AIDS:
October 1998 - Volume 12 - Issue 14 - p 1805-1813
Article
Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study
Sperling, Rhoda S.; Shapiro, David E.; McSherry, George D.; Britto, Paula; Cunningham, Bethann E.; Culnane, Mary; Coombs, Robert W.; Scott, Gwendolyn; Van Dyke, Russell B.; Shearer, William T.; Jimenez, Eleanor; Diaz, Clemente; Harrison, Duane D.; Delfraissy, Jean-Francois; Pediatric AIDS Clinical Trials Group Protocol 076 Study Group
 Author Information
1Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, New York, USA
2Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA
3Department of Pediatrics, University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey, USA
4Frontier Science and Technology Research Foundation, Inc., Amherst, New York, USA
5National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, Maryland, USA
6University of Washington School of Medicine, Seattle, Washington, USA
7Department of Pediatrics, University of Miami School of Medicine, Miami, Florida, USA
8Department of Pediatrics, Tulane University, New Orleans, Louisiana, USA
9Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, USA
10San Juan City Hospital, San Juan, Puerto Rico
11University of Puerto Rico, San Juan, Puerto Rico
12Wayne State University, Detroit, Michigan, USA
13INSERM Service Commun 10, Agence Nationale de Recherche sur le SIDA, Paris, France.
14See Cited Here....
15Requests for reprints to: Dr Rhoda Sperling, Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai Medical Center, Box 1173, 1 Gustave Levy Place, New York, NY 10029, USA.
Sponsorship: Supported in part under NIAID contract N01 AI95030 and cooperative agreement U01 AI41110, the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, the General Clinical Research Center Units funded by the National Center for Research Resources, the Pediatric-Perinatal HIV Clinical Trials Network, National Institute of Child Health and Human Development, Glaxo-Wellcome, Chiron Corporation, Roche Molecular Systems, and Agence Nationale de Recherche sur le SIDA (France).
Date of receipt: 27 March 1998; revised: 11 June 1998; accepted: 17 June 1998.
Abstract
Objective: To determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study.
Design: ACTG 076 was a randomized, double-blind, placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum.
Methods: Maternal complications, pregnancy outcomes, growth and development of the uninfected infants, and HIV-1 disease progression in the women were monitored prospectively.
Results: Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants, the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery, duration of maternal treatment, degree of maternal immunosuppression, or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age, uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women, at 6 months postpartum, there were no differences in clinical, immunologic, or virologic disease progression.
Conclusion: There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother-child HIV-1 transmission.
Introduction
In February 1994, the US National Institutes of Health-sponsored AIDS Clinical Trial Group (ACTG) 076 study was closed to enrollment and unblinded when an interim analysis demonstrated that a regimen of combined maternal and newborn zidovudine (ZDV) could dramatically reduce the risk of mother-infant HIV-1 transmission [1]. Since that time, the use of the ACTG 076 regimen has become part of routine obstetric management [2,3] and additional studies have strongly supported the regimen's efficacy [4-8]. Questions continue to be raised about the regimen's safety. We report the final status of women followed through 6 months postpartum and uninfected infants followed through 18 months of age.
Methods
Trial design
The details of the ACTG 076 trial design have been published previously [1]. ACTG 076 was a randomized, double-blind, placebo-controlled study, which enrolled HIV-infected women between 14 and 34 weeks gestation, with CD4+ cell counts above 200 × 106/l and no maternal indications for antiretroviral therapy. Patients were randomized to either the active regimen, which combined antepartum, intrapartum, and newborn ZDV, or placebo [1].
Patient population
Fifty-five centers in the United States and France participated in this study. The current analysis included women with singleton gestations who were randomized between 11 April 1991 and 20 December 1993 and delivered by 4 January 1994. The December cutoff date was chosen for compatibility with the previously published efficacy analysis [1]; the January cut-off date was chosen to ensure that all infants would have completed 6 weeks of study treatment when the study was unblinded. Antepartum, women were seen every 4 weeks until 32 weeks gestation and then weekly until delivery. Surveillance included serial hematologic and chemistry monitoring and serial ultrasound evaluations at entry and every 4 weeks after 28 weeks to assess fetal growth, development and amniotic fluid volume. After 34 weeks, weekly non-stress tests were performed, and if abnormal, patients were evaluated using biophysical profiles. Gestational age calculations were based on last menstrual period unless corrected by pre-entry ultra-sound. Published 10th and 90th percentiles of birth-weight for gestational age were used to classify infants as either small for gestational age or large for gestational age [9]. Birth before 37 weeks of gestation was defined as premature. Maternal infections were classified as AIDS-defining (class C), HIV-related (class B), or non-HIV-related by the Centers for Disease Control and Prevention 1993 criteria [10]. All obstetrical complications, infant structural abnormalities, and infant adverse events were reviewed blinded to treatment assignment.
Postpartum, women were seen at 6 weeks and 6 months and evaluated for HIV-related and non-HIV-related conditions including gynecologic problems. Lymphocyte typing was obtained at entry and 6 months after delivery. Aliquots of plasma were saved from entry, delivery, and 6 months postpartum, and subsequently assayed for viral load determinations by reverse transcriptase PCR methodology [4]. Women were encouraged to enroll in ACTG 288, a follow-up study of ACTG 076 participants focusing on disease progression and ZDV resistance through 3 years postpartum.
Infants were evaluated at birth and at 1, 2 or 3, 6, 12, 24, 36, 48, 60, 72 and 78 weeks of age. Serial hematologic and chemistry monitoring were performed through 12 and 6 weeks, respectively. Peripheral blood mononuclear cells were cultured for virus [4] at birth and at 12, 24 and 78 weeks of life. Lymphocyte typing was performed at 12, 24, 48 and 78 weeks. HIV serologic testing was performed at 72 and 78 weeks. Infants with two positive viral detection tests on separate occasions or an AIDS-defining condition were classified as HIV-infected. Infants classified as uninfected did not meet the case definition for an infected infant and also had either (i) two or more negative serologies at 6-18 months or a single negative serology after 18 months, or (ii) two negative HIV cultures, one after 1 month and another after 6 months of age. All other infants were classified as indeterminate. Guardians were encouraged to enroll infants in ACTG 219, a follow-up study that monitors late effects through 21 years of age.
Statistical analysis
Two-group comparisons were made using Mann-Whitney-Wilcoxon tests for continuous outcomes, χ2 test or Fisher's exact test for categorical outcomes [11], and the Wei-Johnson procedure [12] for serial measurements (growth and immunologic parameters). The results of intention-to-treat analyses of all eligible subjects are reported. All P values are two-sided. Statistical significance was defined as P < 0.05; no adjustments for multiple comparisons were made. Plasma HIV-1 RNA measurements and CD4+ cell counts were analyzed on a logarithmic (log10) scale. Specimens in which HIV-1 RNA was undetectable were assigned values equal to half the reported detection limit of the assays for those specimens.
Logistic or linear regression models were used to assess whether individual adverse outcomes were associated with timing or duration of ZDV exposure. All models included treatment assignment, gestational age at start of treatment, and duration of maternal study treatment. The association between timing or duration of ZDV exposure and adverse outcome was assessed by testing for a statistically significant treatment effect or interaction between treatment assignment and either of the other two variables. As specified below, models for certain outcomes controlled for other potential confounders, such as preterm birth, as appropriate. Similar models were used to assess whether women with immunosuppression at study entry [as measured by CD4+ cell count (dichotomized at 350 × 106/l), CD4 percentage (continuous) or plasma HIV-1 RNA level (continuous or dichotomized at the 75th percentile, 15 700 copies/ml)], were at higher risk of adverse outcome when controlling for treatment assignment, and if so, whether this association differed between the study groups (significant treatment effect or interaction).
Infant weight, height, and head circumference measurements were converted to age- and sex-adjusted z-scores using published algorithms [13]. For the analyses of association between infant growth and covariates such as duration of in utero ZDV exposure or the occurrence of anemia (defined as hemoglobin below 90 g/l) within the first 6 weeks of life, two summary measures (mean and slope of each infant's z-scores) were calculated for each of the three growth parameters.
Results
Study population
The baseline characteristics of the study cohort have been previously reported [1]. Of the 477 women who were randomized by 20 December 1993 [1], 40 women were excluded from this analysis of maternal and infant outcomes: two (one in each group) who were HIV-negative, 30 (14 ZDV and 16 placebo) who were still pregnant on 4 January 1994, and eight women (two ZDV and six placebo) who had twin gestations. Amongst the 437 women included in the safety analysis cohort, 13 (seven ZDV and six placebo) withdrew from study participation before delivery. Of the 424 eligible women followed, seven (five ZDV and two placebo) had either an intrauterine fetal demise prior to labor or an intrapartum demise (stillbirth), and 417 (209 ZDV and 208 placebo) delivered live-born infants. Of the 417 live-born singletons, 59 (14 ZDV and 45 placebo) were infected with HIV-1, 334 (182 ZDV and 152 placebo) were uninfected, and 24 (13 ZDV and 11 placebo) were of indeterminate infection status.
A total of 342 (82% of all infants and 88% of the uninfected infants) were followed through 18 months of age; 91% of the infants (97% of the uninfected infants) were followed at least through 12 months of age. A total of 261 (63%) of the infants (129 ZDV and 132 placebo) enrolled in ACTG 219, including 225 (67%) of the uninfected infants (121 ZDV and 104 placebo). A total of 314 (72%) women were followed through 6 months postpartum. Forty-four per cent of the women (43% ZDV and 44% placebo) enrolled in ACTG 288.
Antepartum safety monitoring
Serial sonography did not reveal any differences between the groups in antepartum growth or in the development of oligohydramnios or polyhydramnios. Logistic regression models did not detect any significant association between the risk of new-onset oligohydramnios or polyhydramnios and either the timing or the duration of ZDV exposure or the degree of maternal immunosuppression at study entry. Development of new-onset polyhydramnios was not significantly associated with the risk of infant anemia (hemoglobin < 90 g/l during the first 6 weeks of life).
Maternal complications and pregnancy outcomes
Maternal complications and pregnancy outcomes are summarized in Table 1. The number of women who were treated for preterm labor with tocolytic therapy was higher in the ZDV group (P = 0.02). After controlling for gestational age at delivery, no significant association was observed between duration of ZDV treatment and risk of preterm labor.
Newborn/infant safety
The incidence of minor and major structural abnormalities was similar in the two study groups (Table 1). No specific minor or major abnormalities were clustered in either study group.
Fifty seven infants (14%) had anemia (hemoglobin < 90 g/l) within the first 6 weeks of life. Anemia was more common in the ZDV group (19% ZDV versus 8% placebo; P = 0.001). In the ZDV group, the median hemoglobin concentration was 160 g/l at birth (range, 103-254 g/l) and 100 g/l at 6 weeks of age (range, 67-169 g/l). Amongst the 57 infants with anemia, neither dose reduction/dose interruption of study drug, blood transfusions within the first 12 weeks of life, nor other anemia-related treatments were more common in the ZDV group. In the overall population, anemia was more common in preterm infants when compared with full-term infants (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.4; P = 0.02). However, no significant interaction was observed between preterm birth and treatment arm, which suggested that the risk of ZDV-associated anemia was not significantly greater in preterm infants. After controlling for preterm versus full-term birth, no significant association was observed between the duration of in utero ZDV exposure and the risk of anemia. No significant association was observed between maternal immuno-suppression or maternal anemia (hemoglobin < 95 g/l) and the subsequent risk of infant anemia. Anemia within the first 6 weeks of life was not significantly associated with the infant's eventual HIV status.
Growth and immunologic development of uninfected infants
Amongst the uninfected infants, there were no significant differences between the study groups in mean weight (Wei-Johnson P = 0.19), height (P = 0.22), or head circumference z-scores (P = 0.73) through 18 months of age. For each growth parameter, the proportion of uninfected infants below the 5th percentile at three or more visits was balanced between groups (height, 12 versus 13%; weight, 6 versus 9%; head circumference, 10 versus 9%). Amongst infants who had anemia in the first 6 weeks of life, there were no significant differences between the study groups in subsequent growth (as measured by the mean and slope of the infant's z-scores). No significant association was observed between duration of in utero or total ZDV exposure and subsequent growth, after controlling for preterm birth.
Amongst the uninfected infants, there were also no significant differences between the study groups in median CD4+ cell counts (P = 0.74), CD4 cell percentage (P = 0.46), CD8+ cell counts (P = 0.25), or CD8 cell percentage (P = 0.13) through 18 months of age. Forty-three uninfected infants [27 (15%) in the ZDV group and 16 (11%) in the placebo group; P = 0.26] had CD4+ cell counts below 1500 × 106/l during the first year of life or below 750 × 106/l during the second year of life. Median immunoglobulin levels were similar in the two study groups through 18 months of age (IgA, P = 0.55; IgG, P = 0.79; IgM, P = 0.77).
Maternal disease progression
The study groups were balanced with respect to clinical HIV-related disease progression (Table 2). Only one mother (ZDV group) died while on study; this occurred 3 months post-delivery secondary to a ruptured intracerebral aneurysm and was judged to be unrelated to either pregnancy or study drug.
Changes in CD4+ cell counts from baseline to 6 months postpartum could be assessed in 265 women. As of 6 months postpartum, in both groups, there was a slight median increase in CD4+ cell counts from entry (Table 2). At 6 months postpartum, 88% of the women had CD4+ cell counts above 350 × 106/l; only two women had counts that fell below 200 × 106/l. No significant association was observed between change in CD4+ cell count from entry through 6 months post-partum and either the duration of antepartum ZDV treatment, the CD4+ cell count at entry, time between measurements, or mode of delivery.
Changes in plasma HIV RNA levels from baseline to 6 months postpartum could be assessed in 179 women. As reported previously, there was a moderate but statistically significant decrease in plasma HIV RNA levels from baseline to delivery in the ZDV group [4]. By 6 months postpartum, median plasma HIV RNA levels were slightly above entry levels in both groups, but there was no significant difference between the two groups (Table 2). However, there were fewer women in the ZDV group whose plasma HIV RNA levels increased above 10 000 copies/ml at the 6-month evaluation (10 versus 18; P = 0.05). No significant association was observed between change in plasma HIV RNA level from entry through 6 months post-partum and either the duration of antepartum ZDV treatment, the plasma HIV RNA level at entry, the time between measurements, or mode of delivery.
Discussion
The medical treatment of HIV-infected pregnant women includes the routine use of a ZDV regimen for the prevention of mother-child HIV-1 transmission [2,3]. This analysis provides reassuring safety information.
Maternal therapy was well-tolerated. Antepartum ultra-sound surveillance did not detect any treatment-related abnormalities either in fetal growth or in amniotic fluid volume. Most maternal complications and adverse pregnancy outcomes were balanced between groups. Antepartum, non-HIV-related viral infections were less common in the ZDV group as were postpartum urinary tract infections. Postpartum wound complications were more frequent in the ZDV group. Whether these differences were due to any direct [14] or indirect effect of ZDV therapy remains unclear. Although the incidence of preterm labor requiring tocolytic therapy was more frequent in the ZDV group, other factors associated with preterm labor (preterm delivery before 37 weeks, premature rupture of membranes, low birth weight, and small for gestational age infants) did not differ between treatment groups. It is possible that ZDV-associated gastrointestinal side-effects were misdiagnosed as preterm labor. The 22% overall risk of premature delivery (< 37 weeks) in the ACTG 076 cohort is consistent with a 23% preterm birth rate reported from a 2254 patient series from New York State [15].
There were no concerning patterns of newborn toxicities. The current analyses failed to define a group at increased risk for the previously recognized ZDV-associated newborn anemia. Neither prematurity, duration of maternal ZDV treatment, degree of maternal immunosuppression, nor maternal anemia was associated with an increased risk for ZDV-associated infant anemia.
Among ACTG 076 infants, both major and minor structural abnormalities were similar in the two treatment groups. Amongst uninfected infants, there were no differences in growth patterns or immunologic parameters. The similarities between treatment groups in birth weight, birth length, head circumference, and growth through 18 months of age suggests that ZDV does not adversely effect growth and development. Follow-up of neurodevelopment and somatic growth will continue in ACTG 219. No differences were noted by treatment group in lymphocyte subset quantification or immunoglobulin levels amongst uninfected infants. Although functional lymphocyte assays were not performed, there were no differences in the rate of serious infections in the uninfected infants of either group.
No cancers were reported in either exposed or unexposed infants during the study. Concerns have been raised about cancer risks following in utero and newborn exposures to nucleoside analogs during the period of rapid cellular differentiation and proliferation [16,17]. Cancer risks through age 21 years will be assessed in ACTG 219.
At 6 months postpartum, there was no observed increased risk of clinical, immunologic or virologic disease progression in those women who received the ACTG 076 ZDV regimen. In the placebo group, there was a slight trend towards more rapid disease progression, as judged by the number of women who progressed to plasma viral loads > 10 000 RNA copies/ml (P = 0.05) at 6 months postpartum. In addition, from entry to delivery, there was no significant development of genotypic resistance to ZDV [18]. Follow-up will continue in ACTG 288.
The ACTG 076 study was not designed to answer many of the safety questions raised since the interim analysis [1]. A large number of comparisons were required to assess both maternal and infant outcomes. It is possible that one or more of the statistically significant results observed occurred solely due to chance rather than a true treatment difference. Statistical power to detect associations between duration of ZDV exposure or maternal immunosuppression and adverse outcomes was limited by the low incidence rates of many of the outcomes of interest. Despite these limitations, there was no evidence of any maternal or infant safety problems that would alter current treatment recommendations [3]. Because antiretroviral agents are increasingly used during pregnancy both to manage maternal disease and reduce the risk of transmission, the challenge will be to develop a systematic approach to track individuals exposed in utero or in early infancy in order to assess possible short-term and long-term safety risks.
References
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Appendix
The following institutions and persons participated in the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.
M.J. O'Sullivan, C.D. Mitchell, B.H. Jones (University of Miami, Miami, Florida); T. Alchediak, K. Dunlap, M. Perrin (Tulane University/Louisiana State University, New Orleans, Louisiana); H.A. Hammill, M.W. Kline, R. Jacobson (Baylor/Texas Children's Hospital, Houston, Texas); E. O'Neill, L. Perez, E. Abreu (San Juan City Hospital, San Juan, Puerto Rico); T.B. Jones, E.C. Moore (Wayne State University/Children's Hospital of Michigan/Hutzel Hospital, Detroit, Michigan); C. Zorrilla, B. Beauchamp, C. Rivera (University of Puerto Rico, San Juan, Puerto Rico); B. Bazin, C. Rouzioux (INSERM Service Commun 10, ANRS, Paris, France); P. Flynn, J. Shenep, W. Hughes (St Jude Children's Research Hospital, Memphis, Tennessee); J.L. Sullivan, B.W. Stechenberg, P. Krause (University of Massachusetts Medical School, Worcester, Massachusetts); S.A. Spector, M. Besser, M. Caffery (University of California San Diego, San Diego, California); A.D. Bardeguez, J. Oleske, E.M. Connor (UMDNJ-New Jersey Medical School, Newark, New Jersey); D. Hodes, E. Chusid, H. Sacks (Mount Sinai Medical Center, New York, New York); H. Watts, A. J. Melvin, J. Hitti (Children's Hospital and Medical Center, Seattle, Washington); W. Borkowsky, M. Allen, M. Minter (New York University Medical Center, New York, New York); W.A. Lim, V.L. Katz, M.J. McMahon (University of North Carolina, Chapel Hill, North Carolina); R. Aguayo, E.J. Reyes, R. Rodriguez (Ramon Ruiz Arnau University Hospital, Bayamon, Puerto Rico); R. Samelson, M. Lepow, N. Wade (Albany Medical Center, Albany, New York); R. Livingston, J. Anderson, P. Vink (Johns Hopkins University, Baltimore, Maryland); A. Gershon, J. Pitt, G. Brown (Columbia Presbyterian Medical Center, New York, New York); Y.J. Bryson, E.R. Stiehm, P.J. Boyer (UCLA Medical Center, Los Angeles, California); K.C. Rich, M. Vajaranant, M. Moran (University of Illinois, Urbana, Illinois); S. Nachman, D. Baker, D. Hickey (State University of New York at Stony Brook, New York); S. Rana, D. Smith, M. Akinsiku (Howard University Hospital, Washington, DC); A. Rubinstein, J. Youchah, L. Bernstein (Albert Einstein College of Medicine, Bronx, New York); K. Skahan, P. Daniel, J. Leonard (University of Cincinnati, Cincinnati, Ohio); R. Bishop, R. Galvin, A. Buck (Children's Hospital of Boston/Brigham and Women's Hospital (Boston, Massachusetts); Boston City Hospital Pediatric ACTG, (Boston, Massachusetts); D.W. Wara, M. Benson, M. Shannon (University of California, San Francisco, California); R. Yogev (Northwestern University-Children's Memorial Hospital, Chicago, Illinois); C.M. Wilfert, R.E. McKinney, M. Donnelly (Duke University, Durham, North Carolina); A. Kovacs, M. Khoury, A. Stek (Los Angeles County Medical Center/USC, Los Angeles, California); M.J. Levin, E.J. McFarland, C. Salbenblatt (The Children's Hospital, Denver, Colorado); Senih Fikrig (SUNY Brooklyn, New York); J.S. Lambert, J.S. Abramowicz, L. Frenkel (University of Rochester Medical Center, Rochester, New York); N. Kirshenbaum, A. Gupta, M.G. Galvin (New York Medical College, New York); L.B. Weiner, C.K. Cunningham, K. A. Costello (SUNY Health Science Center, Syracuse, New York); M.J. Crain, L. Jones, J. Hauth (University of Alabama, Birmingham, Alabama); S. Starr (Children's Hospital of Philadelphia, Pennsylvania); A. Wiznia (Bronx Lebanon Hospital Center, New York); G.M. Johnson, R. Newman, M.G. Connelly (Medical University of South Carolina, Charleston, South Carolina); P. Smith (Rhode Island Hospital, Brown University, Providence, Rhode Island).
E. Johnson, A. I. Martinez, J. Balsley (National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, Maryland); J. Moye (National Institute of Child Health and Human Development, Bethesda, Maryland); E. Hawkins (PACTG Operations Office/Social and Scientific Systems, Inc., Rockville, Maryland); L. Strusa (PACTG Data Management Center, Frontier Science and Technology Research Foundation, Inc., Amherst, New York); R.D. Gelber, E. Gebhardt, S. Traite (PACTG Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts). Cited Here...
Keywords: Zidovudine safety; perinatal HIV-1 transmission
© 1998 Lippincott Williams & Wilkins, Inc.
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