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Recommendations of the U.S. Public Health Service Task Force on the Use of Zidovudine to Reduce Perinatal Transmission of Human Immunodeficiency Virus
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Accession Number
A00144
Author
US Department of Health and Human Services (HHS), Centers for Disease Control and Prevention (CDC)
Source
Morbidity and Mortality Weekly Report (MMWR)
Release Date
August 5, 1994
Major Descriptors
AZT
Infants
Perinatal transmission
Women
Topic
Perinatal Transmission
Guidelines
Text
Summary
These recommendations update the interim guidelines developed by the U.S. Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal transmission of human immunodeficiency virus (HIV) infection. The recently reported results of AIDS Clinical Trials Group Protocol 076 demonstrated that ZDV administered to a selected group of HIV-infected pregnant women and their infants can reduce the risk for perinatal HIV transmission by approximately two-thirds. The regimen used in this trial included antenatal oral administration of ZDV beginning at 14-34 weeks of gestation and continuing throughout pregnancy, followed by intrapartum intravenous ZDV and postnatal oral administration of ZDV to the infant for 6 weeks after delivery. This document summarizes the results of the trial, discusses limitations in the interpretation of the results, reviews the potential long-term adverse effects of this ZDV regimen for infants and women, and provides recommendations for the use of ZDV to reduce perinatal transmission and for medical monitoring of pregnant women and infants receiving this therapy. Because the clinical status of many HIV-infected women may differ from that of the women in this trial, the recommendations should be tailored to each woman's clinical situation. The potential benefits, unknown long-term effects, and gaps in knowledge about her specific clinical situation must be discussed with the woman. This information is intended to provide a basis for discussion between the woman and her health-care provider so that the woman can weigh the risks and benefits of such therapy and make informed decisions about her treatment.
BACKGROUND
Summary of Results of ACTG Protocol 076 On February 21, 1994, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development announced the interim results of a randomized, multicenter, double-blind, placebo-controlled clinical trial, ACTG Protocol 076. Eligible participants were HIV-infected pregnant women at 14-34 weeks of gestation who had received no antiretroviral therapy during their current pregnancy, had no clinical indications for antepartum antiretroviral therapy, and had CD4+ T-lymphocyte counts greater than or equal to 200/uL at the time of entry into the study (Box 1). The study began in April 1991; as of December 20, 1993, the time of the interim analysis, 477 women had been enrolled and 421 infants born. The racial/ethnic distribution of the HIV-infected women enrolled in the trial was similar to that of the total population of HIV-infected women in the United States.
BOX 1. Eligibility criteria for HIV-infected pregnant women participating in AIDS Clinical Trials Group Protocol 076 o Pregnancy at 14 34 weeks of gestation. o No antiretroviral therapy during the current pregnancy. o No clinical indications for antenatal antiretroviral therapy. o CD4+ T-lymphocyte count greater than or equal to 200 cells/uL at the time of entry into the study.
Enrolled women were assigned randomly to receive a regimen of either ZDV or placebo. The ZDV regimen included oral ZDV initiated at 14-34 weeks of gestation and continued throughout the pregnancy, followed by intravenous ZDV during labor and oral administration of ZDV to the infant for 6 weeks after delivery (Box 2). The placebo regimen was administered identically. Blood specimens were obtained for HIV culture from all infants at birth and at 12, 24, and 78 weeks of age. A positive viral culture was considered indicative of HIV infection. Sera from the infants at 15 and 18 months of age also were tested for HIV antibody.
BOX 2. Zidovudine regimen from AIDS Clinical Trials Group Protocol 076 o Oral administration of 100 mg of zidovudine (ZDV) five times daily, initiated at 14 34 weeks of gestation and continued throughout the pregnancy. o During labor, intravenous administration of ZDV in a 1-hour loading dose of 2 mg per kg of body weight, followed by a continuous infusion of 1 mg per kg of body weight per hour until delivery. o Oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg of body weight per dose every 6 hours) for the first 6 weeks of life, beginning 8 12 hours after birth.
Limitations in Interpretation and Extrapolation of ACTG Protocol 076 Results This clinical trial demonstrated that the ACTG Protocol 076 ZDV regimen can substantially reduce perinatal HIV transmission. However, several important limitations should be noted. First, perinatal HIV transmission was still observed despite drug therapy. Second, the efficacy of this therapy is unknown for HIV-infected pregnant women who have advanced disease, who have received prior antiretroviral therapy, or who have ZDV-resistant virus strains. Third, although the ZDV regimen used in this trial was not associated with serious short-term adverse effects, such effects may be observed when this use of ZDV becomes more widespread. Fourth, the long-term risks for the child associated with exposure to ZDV in utero and early infancy have not been determined. Fifth, it is not known if use of ZDV during pregnancy will affect the drug's efficacy for the woman when it becomes clinically indicated for her own health. Further complicating the incorporation of this ZDV regimen into clinical practice is the fact that some HIV-infected women seek medical care late in pregnancy or when they are already in labor, when the full ZDV regimen used in ACTG Protocol 076 cannot be administered. Moreover, many pregnant women are not aware that they are HIV infected, are not tested before or during pregnancy, and remain undiagnosed. As a result, they do not receive information about therapy that could reduce the risk for HIV transmission to their infants.
In humans, observational studies involving small numbers of subjects have demonstrated no apparent association of fetal malformations with antenatal ZDV use (15-19). In ACTG Protocol 076, the incidence of congenital malformations was similar for ZDV and placebo recipients. However, because ZDV was not administered until after 14 weeks of gestation in this study, the potential teratogenicity of ZDV administered during the first trimester cannot be assessed. Similarly, in a recent report from the Antiretroviral Pregnancy Registry maintained by the Wellcome Foundation and Hoffman LaRoche in conjunction with CDC, no increase in the risk of congenital abnormalities above that expected for all pregnancies was observed among infants born to 121 prospectively registered HIV-infected women who received ZDV during pregnancy, nor was there any unusual pattern of birth defects (20). Use of ZDV during pregnancy could be associated with the development of ZDV-resistant virus, which may lessen the drug's therapeutic benefit for the woman when it is needed for her own health. However, patients with early-stage HIV disease rarely develop ZDV-resistant strains before they have received 18-24 months of continuous therapy (21). After discontinuation of ZDV therapy, an increase in ZDV-susceptible isolates has been observed in some patients who had ZDV-resistant isolates while they were receiving ZDV, although resistance to ZDV has been reported to persist for more than a year after therapy was discontinued (22,23). Because the development of ZDV-resistant viral strains secondary to transient ZDV use during pregnancy is a theoretical concern, considerations for the woman's future health care should include the availability of alternative drugs for treatment of HIV infection.
GENERAL PRINCIPLES REGARDING TREATMENT RECOMMENDATIONS
The following treatment recommendations have been formulated to provide a basis for discussion between the woman and her health-care provider about the use of ZDV to reduce perinatal transmission. HIV-infected women should be informed of the substantial benefit and short-term safety of ZDV administered during pregnancy and the neonatal period observed in ACTG Protocol 076. However, they also must be informed that the long-term risks of ZDV therapy to themselves and their children are unknown. A woman's decision to use ZDV to reduce the risk for HIV transmission to her infant should be based on a balance of the benefits and potential risks of the regimen to herself and to her child. Discussion of treatment options should be noncoercive, and the final decision to accept or reject ZDV treatment recommended for herself and her child is the right and responsibility of the woman. A decision not to accept treatment should not result in punitive action or denial of care, nor should ZDV be denied to a woman who decides to receive the regimen. Various circumstances that commonly occur in clinical practice are described and the factors influencing treatment considerations are highlighted in the following discussion (Box 3). All potential clinical situations cannot be enumerated, and, in many cases, definitive evidence upon which to base a recommendation is not currently available. Therefore, each pregnant woman and her health-care provider must consider the potential benefits, unknown long-term effects, and gaps in knowledge relating to her clinical situation. Furthermore, health-caregivers and institutions should provide culturally, linguistically, and educationally appropriate information and counseling to the HIV-infected woman so that she can make informed decisions.
CLINICAL SITUATIONS AND RECOMMENDATIONS FOR USE OF ZDV TO REDUCE PERINATAL TRANSMISSION
Clinical Situation Meeting the Entry Criteria for ACTG Protocol 076 I. Pregnant HIV-infected women with CD4+ T-lymphocyte counts greater than or equal to 200/uL who are at 14-34 weeks of gestation and who have no clinical indications for ZDV and no history of extensive (greater than 6 months) prior antiretroviral therapy.
Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider.
Clinical Situations Not Meeting the Study Entry Criteria Information about the benefit and short-term risks of ZDV therapy is applicable from this trial only for women who meet the entry criteria of the study. Recommendations about use of the ZDV regimen for women whose clinical conditions differ from the ACTG Protocol 076 eligibility criteria were derived from consensus interpretation of available scientific data.
II. Pregnant HIV-infected women who are at greater than 34 weeks of gestation, who have no history of extensive (greater than 6 months) prior antiretroviral therapy, and who do not require ZDV for their own health.
Discussion: This patient population has clinical characteristics similar to those of women enrolled in ACTG Protocol 076; the major difference is gestational age at which ZDV therapy would begin. Therefore, the ZDV regimen for these women would differ from the ACTG Protocol 076 regimen only in duration of antenatal therapy. As much as 50%-70% of perinatal transmission may occur close to or during delivery (28). Therefore, the ACTG Protocol 076 ZDV regimen may have some benefit when initiated at greater than 34 weeks of gestation, although the intervention is likely to decrease in effectiveness as the duration of antenatal ZDV administration is reduced. A study evaluating the effect of ZDV on quantitative p24 antigen levels indicates that maximal effect is observed after 8-16 weeks of therapy (29). A shorter duration of ZDV therapy may thus be associated with an effect on maternal viral load that is less than can be anticipated when ZDV is initiated before 34 weeks of gestation. Both potential risks and benefits for the woman and her infant may decrease the closer to delivery that the ZDV regimen is initiated. Further clinical trials should be designed to assess the efficacy of interventions that are initiated late in the third trimester for preventing perinatal transmission.
Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester.
III. Pregnant HIV-infected women with CD4+ T-lymphocyte counts less than 200/uL who are at 14-34 weeks of gestation, who have no other clinical indications for ZDV, and who have no history of extensive (greater than 6 months) prior antiretroviral therapy.
Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit (31). The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman.
IV. Pregnant HIV-infected women who have a history of extensive (greater than 6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy.
Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen on a case-by-case basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood that she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status.
V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor.
Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits.
VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy.
Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is greater than 24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant.
RECOMMENDATIONS FOR MONITORING THE ZDV REGIMEN FOR MOTHERS AND INFANTS
Women and their children should receive care together in a family-centered setting. Care should be coordinated between gynecologic, pediatric, internal medicine, infectious disease, and other health-care specialists to ensure that both mother and child receive appropriate medical follow-up. A comprehensive program of support services is necessary to ensure that both mother and child continue to receive health care.
Maternal Monitoring HIV-infected pregnant women should be monitored in accordance with previously published guidelines (31,53). Monitoring during pregnancy should include monthly assessment for ZDV-associated hematologic and liver chemistry abnormalities. Indications of toxicity that might require interrupting or stopping the dose of ZDV include a) hemoglobin less than 8 gm/dL, b) absolute neutrophil count less than 750 cells/uL, or c) AST (SGOT) or ALT (SGPT) greater than five times the upper limit of normal. CD4+ T-lymphocyte counts should be monitored to determine if prophylaxis for opportunistic infections, such as Pneumocystis carinii pneumonia (PCP), should be initiated. Pregnant HIV-infected women with CD4+ T-lymphocyte counts less than 200 cells/uL should receive appropriate PCP prophylaxis. If the CD4+ T-lymphocyte count is less than 600 cells/uL, the evaluation should be repeated each trimester. CD4+ T-lymphocyte counts should be measured at 6 weeks and 6 months postpartum to evaluate if antiretroviral therapy is indicated.
Fetal Monitoring Antepartum testing, including sonographic and nonstress testing and intrapartum fetal monitoring, should be performed only as clinically indicated, not specifically because the patient is being treated with ZDV during pregnancy.
Infant Monitoring A complete blood count and differential should be performed at birth as a baseline evaluation. Repeat measurements of hemoglobin are recommended at 6 and 12 weeks of age. ZDV should be administered with caution to infants born with severe anemia (hemoglobin less than 8 gm/dL), and treatment of the anemia and intensive monitoring are warranted if the drug is administered. Previously published guidelines contain recommendations for diagnosing HIV infection in infants and for initiating PCP prophylaxis and antiretroviral therapy for those who are infected (53-55). The potential efficacy of ZDV therapy for HIV-infected children who require antiretroviral therapy and who received ZDV in utero and during early infancy has not been determined. A specialist in pediatric HIV infection may be consulted if therapy is necessary for infected children whose mothers received ZDV during pregnancy. Further research is needed to describe the response to therapy and progression of disease in such infants.
POTENTIAL LONG-TERM EFFECTS OF ZDV THERAPY FOR MOTHERS AND INFANTS AND RECOMMENDATIONS FOR FOLLOW-UP
Recommendation: Additional efforts are required to characterize the long-term effects of the ACTG Protocol 076 ZDV regimen on women and children. The specific issues of viral resistance and disease progression should be addressed among women who receive ZDV during pregnancy solely to reduce perinatal HIV transmission. Monitoring for these HIV-infected women should include Pap smears and gynecologic examinations as recommended in previously published guidelines (56), as well as an assessment of the patient's future needs for family planning consultation and services. Long-term follow-up of both uninfected and infected infants born to mothers receiving ZDV during pregnancy is important. Assessment of organ system toxicities, neurodevelopment, pubertal development, reproductive capacity, and development of neoplasms should be emphasized. Special studies will need to be developed to address these specific concerns, and innovative methods and support systems should be designed to assist in follow-up of these women and their children.
CONCLUSION
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BOX 3. Summary: Clinical situations and recommendations for use of zidovudine*** to reduce perinatal HIV transmission
I. Pregnant HIV-infected women with CD4+ T-lymphocyte counts greater than or equal to 200/uL who are at 14-34 weeks of gestation and who have no clinical indications for ZDV and no history of extensive (greater than 6 months) prior antiretroviral therapy.
Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider. II. Pregnant HIV-infected women who are at greater than 34 weeks of gestation, who have no history of extensive (greater than 6 months) prior antiretroviral therapy, and who do not require ZDV for their own health.
Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester.
III. Pregnant HIV-infected women with CD4+ T-lymphocyte counts less than 200/uL who are at 14-34 weeks of gestation, who have no other clinical indications for ZDV, and who have no history of extensive (greater than 6 months) prior anti-retroviral therapy.
Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit. The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman.
IV. Pregnant HIV-infected women who have a history of extensive (greater than 6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy.
Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen on a case-by-case basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status.
V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor.
Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits.
VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy.
Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is greater than 24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant.
* A summary of the study's findings is available from the AIDS Clinical Trials Information Service at 1(800)TRIALS-A (1[800]874-2572).
** FDA pregnancy categories are: A, in which adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk during later trimesters); B, in which animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted; C, in which safety in human pregnancies has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, in which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; and X, in which studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.
*** These recommendations do not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question.
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