Strategies for Interrupting Mother-to-Child Transmission
As new AIDS treatments are prolonging lives, many HIV-infected individuals are feeling optimistic for the first time and thinking about their futures. For some this means starting a family, a hope they may have abandoned since the news of their diagnosis. Fortunately, just as there have been advances in the treatment of HIV-infected adults, there have also been advances in the prevention of mother-to-child transmission (vertical transmission). However, choices for pregnant HIV positive women are complex and it is not always clear what is best for mother and baby.
Factors Associated with Vertical Transmission
The condition of the mother's immune system has been shown by several researchers to be related to the rate of vertical transmission. According to Yvonne Bryson, MD, of UCLA, "women with advanced clinical disease and most probably primary infection during pregnancy have a high risk of transmission."
There is some controversy over the role of HIV viral load in vertical transmission. It is thought that viral load is certainly related to transmission but that it is not the only factor. Women who transmit HIV infection to their infants have a wide variation of viral loads. However, women with lower viral loads tend to have lower risk and those transmissions that do take place at lower levels may occur at delivery. In a recently reported study from London, the mother's viral load was found to be a better predictor of vertical transmission than T-cell counts. The estimated rates of transmission were 2 percent for women with 1,000 HIV RNA copies/ml, 11percent for 10,000 copies/ml and 40 percent at 100,000 copies/ml. Ultimately, however, 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 healthier the woman, the better the chance that she will not transmit. For all of the above reasons, lowering the mother's viral load is desirable.
Certain obstetrical factors may increase the risk of transmission by causing trauma to the baby. These include some tests, instruments and procedures used during pregnancy and delivery. Amniocentesis, internal fetal and labor monitoring during delivery, episiotomy (an incision near the vagina to widen the opening for the baby to come through), urinary catheters, and forceps and vacuum extractors should be utilized only if medically necessary for the safety of the mother and fetus. Artificial rupturing of membranes (breaking of the "bag of waters") should also be avoided where possible. According to several studies, the risk of vertical transmission increases when the membranes rupture more than four hours before delivery.
It has been suggested that Cesarean section could reduce the risk of vertical transmission. Numerous studies have examined this question and have come up with conflicting findings. The pooled results of eleven studies found that there was a higher risk of transmission for infants delivered vaginally than infants delivered by C-section. However it is difficult to control for factors such as obstetrical emergencies, degree of illness of the mother, and type and amount of prenatal care. One study that was able to control for time of ruptured membranes found no difference in transmission rate between C-sections and vaginal deliveries.
The increased risk of surgery for an immunocompromised 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 for post-operative complications when delivered by C-section . Many obstetricians prefer antiretroviral drug treatment to C-sections, since AZT has been proven effective in reducing transmission regardless of mode of delivery.
Time of Transmission
Although the exact mechanism of transmission is still unclear, it is known that babies can be infected during pregnancy (in utero), at time of delivery (intrapartum) after delivery, usually by breast-feeding (or postpartum). HIV can infect the infant as early as eight weeks. There appears to be an increased rate of spontaneous abortions (miscarriage) when transmission occurs in the first trimester. Transmission occurring later in pregnancy is more responsive to interventions. The mother can be treated with antiretrovirals that pass through the placenta to the fetus.
Lynne Mofenson, MD, of the National Institutes of Health, feels that the majority of transmissions appear to occur during labor and delivery. Interventions that provide treatment directly to the baby are necessary for preventing transmission at that time. According to Dr. Bryson, evidence in support of intrapartum transmission includes the significant proportion of infants (50% -70%) who are HIV culture-negative at birth and positive at a later date. The other 30% to 50% of positive newborns can be diagnosed positive by culture at birth. This suggests that babies who are negative by culture at birth but eventually test positive are being infected at the time of delivery. Treatments given to newborns who initially test negative may still be worthwhile as post-exposure prophylaxis or early therapy.
ACTG 076: A Watershed Clinical Trial
ACTG 076 was a study to determine if the rate of vertical transmission could be reduced. At the time ACTG 076 was proposed, it was unknown whether AZT would have any impact. In fact, the trial was very controversial as many activists felt AZT might not help the mother or the fetus and might, in fact, do damage. Despite these concerns, the trial was undertaken and the results were impressive enough to change the standard of care for pregnant HIV positive women.
The design of the 076 protocol (see Table 1) demonstrated the uncertainty of the investigators as to when vertical transmission actually took place and at what point an intervention would be most effective. The rationale for the protocol was to interrupt transmission at each of the three possible stages when it might occur. Oral AZT was administered during pregnancy to target transmission that occurred in utero. Treatment began after the first trimester, which is the period during gestation of maximum organ development, to avoid a potentially higher risk of birth defects. AZT infusions were given during delivery so that the drug could cross the placenta and rapidly produce AZT levels in the baby. This was important during the period of intense HIV exposure through infected blood and secretions when the baby was passing through the birth canal. Oral AZT syrup was then administered to the newborn because of the possibility of infected maternal blood having passed into the fetal blood stream during labor and delivery. In this way the AZT possibly switches from pre-exposure prophylaxis to post-exposure prophylaxis for the baby.
|Period of Drug Administration||Drug Dosage and Interval|
|Before birth (antepartum)||100 mg AZT given orally five times daily, beginning at 14-34 weeks gestation and continued throughout pregnancy|
|During labor(intrapartum)||Continuous IV infusion of AZT until delivery|
|Newborn (postpartum)||AZT syrup orally administered to the newborn according to body weight every six hours through the first six weeks|
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, or indeed which component of the regimen worked. Since AZT only modestly reduced maternal viral load, decrease in HIV RNA by AZT did not account for its effect in 076, raising the possibility that effectiveness may, in part, be due to the presence of the drug in the infant during labor. Global studies of short course AZT treatment to determine which part of the protocol was most important recently demonstrated that AZT given in the last four weeks of pregnancy, then orally to the woman during labor but not given to the newborn, reduced transmission by 51%. This finding seems to support the theory that interventions around the time of late gestation and delivery are most efficacious. For the time being, the recommendation for women in the U.S. to use the more effective longer 076 protocol will not change.
ACTG 185: Extending 076 Results to a Sicker Population
ACTG 185 was a study on vertical transmission that added an additional treatment component to the 076 protocol. ACTG 185 looked at combination therapy with HIVIG (an immunoglobulin preparation containing high levels of antibodies to HIV) versus IVIG (a standard immunoglobulin preparation that does not contain HIV antibodies) in addition to the 076 regimen. All participants had more advanced disease than the 076 cohort and required antiretroviral therapy for their own health (see Table 2).
Table 2 Comparison of ACTG 185 and ACTG 076 Participants
|ACTG 076||ACTG 185|
|Entry CD4 Count||Greater than (>)200||Less than (<)500|
|% CD4 <200||0%||23%|
|AZT Prior to Pregnancy||5% (duration: a few weeks)||21% (duration: weeks to months)|
|Median Entry Viral Load||5,700 (PCR)||18,500 (NASBA)|
|% Viral Load >50,000||7%||27%|
Researchers expected the transmission rate to be higher in such a less healthy group. However, the trial was halted in March 1997 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 the 076 study. In the 185 study, the participants received AZT earlier in pregnancy by about 2 months, for 19.3 weeks as opposed to 11 weeks in 076.
Transmission was associated with viral load levels measured at the time of entry into the study and at delivery of the baby, with each one log (10-fold) increment of HIV RNA linked with a 3-4 fold increase in risk of vertical transmission. None of the women with HIV RNA below 500 copies/ml at delivery transmitted, while 5% of those with levels over 500 copies/ml transmitted. Based on these results, Dr. Mofenson suggested that for pregnant women receiving AZT treatment, decreasing viral load to low levels may further reduce transmission.
Concerns About AZT AZT is a category C drug (see Table 3). Concerns regarding its use during pregnancy include the potential risk for the future development of cancer in children born to women taking the drug. This risk could theoretically extend past childhood into adulthood. Two animal studies have looked at the risk of cancer in offspring exposed to AZT. 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. A GlaxoWellcome study demonstrated no increase in tumors in offspring of mice receiving doses whose range was more in line with the human dose, 1/12th to 1/50th of the NCI dose. A National Institute of Health (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 HIVpositive pregnant women during treatment counseling.
|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 and well-controlled studies of 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 research studies or market experiences (after the drug has been approved), but the potential benefits from the use of this 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.
* Some category C drugs that are carcinogenic in animals, such as acyclovir which has been available for many years, have been shown over time to be relatively safe in human pregnancy and not to cause tumors.
Celine Hanson, M.D., of Baylor College of Medicine in Texas, presented information at the National Conference on Women and HIV on the lack of tumors in 734 infants. Dr. Hanson analyzed infants with fetal or neonatal exposure to AZT. No tumors of any nature were reported in any of the children, who have been followed for an average of one to three years, with the longest time being six years. Since the follow up period was relatively short, it is possible that tumors could appear in AZT exposed children during adolescence or adulthood, regardless of the child's HIV status.
Neurodevelopment tests have determined no difference in infants exposed to AZT versus placebo. Growth, including weight, height, and head circumference, have also shown no difference between the groups. In addition, no increase in congenital abnormalities compared to the general population was seen in ACTG 076 or the Antiretroviral Pregnancy Registry. The Antiretroviral Pregnancy Registry has been established to collect observational data on antiretroviral exposure during pregnancy in order to assess the potential for birth defects. Registry data is used to supplement studies and is provided to clinicians to assist patients in making informed treatment decisions. Health care providers can request information and report data on patients by calling 800-0722-9292, extension 38465.
The Public Health Service (PHS) Pregnancy Guidelines
The federal government has released a series of documents that attempt to provide principles and guidelines for the use of antiretroviral therapies. The underlying premise is that HIV infection should almost always be treated with a combination of at least three drugs that include a protease inhibitor and two nucleoside analogs. Principle #8 states, "women should receive optimal antiretroviral therapy regardless of pregnancy status," further explaining that, "in general, pregnancy should not compromise optimal HIV therapy for the mother." By optimal therapy the panel means the timely use of combination therapy.
Clinical scenarios are presented in the pregnancy guidelines to address specific situations and offer recommendations for the use of antiretroviral drugs to reduce vertical transmission. For treatment-naive women in the first trimester of pregnancy, it is recommended, if clinically possible, to delay therapy until after 10 to 12 weeks gestation. This recommendation is based on the fact that there is no scientific information regarding the safety of any antiretroviral during this period. After the first trimester, such women should be offered the three-part ACTG 076 regimen plus other antiretroviral drugs as needed for their own health.
Women who are already on antiretroviral drugs when they become pregnant have to consider whether or not to continue therapy during their first trimester. If a woman decides to stop therapy as a precaution against possibly impairing early development of the fetus, all drugs should be discontinued together, and reintroduced simultaneously to minimize the development of resistance. However, if a woman learns of a pregnancy after the first trimester has ended, it is recommended that she continue antiretroviral therapy. If the current regimen does not include AZT, the addition or subtitution of AZT is recommended regardless of the antiretroviral regimen used during pregnancy.
Stopping treatment is a hard choice and may depend on the woman's disease stage. If she is on highly active antiretroviral therapy (HAART) because of a high viral load, then terminating one or all of her medications risks an increase in viral load or the development of drug resistance which might increase the possibility of vertical transmission. Each woman must weigh the danger to fetal development versus the risk of fetal infection. Due to the lack of research on the safety and efficacy of antiretroviral use during pregnancy, this is a difficult decision.
The thrust of these recommendations is that overall, treatment should continue during pregnancy after the first trimester, but the specifics of the treatment do not go beyond the three-part AZT protocol. Clearly AZT monotherapy is substandard therapy for HIV infection. The goals of treatment for an HIV positive pregnant woman are two-fold: one 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 better for the mother's own treatment. Women need to know how other antiretroviral drugs will affect the fetus at each stage of development. This information is not currently available.
AZT Resistance, Other Antiretroviral Combinations and Current Clinical Trials
Many people 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 federal PHS treatment guidelines for HIV-infected (non-pregnant) adults, asymptomatic individuals with CD4 cell counts above 500 and low viral load 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 continue for an additional five to six months until the birth of the child. Development of AZT resistance during this period would have permanent ramifications on future treatment choices for the mother and resistant maternal virus might not protect the fetus.
In a study presented in January 1997 by Dr. Scott Eastman at the Fourth Conference on Retroviruses and Opportunistic Infections, participants from ACTG 076 were evaluated to determine the prevalence of AZT resistance at entry and delivery. Both the baseline prevalence and the development of resistance were not found to be overwhelming. ACTG 185 demonstrated that the 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. However, two other studies indicated the opposite. French and American studies found higher rates of transmission in women who had used AZT prior to pregnancy. It is still not clear whether AZT-resistant virus and prior AZT use specifically increases the likelihood of vertical transmission, although according to Dr. Mofenson, it seems intuitively possible. It also remains to be seen what would happen if a woman with AZT-resistant virus used another antiretroviral agent or agents during pregnancy.
Clearly more information is needed to understand the safety and efficacy of the other anti-HIV drugs in preventing vertical transmission. This becomes increasingly important as more HIV positive women are treated with antiretroviral agents prior to pregnancy. Such women may, in fact, already be AZT-resistant at the time they become pregnant and need to be treated with combination therapy during pregnancy. Trials are underway looking at the other drugs, including the protease inhibitors (see Table 4), but it will be a long while before there will be conclusive answers. However, as ACTG 076 so powerfully demonstrated, the rate of vertical transmission can be dramatically reduced using antiretroviral drugs. Already, with the wide implementation of this protocol in clinical practice, the rate of vertical transmission nationally and in other industrialized nations has been brought down significantly, to 3%-5%. Hopefully, the combination of even more potent combinations can bring down the rate of vertical transmission even further.
|Protocol Number||Study Design|
|ACTG 316||(nevirapine or placebo) + standard of care|
|ACTG 324||Abbreviated 076 regimen|
Jill Cadman has been with Gay Men's Health Crisis as a volunteer and staff member for the past five years. She is currently the Associate Editor for Treatment Issues, the GMHC AIDS treatment newsletter. Jill is also on CRIA's Board of Directors.