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Rapid Advances in Preventing Vertical Transmission

July/August 1997

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The decision to have a child can be a complicated one under any circumstances, but for an HIV-positive woman it may well be the most difficult decision she will ever face. Being HIV-positive does not automatically supplant the maternal instinct and the desire to have children. As new AIDS treatments are proving more successful and women are beginning to experience reductions in mortality and are living longer, many are facing the dilemma of whether or not to have a child. Treatments are as numerous for pregnant women as for the general population, but choices are more complex. The Public Health Service has recently published recommendations for pregnant women and antiviral use, but it is still not clear as to what is best for mother and fetus. There is still controversy over the use of AZT or other antivirals during pregnancy despite guidelines and recommendations from experts in the field. Access to emerging information is important and although more research is needed, some of the new data have proved encouraging.

Yvonne Bryson, M.D., of UCLA, stated at the May 1997 Pediatric HIV Symposium, a satellite meeting of the National Conference on Women and HIV, "I stand here today more optimistic than I've felt since I saw my first AIDS patient in 1981. Advances in the area of perinatal transmission give women the reproductive option if they wish to have a family." Progress in treatment and prevention can reduce the risk of vertical (mother-to-infant) transmission. AZT, which is the least effective of drugs, can decrease the risk by two-thirds, as demonstrated by ACTG 076. Dr. Bryson stated that there was potential for the rate of transmission to be reduced to below 2% with the use of improved strategies.

Some Factors That May Influence Transmission

The rate of vertical transmission has been shown by several investigators to be related to the status of the maternal immune system. According to an article Dr. Bryson published in the journal AIDS, "Women with advanced clinical disease and primary infection during pregnancy have a high risk of transmission" (AIDS 1996 (suppl 3):S33-42). Other predictive factors include lower CD4 counts, the mother's ability to produce neutralizing antibody, shedding of cervical virus and presence of p24 antigen.

Viral load is associated with transmission but it is not the only factor. Dr. Bryson stated that women she studied who did not transmit had a wide variation of viral load. There was also an overlap of viral load counts between some of the transmitters and the nontransmitters. Women with lower viral load had a lower risk of vertical transmission, though. There are studies that observed transmission at lower viral loads, but Dr. Bryson felt that many of those instances of transmission occurred at delivery. Viral load may be more useful in determining the mother's own treatment than in predicting if she will transmit the virus to her baby. The better the immune status of the woman, the better the chance that she will not transmit. For all of these reasons lowering maternal viral load is desirable.

Certain obstetrical factors may increase the risk of transmission by causing trauma to the newborn baby. These include some tests, instruments and procedures used during pregnancy. If possible, HIV-positive pregnant woman should avoid amniocentesis, chorionic villus sampling (CVs), fetal scalp sampling, cordocentesis, internal fetal and labor monitoring (external fetal monitoring is safe) and percutaneous umbilical blood sampling (PUBS). Procedures performed during delivery, such as episiotomy, urinary catheterization, shaving, forceps and vacuum extractors, should be utilized only if medically necessary for the safety of the mother and fetus.

It has been posited that Cesarean sections could have a protective effect. Numerous studies have examined this question and have come up with conflicting findings. A meta-analysis pooled the results of eleven studies and found that there was a higher risk of transmission for infants delivered vaginally versus infants delivered by C-section (Dunn, DT et al. Journal of Acquired Immune Deficiency Syndrome. October 1994; 7(10):1064-6). But it is difficult to control for covariants such as obstetrical emergencies, illness, condition of mother and type and amount of prenatal care. One study that was able to control for time of ruptured membranes (breaking of the "bag of waters") found no difference in transmission rate between C-sections and vaginal deliveries (Landesman S et al. The New England Journal of Medicine. June 20, 1996; 334(25):1617-23).

The increased risk of surgery for an immune-compromised woman must be balanced against the statistical difference in risk of transmission. A study in Italy found that HIV-positive mothers are at an increased risk of postoperative complications when delivered by C-section (Semprini A.E. et al. AIDS. August 1995, 8(9):913-7). Many obstetricians prefer antiviral drug treatment to C-sections.

Artificial rupturing of membranes should be avoided where possible. According to the Women and Infants Transmission Study (WITS), the risk of vertical transmission nearly doubles when the membranes rupture more than four hours before delivery (Landesman op. cit.). Women should be made aware of the symptoms of ruptured membranes so they can report them immediately to their health care provider. (However, having membranes ruptured for longer than four hours is not necessarily an indication for Cesarean section. Gina Brown, M.D., of Columbia Presbyterian, states that augmentation of labor may be helpful in such instances.)

Premature delivery (prior to 37 weeks) is also associated with a higher risk of vertical transmission (Greenberg BL. XI International Conference on AIDS. abstract Tu.C.2592). This finding was corroborated by a study conducted in France that found delivery prior to 34 weeks was independently associated with transmission and concluded that severe preterm labor should be prevented (L. Mandelbrot, XI International Conference on AIDS. abstract TuC.2603).

Another important consideration is whether any drug taken by the mother can cross the placenta (see the table "Drugs' Placental Passage in Humans") at sufficient levels to protect the baby. Marianne Garland, M.D., of Columbia University, presented her baboon studies on antiviral use and the fetus at the National Conference on Women and HIV held this May (abstract 204.2.). Neonatal drug levels will depend upon compartmentalization and metabolism of the drug in the fetus and placenta as well as elimination of the drug by the fetus. Dr. Garland stressed the importance of proper dosing of the mother so that the fetus would receive adequate levels of the drug.

It is thought that HIV can cross the placenta or a break in the placenta. In some cases HIV has infected the placenta but not the infant, or vice versa. For infection to take place, the viral genome needs to be replicated and inserted into the host genome of the fetus. This is where AZT and the reverse transcriptase agents are effective. They block the genome of the viral particle from being incorporated into the fetal cells. AZT has no effect on the release of the viral particles from the mother.

Time of Transmission and Rationale for ACTG 076

Although the exact mechanism of transmission is still unclear, it is known that it can be in utero (during pregnancy), intrapartum (at time of delivery) or postpartum (after delivery, by breast-feeding). The time when HIV is transmitted has a direct impact upon the types of interventions used.

HIV can infect human fetuses as early as eight weeks after conception. Interventions to prevent such transmissions are difficult. There appears to be an increased rate of spontaneous abortions when transmission occurs in the first trimester. Transmission occurring later in pregnancy is more responsive to interventions. The mother can be treated with antivirals that pass through the placenta to the fetus. Lynne Mofenson, M.D., of the NIH stated at the Women's Conference that the majority of transmission appears to occur during labor and delivery. Interventions that provide treatment directly to the baby are necessary for preventing transmission at that time.

The rationale for the protocol of ACTG 076 was to interrupt transmission at each of these stages. AZT was taken orally five times a day between 14 and 34 weeks, given intravenously during labor, and administered for six weeks to the newborn. The oral AZT was administered during pregnancy to target transmission that occurred in utero. Treatment began after the first trimester (the period during gestation of maximum organ development) so as to avoid a higher risk of birth defects. The infusion during delivery was able to cross the placenta and rapidly produce AZT levels in the baby that were viricidal. This was important because of the intense exposure to infected blood and cervico-vaginal secretions when the baby is passing through the birth canal. Oral AZT syrup was then administered to the newborn because of the possibility of microtransfusions of infected maternal blood cells into the fetal bloodstream during labor and delivery. In this way the AZT possibly switches from pre-exposure prophylaxis to postexposure prophylaxis for the baby.

The results of ACTG 076 demonstrated a 67% reduction in the risk of vertical transmission in the AZT-treated group at all levels of maternal viral load. Yet it is still unclear exactly how AZT reduced transmission (see Treatment Issues, April 1996), or indeed which components of the regimen were critical. Global studies of short-course AZT treatment are underway to answer the latter question.

HIV Immunoglobulin

Enrollment in another study on vertical transmission was stopped in March of this year. ACTG 185 looked at therapy with HIVIG (an immunoglobulin containing high levels of antibodies to HIV) versus IVIG (a standard immunoglobulin that does not contain HIV antibodies) in addition to the 076 regimen. All participants had more advanced disease than the 076 cohort and required antiviral therapy for their own health.

Researchers expected the transmission rate to be higher in such a group. Median CD4 count was 306 and 21% of the cohort had CD4 cell counts below 200. Twenty-three percent had received prior antiviral therapy, some for a prolonged period of time. Twenty-seven percent had a viral load above 50,000. Enrollment was halted when the transmission rate was found to be the same in both treatment arms, 4.8%, which made comparison impossible. This unexpectedly low rate was less than the 8% rate found in 076. Participants in ACTG 185 received AZT earlier in pregnancy by about two months, at 19.3 weeks as opposed to 11 weeks in ACTG 076.

Transmission was observed across all viral load levels including undetectable. Therefore, it did not appear that viral load was helpful in determining transmission in treated women. According to Dr. Mofenson, the 4.8% transmission rate found in this study is what is being reported now in the U.S. with the clinical implementation of the 076 regimen.

Care of the Pregnant HIV-Positive Woman

A woman cannot receive appropriate care if she does not know her HIV status. It is important for all pregnant women to be offered counseling and voluntary testing. HIV-infected women require a knowledgeable medical team, including an HIV specialist and an obstetrician or midwife experienced with high-risk and/or HIV-positive pregnant women. Regular prenatal care is important, as is nutritional counseling. The use of drugs and alcohol during any pregnancy should be avoided, but this is especially true for HIV-positive women. In addition, smoking may increase the risk of vertical transmission (B. Turner et al. JAIDS. April 4, 1997; 14(4):327-37).

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 a category C drug (see the table "HIV/AIDS Drugs during Pregnancy"). Concerns regarding its use during pregnancy include the potential risk for development of cancer and AZT resistance.

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

Clearly AZT monotherapy is substandard therapy for HIV infection; but, the Public Health Service guidelines still promote its use in pregnancy. The goals of treatment are twofold: the first is the use of drugs for improvement or maintenance of maternal health, and the second is the interruption of vertical transmission. Ideally these two intentions do not conflict. While AZT monotherapy is the only proven means of reducing the risk of transmission, combination therapy may be optimal for the mother's own treatment. Pregnancy should not prevent the administration of combination therapy for maternal health considerations. However, women need to know how other drugs will affect the fetus at each stage of development, whether the drug will cross the placenta and if the dose should change.

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

There are numerous clinical trials underway in the U.S. and around the world. Dr. Mofenson presented an overview of the global trials at the Women's Conference (abstract 204.1). The current studies focus on interrupting transmission through lowering maternal viral load, enhancing maternal/fetal/infant immune response, fetal/infant prophylaxis, providing drugs to the fetus and reducing intrapartum and postpartum exposure to the infant.

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.

Ongoing Trials of Vertical Transmission Prophylaxis in the U.S. and Developing Countries
Protocol/ Sponsor Country Target Enrollment Study Design
ACTG 316 USA/Europe 800/400 (nevirapine or placebo) + standard of care
ACTG 353 USA 10 nelfinavir/3TC/ AZT, no placebo
ACTG 354 USA 10 ritonavir/3TC/ AZT, no placebo
ACTG 357 USA 10 1592/3TC/AZT, no placebo
ACTG 358 USA 10 indinavir/3TC/ AZT, no placebo
ACTG 332 USA 17 d4T + 3TC, no placebo
ACTG 324 USA 18 Abbreviated 076 regimen: AZT, no placebo
NIH Thailand 1200 Abbreviated 076 regimen: AZT 4 arms, no placebo
CDC Thailand 372 Abbreviated 076 regimen: AZT or placebo
WHO Africa 1900 AZT/3TC or placebo
CDC Ivory Coast 1534 Abbreviated 076 regimen: AZT or placebo
NIH Uganda 1200 Abbreviated 076 regimen: AZT, nevirapine or placebo
NIH Ethiopia 940 Abbreviated 076 regimen: AZT or placebo

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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