases. In advanced stages of HIV disease (CD4 count <50 cells/mm(3)), patients may develop opportunistic cytomegalovirus (CMV) nerve infection, which can present as progressive polyradiculopathy (PP) or mononeuropathy multiplex (MM). In addition to the neuromuscular disorders caused by HIV and its concomitant immunosuppression, the use of antiretroviral (ARV) drugs and other therapeutic agents in HIV disease is frequently limited by neuromuscular side effects. This paper will review the symmetrical forms of polyneuropathy that occur in association with HIV infection and nucleoside analogue therapy. The clinical, electrophysiologic, and pathologic features of these disorders will be described along with a discussion of theories of pathogenesis and results of treatment to date.
    Article · Jan 2003
    • "Original magnification, 400 each; Masson Trichrome. diographic changes were essentially absent in another recent study of neonatal patients treated in utero with AZT (Lipshultz et al, 2000). It now appears axiomatic to consider AZT treatment of HIV-1-infected mothers as a potent therapeutic tool to prevent vertical HIV-1 transmission (Lewis, 2001; Mofenson, 2000). "
    [Show abstract] [Hide abstract] ABSTRACT: Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.
    Full-text · Article · Dec 2001
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