Bulletin of Experimental Treatments for AIDS, No. 30; September, 1996
Ellen J. Landsberger, MD

Abstract

When the AIDS Clinical Trial Group broke the code for Protocol 076, researchers discovered that giving AZT (Retrovir) to HIV-infected women during pregnancy (100 mg orally 5 times daily) and labor (2 mg/kg of body weight intravenously, given over 1 hour, then 1 mg/kg hr until delivery), plus to the newborn (2 mg/kg, orally, every 6 hours for 6 weeks), could cut the perinatal HIV transmission rate by two-thirds. Now, further studies are adding to the databank of information about HIV in pregnancy. For example, one study has shown that pregnancy does not hasten the progression of HIV; another has indicated that, although vertical HIV transmission often occurs late in gestation, it also can occur as early as 8 weeks. One group of researchers discovered that AZT is highly effective in blocking viral transmission but also that, when the mother develops resistance, she is likely to pass the resistant viral strain to the fetus. The importance of measuring viral load has been suggested by research demonstrating that the number of HIV RNA copies can help predict which women are most likely to transmit the virus to the fetus. In one study, all women with more than 80,000 RNA copies/mL transmitted the virus, whereas none with less than 20,000 copies/mL transmitted. Of great interest is that the 22 women in this study who took AZT showed an 8-fold median decrease in plasma RNA levels.

Introduction

In examining how best to treat an HIV-infected woman during pregnancy, the first point of concern often is how to prevent the vertical transmission of HIV from mother to child during pregnancy. Today, most clinicians are guided by the results of the AIDS Clinical Trial Group Protocol 076 (ACTG 076), which demonstrated that giving AZT to HIV-infected women during pregnancy (100 mg orally 5 times daily) and labor (2 mg/kg body weight intravenously, given over 1 hour, then 1 mg/kg per hour until delivery), plus to the newborn (2 mg/kg orally every 6 hours for 6 weeks), could cut the perinatal HIV transmission rate by two-thirds (Connor and others).

Other issues concerning perinatal HIV care are also important. One concern is the high rate of HIV infection in pregnant teens; another is the relationship between HIV infection and reproductive choice. In "Pregnancy Rates Among Women Infected With HIV," Susan Chu and others, from the Centers for Disease Control and Prevention (CDC) and the Adult and Adolescent HIV Spectrum of Disease Project Group, discussed data from an ongoing survey of the medical records of 3,915 women, 15 to 44 years old, who were infected with HIV and receiving care in 90 centers in 11 cities between January 1990 and August 1994 (Chu and others). At the time they entered the project, 570 (14.5%) women were pregnant. Women who were pregnant upon enrollment had higher CD4 counts than women who were not pregnant; hence, pregnancy generally occurred in healthier HIV positive women without AIDS-related symptoms.

More than 90% of the pregnancies were unplanned. Also, the pregnancy rate varied significantly by age: of the teenagers who entered, almost half (47% of the 15- to 19-year-olds) were pregnant at the time of enrollment. Most of the teens were identified as HIV positive because they had become pregnant. During each year of care, however, only 5.8% of the women became pregnant, which is about 12% lower than the pregnancy rate of all women in the U.S. from the ages of 15 to 44. New pregnancies were evenless common among women with an AIDS-related opportunistic infection (OI). This finding speaks to reproductive choice and to the importance of HIV counseling and testing as a regular part of gynecologic care. A central point is that early identification of HIV in a gynecologic practice could potentially decrease unwanted pregnancies.

Does Pregnancy Hasten Decline from HIV Infection?

Another key issue is the effect of pregnancy on HIV infection. In a prospective cohort study conducted in France, researchers compared 57 women who completed pregnancy during the course of their infection with 114 HIV-infected women who had never conceived (Hocke and others). The 2 groups were matched on CD4 cell counts, age and year of HIV diagnosis. Each woman was followed until she reached the first of 3 endpoints: CD4 count below 200 cells/mm3, the first AIDS-defining event or death. The results indicated no significant differences in the endpoints between the pregnant and nonpregnant HIV positive women; pregnancy did not accelerate HIV progression to AIDS or death. AZT, prescribed only for women with a CD4 count less than 200 cells/mm3, was used in 57.7% of the pregnant women versus 45.6% of nonpregnant women. Although CD4 counts were not significantly different, there was a significant difference in clinical symptoms at the time of HIV diagnosis. Ninety percent (90%) o! f the pregnant women compared with 76% of the nonpregnant women were asymptomatic at the time of HIV diagnosis, which is similar to what was seen in the Chu study.

Previous studies, especially those conducted early in the AIDS epidemic, had suggested that pregnancy had an adverse effect on the progression of AIDS. More recent studies, such as this one from France (Hocke), indicated that pregnancy really may not have a detrimental effect on HIV-infected women.

Vertical Transmission of HIV from Mother to Child

Another study, by Soeiro and colleagues, is important in the discussion of vertical transmission of HIV from mother to baby and its prevention. These researchers were among the first to prove fetal infection in utero when they identified HIV in 7 of 23 fetuses from pregnancies interrupted before the third trimester. Investigators primarily looked at liver, lung and brain tissue. Positive maternal-fetal transmission was defined as the presence of at least 10 genome equivalents of viral DNA in at least 1 fetal tissue sample. Thirty percent (30%) of the fetuses had evidence of infection, including 1 fetus in the first trimester. This study suggests that any approach used to decrease viral transmission must be multipronged, and must begin early in pregnancy. Using only measures that attempt to block HIV transmission during and after delivery will fail to prevent, according to some estimates, as much as 50% of HIV transmission from mother to fetus.

The importance of early interventions to block the vertical transmission of HIV to the fetus is further supported by a report on excess intrauterine fetal deaths/losses associated with maternal HIV infection (Langston and others). Although there is much evidence to support that most transmission of HIV to the fetus occurs late in gestation (Alimenti and others; Lewis and others), studies have identified HIV infection in fetuses as early as 8 weeks (Ehrnst and others). Today, it remains easiest to treat HIV at the end of gestation, around the time of delivery. Still, timing of fetal HIV infection is a concern that mandates finding ways to block transmission early on, before the virus becomes established in fetal tissue. The group from Baylor College in Texas and Texas Children's Hospital in Houston (Langston and others) studied seropositive pregnant women who had 109 live births and 16 fetal losses. Of the fetal losses, 2 were therapeutically induced in ill women but 14 were! spontaneous, representing an 11% spontaneous intrauterine fetal loss rate. Of the 14 spontaneous fetal losses, 7 were positive for HIV by in situ hybridization. In 3 of the early losses, fetal tissue was not examined, but the chorionic villi, endometrium and desidual tissue showed heavy viral burden at the implantation site in 2 out of the 3 placental tissues. Fetal-placental tissue pairs were available in 10 pregnancies; 8 fetal-placental tissue pairs were concordant for HIV status by in situ hybridization. In 6 of the 10 lost pregnancies, fetal tissue was HIV positive, but only 4 of the associated placentas showed chorionic villi positivity.

Impact of Drug Resistance

In the well known double-blind AZT trials, the risk of vertical transmission was reduced from 26% among asymptomatic HIV-infected pregnant women on placebo to 8% among those receiving AZT (Connor and others). But what about viral resistance, which has been a long-standing critical concern in AZT therapy? In immunocompromised individuals, resistance to AZT typically develops after about 6 to 12 months of therapy; then, primary infection can occur with the resistant virus. What negative impact might there be from treating women with AZT during pregnancy, only to have them develop resistance to the drug? Would the women's resistance to AZT facilitate the transmission of AZT-resistant virus to the fetus?

To address such questions, a group from the Department of Pediatrics at the University of Rochester in New York reported a study of drug resistance and vertical transmission of drug-resistant HIV strains when AZT was given during pregnancy (Frenkel and others). The Rochester group retrospectively reviewed 62 infants who were followed from birth to over 6 months of age. Only 1 of the 20 infants born to AZT-treated mothers became HIV-infected, and this infant's isolate was resistant to AZT, like its mother's. That is, both mother and baby had resistant infection.

By contrast, 11 of the 42 women (26%) who did not take AZT transmitted HIV to their fetuses. Among the 20 women taking AZT -- all of whom had been taking the drug for more than a year -- 4 women had resistant isolates. Although this is of concern, not everyone transmitted to the baby, even if they developed the resistant virus. In the AZT group, only 1 woman with a highly resistant strain vertically transmitted the virus, and her infant's viral strain was also highly resistant to AZT. It remains to be seen what will happen as more and more women take AZT during pregnancy. This study suggests that, although maternal treatment with oral AZT reduces the rate of vertical transmission of HIV-1, transmission that does occur may involve transmission of virus that is resistant to AZT.

Interestingly, AZT and other antiviral drugs do not seem to be harmful. The Acyclovir Registry, which has existed for years for pregnant women on acyclovir, has not shown any harmful effects of this drug to the fetus, even though the drug is used fairly frequently. To date, there are no data on the effects of protease inhibitors on pregnant women. A general approach, subscribed to in our practice, has been that women who need drugs get the drugs they need, unless there is a specifically known fetal toxicity.

FDA Pregnancy Risk Categories

The risk posed by maternal drug use to a fetus bears closer examination in a discussion of fetal risk in general. The FDA has established Pregnancy Categories A, B, C, D and X, according to an assigned risk. But what do these categories really mean? According to the FDA, category A consists of drugs for which controlled studies in women have failed to demonstrate a risk to the fetus in the first trimester (or subsequent trimesters), and thus the possibility of fetal harm appears remote. Although very few drugs have ever had controlled studies that "prove" no fetal harm in the first trimester, this does not mean that they are harmful.

Category B consists of drugs for which either (1) animal reproduction studies have not demonstrated a fetal risk, but there are no corresponding human studies, or (2) animal studies have shown adverse effects that have not been confirmed in controlled studies of women in the first trimester (or subsequent trimesters). Category B means that there really is not enough information.

Category C means that (1) animal studies have revealed adverse fetal effects but that no controlled studies in women have been done, or (2) no studies in women or animals are available.

Category D means that there is clear evidence of human fetal risk, but the benefits derived from using these drugs in pregnant women may outweigh the risks (e.g., these are drugs that may be used to treat a pregnant woman with a life-threatening or otherwise serious condition when there is no other effective alternative).

Acyclovir is an interesting example. Reviews of acyclovir, a category C drug, have been available for more than 10 years; it is known to be fairly "safe." Famciclovir, a relatively newer drug and a relative of acyclovir, for some reason has been assigned to category B. Someone called our clinic and asked, "Why are you using acyclovir when it is more dangerous than famciclovir?" The point is that, if one does not really consider what is behind the assignment of the category, these categories can be misleading.

Finally, category X encompasses drugs in which human and animal studies (or actual human experience) have demonstrated fetal abnormalities. The risk of using a category X drug in a pregnant woman clearly outweighs any benefit.

Impact of Immunologic, Virologic and Placental Factors on Vertical Transmission

One of the larger studies on vertical transmission examined the immunologic, virologic and placental factors associated with transmission (St. Louis and others). Conducted in Zaire, it was a prospective, observational, cohort study of more than 324 HIV positive women who were matched with 254 HIV negative controls. This group of researchers found that the highest transmission rate was associated with maternal p24 antigen; 71% of the children born to women with p24 antigenemia were HIV positive, compared with 23% born to women without p24 antigenemia.

Researchers also found that high maternal CD8 cell counts were associated with high levels of vertical transmission. Among women with CD8 counts of less than 1,800 cells/mm3, CD4 counts below 600 cells/mm3 were a risk factor. In women with neither high CD8 nor low CD4 counts, inflammation in the placenta was the crucial factor associated with a higher rate of vertical transmission: the vertical transmission rate was only 7%. However, when p24 antigen was absent, CD8 count was lower than 1800 cells/mm3, CD4 count was higher than 600 cells/mm3 and the placenta was uninflamed.

Significance of Viral Load

Another key question is how important it is to measure viral load. In a study of 19 mother-child pairs, HIV transmission occurred in 5 pairs (Weiser and others). Researchers used an endpoint dilution culture of the peripheral blood mononuclear cells to determine viral titers as a measure of the viral load. They found that, of 6 women with viral titers greater than 125 HIV-infectious units per 106 cells, 4 (67%) transmitted HIV to their infants. On the other hand, of 13 women who had low viral titers, only 1 (7.7%) transmitted the virus to the infant. This finding demonstrates the importance of examining viral titers and shows that a high viral load promotes transmission.

Although HIV load varied greatly among the women, viral load in each woman remained stable over time during pregnancy. This observation, coupled with the finding that the greater the maternal viral burden, the more likely that viral transmission would occur, led researchers to conclude that determination of titers early in pregnancy may predict which women are at risk for vertical transmission.

The Weiser study offers a scientific rationale for therapeutic strategies based on lowering the viral load, as well as a quantitative virologic foundation for directly linking the risk of vertical transmission to the severity of maternal primary infection, advanced disease and surrogate markers such as p24 antigen and low CD4 counts. Arguably, obstetricians should measure viral load in pregnant HIV positive women.

A prospective cohort study by Dickover and associates addressed the concern regarding viral load measurement in HIV positive pregnant women. In this study, 92 HIV positive women who had 95 pregnancies and 97 infants were examined. In 20 of 97 infants, there was vertical transmission. The most striking difference among the virologic and immunologic variables was in the number of HIV RNA copies at delivery. Transmitting mothers were more likely to have plasma HIV RNA levels higher than 50,000 copies/mL at delivery. Of 20 transmitting mothers, 15 (75%) had high HIV RNA copy levels compared with just 4 out of 75 (5%) of the nontransmitters, a highly significant difference.

None of the 63 women who had fewer than 20,000 copies/mL of HIV RNA transmitted the virus to the fetus. Plus, there was a clear cut-off-all of the women with more than 80,000 copies/mL transmitted the virus to their infants, whereas none of the women with less than 20,000 copies/mL did. Of great interest is that 22 women who took AZT showed an 8-fold median decrease in the plasma RNA levels from an average of 43,043 RNA copies/mL before AZT therapy to 4,238 copies/mL at delivery; none of these 22 women transmitted the virus to the fetus. Thus, if AZT was effective, the women did not transmit the virus. In ACTG 076, the women took AZT, on average, for 12 weeks. In this study, the women took the drug for an average of 8 weeks (median, 7 weeks; range, 4-11 weeks). Four AZT-treated women with high HIV levels transmitted the virus to their newborns, even though the HIV virus in both mothers and infants was AZT-sensitive. Those who transmitted in utero had the highest viral load,! and those who transmitted during delivery had higher HIV RNA levels than the nontransmitting women.

[Ed. note: The SFAF Scientific Advisory Committee comments that data from the XI International Conference on AIDS do not clearly support the association of any specific viral load with the certainty of vertical transmission.]

Which Fetuses Get Infected: In Utero versus Intrapartum?

The issue of which infants get infected and when again raises the question of where to try to block transmission. A study published in The American Journal of Public Health showed that events around the time of delivery that increased the infant s exposure to the birth canal, to maternal blood or to vaginal secretions increased vertical transmission (Kuhn and others). In this study, epidemiologists compared the New York City birth records of 632 children with AIDS to 5 controls per case, matched for race, year of birth and institution of birth, and reviewed complications and risk factors during the deliveries.

They found that children born via cesarean section (C-section), in women who had no placenta previa, abruptions or other complications that would have increased exposure to maternal blood, had the lowest rate of transmission. Vaginal deliveries with risk factors had the highest rate of transmission (Kuhn and others).

An estimated 50% to 70% of vertical viral transmission occurs during intrapartum events (i.e., during birth). This estimate is based on studying the children after birth to see whether the virus can be cultured. In other words, if the infant was infected at the time of birth, the HIV culture was negative at birth but positive later. These data have added to the argument in favor of performing C-sections to protect infants from intrapartum HIV transmission. From Italy, there is a review of 1,624 children born to HIV-infected women (Tovo and others). These infants were prospectively followed from birth to age 18 months, unless they died of HIV-related illness before the study s end. A significantly higher rate of vertical transmission was shown in children delivered vaginally by women who were symptomatic at the time of delivery. Multivariate stepwise analysis showed that vaginal delivery and development of symptoms in the mother were significantly and independently associated with a high transmission rate. This study is being cited, as well as others such as the European Collaborative Study, as demonstrating that C-sections help prevent vertical transmission of HIV virus.

In our practice, we are very liberal about doing C-sections with HIV positive women. Although we have no adopted policy of C-sections for these patients, we do try to avoid prolonged ruptured membranes, and we will not use forceps or a vacuum on these babies.

Could Antiretrovirals Damage Fetal Hearts?

HIV in children can be complicated by the development of cardiac disease. In adults, decreased left ventricular function has been associated with AZT use. The question that arises is, can the use of antiretrovirals in an attempt to prevent vertical transmission damage the fetal heart in the process? Or, are the cardiac problems seen in HIV-infected patients related to the viral infection rather than to the antiretroviral therapy?

A study done to determine whether cardiac disease in children is related to antiretroviral therapy or to HIV disease progression could provide some clues (Domanski and others). Researchers retrospectively reviewed echocardiograms, clinical information and laboratory data from 137 HIV-infected children who were treated with AZT and/or ddI (Videx).

Despite correction of the echocardiogram results for HIV-disease severity with markers such as CD4 cell counts, time since infection, mode of acquisition and age, children who were treated with AZT had a lower average fractional shortening than those who were not treated with AZT. The odds that a cardiomyopathy [heart muscle disease] would develop were 8.4 times greater in children who had taken AZT than in those who had never taken AZT; ddI was not associated with the development of cardiomyopathy.

The U.S. Public Health Service now recommends routinely offering AZT to all HIV-infected women during their pregnancy. What is the effect of this drug on the fetus? Even though AZT appears to be remarkably safe, fetuses not prone to sickness may be being exposed in utero to a drug that may give them heart disease at a later time. Will evidence of heart disease emerge in the first year of life, or will the children be 10 years old when they start to present with cardiomyopathy?

Discussion

What obstetric principles can be followed at this time? One clear principle is that viral load has a real effect. If babies are identified as being at relatively high risk or low risk for infection, interventions can be "bull's-eyed" with a timely course of antivirals.

Another principle stems from the finding that all women with more than 80,000 RNA copies/mL vertically transmitted the virus to their child (Dickover and others). This finding, coupled with the observation that the viral load tends to remain stable throughout pregnancy, suggests that another obstetric principle may be to measure viral load and target interventions early in pregnancy in order to lower the RNA count to prevent vertical transmission.

On the other hand, if 50% to 70% of the transmission occurs during the intrapartum period, what about routinely delivering infants of HIV-infected women via C-section? Personally, I would prefer drug treatment over C-section. Giving a C-section to women who have a high viral load may mean that the sickest patients are being given an operation that may be essentially unnecessary, particularly if the virus has already been transmitted. I am certainly not opposed to C-sections. In fact, we have a 30% C-section rate in our HIV population. However, C-sections are not routine, and we do not always know when it is the best procedure to follow.

Ideally, ACTG 076 would have given us the answer about timing. Unfortunately, it did not. The researchers who formulated the study apparently felt that it would take too long for them to be able to determine whether intrapartum versus antepartum [before birth] AZT worked best. If we knew the answer to that question, we could monitor our therapy and direct it toward the antepartum period, the late third trimester, or during labor and delivery -- whenever it would be most effective.

Currently, an objective is not to start too early. Starting AZT after the first trimester could mean that babies will be born right about the time that they are developing drug resistance. Furthermore, it may be important to boost them during delivery.

Although some of these babies may already be infected, 50% to 70% may not be infected. We also need to look at using the protease inhibitor drugs during pregnancy. These drugs have not yet been studied in pregnant women, and we need to study if and when to use them. As obstetricians, we are extremely reticent about starting new drugs. But since HIV is a killer disease, we need to consider any drug in the armamentarium that may help combat it.

Dr. Landsberger is the Director of the High-Risk Obstetrics Clinic at The New York Hospital-Cornell Medical Center in New York City.

Copyright, Medscape, Inc., 1996 , all rights reserved. Medscape, the online resource for better patient care, can be accessed at http://www.medscape.com.

References

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