97-17854. U.S. Public Health Service Recommendations for Use of Antiretroviral Drugs During Pregnancy for Maternal Health and Reduction of Perinatal Transmission of Human Immunodeficiency Virus Type 1 in the United States; Request for Comment

[Federal Register Volume 62, Number 131 (Wednesday, July 9, 1997)]
[Notices]
[Pages 36809-36823]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-17854]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Office of Public Health and Science, HHS


U.S. Public Health Service Recommendations for Use of 
Antiretroviral Drugs During Pregnancy for Maternal Health and Reduction 
of Perinatal Transmission of Human Immunodeficiency Virus Type 1 in the 
United States; Request for Comment

AGENCY: Office of Public Health and Science, HHS.

ACTION: Notice.

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SUMMARY: The Department of Health and Human Services, Office of Public 
Health and Science is establishing guidelines for use of antiretroviral 
drugs by HIV-1-infected pregnant women for maternal health indications 
and reduction of perinatal HIV-1 transmission.

DATES: Comments on the proposed guidelines must be received on or 
before August 8, 1997 in order to ensure that NIH will be able to 
consider the comments in preparing the final guidelines.

ADDRESSES: Written comments to this notice should be submitted to: The 
HIV/AIDS Treatment Information Service, P.O. Box 6303, Rockville, MD 
20849-

[[Page 36810]]

6303. Only written comments will be accepted. After consideration of 
the comments, the final document will be published in the Centers for 
Disease Control and Prevention (CDC) ``Morbidity and Mortality Weekly 
Report'' (MMWR).

FOR FURTHER INFORMATION CONTACT: Copies of the ``U.S. Public 
HealthService Recommendations for Use of Antiretroviral Drugs During 
Pregnancy for Maternal Health and Reduction of Perinatal Transmission 
of Human Immunodeficiency Virus Type 1 in the United States'' are 
available from the National AIDS Clearinghouse (1-800-458-5231) and on 
the Clearinghouse Web site (http://www.cdcnac.org) and from the HIV/
AIDS Treatment Information Service (1-800-448-0440; Fax: [phone]; 
TTY: 1-800-243-7012) and on their Web site (http://www.hivatis.org).

SUPPLEMENTARY INFORMATION: The U.S. Public Health Service Task Force 
Recommendations for Use of Antiretroviral Drugs During Pregnancy for 
Maternal Health and Reduction of Perinatal Transmission of Human 
Immunodeficiency Virus Type 1 would update the 1994 guidelines 
developed by the U.S. Public Health Service for use of zidovudine (ZDV) 
to reduce the risk of perinatal human immunodeficiency virus (HIV) type 
1 transmission.(MMWR 1994)
    On May 9, 1997 the U.S. Public Health Service convened a ``Workshop 
on Antiretroviral Therapy to Reduce the Risk of Perinatal 
Transmission'' to review information related to use of antiretroviral 
drugs to reduce perinatal HIV transmission and for treatment of HIV 
infection in women in the United States. The medical, scientific, 
public health and bioethics communities and interested professional, 
community and advocacy organizations were represented. These guidelines 
represent a consensus of 35 expert consultants, including medical, 
public health, and bioethics specialists, HIV-infected women and AIDS 
advocacy organization representatives, who have reviewed and revised 
the document twice since that meeting. The document has also been sent 
for review by 22 representatives of professional and AIDS advocacy 
organizations.
    In February 1994, the results of Pediatric AIDS Clinical Trials 
Group (PACTG) Protocol 076 demonstrated that ZDV chemoprophylaxis could 
reduce perinatal HIV-1 transmission by nearly 70%.(Connor 1994) Since 
that time, epidemiologic data have confirmed the efficacy of ZDV for 
reduction of perinatal transmission and extended this efficacy to 
children of women with advanced disease, low CD4 lymphocyte count and 
prior ZDV therapy. Additionally, there have been major advances in 
understanding the pathogenesis of HIV-1 infection and in the treatment 
and monitoring of HIV-1 disease. These advances have resulted in 
changes in standard antiretroviral therapy recommendations for HIV-1-
infected adults in the United States to more aggressive combination 
drug regimens that maximally suppress viral replication. Although 
considerations related to pregnancy may factor into decisions as to 
timing and choice of therapy, pregnancy per se is not an adequate 
reason to defer standard therapy. There are unique considerations 
regarding use of antiretroviral drugs in pregnancy, including the 
potential need to alter dosing due to physiologic changes associated 
with pregnancy, the potential for adverse short- or long-term effects 
on the fetus and newborn, and effectiveness for reducing the risk of 
perinatal transmission. Data to address many of these considerations 
are not yet available. Therefore, offering antiretroviral therapy to an 
HIV-1-infected woman during pregnancy, whether primarily to treat her 
HIV-1 infection, primarily to reduce perinatal transmission, or for 
both purposes, should be accompanied by a discussion of the known and 
unknown short- and long-term benefits and risks of such therapy for her 
and her infant. Standard antiretroviral therapy should be discussed 
with and offered to HIV-1-infected pregnant women. Additionally, to 
prevent perinatal transmission, ZDV chemoprophylaxis should be 
incorporated into whatever antiretroviral regimen is offered. This 
document is intended to give the health care professional information 
for discussion with the woman to enable her to make an informed 
decision regarding use of antiretroviral drugs during pregnancy.

Introduction

    In February 1994, PACTG Protocol 076 demonstrated that a 3-part 
regimen of ZDV could reduce the risk of mother to child HIV-1 
transmission by nearly 70%.(Connor 1994) The regimen includes oral ZDV 
initiated at 14 to 34 weeks gestation and continuing throughout 
pregnancy, followed by intravenous ZDV during labor and oral 
administration of ZDV to the infant for 6 weeks after delivery (Table 
1). In August 1994, a U.S. Public Health Service (USPHS) Task Force 
issued recommendations for use of ZDV for reduction of perinatal HIV-1 
transmission (MMWR 1994), and in July 1995, the USPHS issued 
recommendations for universal prenatal HIV-1 counseling and HIV-1 
testing with consent for all pregnant women in the U.S..(MMWR 1995) In 
the three years since these results became available, epidemiologic 
studies in the U.S. and France have demonstrated dramatic decreases in 
perinatal transmission following incorporation of the PACTG 076 ZDV 
regimen into general clinical practice. (Cooper 1996; Fiscus 1996; 
Fiscus 1997; Thomas 1997; Blanche 1997;Simonds 1996)
    Since 1994 there have been major advances in understanding the 
pathogenesis of HIV-1 infection and in the treatment and monitoring of 
HIV-1 disease. It is now appreciated that the rapidity and magnitude of 
viral turnover during all stages of HIV-1 infection is much greater 
than previously recognized; plasma virions are estimated to have a mean 
half-life of only 6 hours.(Perelson 1996) Thus, current therapeutic 
interventions focus on early initiation of aggressive combination 
antiretroviral regimens to maximally suppress viral replication, 
preserve immune function, and reduce the development of 
resistance.(Havlir 1996) New, potent antiretroviral drugs which inhibit 
the protease enzyme of HIV-1 are now available. When a protease 
inhibitor is used in combination with nucleoside analogue reverse 
transcriptase inhibitors, plasma HIV-1 RNA levels may be reduced for 
prolonged periods of time to undetectable levels using current assays. 
Improved clinical outcome and survival have been observed in adults 
receiving such regimens. Additionally, more direct quantitation of 
viral load has become available through assays that measure HIV-1 RNA 
copy number; these assays have provided powerful new tools to assess 
disease stage and risk for progression as well as the effects of 
therapy. These advances have led to major changes in the standard of 
care for treatment and monitoring for HIV-1-infected adults in the 
United States.
    There have also been advances in the understanding of the 
pathogenesis of perinatal HIV-1 transmission. It is now recognized that 
the majority of perinatal transmission likely occurs near to or during 
delivery.(Mofenson 1997) Additional data and follow-up are now 
available on infants and women enrolled in PACTG 076 demonstrating the 
short-term safety of the ZDV regimen, but new data from animal studies 
affirm the need for long-term follow-up of children with antiretroviral 
exposure in utero.

[[Page 36811]]

    These developments have important implications for maternal and 
fetal health. Antiretroviral use in HIV-1 infected women during 
pregnancy must take into account two separate but elated issues: (1) 
Antiretroviral treatment of the woman's HIV infection, and (2) 
Antiretroviral chemoprophylaxis to reduce the risk of perinatal HIV-1 
transmission. While ZDV chemoprophylaxis alone has been shown to 
significantly reduce the risk of perinatal transmission, antiretroviral 
monotherapy is now considered to be suboptimal for treatment of HIV 
infection, and combination drug therapy is the current standard of care 
when considering treatment of the woman's HIV infection in the United 
States. The USPHS Panel on Clinical Practices for Treatment of HIV 
Infection will soon release guidelines for use of antiretrovirals in 
infected adolescents and adults, including use of antiretrovirals for 
treatment of infected women who are pregnant.(Panel 1997) The current 
document will focus on antiretroviral chemoprophylaxis for reduction of 
perinatal transmission, and will review the special considerations 
regarding use of antiretroviral drugs in pregnant women; update the 
results of PACTG 076 and related clinical trials and epidemiologic 
studies; discuss use of HIV-1 RNA assays during pregnancy; and provide 
updated recommendations on antiretroviral chemoprophylaxis for the 
reduction of perinatal transmission.
    These recommendations have been developed for use in the United 
States. Although perinatal HIV-1 transmission is an international 
problem, alternative strategies may be appropriate in other countries. 
The policy and practices in other countries regarding use of 
antiretroviral drugs for reduction of perinatal HIV-1 transmission may 
differ from these recommendations, and will depend on local 
considerations, including availability and cost of ZDV, access to 
facilities for safe intravenous infusions during labor, and alternative 
interventions that may be under evaluation in that area.

Special Considerations Regarding the use of Antiretroviral Drugs by 
HIV-1-Infected Pregnant Women and Their Infants

    Treatment recommendations for HIV-1-infected pregnant women have 
been based on the belief that therapies of known benefit to women 
should not be withheld during pregnancy unless there are known adverse 
effects on the mother, fetus or infant and these adverse effects 
outweigh the benefit to the woman.(Minkoff 1997) Thus, given the 
absence of demonstrated risk and compelling evidence of therapeutic 
advantage, guidelines for optimal antiretroviral therapy in pregnant 
HIV-1-infected women should be the same as those delineated for non-
pregnant adults. However, it must be realized that the potential impact 
of such therapy on the fetus and infant is unknown, and long-term 
follow-up is needed for children who have had exposure to 
antiretroviral drugs in utero. The decision to use any antiretroviral 
drug during pregnancy should be made by the woman following discussion 
with her health care provider regarding the known and unknown benefits 
and risks to her and her fetus.
    Combination antiretroviral therapy, generally consisting of two 
nucleoside analogue reverse transcriptase inhibitors and a protease 
inhibitor, is the currently recommended standard treatment for non-
pregnant HIV-1-infected adults with CD4 lymphocyte count <500 m\3\,="" hiv-1="" rna="" copy="" number="">10,000/mL, or clinical symptoms of HIV disease. 
Pregnancy per se should not preclude use of optimal therapeutic 
regimens. However, recommendations regarding the choice of 
antiretroviral drugs for treatment of infected pregnant women are 
subject to unique considerations, including potential changes in dosing 
requirements due to the physiologic changes associated with pregnancy 
and the potential effects of the antiretroviral drug on the fetus and 
newborn.
    Physiologic changes that occur during pregnancy may affect the 
kinetics of drug absorption, distribution, biotransformation and 
elimination in the pregnant woman, thereby affecting drug dose 
requirements. During pregnancy, gastrointestinal transit time becomes 
prolonged; body water and fat increase over gestation accompanied by 
increases in cardiac output, ventilation, and liver and renal blood 
flow; plasma protein concentrations decrease; renal sodium reabsorption 
increases; and there are changes in metabolic enzyme pathways in the 
liver. Placental transport of drugs, compartmentalization of drugs in 
the embryo/fetus and placenta, and biotransformation of drugs by the 
fetus and placenta as well as elimination of drugs by the fetus can 
also affect drug pharmacokinetics in the pregnant woman. Additional 
important considerations regarding drug use in pregnancy are the 
effects of the drug on the fetus and newborn, including the potential 
for teratogenicity, mutagenicity, or carcinogenicity, and the 
pharmacokinetics and toxicity of transplacentally-transferred drugs. 
The potential harm to the fetus from maternal ingestion of a specific 
drug depends not only on the drug itself, but the dose ingested, the 
gestational age at exposure, duration of exposure, the interaction with 
other agents to which the fetus is exposed, and to an unknown extent, 
the genetic makeup of the mother and fetus.
    Information about the safety of drugs in pregnancy comes from 
animal toxicity data, anecdotal experience, registry data and clinical 
trials. There are currently minimal data available on the 
pharmacokinetics and safety of antiretrovirals during pregnancy for 
antiretrovirals other than ZDV. In the absence of data, drug choice 
needs to be individualized based on discussion with the woman and 
available data from preclinical and clinical testing of the individual 
drugs.
    Preclinical data include in vitro and animal in vivo screening 
tests for carcinogenicity, clastogenicity/mutagenicity, and 
reproductive and teratogenic effects. It is important to recognize that 
the predictive value of such tests for adverse effects in humans is 
unknown. For example, of approximately 1,200 known animal teratogens, 
only about 30 are known to be teratogenic in humans. (Mills 1995) In 
addition to antiretroviral agents, many drugs commonly used to treat 
the consequences of HIV-1 infection may have positive findings on one 
or more of these screening tests. For example, acyclovir is positive on 
some in vitro carcinogenicity and clastogenicity assays and is 
associated with some fetal abnormalities in rats; however, data on 
human experience from the Acyclovir in Pregnancy Registry indicate no 
increased risk of birth defects in infants with in utero exposure to 
acyclovir to date. (MMWR 1993) Table 2 shows the FDA Pregnancy Category 
and available data regarding placental passage and long-term animal 
carcinogenicity studies for currently approved antiretroviral drugs.

Nucleoside Analogue Reverse Transcriptase Inhibitors

    Of the five currently approved nucleoside analogue antiretrovirals, 
only ZDV and lamivudine (3TC) pharmacokinetics have been evaluated in 
clinical trials in human pregnancy to date. ZDV is well-tolerated in 
pregnancy at usual adult doses and in the full-term neonate at 2 mg per 
kg body weight orally every 6 hours, as observed in PACTG 076. A small 
phase I study in South Africa evaluated the safety and pharmacokinetics 
of 3TC alone or in combination with ZDV in 20 infected pregnant women 
starting at 38 weeks gestation through labor and given for 1 week 
following birth to their infants.

[[Page 36812]]

(Johnson 1996, Moodley 1997) The drug was well-tolerated in the women 
at the usual adult dose of 150 mg orally twice daily, had 
pharmacokinetics similar to those observed in non-pregnant adults, and 
no pharmacokinetic interaction with ZDV was observed. No data are 
currently available regarding the pharmacokinetics of 3TC administered 
earlier than 38 weeks gestation. The drug crossed the placenta, 
achieving comparable serum concentrations in the woman, umbilical cord 
and neonate, and no short-term adverse effects were observed in the 
neonates. Oral clearance of 3TC in infants at 1 week of age was 
prolonged compared to older pediatric populations (0.35 L per kg per 
hour compared to 0.64-1.1 L per kg per hour, respectively). There are 
currently no data on 3TC pharmacokinetics between 2-6 weeks of age, and 
the exact age at which 3TC clearance begins to approximate that in 
older children is not known. Based on these limited data, 3TC in a dose 
of 150 mg administered orally twice daily in pregnant HIV-1-infected 
women and 2 mg per kg body weight administered orally twice daily in 
their neonates (half the dose recommended for older children) is being 
evaluated in several phase I studies in combination with ZDV and other 
drugs in the U.S., and in a phase III perinatal prevention trial in 
Africa.
    In rodent studies, prolonged, continuous high doses of ZDV 
administered to adult rodents have been associated with the development 
of noninvasive squamous epithelial vaginal tumors in 3% to 12% of 
females. (Ayers 1996) In humans, ZDV is extensively metabolized, and 
the major form of ZDV excreted in the urine is the glucuronide, whereas 
in mice, high concentrations of unmetabolized ZDV are excreted in the 
urine. It is hypothesized by scientists at Glaxo-Wellcome, Inc., the 
manufacturer of ZDV, that the vaginal tumors in mice may be a topical 
effect of chronic local ZDV exposure of the vaginal epithelium, 
resulting from reflux of urine containing highly concentrated ZDV from 
the bladder into the vagina. Consistent with this hypothesis, in a 
study conducted by Glaxo-Wellcome, Inc. in which 5 or 20 mg ZDV/mL 
saline was administered intravaginally to female mice, vaginal squamous 
cell carcinomas were observed in mice receiving the highest 
concentration. (Ayers 1996) No increase in the incidence of tumors in 
other organ sites has been seen in other studies of ZDV conducted in 
adult mice and rats. High doses of zalcitabine (ddC) have been 
associated with the development of thymic lymphomas in rodents. Long-
term animal carcinogenicity screening studies in rodents administered 
ddI or 3TC are negative; similar studies for stavudine (d4T) have not 
been completed.
    Two rodent studies evaluating the potential for transplacental 
carcinogenicity of ZDV have had differing results. In one ongoing study 
carried out by scientists at the National Cancer Institute, two very 
high daily doses of ZDV were administered during the last third of 
gestation in mice. The doses chosen for this study were near the 
maximum dose beyond which fetal toxicity would be observed and 
approximately 25 and 50 times greater than the daily dose given to 
humans, although the cumulative dose received by the pregnant mouse was 
similar to the cumulative dose received by a pregnant woman taking 6 
months of ZDV.
    In the offspring of ZDV-exposed pregnant mice at the highest dose 
level followed for 12 months, a statistically significant increase in 
lung, liver, and female reproductive organ tumors were observed; the 
investigators also documented incorporation of ZDV into the DNA in a 
variety of newborn mouse tissues, although this did not clearly 
correlate with the presence of tumors. The second study was carried out 
by scientists at Glaxo-Wellcome, Inc. In that study, pregnant mice were 
given one of several regimens of ZDV; doses were based on 
pharmacokinetic data in mice and humans and were intended to achieve 
blood levels somewhat higher (approximately 3-fold) than those achieved 
in clinical practice. The daily doses received by mice during gestation 
ranged from one-twelfth to one-fiftieth the daily doses received by 
mice in the previous study. Some of the offspring also received ZDV for 
varying periods of time over their lifespan. No increase in the 
incidence of tumors was observed in the offspring of these mice, except 
in those offspring that had received additional lifetime ZDV exposure 
in whom the previously noted vaginal tumors once again were noted.
    The relevance of these data to humans is unknown. An expert panel 
convened by the National Institutes of Health in January 1997 to review 
these data concluded that the proven benefit of ZDV in reducing the 
risk of perinatal transmission outweighed the hypothetical concerns of 
transplacental carcinogenesis raised by the rodent study. The panel 
also concluded that the information regarding the theoretical risk of 
transplacental carcinogenesis should be discussed with all HIV-infected 
pregnant women in the course of counseling them on the benefits and 
potential risks of antiretroviral therapy during pregnancy, and 
emphasized the need for careful long-term follow-up of all children 
exposed in utero to antiretroviral drugs. It is important to recognize 
that transplacental carcinogenicity studies have not been performed for 
any of the other available antiretroviral drugs, and no long-term or 
transplacental animal carcinogenicity studies of combinations of 
antiretroviral drugs have been performed.
    All of the nucleoside analogue antiretroviral drugs except 
didanosine (ddI) are classified as FDA Pregnancy Category C (see 
footnote to Table 2 for definitions); ddI is classified as Category B. 
While all the nucleoside analogues cross the placenta in primates, in 
primate and placental perfusion studies ddI and ddC undergo 
significantly less placental transfer (fetal/maternal drug ratios of 
0.3 to 0.5) than do ZDV, d4T and 3TC (fetal/maternal drug ratios >0.7).

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors

    There are 2 FDA-approved non-nucleoside reverse transcriptase 
inhibitors, nevirapine and delavirdine. A phase I study in the U.S. 
evaluated the safety and pharmacokinetics of nevirapine in 7 HIV-1-
infected pregnant women and their infants. Nevirapine was administered 
as a single 200 mg oral dose at the onset of labor, and as a single 
dose of 2 mg per kg body weight at 2-3 days of age to their infants. 
(Mirochnick 1997) The drug was well-tolerated by the women, crossed the 
placenta and achieved neonatal blood concentrations equivalent to that 
in the mother. No short-term adverse effects were observed in mothers 
or neonates. Elimination of nevirapine in the pregnant women in this 
study was prolonged (mean half-life, 66 hours) compared to non-pregnant 
individuals (mean half-life, 45 hours following a single dose). Data on 
chronic dosing with nevirapine beginning at 38 weeks gestation is under 
study but not yet available; no data are available regarding the safety 
and pharmacokinetics of chronic dosing with nevirapine beginning 
earlier in pregnancy. The half-life of nevirapine was prolonged in 
neonates (median half-life, 36.8 hours) compared to what is observed in 
older children (mean half-life, 24.8 hours following a single dose). A 
single dose of nevirapine at 2-3 days of age in neonates whose mothers 
received nevirapine during labor maintained levels associated with 
antiviral activity for the first week of life. (Mirochnick 1997) Based 
on these data, a phase III perinatal transmission

[[Page 36813]]

prevention clinical trial sponsored by the PACTG will evaluate 
nevirapine administered as a 200 mg single dose to the woman during 
active labor and a single dose to the newborn at 2-3 days of age in 
combination with standard maternal antiretroviral therapy and ZDV 
chemoprophylaxis.
    Delavirdine has not been studied in pregnant women. Delavirdine is 
positive on at least one in vitro screening test for carcinogenic 
potential. Long-term and transplacental animal carcinogenicity studies 
are not available for either of these drugs at the present time. Both 
drugs are associated with impaired fertility in rodents when 
administered at high doses, and delavirdine is teratogenic in rodents 
when very high doses are administered during pregnancy (ventricular 
septal defects were observed at doses associated with severe maternal 
toxicity). Both nevirapine and delavirdine are classified as FDA 
Pregnancy Category C.

Protease Inhibitors

    Although phase I studies of several protease inhibitors (indinavir, 
ritonavir and nelfinavir in combination with ZDV and 3TC) in pregnant 
infected women and their infants will soon start in the U.S., there are 
currently no data available regarding drug dosage, safety and tolerance 
of any of the protease inhibitors in pregnancy or in neonates. In mice, 
indinavir and ritonavir both have significant placental passage; 
however, in rabbits, indinavir shows little placental passage. Rodent 
data are not available on placental passage for saquinavir and 
nelfinavir, and transplacental passage of any of the protease 
inhibitors in humans is unknown.
    Administration of indinavir to pregnant rodents has revealed no 
evidence of teratogenicity. However, treatment-related increases in the 
incidence of supernumerary and cervical ribs were observed in offspring 
of pregnant rodents receiving indinavir at doses comparable to those 
administered to humans. In pregnant rats receiving high doses of 
ritonavir that were associated with maternal toxicity, some 
developmental toxicity was observed in the offspring, including 
decreased fetal weight, delayed skeletal ossification, wavy ribs, 
enlarged fontanelles and cryptorchidism; however, in rabbits, only 
decreased fetal weight and viability was observed at maternally toxic 
doses. Rodent studies have not demonstrated embryotoxicity or 
teratogenicity with saquinavir or nelfinavir.
    Indinavir is associated with infrequent side effects in adults 
(hyperbilirubinemia and renal stones) that could be problematic for the 
newborn if transplacental passage occurs and the drug is administered 
near to delivery. Due to the immature hepatic metabolic enzymes in 
neonates, the drug would likely have a prolonged half-life and possibly 
exacerbate the physiologic hyperbilirubinemia observed in neonates. 
Additionally, due to immature neonatal renal function and the inability 
of the neonate to voluntarily ensure adequate hydration, high drug 
concentrations and/or delayed elimination in the neonate could result 
in a higher risk for drug crystallization and renal stone development 
than observed in adults. These concerns are theoretical and such 
effects have not been reported; because the half-life of indinavir in 
adults is short, these concerns may only be relevant if drug is 
administered near the time of delivery. Saquinavir, ritonavir and 
nelfinavir are classified as FDA Pregnancy Category B; indinavir is 
classified as Category C.

Update on PACTG 076 Results and Other Studies Relevant to ZDV 
Chemoprophylaxis of Perinatal HIV-1 Transmission

    Final results were reported in 1996 for all 419 infants enrolled in 
PACTG 076. The results are the same as those initially reported in 
1994; the Kaplan-Meier estimated transmission rate in infants who 
received placebo was 22.6% compared to 7.6% within those who received 
ZDV, a 66% reduction in transmission risk.(Sperling 1996)
    The mechanism by which ZDV reduced transmission in PACTG 076 has 
not been fully defined. The effect of ZDV on maternal HIV-1 RNA did not 
fully account for the observed efficacy of ZDV in reducing 
transmission, raising the possibility that pre-exposure prophylaxis of 
the fetus/infant is an important component of protection. If so, 
transplacental passage of antiretroviral drugs would be important for 
prevention of transmission. Additionally, in placental perfusion 
studies, ZDV has been shown to be metabolized into the active tri-
phosphate within the placenta (Sandberg 1995, Qian 1994), and this 
could have provided additional protection against in utero 
transmission. This phenomenon may be unique to ZDV, as metabolism to 
the active tri-phosphate form within the placenta has not been observed 
in the other nucleoside analogues that have been studied in this 
fashion (ddI and ddC).(Dancis 1993, Sandberg 1994) Development of ZDV-
resistant virus was not necessarily associated with failure to prevent 
transmission. In a preliminary evaluation of genotypic resistance in 
women in PACTG 076, ZDV-resistant virus was present at delivery in only 
one of 7 transmitting women who had received ZDV and had evaluable 
samples; this woman had ZDV resistant virus at study entry despite no 
prior ZDV experience. (Eastman 1997) Additionally, the one woman in 
whom virus developed ZDV genotypic resistance between entry and 
delivery in this evaluation did not transmit HIV-1 to her infant.
    No increase in congenital abnormalities compared to the general 
population was seen in PACTG 076 or observed in evaluation of data from 
the Antiretroviral Pregnancy Registry.(AntiReg 1997) Follow-up data on 
uninfected infants from PACTG 076 to a median age of 3.9 years has not 
shown any differences in growth, neurodevelopment or immunologic status 
between infants born to mothers who received ZDV compared to those born 
to mothers who received placebo.(Connor1995) No malignancies have been 
observed in short-term (up to 6 years of age) follow-up over 734 
infants from PACTG 076 and natural history studies who had in utero ZDV 
exposure.(Hanson 1997) However, follow-up is too limited at this time 
to provide a definitive assessment of carcinogenic risk with human 
exposure. Long-term follow-up continues to be recommended for all 
infants with in utero ZDV exposure (or in utero exposure to any of the 
antiretroviral drugs).
    The effect of temporary administration of ZDV during pregnancy to 
reduce perinatal transmission on the induction of viral resistance to 
ZDV and long-term maternal health requires further evaluation. 
Preliminary data from an interim analysis of PACTG protocol 288 (a 
study following women enrolled in PACTG 076 through 3 years postpartum) 
indicate no significant differences at 18 months postpartum in CD4 
lymphocyte count or clinical status between those women who received 
ZDV compared to those who received placebo. (Bardeguez 1997) Limited 
data on the development of genotypic ZDV resistance mutations (codons 
70 and/or 215) in PACTG 076 are available from a subset of women 
receiving ZDV, including the majority of those with infected infants. 
(Eastman 1997) Virus from one of 36 ZDV-receiving women (3%) with 
paired isolates from entry and delivery developed a ZDV genotypic 
resistance mutation. However, the population of women in PACTG 076 had 
very low HIV-1 RNA copy number, and while the

[[Page 36814]]

risk of inducing resistance with administration of ZDV chemoprophylaxis 
alone for several months during pregnancy was low in this substudy, it 
would likely be higher in a population of women with more advanced 
disease and higher levels of viral replication.
    The efficacy of ZDV chemoprophylaxis for reducing transmission 
among populations of infected women with characteristics unlike those 
in PACTG 076 has been evaluated in another perinatal protocol (PACTG 
185) as well as natural history studies. PACTG 185 evaluated the 3-part 
ZDV regimen combined with passive immunization with hyperimmune HIV-1 
immunoglobulin (HIVIG), an immunoglobulin containing high levels of 
antibody to HIV-1, in infected pregnant women with advanced HIV-1 
disease receiving antiretroviral therapy. Twenty-one percent of the 
women in this trial had CD4 count <200 m\3\="" and="" 23%="" had="" received="" zdv="" prior="" to="" the="" current="" pregnancy,="" many="" for="" prolonged="" periods="" of="" time.="" all="" women="" and="" infants="" in="" this="" study="" received="" the="" 3-part="" zdv="" regimen,="" and="" were="" randomized="" to="" receive="" hivig="" vs="" standard="" intravenous="" immunoglobulin="" (ivig).="" because="" it="" was="" known="" that="" advanced="" disease="" and="" low="" cd4="" count="" were="" associated="" with="" high="" risk="" for="" perinatal="" transmission,="" it="" was="" hypothesized="" that="" even="" with="" zdv="" chemoprophylaxis,="" the="" perinatal="" transmission="" rate="" would="" be="" 11-15%.="" however,="" at="" the="" first="" interim="" analysis,="" the="" combined="" group="" transmission="" rate="" was="" only="" 4.8%,="" and="" did="" not="" significantly="" differ="" by="" duration="" of="" zdv="" use="" or="" treatment="" arm="" (hivig="" vs="" ivig).(execsum="" 1997)="" enrollment="" was="" halted="" because="" the="" unexpectedly="" low="" transmission="" rate="" resulted="" in="" an="" inability="" to="" answer="" the="" primary="" protocol="" question="" in="" a="" timely="" fashion.="" however,="" the="" results="" of="" the="" trial="" confirm="" the="" efficacy="" of="" zdv="" observed="" in="" pactg="" 076,="" and="" extend="" this="" efficacy="" to="" women="" with="" advanced="" disease,="" low="" cd4="" count="" and="" prior="" zdv="" therapy.="" these="" data="" are="" also="" consistent="" with="" epidemiologic="" data="" from="" several="" natural="" history="" studies.="" in="" a="" study="" in="" connecticut,="" 39%="" of="" women="" with="" cd4="" count=""><200>3 who did not receive ZDV therapy during 
pregnancy had infected infants compared to 4% of women with similar CD4 
counts who received ZDV. (Simpson 1997) In North Carolina, perinatal 
HIV-1 transmission has declined over time from 21% in 1993 to 6% in 
early 1996; only 3% of women who received all three components of the 
ZDV regimen had infected infants. (Fiscus 1997) In a large U.S. 
prospective multicenter natural history cohort of 556 mother-infant 
pairs, perinatal transmission declined from 19% in infants born before 
March 1994, before the results of PACTG 076 were available, to 8% in 
infants born after March 1994; decline in transmission was observed 
regardless of maternal CD4 lymphocyte count, duration of membrane 
rupture, mode of delivery, gestational age, and illicit drug use. 
(Cooper 1996) In another multicenter U.S. cohort, perinatal 
transmission declined from 20% among 1,160 children born before March 
1994 to 12% among 373 born afterwards. (Simonds 1996)
    At the present time, there are no clinical trials which demonstrate 
that antiretroviral drugs other than ZDV are effective in reducing 
perinatal transmission. Potent combination antiretroviral regimens have 
been shown to significantly suppress viral replication and improve 
clinical status in infected adults. However, the efficacy of ZDV 
exceeds the magnitude of reduction in plasma HIV-1 RNA copy number 
observed in PACTG 076. If pre-exposure prophylaxis of the infant is an 
important mechanism of prevention, it is possible that any 
antiretroviral drug with significant placental passage may be equally 
effective, although if antiretroviral activity within the placenta is 
important for protection, ZDV may be unique among the available 
nucleoside analogue drugs. While there are advantages of combination 
therapy for the woman's own health, further research is needed before 
it can be determined if there is an additional advantage to combination 
antiretroviral therapy for reducing perinatal transmission.

Perinatal HIV-1 Transmission and Maternal HIV-1 RNA Copy Number

    The clear correlation of HIV-1 RNA levels with disease progression 
risk in non-pregnant infected adults suggests that HIV-1 RNA should be 
monitored during pregnancy at least as often as recommended for non-
pregnant individuals (e.g., every 3 to 4 months or approximately once 
each trimester). Whether increased frequency of testing is needed 
during pregnancy is unclear and requires further study. Although there 
is no convincing data that pregnancy accelerates HIV-1 disease 
progression, longitudinal measurements of HIV-1 RNA levels during and 
after pregnancy have been evaluated in only one prospective cohort to 
date. In this cohort of 198 HIV-1-infected women, plasma HIV-1 RNA 
levels were higher at 6 months post partum than ante partum in many 
women; this increase was observed in women who had received and not 
received ZDV during pregnancy, as well as in women who continued 
therapy post partum. (Cao 1997)
    Data on the correlation of viral load with risk of perinatal 
transmission have been conflicting, with some small studies suggesting 
an absolute correlation between HIV-1 RNA copy number and transmission 
risk. (Dickover 1996) However, in several larger studies while higher 
HIV-1 RNA levels were observed in transmitting women, there was large 
overlap in HIV-1 RNA copy number between transmitting and non-
transmitting women, transmission was observed across the entire range 
of HIV-1 RNA levels (including in women with undetectable HIV-1 RNA), 
and the positive predictive value of RNA copy number for transmission 
was relatively low. (Mayaux 1997, Burchett 1996, Cao 1997, Thea 1997) 
In PACTG 076, there was a relationship between HIV-1 RNA copy number 
and transmission in women receiving placebo, but in ZDV-receiving women 
the relationship was markedly attenuated and no longer statistically 
significant. (Sperling 1996) No HIV-1 RNA threshold below which there 
was no risk of transmission was identified, and ZDV was effective in 
reducing transmission regardless of maternal HIV-1 RNA copy number.
    While a general correlation between plasma and genital viral load 
has been described, women with undetectable plasma HIV-1 RNA levels in 
whom virus was detectable in the genital tract have been reported. 
(Rasheed 1996) If exposure to virus in the maternal genital tract 
during delivery is an important risk factor for perinatal transmission, 
then plasma HIV-1 RNA levels may not be a fully accurate indicator of 
risk.
    Whether lowering maternal HIV-1 RNA copy number during pregnancy 
would reduce perinatal transmission risk requires more study. In a 
virologic study in 44 infected pregnant women, ZDV was effective in 
reducing transmission despite minimal effect on HIV-1 RNA levels, 
similar to what was observed in PACTG 076. (Melvin 1997) However, it is 
not known if a more potent antiretroviral regimen that more 
significantly suppresses viral replication would be associated with 
enhanced efficacy in reducing transmission risk over and above that 
observed with ZDV alone. At the present time, determination of HIV-1 
copy number is important for decisions related to treatment. However, 
because ZDV benefit is observed regardless of maternal HIV-1 RNA level 
and because transmission may occur when HIV-1 RNA is not detectable, 
HIV-1 RNA

[[Page 36815]]

should not be the determining factor in decisions regarding use of ZDV 
chemoprophylaxis against perinatal transmission.

General Principles Regarding Use of Antiretrovirals in Pregnancy

    Care of the HIV-1-infected pregnant woman should involve a 
collaboration between the HIV-specialist caring for the woman when she 
is not pregnant, her obstetrician, and the woman herself. Decisions 
regarding use of antiretroviral drugs during pregnancy should be made 
by the woman following discussion with her health care provider of the 
known and unknown benefits and risks of therapy. Initial evaluation of 
an infected pregnant woman should include an assessment of HIV-1 
disease status and recommendations regarding antiretroviral treatment 
or alteration of her current antiretroviral regimen. This assessment 
should include evaluation of the degree of existing immunodeficiency 
determined by CD4 count; risk of disease progression determined by the 
level of plasma RNA; history of prior or current antiretroviral 
therapy; and gestational age. For those women not currently receiving 
antiretroviral therapy, decision-making regarding initiation of therapy 
should be the same as for non-pregnant individuals, with the additional 
consideration of the potential impact of such therapy on the fetus and 
infant. (PanelRec 1997) Similarly, for women currently receiving 
antiretrovirals, decisions regarding alterations in therapy should use 
the same parameters as for non-pregnant individuals. Additionally, use 
of the 3-part ZDV chemoprophylaxis regimen, alone or in combination 
with other antiretrovirals, should be discussed with and offered to all 
infected pregnant women for the purpose of reducing perinatal 
transmission risk.
    Decisions regarding the use and choice of antiretroviral drugs 
during pregnancy are complex and must balance a number of competing 
factors influencing risk and benefit. Discussion regarding use of 
antiretroviral drugs during pregnancy should include what is known and 
not known about the effects of such drugs on the fetus and newborn, 
including lack of long-term outcome data on use of any of the available 
antiretroviral drugs in pregnancy; what would be recommended in terms 
of treatment for her own health; and the efficacy of ZDV for reduction 
of perinatal transmission. These discussions should include what is 
known from preclinical and animal studies and available clinical 
information about use of the various antiretroviral agents during 
pregnancy. It is important to place the hypothetical risks of these 
drugs during pregnancy in perspective to the proven benefit of 
antiretroviral therapy for her own health and ZDV chemoprophylaxis for 
reducing the risk of HIV-1 transmission to her infant.
    Discussion of treatment options should be noncoercive, and the 
final decision regarding the use of antiretroviral drugs is the 
responsibility of the woman. Decisions regarding use and choice of 
antiretroviral drugs in non-pregnant individuals are becoming 
increasingly complicated, as the standard of care moves toward 
simultaneous use of multiple antiretroviral drugs to suppress viral 
replication below detectable limits. These decisions are further 
complicated in pregnancy, as the long-term consequences of in utero 
exposure to antiretroviral drugs, alone or in combination, for the 
infant are unknown. A decision to not accept treatment with ZDV or 
other drugs should not result in punitive action or denial of care, nor 
should use of ZDV be denied to a woman who wishes to minimize exposure 
of the fetus to other antiretroviral drugs and therefore chooses to 
receive only ZDV during pregnancy to reduce the risk of perinatal 
transmission after receiving appropriate counseling.
    A long-term treatment plan should be developed with the patient and 
the importance of adherence to any prescribed antiretroviral regimen 
discussed with her. Depending on individual circumstances, provision of 
support services, drug treatment, and coordination of services between 
the criminal justice system, drug treatment programs and prenatal care 
providers may each play an important role in assisting women with 
adherence to antiretroviral regimens.
    Public Health Service recommendations for infected women in the 
U.S. to refrain from breastfeeding to avoid postnatal transmission of 
HIV-1 to their infants through breast milk should not be altered for 
women receiving antiretroviral therapy. (CDC 1985, CDC 1995) Passage of 
antiretroviral drugs into breast milk has been evaluated for only a few 
antiretroviral drugs: ZDV, 3TC and nevirapine can be detected in the 
breast milk of women receiving the drugs, and ddI, d4T, and indinavir 
can be detected in the breast milk of lactating rats receiving therapy. 
The efficacy of antiretroviral therapy for prevention of postnatal 
transmission of HIV-1 through breast milk and the toxicity of chronic 
antiretroviral exposure of the infant via breast milk are unknown.
    It is strongly recommended that health care providers who are 
treating HIV-1-infected pregnant women report cases of prenatal 
exposure to ZDV, ddI, ddC, d4T, 3TC, saquinavir or indinavir alone or 
in combination to the Antiretroviral Pregnancy Registry. The registry 
is an epidemiologic project to collect observational, non-experimental 
data on antiretroviral exposure during pregnancy for the purpose of 
assessing potential teratogenicity of these drugs in pregnancy. 
Registry data will be used to supplement animal toxicology studies and 
assist clinicians in weighing the potential risks and benefits of 
treatment for individual patients.
    The registry is a collaborative project jointly managed by Glaxo 
Wellcome, Hoffmann-LaRoche Inc., Bristol-Myers Squibb Co., and Merck & 
Co. Inc., with an advisory committee of practitioners and CDC and NIH 
staff; it is anticipated that additional antiretroviral drugs will be 
added to the registry in the future. The registry does not use patient 
names, and birth outcome follow-up is obtained by registry staff from 
the reporting physician. Referrals should be directed to Antiretroviral 
Pregnancy Registry, Post Office Box 13398, Research Triangle Park, NC 
27709-3398; telephone [phone] or [phone], ext. 39437; fax 
919-315-8981.

Recommendations for Antiretroviral Chemoprophylaxis to Reduce Perinatal 
HIV Transmission

    The following recommendations for use of antiretroviral 
chemoprophylaxis to reduce the risk of perinatal transmission are based 
upon various circumstances that may be commonly encountered in clinical 
practice (Table 3), with relevant considerations highlighted in the 
subsequent discussion section. These scenarios present only 
recommendations and flexibility should be exercised according to the 
circumstances of the individual patient. In the 1994 recommendations, 6 
clinical scenarios were delineated based on maternal CD4 count, 
gestational age and prior antiretroviral use. Because current data 
indicate that the PACTG 076 ZDV regimen is also effective women with 
advanced disease, low CD4 count and prior ZDV therapy, clinical 
scenarios by CD4 count and prior ZDV use are not presented. 
Additionally, because current data indicate most transmission occurs 
near to or during delivery, it was felt that ZDV chemoprophylaxis 
should be recommended regardless of gestational age; thus, clinical 
scenarios by gestational age are also not presented.

[[Page 36816]]

    Table 1 shows the ZDV dosage and regimen used in PACTG 076. The 
antenatal dosing regimen in PACTG 076 (100 mg orally five times daily) 
was selected based on standard ZDV dosage for adults at the time of the 
study. Recent reports from several laboratories have demonstrated that 
administration of ZDV three times a day will maintain intracellular ZDV 
tri-phosphate at levels comparable to that observed with more frequent 
dosing. (Rodman 1996; Barry 1996; Gambertoglio 1996) Additionally, 
comparable clinical response with twice daily dosing has been observed 
in some clinical trials. (Mulder 1994, Mannucci 1994, Cooper 1993) 
Thus, the current standard adult ZDV dosing regimen is 200 mg three 
times daily or 300 mg twice daily. Because the mechanism by which ZDV 
reduces perinatal transmission is not known, it cannot be known with 
certainty that these dosing regimens will have equivalent efficacy to 
that observed in PACTG 076. However, it would be anticipated that a two 
or three times daily regimen might be associated with enhanced maternal 
adherence over a five times daily regimen.
    The recommended ZDV dosage for infants was derived from 
pharmacokinetic studies performed in term infants. (Boucher 1993) ZDV 
is primarily cleared through hepatic glucuronidation to an inactive 
metabolite. The glucuronidation metabolic enzyme system is immature in 
neonates, leading to prolonged ZDV half-life and clearance compared to 
older infants (ZDV half-life, 3.1 hours vs 1.9 hours, and clearance, 
10.9 vs 19.0 mL per minute per kg body weight, respectively). Because 
premature infants have even greater immaturity in hepatic metabolic 
function than term infants, further prolongation in clearance may be 
expected. In a small pharmacokinetic study of 7 premature infants who 
were 28 to 33 weeks gestation and received a variety of ZDV dosing 
regimens, mean ZDV half-life was 6.3 hours and mean clearance was 2.8 
mL per minute per kg body weight during the first 10 days of life. 
(Capparelli 1996) Appropriate ZDV dosing for premature infants has not 
been defined, but is being evaluated in a phase I clinical trial in 
premature infants less than 34 weeks gestation. The dosing regimen 
being studied is 1.5 mg per kg body weight orally or intravenously 
every 12 hours for the first 2 weeks of life; from 2 to 6 weeks of age, 
the dose is increased to 2 mg per kg body weight every 8 hours.
    Because subtherapeutic dosing of antiretroviral drugs may be 
associated with enhancing the likelihood for the development of drug 
resistance, women who must temporarily discontinue therapy due to 
pregnancy-related hyperemesis should not reinstitute therapy until 
sufficient time has elapsed to assure that the drugs will be tolerated. 
In order to reduce the potential for emergence of resistance, if 
therapy requires temporary discontinuation for any reason during 
pregnancy, all drugs should be stopped and reintroduced simultaneously.

Clinical Scenarios

Scenario #1

HIV-Infected Pregnant Women Without Prior Antiretroviral Therapy
    Recommendation: HIV-1 infected pregnant women must receive standard 
clinical, immunologic and virologic evaluation, and recommendations for 
initiation and choice of antiretroviral therapy should be based on the 
same parameters used in non-pregnant individuals, with consideration 
and discussion of the known and unknown risks and benefits of such 
therapy during pregnancy.
    The 3-part ZDV chemoprophylaxis regimen should be recommended for 
all HIV-infected pregnant women to reduce the risk of perinatal 
transmission. If the woman's clinical, immunologic and virologic status 
indicates that more aggressive therapy is recommended to treat her 
infection (Panelrec, 1997), other antiretroviral drugs should be 
recommended in addition to ZDV. If the woman's status is such that 
therapy would be considered optional, the use of additional 
antiretrovirals may be offered, although whether this will provide 
additional benefit to the woman or her child is not known. Women who 
are in the first trimester of pregnancy may wish to consider delaying 
initiation of therapy at least until after 10 to 12 weeks gestation.
    Discussion: The only drug that has been shown to reduce the risk of 
perinatal HIV-1 transmission is ZDV when administered in the 3-part 
PACTG 076 regimen; this regimen was shown to reduce transmission risk 
by approximately 70%. The mechanism by which ZDV reduced transmission 
is not known, and there are insufficient data available at present to 
justify the substitution of any antiretroviral drug other than ZDV for 
the purpose of reducing perinatal transmission. Therefore, if 
combination antiretroviral therapy is initiated during pregnancy, it is 
recommended that ZDV be included as a component of antenatal therapy 
and the intrapartum and newborn ZDV parts of the chemoprophylactic 
regimen should be recommended for the specific purpose of reducing 
perinatal transmission.
    Women should be counseled that combination therapy may have 
significant benefit for their own health but is of unknown benefit to 
the fetus. Potent combination antiretroviral regimens may be shown in 
the future to provide enhanced protection against perinatal 
transmission, but this benefit is not yet proven. Decisions regarding 
the use and choice of an antiretroviral regimen will need to be 
individualized based on discussion with the woman about her risk for 
disease progression and the risks and benefits of delaying initiation 
of therapy; potential drug toxicities and interactions with other 
drugs; the need for adherence to the prescribed drug schedule; and 
preclinical, animal and clinical data relevant to use of the currently 
available antiretrovirals during pregnancy.
    Because the period of organogenesis when the embryo is most 
susceptible to potential teratogenic effects of drugs is the first 10 
weeks of gestation and the risks of antiretroviral therapy during that 
period are unknown, women who are in the first trimester of pregnancy 
may wish to consider delaying initiation of therapy until after 10 to 
12 weeks gestation. This decision should be carefully considered and 
discussed between the health care provider and the patient, including 
an assessment of the woman's health status and the benefits and risks 
of delaying initiation of therapy for several weeks.
    Women for whom initiation of antiretroviral therapy for the 
treatment of their HIV infection would be considered optional (eg. high 
CD4 count and low or undetectable RNA copy number) should have the 
potential benefits of standard combination therapy discussed with them 
and standard therapy, including the 3-part ZDV chemoprophylaxis 
regimen, offered to them. Some women may wish to restrict their 
exposure to antiretroviral drugs during pregnancy but still wish to 
reduce the risk of transmitting HIV-1 to their infant; the 3-part ZDV 
chemoprophylaxis regimen should be recommended in this situation. In 
these circumstances, the development of resistance should be minimized 
by the limited viral replication in the patient and the time-limited 
exposure to ZDV.
    Because ZDV alone does not suppress HIV replication to undetectable 
levels, there are theoretical concerns that use of ZDV chemoprophylaxis 
alone might select for ZDV resistant viral variants which might limit 
future ability to favorable response to combination antiretroviral 
regimens that include

[[Page 36817]]

ZDV. There are currently insufficient data to determine if such use 
would have adverse consequences for the woman postpartum. In some adult 
combination antiretroviral clinical trials, patients with previous ZDV 
therapy experienced less benefit from combination therapy than those 
who were antiretroviral naive. (Delta 1996, Hammer 1996, Saravolatz 
1996) However, the median duration of prior ZDV in these studies was 12 
to 20 months and enrolled patients had more advanced disease and lower 
CD4 counts than the population of women enrolled in PACTG 076 or for 
whom initiation of therapy would be considered optional. In one study, 
patients with less than 12 months of ZDV responded as favorably to 
combination therapy as did those without prior ZDV therapy.(Saravolatz 
1996) In PACTG 076, the median duration of ZDV therapy was 11 weeks, 
and the maximal duration of ZDV begun at 14 weeks gestation would be 
6.5 months for a full-term pregnancy.
    However, for women initiating therapy who have more advanced 
disease, concerns about development of resistance with use of ZDV alone 
as chemoprophylaxis during pregnancy would be greater. Factors that 
predict more rapid development of ZDV resistance include more advanced 
HIV-1 disease, low CD4 count, high HIV-1 RNA copy number, and possibly 
syncytium-inducing viral phenotype.(Kuritzkes 1996, Japour 1995) 
Therefore, women with advanced disease, low CD4 count or high RNA copy 
number should be counseled that therapy with a combination 
antiretroviral regimen that includes ZDV for reducing transmission risk 
would be more optimal for their own health than use of ZDV 
chemoprophylaxis alone.

Scenario #2

HIV-Infected Women Receiving Antiretroviral Therapy During the Current 
Pregnancy
    Recommendation: HIV-1 infected women receiving antiretroviral 
therapy in whom pregnancy is identified after the first trimester 
should continue therapy. For women receiving antiretroviral therapy in 
whom pregnancy is recognized during the first trimester, the woman 
should be counseled regarding the benefits and potential risks of 
antiretroviral administration during this period, and continuation of 
therapy should be considered. If therapy is discontinued during the 
first trimester, all drugs should be stopped and reintroduced 
simultaneously to avoid the development of resistance. If the current 
therapeutic regimen does not contain ZDV, the addition of ZDV or 
substitution of ZDV for another nucleoside analogue antiretroviral is 
recommended after 14 weeks gestation. Intrapartum and newborn ZDV 
administration is recommended regardless of the antepartum 
antiretroviral regimen.
    Discussion: Women who require antiretroviral treatment for their 
HIV infection should continue treatment during pregnancy. 
Discontinuation of therapy could lead to rebound in viral load, which 
theoretically could result in decline in immune status and/or disease 
progression, all of which might have adverse consequences for the fetus 
as well as the woman. Because the efficacy of non-ZDV containing 
antiretroviral regimens for reduction of perinatal transmission is 
unknown, it is recommended that ZDV be a component of the antenatal 
antiretroviral treatment regimen after 14 weeks gestation, and that 
intrapartum and newborn ZDV be administered. If a woman does not 
receive ZDV as a component of her antepartum antiretroviral regimen 
(eg. because of prior history of ZDV-related severe toxicity or 
personal choice), intrapartum and newborn ZDV should continue to be 
recommended.
    Some women receiving antiretroviral therapy may recognize their 
pregnancy early in gestation, and concern for potential teratogenicity 
may lead some to consider temporarily stopping antiretroviral treatment 
until after the first trimester. There are insufficient data to support 
or refute the teratogenic risk of antiretroviral drugs when 
administered during the first 10 weeks of gestation. The decision to 
discontinue therapy during the first trimester should be carefully 
considered and discussed between the clinician and the woman. 
Considerations include gestational age of the pregnancy, the woman's 
clinical, immunologic and virologic status, and what is known and not 
known about the potential effects of the antiretroviral drugs on the 
fetus. If antiretroviral therapy is discontinued during the first 
trimester, all agents should be stopped and restarted in the second 
trimester simultaneously to avoid the development of resistance. There 
are currently no data to address whether transient discontinuation of 
therapy in this manner would be harmful for the woman and/or fetus.
    The impact of prior antiretroviral exposure on the efficacy of ZDV 
chemoprophylaxis is unclear. Data from PACTG 185 indicate that duration 
of prior ZDV therapy in women with advanced HIV-1 disease, many of whom 
received prolonged ZDV prior to pregnancy, did not appear to be 
associated with diminished ZDV efficacy for reduction of transmission: 
perinatal transmission rates were similar among women who first 
initiated ZDV during pregnancy and women who had received ZDV prior to 
pregnancy. Thus at the present time, a history of ZDV therapy prior to 
the current pregnancy should not limit recommendations for 
administration of ZDV chemoprophylaxis to reduce perinatal 
transmission.
    Some experts might consider administration of ZDV in combination 
with other antiretroviral drugs to newborns of women with a history of 
prior antiretroviral therapy, particularly in situations where the 
woman is infected with HIV-1 with documented high-level ZDV resistance, 
had disease progression while receiving ZDV, or had extensive prior ZDV 
monotherapy. However, the efficacy of this approach is not known. The 
appropriate dose and short and long-term safety for most antiretroviral 
agents other than ZDV are not defined for neonates. Because of immature 
liver metabolism and renal function, the half-life of many drugs 
(including ZDV, 3TC and nevirapine) is prolonged during the neonatal 
period, requiring specific dosing adjustments. Phase I studies of a 
number of other antiretroviral drugs in neonates are ongoing, but data 
are not yet available. The infected woman should be counseled regarding 
the postulated benefit of combination antiretroviral drugs in the 
neonate and the potential risks, what is known about appropriate dosing 
of the drugs in newborn infants, and that use of additional 
antiretroviral drugs for newborn prophylaxis is of unknown efficacy for 
reducing perinatal transmission risk.

Scenario #3

HIV-Infected Women in Labor Who Have Had no Prior Therapy
    Recommendation: Administration of intrapartum intravenous ZDV 
should be recommended along with the 6 week newborn ZDV regimen. In the 
immediate postpartum period, the woman should have appropriate 
assessments (eg., CD4 count, HIV-1 RNA copy number) to determine if 
antiretroviral therapy is recommended for her own health.
    Discussion: Intrapartum ZDV will not prevent the portion of 
perinatal transmission that occurs prior to labor. Therefore, the 
efficacy of an intrapartum/newborn antiretroviral regimen in reducing 
perinatal transmission is likely to be less than the

[[Page 36818]]

efficacy observed in PACTG 076. However, increasing data indicate that 
a majority of perinatal transmission occurs near to or during birth. 
Additionally, the efficacy of ZDV in reducing perinatal transmission is 
not primarily related to treatment-induced reduction in maternal HIV-1 
RNA copy number. This implies that the presence of systemic 
antiretroviral drug levels in the neonate just prior to, during and for 
a period following birth may be a critical component for reducing 
transmission.
    There are minimal data to address the efficacy of a regimen that 
lacks the antenatal ZDV component. An epidemiologic study from North 
Carolina compared perinatal transmission rates from mother-infant pairs 
who received different parts of the ZDV chemoprophylactic regimen. 
(Fiscus 1997) Among those who received all 3 components, 6 of 188 
infants were infected (3%). While the numbers were small, only one of 
16 infants (6%) were infected among those who received intrapartum and 
newborn ZDV.
    ZDV readily crosses the placenta. Administration of the intravenous 
ZDV loading dose followed by continuous ZDV infusion during labor to 
the woman will provide ZDV levels in the newborn during passage through 
the birth canal that are nearly equivalent to maternal ZDV levels. The 
initial intravenous ZDV loading dose assures rapid attainment of 
virucidal ZDV levels in the woman and her infant, and the continuous 
ZDV infusion assures stable drug levels in the infant during the birth 
process regardless of the duration of labor. A study is currently 
ongoing in the U.S. to evaluate if oral dosing of ZDV during labor in a 
regimen of 300 mg orally every 3 hours would provide equivalent infant 
drug exposure to intravenous ZDV administration. Until this data is 
available, oral intrapartum administration of ZDV cannot be assumed to 
be equivalent to the intravenous intrapartum ZDV.
    ZDV administered both during the intrapartum period and to the 
newborn provides both pre-and post-exposure prophylaxis to the infant. 
Some clinicians might consider administration of ZDV in combination 
with other antiretroviral drugs to the newborn, analogous to 
recommendations for post-exposure prophylaxis of nosocomial HIV-1 
exposure. (CDC 1996) Any decision to use combination antiretroviral 
prophylaxis in the newborn must be accompanied by a discussion with the 
woman of potential benefits and risks and that there currently are no 
data to address the efficacy and safety of this approach.

Scenario #4

Infants Born to Mothers Who Have Received No Antiretroviral Therapy 
During Pregnancy or Intrapartum
    Recommendation: The 6 week neonatal ZDV component of the ZDV 
chemoprophylactic regimen should be discussed with the mother and 
offered for the newborn; ZDV should be initiated as soon as possible 
after birth, preferably within 12-24 hours after birth. Some clinicians 
may choose to use ZDV in combination with other antiretroviral drugs, 
particularly if the mother has known or suspected ZDV-resistant virus. 
However, the efficacy of this approach is unknown and appropriate 
dosing regimens for neonates are incompletely defined. In the immediate 
postpartum period, the woman should undergo appropriate assessments 
(e.g., CD4 count, HIV-1 RNA copy number) to determine if antiretroviral 
therapy is required for her own health.
    Discussion: Definitive data are not available to address whether 
ZDV administered solely during the neonatal period would reduce the 
risk of perinatal transmission. However, data from a case-control study 
of post-exposure prophylaxis of health care workers who had nosocomial 
percutaneous exposure to blood from HIV-1-infected individuals indicate 
that ZDV administration was associated with a 79% reduction in the risk 
for HIV-1 seroconversion following exposure. (CDC 1995) Post-exposure 
prophylaxis has also been shown to prevent retroviral infection in some 
animal studies. (Van Rompay 1995, Tsai 1995, Bottiger 1997)
    The interval for which benefit may be gained from post-exposure 
prophylaxis is undefined, but data from animal studies indicate that 
the longer the delay in institution of prophylaxis, the less likely 
prevention will be observed. In most animal studies, antiretroviral 
prophylaxis initiated after 24-36 hours is usually not effective for 
preventing infection, although later administration has been associated 
with decreased viremia in ultimately infected animals in some cases. 
(VanRompay 1995, Bottiger 1997, Tsai 1995) In the feline leukemia virus 
cat model, ZDV treatment initiated within the first 4 days after viral 
challenge afforded protection, while treatment initiated one week 
postexposure did not prevent infection. (Mathes 1992) The relevance of 
the animal studies to prevention of perinatal transmission in humans is 
unknown. HIV-1 infection is established in the majority of infected 
infants by 1 to 2 weeks of age. In a study of 271 infected infants, 
HIV-1 DNA polymerase chain reaction (PCR) was positive in 38% of 
infected infants tested within 48 hours of birth. No major change in 
diagnostic sensitivity was observed over the first week of life, but 
detection rose rapidly during the second week of life, reaching 93% by 
14 days of age. (Dunn 1995) Therefore, it would be unlikely that 
initiation of post-exposure prophylaxis after 14 days of age would have 
efficacy in preventing transmission, as infection would already be 
established in most children.
    Recommendations have been made for antiretroviral post-exposure 
prophylaxis of nosocomial HIV-1 exposure. It was recommended that ZDV 
be administered as soon after exposure as possible, and the addition of 
3TC was recommended in most cases to provide increased antiretroviral 
activity and presumed activity against ZDV-resistant HIV-1 strains. 
(CDC 1996) The addition of a protease inhibitor was recommended for 
particularly high-risk exposures. There are no data to address whether 
the addition of other antiretroviral drugs to ZDV increase the 
effectiveness of post-exposure prophylaxis. However, some clinicians 
may wish to provide ZDV in combination with one or more other 
antiretroviral agents in situations in which only post-exposure newborn 
prophylaxis is administered. Such a decision must be accompanied by a 
discussion with the woman of potential benefits and risks of this 
approach.

Recommendations for Monitoring of Women and Their Infants

Pregnant Woman and Fetus

    HIV-1-infected pregnant women should be monitored in the same 
fashion that nonpregnant individuals are monitored. This should include 
measurement of CD4 lymphocyte count and HIV-1 RNA levels approximately 
every trimester (every 3 to 4 months) to determine need for 
antiretroviral therapy of maternal HIV-1 disease or alterations in such 
therapy, and/or initiation of prophylaxis against Pneumocystis carinii 
pneumonia. Some studies have found that changes in absolute CD4 count 
during pregnancy may reflect the physiologic changes of pregnancy on 
hemodynamic parameters and blood volume as opposed to a longterm 
influence of pregnancy upon CD4 count; CD4 percent appears to be more 
stable and may be a more accurate reflection of immune status during 
pregnancy. (Miotti 1992, Tuomala 1997)

[[Page 36819]]

Long-range plans should be developed with the woman regarding 
continuity of medical care and antiretroviral therapy for her own 
health after she delivers her infant.
    Monitoring for potential complications of antiretroviral 
administration during pregnancy should take into account what is known 
about the side effects of the drugs the woman is receiving. For 
example, routine hematologic and liver chemistry monitoring is 
recommended for women receiving ZDV. Because there is less experience 
with use of combination antiretroviral regimens during pregnancy, more 
intensive monitoring may be warranted for women receiving drugs other 
than or in addition to ZDV.
    Antepartum fetal monitoring for women who receive only ZDV 
chemoprophylaxis should be performed as clinically indicated, as the 
available data do not indicate that ZDV use in pregnancy is associated 
with increased risk for fetal complications. However, much less is 
known about the effect of combination antiretroviral therapy during 
pregnancy on the fetus. More intensive monitoring should be considered, 
including assessment of fetal anatomy with a level II ultrasound and 
continued assessment of fetal growth and well-being during the third 
trimester.

Neonate

    A complete blood count and differential should be performed as a 
baseline evaluation prior to administration of ZDV. Anemia has been the 
primary complication of the 6 week ZDV regimen in the neonate, thus at 
a minimum, repeat measurement of hemoglobin is required at the 
completion of the 6 week ZDV regimen; repeat measurement may be 
performed at 12 weeks of age, by which any ZDV-related hematologic 
toxicity should be resolved. Infants who have anemia at birth or who 
are premature warrant more intensive monitoring.
    There is little experience with potential toxicities in infants 
whose mothers have received combination antiretroviral therapy. More 
intensive monitoring of hematologic and chemistry measurements during 
the first few weeks of life would be advised in these infants.
    All infants born to HIV-1-infected women should be placed on 
prophylaxis to prevent Pneumocystis carinii pneumonia at 6 weeks of 
age, following completion of the ZDV prophylaxis regimen. (CDC 1995) 
Monitoring and diagnostic evaluation of HIV-1-exposed infants should 
follow current standards of care. The available data do not indicate 
any delay in HIV-1 diagnosis in infants who have received the ZDV 
regimen. (Connor 1994, Kovacs 1995) However, the effect of combination 
antiretroviral therapy in the mother and/or newborn on the sensitivity 
of infant virologic diagnostic testing is unknown. Infants with 
negative virologic tests during the first 6 weeks of life should have 
diagnostic evaluation repeated after completion of the neonatal 
antiretroviral prophylaxis regimen.

Postpartum Follow-Up of Women

    Comprehensive care and support services are required for women 
infected with HIV-1 and their families. Components of comprehensive 
care include the full range of medical care services including family 
planning and drug treatment; coordination of care for the woman, her 
children and other family members; support services such as case 
management and childcare; assistance with basic life needs such as 
housing, food, and transportation; and legal and advocacy services. 
This care should begin prior to pregnancy, with continuity of care 
ensured throughout pregnancy and postpartum.
    Maternal medical services during the postpartum period must be 
coordinated between obstetric and HIV-specialist health care providers. 
Continuity of antiretroviral treatment when therapy is required for 
treatment of the woman's HIV infection is especially critical and must 
be assured. All women should have linkage with comprehensive health 
care services for her own medical care and for assistance with family 
planning and contraception.
    Data from PACTG Protocols 076 and 288 do not indicate adverse 
effects through 18 months postpartum among women who received ZDV 
during pregnancy; however, continued clinical, immunologic and 
virologic follow-up of these women is ongoing. Women who have received 
only ZDV chemoprophylaxis during pregnancy should receive appropriate 
evaluation to determine the need for antiretroviral therapy in the 
postpartum period.

Long-Term Follow-Up of Infants

    Data remain insufficient to address the effect that exposure to ZDV 
or other antiretroviral agents in utero might have on long-term risk 
for neoplasia or organ system toxicities in children. Data from follow-
up of PACTG 076 infants through 18 to 36 months of age do not indicate 
any differences in immunologic, neurologic and growth parameters 
between infants who were exposed to the ZDV regimen compared to 
placebo; continued intensive follow-up through PACTG 219 is ongoing. 
PACTG 219 will also provide intensive follow-up for infants born to 
women who receive other antiretroviral drugs as part of PACTG perinatal 
protocols, so some data regarding follow-up of exposure to other 
antiretroviral agents alone or in combination will be available in the 
future.
    Innovative methods are needed to provide follow-up to infants with 
in utero exposure to ZDV or any other antiretrovirals outside of PACTG 
protocols. Information regarding such exposure should be part of the 
ongoing medical record of the child, particularly for uninfected 
children. Follow-up of children with antiretroviral exposure should 
continue into adulthood because of the theoretical concerns regarding 
potential for carcinogenicity of the nucleoside analogue antiretroviral 
drugs. Long-term follow-up should include at least yearly physical 
examination of all antiretroviral-exposed children, and for older 
adolescent females, gynecologic evaluation with pap smears.
    On a population basis, HIV-1 surveillance databases from states 
that require HIV-1 reporting provide an opportunity to collect 
information on in utero antiretroviral exposure. To the extent 
permitted by federal law and regulations, these confidential registries 
can be used to compare to birth defect and cancer registries to look 
for potential adverse outcomes.

Future Research Needs

    An increasing number of HIV-1-infected women will be receiving 
antiretroviral therapy for their own health during pregnancy. 
Preclinical evaluations of antiretroviral drugs for potential 
pregnancy- and fetal-related toxicities should be completed for all 
current and new antiretroviral drugs. More data are needed regarding 
the safety and pharmacokinetics of antiretroviral drugs during 
pregnancy and in the neonate, particularly when used in combination 
regimens. Results from a number of phase I studies will be available in 
the next year which will assist in delineating appropriate dosing and 
provide data on short-term safety of these drugs in pregnant women and 
infants. However, the long-term consequences of in utero antiretroviral 
exposure for the infant is unknown, and mechanisms must be developed to 
gather information about the long-term outcome for exposed infants. 
Innovative methods are needed to enable identification and follow-up of 
populations of children with in utero antiretroviral exposure.

[[Page 36820]]

    Additional studies are needed to determine the long-term 
consequences of transient use of ZDV chemoprophylaxis during pregnancy 
for women who do not desire to receive combination therapy antenatally, 
including the risk for development of ZDV-resistance.
    While there are theoretical reasons to believe that more potent 
antiretroviral combination regimens that dramatically diminish viral 
load may also prevent perinatal transmission, there are currently no 
data to address this hypothesis. The efficacy of combination 
antiretroviral therapy specifically to decrease the risk of perinatal 
HIV-1 transmission needs to be evaluated in ongoing and future 
perinatal clinical trials. Additionally, epidemiologic studies and 
clinical trials are needed to delineate the relative efficacy of the 
various components of the 3-part ZDV chemoprophylactic regimen. 
Improved understanding of the factors associated with perinatal 
transmission despite ZDV chemoprophylaxis is needed in order to develop 
alternative effective regimens. Because of the dramatic decline in 
perinatal HIV-1 transmission with widespread implementation of ZDV 
chemoprophylaxis, the conduct of such epidemiologic studies and 
clinical trials requires an international collaborative effort.
    Additionally, regimens that are more feasible for implementation in 
the developing world are urgently needed. The 3-part ZDV 
chemoprophylactic regimen is complex and may not be a feasible option 
for many developing countries: most pregnant women show up in health 
care systems only around the time of delivery; widespread safe 
administration of intravenous ZDV infusions during labor may not be 
possible; and the cost of the regimen may be prohibitive and many times 
greater than the per capita health expenditures for the country. There 
are several ongoing studies in developing countries that are evaluating 
the efficacy of more practical, abbreviated modifications of the ZDV 
regimen. Additionally, a number of non-antiretroviral interventions are 
also under study. Results of these studies will be available in the 
next few years.

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[[Page 36822]]

Tuomala RE, Kalish LA, Zorilla C, et al. A longitudinal study of 
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    Dated: June 26, 1997.
John M. Eisenberg,
Principal Deputy Assistant Secretary for Health, U.S. Department of 
Health and Human Services.

                                         Table 1.--PACTG 076 ZDV Regimen                                        
----------------------------------------------------------------------------------------------------------------
                                                                                                                
----------------------------------------------------------------------------------------------------------------
Antepartum..........................................  Oral administration of 100 mg ZDV five times daily,       
                                                       initiated at 14-34 weeks gestation and continued         
                                                       throughout the pregnancy.                                
Intrapartum.........................................  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.                                 
Postpartum..........................................  Oral administration of ZDV to the newborn (ZDV syrup at 2 
                                                       mg per kg body weight per dose every 6 hours) for the    
                                                       first 6 weeks of life, beginning at 8-12 hours after     
                                                       birth (Note: intravenous dosage for infants who cannot   
                                                       tolerate oral intake is 1.5 mg per kg body weight        
                                                       intravenously every 6 hours).                            
----------------------------------------------------------------------------------------------------------------


                                 Table 2.--Preclinical and Clinical Data Relevant to Use of Antiretrovirals in Pregnancy                                
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                  Long-term animal      
          Antiretroviral drug               FDA pregnancy category*      Placental passage [newborn: maternal drug ratio]     carcinogenicity  studies  
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nucleoside Analogue Reverse                                                                                                                             
 Transcriptase Inhibitors:                                                                                                                              
    Zidovudine (ZDV)..................  C                               Yes (human) [0.85]...............................  Positive (rodent, noninvasive
                                                                                                                            vaginal epithelial tumors). 
    Zalcitabine (ddC).................  C                               Yes (rhesus) [0.30-0.50].........................  Positive (rodent, thymic     
                                                                                                                            lymphomas).                 
    Didanosine (ddI)..................  B                               Yes (human) [0.5]................................  Negative (no tumors, lifetime
                                                                                                                            rodent study).              
    Stavudine (d4T)...................  C                               Yes (rhesus) [0.76]..............................  Not completed.               
    Lamivudine (3TC)..................  C                               Yes (human) [1.0]................................  Negative (no tumors, lifetime
                                                                                                                            rodent study).              
Non-Nucleoside Reverse Transcriptase                                                                                                                    
 Inhibitors:                                                                                                                                            
    Nevirapine........................  C                               Yes (human) [1.0]................................  Not completed.               
    Delavirdine.......................  C                               Unknown..........................................  Not completed.               
Protease Inhibitors:                                                                                                                                    
    Indinavir.........................  C                               Yes (rats) ``Significant'' in rats, but low in     Not completed.               
                                                                         rabbits.                                                                       
    Ritonavir.........................  B                               Yes (rats) [mid-term fetus, 1.15; late-term        Not completed.               
                                                                         fetus, 0.15-0.64].                                                             
    Saquinavir........................  B                               Unknown..........................................  Not completed.               
    Nelfinavir........................  B                               Unknown..........................................  Not completed.               
--------------------------------------------------------------------------------------------------------------------------------------------------------
* FDA Pregnancy Categories are:                                                                                                                         
  A--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 risk during later trimesters);                                                                                                      
  B--Animal reproduction studies fail to demonstrate a risk to the fetus and adequate but well-controlled studies of pregnant women have not been       
  conducted;                                                                                                                                            
  C--Safety in human pregnancy 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--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;                                                                  
  X--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.                                                                                                                       


  Table 3.--Summary: Clinical Situations and Recommendations for Use of 
        Antiretroviral Drugs To Reduce Perinatal HIV Transmission       
------------------------------------------------------------------------
      Clinical scenario                     Recommendation*             
------------------------------------------------------------------------
Scenario #1: HIV-infected      HIV-1 infected pregnant women must       
 pregnant women without prior   receive standard clinical, immunologic  
 antiretroviral therapy.        and virologic evaluation, and           
                                recommendations for initiation and      
                                choice of antiretroviral therapy should 
                                be based on the same parameters used in 
                                non-pregnant individuals, with          
                                consideration and discussion of the     
                                known and unknown risks and benefits of 
                                such therapy during pregnancy.          
                               The 3-part ZDV chemoprophylaxis regimen  
                                should be recommended for all HIV-      
                                infected pregnant women to reduce the   
                                risk of perinatal transmission.         
                               If the woman's clinical, immunologic and 
                                virologic status indicates that more    
                                aggressive therapy is recommended to    
                                treat her infection (Panelrec, 1997),   
                                other antiretroviral drugs should be    
                                recommended in addition to ZDV.         

[[Page 36823]]

                                                                        
                               If the woman's status is such that       
                                therapy would be considered optional,   
                                the use of additional antiretrovirals   
                                may be offered, although whether this   
                                will provide additional benefit to the  
                                woman or her child is not known.        
                               Women who are in the first trimester of  
                                pregnancy may wish to consider delaying 
                                initiation of therapy at least until    
                                after 10 to 12 weeks gestation.         
Scenario #2: HIV-infected      HIV-1 infected women receiving           
 women receiving                antiretroviral therapy in whom pregnancy
 antiretroviral therapy         is identified after the first trimester 
 during the current pregnancy.  should continue therapy.                
                               For women receiving antiretroviral       
                                therapy in whom pregnancy is recognized 
                                during the first trimester, the woman   
                                should be counseled regarding the       
                                benefits and potential risks of         
                                antiretroviral administration during    
                                this period, and continuation of therapy
                                should be considered.                   
                               If therapy is discontinued during the    
                                first trimester, all drugs should be    
                                stopped and reintroduced simultaneously 
                                to avoid the development of resistance. 
                               If the current therapeutic regimen does  
                                not contain ZDV, the addition of ZDV or 
                                substitution of ZDV for another         
                                nucleoside analogue antiretroviral is   
                                recommended after 14 weeks gestation.   
                                Intrapartum and newborn ZDV             
                                administration is recommended regardless
                                of the antepartum antiretroviral        
                                regimen.                                
Scenario #3: HIV-infected      Administration of intrapartum intravenous
 women in labor who have had    ZDV should be recommended along with the
 no prior therapy.              6-week newborn ZDV regimen.             
                               In the immediate postpartum period, the  
                                woman should have appropriate           
                                assessments (e.g., CD4 count, HIV-1 RNA 
                                copy number) to determine if            
                                antiretroviral therapy is recommended   
                                for her own health.                     
Scenario #4: Infants born to   The 6 week neonatal ZDV component of the 
 mothers who have received no   ZDV chemoprophylactic regimen should be 
 antiretroviral therapy         discussed with the mother and offered   
 during pregnancy or            for the newborn.                        
 intrapartum.                                                           
                               ZDV should be initiated as soon as       
                                possible after birth, preferably within 
                                12-24 hours after birth.                
                               Some clinicians may choose to use ZDV in 
                                combination with other antiretroviral   
                                drugs, particularly if the mother has   
                                known or suspected ZDV-resistant virus. 
                                However, the efficacy of this approach  
                                is unknown and appropriate dosing       
                                regimen for neonates are incompletely   
                                defined.                                
                               In the immediate postpartum period, the  
                                woman should undergo appropriate        
                                assessments (e.g., CD4 count, HIV-1 RNA 
                                copy number) to determine if            
                                antiretroviral therapy is required for  
                                her own health.                         
------------------------------------------------------------------------
* General note: Discussion of treatment options and recommendations     
  should be noncoercive, and the final decision regarding the use of    
  antiretroviral drugs is the responsibility of the woman. A decision to
  not accept treatment with ZDV or other drugs should not result in     
  punitive action or denial of care, nor should use of ZDV be denied to 
  a woman who wishes to minimize exposure of the fetus to other         
  antiretroviral drugs and therefore chooses to receive only ZDV during 
  pregnancy to reduce the risk of perinatal transmission.               

[FR Doc. 97-17854 Filed 7-8-97; 8:45 am]
BILLING CODE 4140-01-P