Rapid Advances in Preventing Vertical Transmission

Lab tests should assess the possibility of infection, anemia (especially for women who are taking AZT) and thrombocytopenia (low platelets). Screening tests for sexually transmitted diseases (STDs) should be done at the beginning of the pregnancy and if symptoms develop. Women who test positive for STDs should be monitored to insure the treatment has been successful. Urinary tract infections can be troublesome in pregnancy and may be a possible cause of premature births. Urine cultures and urinalysis should be performed whenever symptoms occur.

If a woman requires PCP prophylaxis for her own health, it is advisable for her to continue treatment if she becomes pregnant. The use of TMP/SMX (Bactrim or Septra) may cause an elevation in the serum bilirubin level and jaundice in the newborn. This can lead to a more serious condition called kernicterus. Despite this risk, large studies have not demonstrated any adverse effects on the newborns (H. Minkoff. JAMA. November 20, 1987; 258(19):2714-17). As there have been various congenital malformations reported with the use of TMP/SMX in some animal models (R. Sperling et al. "Treatment Options for HIV-infected Pregnant Women," OB/GYN Working Group of the ACTG and NIAID, 1992), some clinicians prescribe dapsone in the first trimester. However, dapsone is less effective than TMP/SMX for PCP prophylaxis. In either case, the mother's need for PCP prophylaxis outweighs potential risks to the fetus.

Treatment and screening for opportunistic infections (OIs) is recommended. There are some OIs, such as toxoplasmosis, herpes and CMV, that can be transmitted to the fetus, causing serious repercussions. Maternal weight should be closely observed as losses of greater than 10% may indicate HIV wasting. Surveillance of the fetus is also important and can be done safely through external fetal monitoring (fetal nonstress tests) and serial ultrasound tests (S. MacGregor. Clinics in Perinatology. March 1991; 18(1):33-51). -JC

Concerns about AZT

AZT is positive for carcinogenic risk when screened in the test tube. Benign vaginal tumors develop when high doses are given to mice. However, there is a difference in the manner in which AZT is broken down in humans and mice. In humans, AZT is metabolized in the liver and is excreted in an inactive state in the urine. In mice, AZT is not metabolized and is excreted in high concentrations in the urine, which refluxes into the vagina. Dr. Mofenson stated that the development of tumors in mice might be due to a topical effect of AZT on the vaginal mucosa.

Additionally, two studies have looked at the risk of transplacental carcinogenicity. A National Cancer Institute (NCI) study showed an increased rate of tumors in offspring of mice given very large quantities of AZT, just below the maximum tolerable dose. Although the mouse doses were 25 to 50 times greater than daily doses given to humans, the cumulative dose received was similar to the cumulative dose received by a pregnant woman after six months of AZT use. A Glaxo-Wellcome study demonstrated no increase in tumors in offspring of mice receiving doses whose range was more in line with the human dose, one-twelfth to one-fiftieth of the NCI dose.

Attempts to extrapolate results of mice studies to humans have been difficult. An NIH panel convened to evaluate the studies voted unanimously that the benefits of AZT use outweigh the risks. The panel also concluded that information regarding the carcinogenic risk should be discussed with all HIV-positive pregnant women during treatment counseling (see Treatment Issues, January 1997).

Dr. Mofenson stated that examination of children from ACTG 076, ACTG 219 (long-term follow-up trial for children with previous enrollment in any ACTG trial) and ACTG 185 has not indicated any evidence of tumors in children followed to three years of age.

Celine Hanson, M.D., of Baylor College of Medicine in Texas, presented information at the National Conference on Women and HIV regarding the lack of tumors in 734 infants from ACTG 076, ACTG 219 and WITS (Abstract 304.3). Dr. Hanson analyzed infants with fetal or neonatal exposure to AZT. Median follow up was 37.8 months in infants from ACTG 076/219 and 11.4 months in infants from WITS. No tumors of any nature were reported in any of the children. Limitations of this study included the fact that surveillance of tumors was passive (no diagnostic tests were performed unless there was a clinical indication that a tumor was present). Since the follow-up period was relatively short, six years at the longest, it is possible that tumors could appear in AZT-exposed children during adolescence or adulthood (regardless of whether child is HIV-positive or not). No increase in congenital abnormalities compared to the general population was seen in 076 or in the Antiretroviral Pregnancy Registry.

Neurodevelopment tests have determined no difference in infants exposed to AZT versus placebo. CD4 counts at 6, 12 and 18 months and growth, including weight, height and head circumference, have also shown no difference between the groups.

Many activists have expressed concern over the possible development of drug resistance in women who receive AZT monotherapy during pregnancy. Resistance can develop in some individuals in as little as six months on AZT monotherapy. According to the new Public Health Service treatment guidelines for HIV-infected (nonpregnant) adults, asymptomatic individuals with CD4 cell counts above 500 and viral load (by PCR) below 20,000 would have the option of delaying treatment. However, pregnant women in this category will be offered AZT monotherapy to begin as early as 14 weeks and to continue for an additional five to six months until the birth of the child. Development of AZT resistance during a pregnancy would have permanent ramifications on future treatment choices for the mother, and AZT might fail to protect the fetus from emerging AZT-resistant maternal virus.

In a study presented in January 1997 by Dr. Scott Eastman of Chiron Corporation at the Fourth Conference on Retroviruses and Opportunistic Infections, participants from ACTG 076 were evaluated to determine the prevalence of genotypic AZT resistance at entry and at delivery (abstract 516). AZT resistance was not found to be overwhelming. One of seven evaluable AZT-treated transmitters had evidence of AZT resistance. This woman had AZT-resistant virus at entry despite being AZT-naive. One participant developed resistant virus during the pregnancy but did not transmit HIV to her baby. AZT resistance did not account for the majority of infants that became infected in 076. Data from ACTG 185 indicated that duration of AZT use in women with more advanced disease, many of whom received prolonged AZT prior to pregnancy, was not associated with increased risk of transmission.

Other Combinations

A pregnant woman on combination therapy will have to decide whether to continue using her medication during the first trimester. Stopping treatment is a hard choice and may depend on the woman's disease stage. If she is on highly active antiviral therapy (HAART) because of a high viral load, then terminating her medication risks a rapid return of her infection to its pretreatment state, along with the further development of drug-resistant HIV. Each woman must weigh her own health concerns, the possible effects of drugs on the fetus and the risk of vertical transmission infection. Since there is not much data on the use of antivirals in pregnancy, this is a difficult decision.

The only drugs that have had pharmacokinetic studies in pregnancy are AZT, 3TC and nevirapine. Each of these is well tolerated by pregnant women, crosses the placenta and achieves neonatal blood concentrations equivalent to those in the mother. Most of the other approved antivirals are either being studied now or have studies planned.

Of the non-nucleoside reverse transcriptase inhibitors (NNRTIs), only nevirapine has been investigated during pregnancy and labor. It appears to be safe although drug levels in newborns are prolonged for a week because of immature liver function (a possibly helpful effect). The mutagenic and carcinogenic potential appears less than in nucleoside analogs, according to Dr. Mofenson, although the studies are not completed. Both nevirapine and delavirdine pose potential risk to the fetus. Delavirdine has been shown to be teratogenic (i.e., interfere with proper fetal development) when administered to rodents in high doses. NNRTIs' ability to prevent vertical transmission is as yet undetermined.

There is very little known regarding the protease inhibitors. Studies in test tubes looking for carcinogenesis and mutagenesis appear to be negative, although none of the drugs have been studied in animals or humans. Their ability to reduce vertical transmission is unknown.

Current Clinical Trials: Issues and Overview

Dr. Mofenson stated that an international panel was convened in June of 1994 by the World Health Organization (WHO) in Geneva shortly after ACTG 076 ended. The panel recommended that all industrialized countries implement the 076 protocol where feasible. The panel also advised that placebo-controlled trials were necessary to rapidly provide alternative methods adoptable in countries where the current protocol was unworkable due to the cost and availability of AZT. The WHO panel explained this conclusion by stating, "the choice of a placebo for the control group would be appropriate as there is currently no effective alternative for HIV-infected pregnant women (in the developing world)." Numerous international trials are underway using a shorter course of AZT later in pregnancy, replacing intravenous AZT with oral during labor and eliminating or reducing the AZT given to the infant in an attempt to identify simpler, less expensive protocols.

Activists have raised concerns about the ethics of these trials. Marion Banzhaf, former Executive Director of the New Jersey Women and AIDS Network (NJWAN), stated that these trials would not be permitted in this country and should not be funded overseas by the U.S. government through the National Institutes of Health (NIH) and Centers for Disease Control (CDC). Ms. Banzhaf dismissed the argument that pregnant women in the developing world would not be receiving any treatment. "It's exploiting people's desire for access to the drug to coercively entice them into joining a trial and then randomizing them into a placebo group. It wouldn't happen here."

Public Citizen, a Washington-based watchdog group, spearheaded a campaign to have the placebo-controlled trials redesigned as equivalency trials and require all participants be offered some regimen of AZT. Health and Human Services Secretary Donna Shalala and the CDC have both upheld the WHO panel recommendations. Ms. Shalala stated in a letter of response that it was not appropriate to use the original 076 protocol as a comparison arm since it is not the standard of care in developing countries and could not act as a control arm. Further, all countries involved had approved the trials, which will proceed as planned in order to find a feasible intervention as soon as possible.

In this country, combination therapies are being studied to determine safety and efficacy during pregnancy. There are several small open-label Phase I studies with protease inhibitors opening (ACTG trials 353, 354 and 358), plus one in development (ACTG 357) which uses abacavir, Glaxo's experimental nucleoside also known as 1592U89. All four trials involve combinations with AZT and 3TC. There is also a Phase I d4T/3TC study that just opened for women who cannot tolerate AZT, or have had disease progression (ACTG 332). A large Phase III trial (ACTG 316) is currently enrolling women to study nevirapine in delivery and labor in combination with standard of care. For information on these trials, call 800/TRIALS-A.

Other studies are looking at Vitamin A deficiency and vertical transmission. The incidence of severe Vitamin A deficiency is low in the U.S., so it is difficult to determine if this is a potential risk factor here. However, in the developing world, where Vitamin A deficiency is more common, a study by Richard D. Semba, M.D., and colleagues from Johns Hopkins University found that higher levels of deficiency were associated with higher rates of vertical transmission in Malawi (Lancet, June 25, 1994; 343(8913): page1593-7). Care needs to be exercised with Vitamin A because high doses can cause birth defects during the early stages of pregnancy. Prenatal vitamins contain 8000 IUs of Vitamin A, which is the maximum amount recommended for any pregnant woman in the U.S.

In an attempt to determine if Cesarean sections can reduce vertical transmission, a study in Italy is comparing vaginal births to C-sections. This is a controversial trial because a C-section is a major operation for an immune-compromised woman. In addition, the study will be hard to complete, as a quarter of the women randomized to have vaginal deliveries will wind up needing C-sections.

Other studies are looking at vaginal viricides to prevent the infant from coming into contact with infectious secretions. One large study in Malawi involving over 7,000 volunteers failed to interrupt transmission when using vaginal swabbing with chlorhexidine (a detergent), except when membranes were ruptured more than four hours before delivery (Biggar R et al. Lancet. June 15, 1996; 347(9016):1647-50). Dr. Mofenson stated that it might be more effective to employ a chlorhexidine lavage that utilizes a catheter to wash out the whole vagina. A study is underway to examine the efficacy of this method as well as one using another viricide as a suppository beginning about two weeks before delivery.

Other studies are looking at the mode of infant feeding. It is generally agreed that breast-feeding increases the risk of transmission. In the U.S. breast-feeding is not recommended. However, in many countries in the developing world, it is the only option due to the lack of clean water to make formula.

The Antiretroviral Pregnancy Registry has been established to collect observational data on antiviral exposure during pregnancy in order to assess the potential teratogenicity. Registry data is used to supplement studies and is provided to clinicians to assist patients in making informed treatment decisions. Data are being compiled on most of the currently approved anitvirals and more will probably be added in the future. Health care providers can request information and report data on patients by calling 800/722-9292, ext. 38465.