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Treating the HIV-Infected Pregnant Woman and Her Child

The past year has been a watershed time for the management of HIV infection in children and pregnant women as well as in nonpregnant adults. This review will cover recent developments in the area of perinatal and pediatric HIV infection and the impact of treatment recommendations for HIV-infected adults on the management of HIV-infected pregnant women and children.

Prevention of Perinatal Infection: ACTG 076 and the 1994 USPHS Guidelines

The success of AZT treatment in interrupting mother-to-infant HIV transmission, as first demonstrated by the clinical trial ACTG 076, has now been confirmed for pregnant women with CD4 cell counts lower than 200 and for those who have had previous AZT exposure. In fact, a recent ACTG study to determine the safety and efficacy of adding HIV immune globulin to the standard AZT prophylaxis had to be stopped prematurely because the transmission rate in the two treatment arms (the control arm was AZT plus nonspecific immune serum globulin) was 4.8%, making it highly unlikely that the study could demonstrate a significant difference between these strategies.

Findings in nonpregnant adults that support the efficacy of AZT administered three rather than five times per day have led to this dosing schedule in pregnancy, based on the belief that what may possibly be lost in the potency of the regimen will be gained in overall compliance. Revisions to the official USPHS recommendations are currently under review and will address these issues as well as the issue of other antiretroviral treatment of HIV-infected women who are pregnant. Attempts to determine which of the three parts of AZT prophylaxis -- prenatal, perinatal, neonatal -- are effective have suggested that all three may be helpful; thus, there is now general support for starting the protocol when a woman presents for care any time beyond 14 weeks gestation or in neonates of HIV-infected women up to 1 week after birth.

The Evolving Treatment of HIV-Infected Pregnant Women

Experts emphasize that pregnant women should receive optimal antiretroviral treatment for their own disease, as well as optimal prophylaxis to prevent perinatal transmission. Considering currently published treatment guidelines, this means that the majority of pregnant women with HIV now meet contemporary guidelines for treatment.

However, the aggressive combination therapies that are increasingly being employed introduce formidable complexity to the management of the HIV-infected woman. First, there is virtually no information on the safety or efficacy of most antiretrovirals during pregnancy. Second, although AZT may not be an ideal component of a given woman's treatment, because of the possibility of resistance, most experts still strongly recommend including it in pregnancy regimens, since no other drug has been shown to prevent perinatal transmission.

Investigation of Combination Regimens in the Pregnant Woman and the Neonate

While combination therapy with protease inhibitors is a far more potent antiretroviral regimen than is AZT monotherapy, it is not necessarily more effective in preventing mother-to-infant HIV transmission. The potency of combination therapy regimens is strongly associated with the ability of protease inhibitors to reduce plasma HIV RNA levels to undetectable levels. However, only about one third the reduction of vertical transmission with the AZT regimen can be explained by a reduction in viral load. Since the majority of the effect is due to mechanisms not as yet ascertained, it cannot be predicted whether other drugs share that same mechanism. Other factors relevant to the potential capacity of a drug to prevent maternal-infant HIV transmission are the extent to which it crosses the placenta; its pharmacokinetics in pregnant women, the placenta, and the fetus; and whether or not its mechanism of action successfully prevents infection in the infant. For example, if AZT acts in part by blocking infection of fetal or newborn cells, protease inhibitors may not provide a similar protective effect because their mechanism of action requires the presence of replicating virus.

Although women and their infants are already receiving the full spectrum of antiretroviral drugs in routine practice, phase 1 studies of prototypic triple-therapy protocols in pregnancy are only about to begin. These studies will provide information about dosing in pregnancy and in the neonate and preliminary safety and tolerance data. However, since these studies involve only 12 patients each, results will mainly provide information about pharmacokinetics, and little about safety and efficacy. Until more extensive investigations into safety and efficacy can be conducted, physicians are encouraged to register these patients prospectively so that the outcome of pregnancy and the medical history of their children can be followed. No personal identifiers of the patients are required, and follow-up information is obtained through the registering physician. (The Antiretroviral Pregnancy Registry collects prospective data on HIV-infected pregnant women exposed to antiretroviral agents. Health care providers are encouraged to enroll patients by contacting the Antiretroviral Pregnancy Registry, PO Box 13398, Research Triangle Park, NC 27709. Telephone 800-722-9292, ext. 39437; fax 919-315-8747.)

By their very nature, questions about the toxicity of intrauterine drug exposure are difficult to answer. While clinical experience with thousands of pregnant women receiving AZT in pregnancy has not revealed any fetal toxicity other than a transient anemia, animal studies have raised the possibility of carcinogenesis following intrauterine exposure to the drug. One study, from the National Cancer Institute (NCI), exposed pregnant mice to near-toxic doses of AZT. This resulted in an excess of lung, liver, and reproductive tract malignancies in the exposed offspring. Another study, reported by Glaxo Laboratories, used doses that resulted in serum levels about three times that attained in human treatment protocols, and about 20% those of the NCI study. There was no excess carcinogenesis except in an arm of the study in which offspring were maintained on lifetime exposure to drug. In that arm, as in previously reported studies, there was an excess of urethral malignancies in offspring. However, an expert panel concluded that these studies raised theoretical concerns that at this time seem to be outweighed by the actual benefits of AZT given in pregnancy to reduce transmission. It will take many years to determine the relevance of these animal studies to human health.

Treatment of HIV-Infected Neonates, Infants, and Children

An increasing number of infants who are born to HIV-infected women will be exposed to a variety of antiretroviral agents. The safety, pharmacokinetics, and efficacy of these agents in the neonatal period and infancy are unknown. Some experts favor the use of drugs in addition to AZT, depending on the treatment history of the mother and the likelihood that her virus is AZT resistant. Ongoing studies should provide data on appropriate neonate dosing and pharmacokinetics within the year.

It is clear that combination antiretroviral therapy provides distinct laboratory and clinical advantages for children as well as for adults. Studies and clinical experience show that plasma HIV RNA levels can be brought to undetectable levels in infants and children with combination regimens. Phase 2 studies are underway to evaluate such regimens in children, but data are not expected for more than a year. In the absence of these data, the following observations may be relevant

• Natural history of HIV RNA levels in infants and children: Infants have much higher levels of HIV RNA at the time of primary infection than adults. One study reported peak levels of 256,000 at 1 and 2 months, which declined to 34,000 by 24 months. In comparison, adults with primary infection generally reach a plateau by 6 months. This difference between infant and adult possibly reflects the immature host defense mechanisms of the former.
  
• Prognostic meaning of baseline HIV RNA level in infants and children: Peak HIV RNA levels in infants at 1 to 2 months of life are higher in rapid progressors (defined as progression to AIDS or HIV-related death by 18 months of age) than in nonrapid progressors. In one study, 44% of infants with a peak level over 229,000 copies/ml in the first 2 months of life were rapid progressors, while only 15% below that level progressed rapidly (P = 0.008).
  

In another study of 254 children from one month to over nine years of age, the HIV RNA level at baseline predicted AIDS-related death over a mean follow-up of more than five years. Moreover, both % CD4 and HIV RNA copy number independently contributed to the likelihood of death, as has been reported in adults. Thus, while quantitative aspects of these measurements may be different in children and adults, the same qualitative relationships pertain.

• Availability of liquid preparations: One of the problems limiting evaluation of antiretroviral drugs in infants is the unavailability of protease inhibitors in liquid formulations that have good bioavailability. While all the available nucleoside reverse transcriptase inhibitors (NRTIs) are available in liquid form, among the protease inhibitors only ritonavir and nelfinavir are available in liquid form. Among the nonnucleoside reverse transcriptase inhibitors, nevirapine's liquid formulation is available for investigational and limited compassionate use only, and delavirdine is not available in liquid form at all.
  

Available pharmacokinetics, toxicity, and efficacy of specific antiretroviral agents in infants and children are summarized in Table 1.

Recently a group of HIV specialists, community representatives, and parents produced a consensus statement on the treatment of HIV-infected infants and children, which appeared in the Federal Register October 30, 1997. Based on the information currently available, the group agreed upon the following indications for treatment:

• All HIV-infected infants under 12 months of age regardless of immune or clinical status, as soon as diagnosis is confirmed
  
• All children over a year of age with clinical symptoms of HIV infection (CDC category A, B, or C), or evidence of immune suppression as measured by CD4 cell counts (absolute count varies but % CD4 stays constant with age)
  

In the case of asymptomatic children over a year of age, some felt that all should be treated, while others suggested waiting until the CD4 cell count falls or the HIV RNA copy number reaches certain threshold levels: certainly by 100,000, possibly by 15,000 to 20,000 in children over 30 months of age.

The majority of the group preferred to initiate therapy in infants over three months of age with a protease inhibitor (limited to those with well-tolerated liquid preparations) combined with two NRTIs (with preference for AZT and ddI or 3TC, because of more available information about these than about combinations that include D4t or ddC). Alternatives included nevirapine in combination with two NRTIs, as well as simply two NRTIs. Nevirapine is approved for use in infants, but the liquid preparation is only available through a limited compassionate use program from Boeringer-Ingelheim. The pharmacokinetics, safety, and efficacy of most of the treatment protocols for infants containing protease inhibitors or nevirapine are currently under study. Since none of them involve a placebo arm, it will be difficult to assess their efficacy except against historic controls and alternative treatment protocols.

When to Modify a Treatment Regimen

Certain principles guiding treatment modification for adults seem to make sense for infants and children also. Clinical or laboratory markers indicating the need for change include the following

• A poor initial virologic response, for the moment defined as less than a 1 log drop in RNA for triple therapy containing at least one protease inhibitor, or a less than fivefold drop with combination therapy including two NRTIs; possibly if virologic suppression is not down to undetectable range by four to six months despite compliance with drug regimen and no evidence for drug interactions that could have altered levels of protease inhibitors
  
• Sustained increase in HIV RNA copy number after issues of adherence and bioavailability are reviewed
  
• Evidence of clinical disease progression, neurodevelopmental deterioration, or growth failure
  
• Toxicity
  

When treatment must be changed, consider these guidelines

• Review adherence issues with the patient's caretaker or parent.
  
• Review all drugs the patient is receiving, to determine whether adverse drug interactions are responsible for apparent treatment failure.
  
• If change is necessitated by one of the first three indications in the preceding list, introduce at least two drugs that are new to the patient.
  
• If change is necessitated by toxicity, try to choose agents bearing different toxicity profiles from those the patient is currently taking.
  

The details of interactions and specific choices for change in therapy are for the moment analogous to those in adults.

Summary

The field of perinatal and pediatric treatment is replete with uncertainties and undergoing continuous evolution. Currently, health care providers who do not specialize in HIV management are well advised to consult experts in the treatment of perinatal and pediatric HIV before making therapeutic decisions in the HIV-infected pregnant woman or her child.

— Jane Pitt, MD, and Deborah Cotton, MD, MPH

Dr. Pitt is an ACC Associate Editor. Dr. Cotton is editor of ACC.

Published in Journal Watch HIV/AIDS Clinical Care December 1, 1997

Citation(s):

Centers for Disease Control. Public Health Service Task Force on use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1994 43 RR-11 1-21.

Cooper ER et al. After AIDS Clinical Trial 076: the changing pattern of zidovudine use during pregnancy, and the subsequent reduction in vertical transmission of human immunodeficiency virus in a cohort of infected women and their infants. J Infect Dis 1996 174 1207-1211.

• Medline abstract (Free)

Fiscus SA et al. Perinatal HIV infection and the effect of zidovudine therapy on transmission in rural and urban counties. JAMA 1996 275 1483-1488.

• Medline abstract (Free)

Mofenson LM et al. The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1 infected children. J Infect Dis 1997 175 1029-1038.

• Medline abstract (Free)

Shearer WT et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. N Engl J Med 1997 336 1337-1342.

• Original article (Subscription may be required)
• Medline abstract (Free)

Simpson BJ et al. Reduction in the risk of vertical transmission of HIV-1 associated with treatment of pregnant women with orally administered zidovudine alone. J Acquir Immune Defic Syndr Hum Retrovirol 1997 14 145-152.

• Medline abstract (Free)

U.S. Public Health Service recommendations for the use of antiretroviral agents in pediatric HIV infection. Federal Register 1997 Oct 30 .

131. 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 Federal Register 1997 Jul 3 62.