Original Article
Cardiac Structure and Function in Children with Human Immunodeficiency Virus Infection Treated with Zidovudine
N Engl J Med 1992; 327:1260-1265October 29, 1992
- Abstract
- Abstract
Background.
Abnormalities of cardiac structure and function are common in children infected with the human immunodeficiency virus (HIV). It is unclear, however, whether these abnormalities are attributable to the disease itself, associated infections, or possible cardiotoxic effects of the most commonly used treatment, zidovudine.
Methods.
We performed echocardiography in 24 children with symptomatic HIV infection immediately before they started zidovudine therapy and a mean of 1.32 years after therapy began. Sixteen of these children were also studied a mean of 1.26 years before starting zidovudine treatment. Comparison groups included 27 age-matched children with symptomatic HIV infection who had not received zidovudine and 191 normal children.
Results.
As compared with the normal children, the children treated with zidovudine had progressive left ventricular dilatation and an increase in ventricular-wall stress at end-systole (a measure of ventricular afterload); dilatation and stress were significantly elevated both before and during zidovudine treatment. The ratio of ventricular thickness to internal dimension was below normal before zidovudine treatment began (P<0.001). After treatment with zidovudine, however, overall left ventricular mass was increased (P = 0.02), as was peak wall stress (a stimulus to ventricular hypertrophy) (P = 0.01). Ventricular contractility remained normal, but fractional shortening of the left ventricle was decreased (P = 0.004). No statistically significant differences were detected at follow-up in any of these measurements between HIV-infected children treated with zidovudine and those not so treated.
Conclusions.
Progressive left ventricular dilatation occurred in children with symptomatic HIV infection. Compensatory hypertrophy also occurred but was inadequate to maintain peak systolic wall stress within the normal range. The progressive elevation of ventricular afterload due to dilatation resulted in depressed ventricular performance, but intrinsic ventricular contractility remained normal. Zidovudine did not appear to worsen or ameliorate these cardiac changes. (N Engl J Med 1992;327: 1260–5.)
Media in This Article
Table 1
Characteristics of the Children Treated with Zidovudine.*Table 2
Comparison between Children with HIV Infection Treated and Not Treated with Zidovudine.*Article Activity
- Article
CARDIOVASCULAR abnormalities are common in children with human immunodeficiency virus (HIV) infection,1 2 3 4 5 6 but little is known about their cause or clinical course. The cardiovascular effects of zidovudine, which is used to treat most children with symptomatic HIV infection in the United States,7 , 8 have also not been well characterized. This drug has been reported to affect cardiac muscle adversely in rats.9 10 11 The mechanism appears similar to that noted in skeletal muscle in humans, in which a distinct myopathy has been observed.12 13 14 15 16 17 Recent recommendations to withhold antiretroviral therapy in HIV-infected patients with cardiomyopathy or congestive heart failure18 , 19 and to consider serial endomyocardial biopsies to monitor cardiac effects in patients taking these agents11 necessitate a critical examination of the effects of zidovudine on myocardial structure and function in treated children. We carried out a longitudinal study to examine myocardial function and structure in HIV-infected children before and after they received zidovudine, and we compared these results with those in an age-matched set of HIV-infected children who were not taking zidovudine.
Methods
Study Groups
The treated study patients consisted of all the children at Children's Hospital, Boston, who had symptomatic HIV infection (pediatric class P-2 of the Centers for Disease Control [CDC]20), were treated with zidovudine between May 1, 1988, and July 31, 1991, and had echocardiography performed both at the start of zidovudine therapy and while receiving zidovudine. For patients who had more than one follow-up echocardiogram during treatment with zidovudine, the latest echocardiogram was selected for this analysis. A total of 24 children with serial echocardiograms formed the study cohort. In 16 of these children, echocardiograms were available from the period before they started zidovudine therapy, and the earliest such echocardiogram was used to assess cardiac function before treatment.
All the treated children either met the CDC criteria for the acquired immunodeficiency syndrome (AIDS) or had symptomatic HIV infection.20 Infection with HIV was documented by culture of the virus or detection of HIV p24 antigen in serum. In children over 15 months of age, HIV infection was also assessed according to the presence of HIV antibody on enzyme-linked immunosorbent assay and Western blotting. The treated children received zidovudine according to one of three pediatric AIDS Clinical Trials Group (ACTG) protocols (10 children on protocol 043, 7 on protocol 051, and 4 on protocol 128) or by prescription (3 children). Nineteen of the 20 children receiving unblinded doses of zidovudine were initially given 180 mg per square meter of body-surface area every six hours (the other child received an initial dose of 200 mg per square meter). The four children on protocol 128 were randomly assigned to receive either 90 or 180 mg of zidovudine per square meter every six hours; information on dosage remains blinded. Eleven children required a reduction in the dose of zidovudine to 120 mg per square meter because of toxicity.
Lymphocyte subclasses were measured by standard flow-cytometric methods in an ACTG-certified laboratory. Levels of p24 antigen were determined in real time with the use of commercial reagents in an ACTG-certified laboratory. The test results were interpreted as positive if the level was above 30 pg per milliliter.
The treated children who were evaluated before they started zidovudine treatment provided control data for a comparison of cardiac abnormalities with and without therapy. To explore further whether changes in weight, height, and echocardiographic findings could be attributed to the natural history of the disease rather than to zidovudine therapy, we identified a group of HIV-infected children who had not received zidovudine. Most of the untreated children were followed at a time when zidovudine was not licensed for use in children. Other untreated children did not receive zidovudine therapy because of parental refusal or the absence of an available protocol or because their physicians did not refer them for therapy. These untreated children had echocardiography performed at Children's Hospital between January 1986 and August 1991. The untreated children were matched according to age with the children in the treated group— 19 at the age when treatment started and 18 at the age of the most recent echocardiogram. Ten of these comparison children had serial echocardiograms.
Echocardiographic data from the children with HIV infection were compared with data from 191 normal infants and children under 13 years of age,21 a range that corresponded to the ages of the study population. Weight and height were measured in all the children at the time of echocardiography and were standardized according to National Center for Health Statistics percentiles.22
Echocardiography
Two-dimensional echocardiography and Doppler studies were performed in each child, and the results were analyzed by cardiologists unaware of the clinical status or medications of the children. Echocardiography was performed for routine patient care or as mandated by research protocols. No echocardiography was performed because of a suspicion of cardiac disease.
An M-mode echocardiogram, phonocardiogram, pulse tracing, electrocardiogram, and blood-pressure reading were recorded simultaneously and analyzed by a computer program.21 , 23 24 25 We determined left ventricular contractility using the relation between end-systolic left-ventricular-wall stress and the rate-adjusted velocity of fiber shortening, a previously validated index of contractility that incorporates afterload and is independent of preload.23 Afterload was measured as end-systolic left-ventricular-wall stress. Left ventricular mass (in grams) was calculated from M-mode measurements with the method of Devereux et al.26
Statistical Analysis
All cardiac data for the HIV-infected children (except ratios of thickness to internal dimension) were converted to z scores.27 This standardization was necessary to adjust for the changes in cardiac size and structure associated with growth.21 For some cardiac measurements, change is closely related to age; for others, it is more closely related to body-surface area. To standardize cardiac measures we used the SAS procedure NLIN to fit a nonlinear model describing the relation between the cardiac measurement and age (or body-surface area) in the 191 uninfected controls. This model was then used to predict a cardiac value for each HIV-infected child on the basis of age or body-surface area. To calculate a z score (a measure of the difference of this value from the normal value), the difference between an infected child's observed value and the normal predicted value was divided by 1 SD.27 The z score therefore represents the difference between the observed value and the predicted value expressed as the number of standard deviations. For the resulting normal deviate or z score, zero indicates that the measure is at the normal population mean, whereas a score of 2 indicates that the measure is at the 95th percentile of the distribution of values in the normal population. A negative z score indicates that the value is below the predicted population mean.
The z scores for mass, afterload, dimension, and wall thickness have been adjusted for body-surface area. The z scores for fractional shortening, blood pressure, and peak systolic wall stress have been adjusted for age. More details on the data from normal children and the nonlinear model have been published elsewhere.21
Average z scores were compared with a score of zero with use of a one-sample t-test27 at each time point. To assess whether there were changes over time, data for the three time points were compared by analysis of variance with repeated measures for each child,27 with the Bonferroni correction for comparisons of specific pairs of time points.28 The smaller group of HIV-infected children who had not received zidovudine was analyzed in a similar manner and compared by paired t-tests with the subgroup of matched children given zidovudine.27 Results were considered to be significant if the two-sided P value was less than 0.05.
Results
Children Treated with Zidovudine
The study population of 24 children represented 89 percent of the 27 patients at Children's Hospital during the study period who were treated with zidovudine for at least eight months. Nine children were black (3 of them Haitian), 5 were Hispanic, and 10 were non-Hispanic white. Eight of the children were girls, 11 were under two years of age at the start of treatment, and 21 had acquired HIV through perinatal transmission. None had heart failure, and none were taking cardioactive medications. Zidovudine therapy began an average of 1.26 years after initial echocardiography. The final evaluation occurred an average of 1.32 years after zidovudine therapy began. Eight children had AIDS when therapy began, and the remaining 16 had other symptoms of HIV infection. At follow-up, 12 children had AIDS and 12 others had symptomatic HIV infection. The median CD4 cell count fell from 452 per cubic millimeter at the start of therapy to 147 per cubic millimeter at the time of the most recent echocardiogram. The proportion of children who were positive for p24 antigen fell from 79 percent to 62 percent with therapy. The median hemoglobin level at the start of zidovudine therapy was 11.1 g per deciliter, and it remained stable at 10.5 g per deciliter. Of the 24 children, 1 had a hemoglobin level below 7.5 g per deciliter at the start of therapy, and 2 had anemia at the last follow-up examination. Two children had their doses of zidovudine modified because of anemia, and two had transfusions for anemia.
Weight and Height
The weight and height of the children treated with zidovudine were significantly below normal at the time of the first echocardiogram and did not improve (Table 1Table 1
Characteristics of the Children Treated with Zidovudine.*). Body-surface area increased at each of the three study points (mean value at the initial examination, 0.55 m2; at the start of zidovudine treatment, 0.65 m2; and at the most recent examination, 0.73 m2).Echocardiographic Analysis
Left ventricular dimension was normal at the time of the first echocardiogram but increased progressively on subsequent studies. The increase in dimension from the first echocardiogram to the latest one was statistically significant. Left ventricular posterior-wall thickness tended to be below normal on the first echocardiogram and was significantly below normal at the start of zidovudine therapy. During zidovudine therapy, the posterior-wall thickness increased significantly. The mean ratio of thickness to dimension among children without HIV infection was 0.19 (95 percent confidence interval, 0.14 to 0.25). The treated children had a mean ratio of 0.19 at the time of the initial echocardiogram, 0.16 at the start of zidovudine therapy, and 0.18 on the latest echocardiogram. The ratio at the start of zidovudine therapy was significantly below the mean for normal controls (P<0.001).
Left ventricular mass was below normal on the first echocardiogram and tended to be reduced at the start of zidovudine treatment. However, an increase in mass was noted on the most recent echocardiogram, resulting in a mean z score significantly above normal. The changes in mass from the initial echocardiogram to the follow-up examination and from the start of zidovudine therapy to the follow-up examination were statistically significant. This increase in mass occurred in spite of malnutrition and was temporally related to the use of zidovudine. In 15 of the 24 children (62 percent) the increase in the z score for mass exceeded 1 SD.
Fractional shortening was depressed on the initial echocardiogram and remained depressed throughout follow-up. End-systolic and systolic blood pressure were not significantly different from normal at any time (data not shown). Diastolic blood pressure was mildly but significantly elevated in the treated children at the start of therapy and at follow-up. Afterload (end-systolic wall stress) was above normal at all three examinations and increased progressively from the first to the last study. Peak systolic wall stress did not differ from normal before zidovudine therapy but was significantly elevated at the start of therapy and remained high during treatment. Contractility was normal at all times, and there were no significant changes with time.
Serial Analyses
During the administration of zidovudine, the HIV-infected children had a significant increase in left ventricular end-diastolic dimension, wall thickness, and mass and a significant decrease in fractional shortening. All other measures, whether normal or abnormal, showed no significant progression after 1.32 years of therapy.
The increase in end-diastolic dimension was similar in magnitude to that observed before the administration of zidovudine, although ventricular dilatation was not found in the group of untreated children with HIV infection. The increase in wall thickness during therapy resulted in the return of thickness to normal. The increase in mass during therapy contrasted with the trend observed before zidovudine treatment began. The changes in fractional shortening in all groups were commensurate with the alterations in wall stress, reflecting the known dependence on afterload of this index of systolic performance.
Comparison between Children Treated and Not Treated with Zidovudine
Treated and untreated children did not differ significantly in weight and height, and small increases over time were similar in the two groups (Table 2Table 2
Comparison between Children with HIV Infection Treated and Not Treated with Zidovudine.*). Age and the severity of HIV infection were also similar in the two groups. At the start of treatment, end-diastolic thickness, left ventricular mass, and the ratio of thickness to dimension differed significantly between treated and untreated children. Untreated children had values that were closer to normal for all three measurements. No other measurements at the start of therapy and no measurements at the latest follow-up differed significantly between treated and untreated children. As the 95 percent confidence intervals (Table 2) suggest, however, there may have been differences between the groups that could not be identified with our small sample.For the three measurements among the treated children that showed significant change after the initiation of zidovudine therapy (Table 1), wall thickness and mass increased among both the treated and the untreated children, but fractional shortening improved among the untreated children and worsened among the treated children.
Discussion
This study found progressive abnormalities of left ventricular size and function in children with HIV infection both before and after they received zidovudine. Before therapy began, progressive left ventricular dilatation with associated wall thinning resulted in a decrease in the ratio of thickness to dimension and an increase in both peak systolic and end-systolic wall stress (afterload). The increase in afterload was associated with a decrease in ventricular performance, although intrinsic contractility was not impaired. During treatment, dilatation progressed and, in spite of hypertrophy with normalization of the ratio of thickness to dimension, the elevation of peak systolic wall stress persisted. Left ventricular mass increased significantly during the study but failed to keep pace with ventricular dilatation, a result consistent with inadequate hypertrophy.
Our data on children with HIV infection suggest that ventricular dilatation of unclear and possibly multifactorial cause evoked compensatory hypertrophy (an increase in left ventricular mass), as would be expected. In this case, unlike the situation in normal children, however, the magnitude of the hypertrophy was inadequate to reduce peak systolic wall stress, the principal stimulus to mechanically induced hypertrophy, to normal. The continued excess afterload resulted in further dilatation. The continuing elevation of peak systolic wall stress indicates that hypertrophy was inadequate to counterbalance the progressive increase in left ventricular dimension. The dilatation and compensatory increase in left ventricular mass in the children with HIV infection occurred despite a normal intrinsic contractile state. The elevated left ventricular mass observed in these children was also observed in a separate study of HIV-infected children whose mean cardiac weight at autopsy was 184 percent of normal.1 , 4 , 5
There are many possible reasons for the sustained increase in left ventricular dimension and mass in children with HIV infection. Anemia does not appear to play an important part, because hemoglobin levels in our patients, although below normal,29 remained constant. Stable, mild anemia would not be expected to cause the progressive ventricular dilatation observed in this study. Cardiac infection with HIV or other viruses may directly affect the growth and dilatation of the heart in children2 , 4 or may indirectly affect them by the activation of proto-oncogenes30 31 32 or changes in cytokines.31 , 33 Malnutrition was common in these children at all ages. In the absence of HIV infection, malnutrition has been linked to decreases in left ventricular mass, left ventricular volume, ventricular function, and blood pressure.34 In contrast, in our patients left ventricular mass and volume were increased or preserved, blood pressure normal or elevated, and contractility stable, indicating that other variables overrode the effects of malnutrition. Inadequate nutrition may have contributed to the observed subnormal hypertrophic responses relative to left ventricular dimension.
Cardiotoxicity has been observed with various agents used to treat patients with HIV infection (such as pentamidine,1 , 6 , 35 , 36 ganciclovir,37 and interferon alfa-2a38). However, the potential cardiotoxic effects of zidovudine are controversial. Conflicting reports suggest a relation between the administration of zidovudine and the improvement,39 preservation,40 or deterioration18 of ventricular function in adults. Recent studies9 10 11 report cardiotoxic effects of zidovudine on mitochondria in rats. Zidovudine inhibits mitochondrial gamma-DNA polymerase.16 , 41 , 42 Up to 78 percent of the mitochondrial DNA is reversibly depleted in zidovudine-associated skeletal myopathy.41 A study of zidovudine in children found moderate transient elevations in total creatine kinase but no evidence of skeletal myopathy.12 , 43 We found no relation between creatine kinase levels and contractility (data not shown), suggesting that total serum creatine kinase is not a reliable marker of functional myocardial damage.
Despite laboratory and clinical studies suggesting that zidovudine can cause skeletal-muscle myopathy, our cohort had normal cardiac contractility. The major abnormalities observed were progressive dilatation and inadequate hypertrophy. However, these changes were no more marked during zidovudine therapy than during the period before therapy began. This suggests that the cause of the cardiac abnormalities was related to the primary disease process itself rather than to zidovudine therapy. This point is supported by the comparability of the cardiac measures in the treated and untreated children who were matched for age. These comparisons should be viewed with caution, however, because our study had limited statistical power to detect differences. Even though the differences between the groups were not statistically significant, it is apparent that the trends in the groups were different, with greater dilatation and inadequate hypertrophy apparent in the treated group. The comparison between treated and untreated groups is limited, however, by the fact that only half the data on untreated patients came from serial studies in the same children. Although it is possible that with matched data or larger numbers of children these trends might attain statistical significance, our direct comparison of values before and after treatment in the same group of children appears more convincing. Also, control children, although matched for age with the treated children, could not be matched for severity of disease, since virtually all children with progressive disease are now treated with zidovudine. Because of the limitations of the comparison group, we were not able to evaluate the possibility that zidovudine slows the rate of progression of cardiac abnormalities to that seen in an earlier phase of the disease. Current standards of care make it impossible to collect better control information without a prospective trial that withholds zidovudine from some patients in whom it is clinically indicated. Moreover, although our results may be applicable to children, they are not necessarily applicable to adults with HIV infection.
The recommendation18 , 19 that antiretroviral therapy be interrupted in HIV-infected patients with evidence of cardiomyopathy or congestive heart failure may deny them potentially beneficial or even lifesaving therapy. It is likely that our patients would have had zidovudine therapy interrupted on the basis of this recommendation, since measures of left ventricular dimension and load-dependent ventricular performance suggested the appearance of a dilated cardiomyopathy associated with zidovudine treatment. Contractility remained normal, however, and the same progressive cardiac abnormalities were seen before the initiation of zidovudine therapy. Our data do not support the recommendation that zidovudine therapy be withheld in children with reduced cardiac function.
Supported in part by grants (U01-AI-25934, R01HL48012–01, and 5M01RR02172) from the National Institutes of Health and by a Clinical Investigator Award (HL01816) from the National Heart, Lung, and Blood Institute.
We are indebted to Tracie L. Miller, M.D., for critical review of the manuscript and to Nancy J. Smith, Nancy Karthas, R.N., Emily Flynn-McIntosh, and J.P. LaFond for technical assistance.
Source Information
From the Department of Cardiology (S.E.L., S.P.S., S.D.C.) and the Division of Infectious Diseases (A.R.H., K.M.), Children's Hospital; the Department of Pediatrics, Harvard Medical School (S.E.L., S.P.S., K.M., S.D.C); the Department of Biostatistics, Harvard School of Public Health (E.J.O.); the Department of Pediatrics, Boston City Hospital (S.E.L.); and the Department of Pediatrics, Boston University School of Medicine (S.E.L.) — all in Boston. Address reprint requests to Dr. Lipshultz at the Department of Cardiology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
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Avinash K. Shetty, Yvonne A. Maldonado. 2011. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Infant. , 622-660.
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