Being Alive - November, 1999
Mark Katz, M.D
As far back as the release of the heralded ACTG 076 data in early 1994--data which left little doubt as to the efficacy of antiretroviral therapy (this was the study which showed a reduction in maternal-fetal transmission by two-thirds by using AZT from the second trimester of pregnancy through early neonatal life)--the issues surrounding pregnancy and HIV treatment have given patients and clinicians alike considerable food for thought.
In this article, I will summarize some of the major recently published articles concerning antiviral therapy in pregnancy, including the pros and cons of considering cesarean section, and the exciting news about nevirapine used at the time of labor.
In 1994, the year of release of ACTG 076 data, more than 400,000 women globally gave birth to HIV+ infants. Despite the awareness of the efficacy of antiviral therapy, estimates for 1998 were that 700,000 such infants would be born. The disparity between those who have and those who do not is sharply magnified when we consider that more than 90% of HIV-infected persons in the world live in developing nations. The percentage of infected infants who are presumed to have acquired HIV through breast feeding has remained in the neighborhood of 30% -- 40%.
Formal U.S. guidelines for how to treat pregnant HIV+ women have been published, and are available at www.hivatis.org, as "Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States.
The document contains a thorough discussion of several scenarios of antiretroviral use in pregnancy (although they tend to be conservative and perhaps, as is the case with so many HIV-related treatment documents, outmoded). This is because AZT had been the only drug actually shown in a prospective, randomized, placebo-controlled trial to reduce transmission (until a few months ago, when nevirapine joined its ranks).
Despite what may be written in the guidelines, virtually all HIV providers (essentially 100% of a group of HIV-treating physicians attending a conference I went to last month) recommend HAART for pregnant women. The important role of reducing the viral load to undetectable was underscored by two articles published in the August 5, 1999 New England Journal of Medicine. In the lead article by Lynne Mofenson et al., zero of 84 women who had undetectable viral loads (<500 copies/mL) at the start of the study, and zero of the 107 who were undetectable at the time of delivery, transmitted HIV to their offspring.
The accompanying article by Patricia Garcia et al. found a comparable zero rate of transmission in women with viral loads of less than 1000 copies/mL, and an almost unheard of rate of 63.3% (19 of 30) in women at the other extreme--those with viral loads greater than 100,000 copies/mL and with no antiviral therapy.
What about the safety of antiretrovirals in pregnancy? Concerns here are more than appropriate, but the good news is that several retrospective studies which have observed women already on antiretrovirals who then became pregnant have shown no significant untoward outcomes. To further delineate, in one well-defined group, The Swiss Cohort, (presented at the 12th World AIDS Conference, Geneva, 1998), 43% of the women were on protease inhibitors at the time of conception.
The drug efavirenz (Sustiva), however, due to reports of deformities in fetal primates, should be avoided in pregnancy -- and, to be sure, in any women of child-bearing age and capability.
One of the major areas of debate over the last several years has been whether or not a pregnant women with HIV should have a elective cesarean section performed, in the hope of reducing vertical transmission. Several earlier reports, dating as far back as 1993, had talked about the potential advantages, and an article published last year, (although not a randomized clinical trial) revealed that there was an 80% reduction in transmission to the infant in an elective C-section compared to vaginal delivery. It should be noted, however, that there was a much greater likelihood (1.6 times) of transmission to the infant in an emergency C-section compared to vaginal delivery. A possible explanation is that in an elective C-section, AZT is started sooner than in an emergency C-section. Also, the chance of the fetus being exposed to the mother's blood at the time of delivery is five times lower in an elective C-section.
The issue was fueled earlier this year, when the International Perinatal Group published the results of a meta-analysis of 15 studies, which together showed a reduction in transmission of more than 50% for elective cesarean section, when compared to other modes. The efficacy of prophylaxis with antivirals was confirmed when the analysis further delineated that, for elective C-section plus AZT, the relative risk of transmission was reduced more than 85%!
The enthusiasm for offering elective cesarean section was adopted by the American College of Obstetricians and Gynecologists (which represents approximately 39,000 physicians who provide health care for women in the US), when it released a statement this summer indicating that "all HIV+ pregnant women should be offered scheduled cesarean delivery at 38 weeks of gestation to reduce the risk of passing the AIDS-causing virus on to their newborns.
From the onset, however, the recommendations were not universally well-received or agreed upon.
"The case for restraint" was part of the title of a Journal of the American Medical Association editorial published in May, which described the limitations of meta-analyses and underscored the need to reassess the finding in the light of HAART. (Remember, any study of cesarean sections up to this time which also involved antiviral therapy had only AZT to speak of--but the treating community was already using two and three drugs routinely. Anecdotally, many centers noted a virtual absence of vertical transmission in women treated with HAART regimens.)
Published almost simultaneously was an article from Europe, a study of hundreds of women, which disclosed the following: those who had elective cesarean section had an only 1.8% vertical transmission rate (3/170), versus 10.5% (21/200) for babies with vaginal delivery. This statistical significance, however, was lost amongst the 230 women who received AZT, regardless of the type of deliveryF.
So, the world asked, if AZT alone was enough to ablate the difference in outcomes between vaginal delivery and cesarean sections, what would HAART do?
Right now, a consensus seems to have emerged that the cesarean option should be discussed with patients, but when viral load can be held to undetectable through most of pregnancy, this may well be sufficient to minimize the transmission. Needless to say, a study prospectively randomizing HAART-treated women, with low to undetectable viral loads, and comparing modes of delivery, might shed further light on this issue.
Another body of literature which has emerged just over the past months involves the use of the non-nucleoside reverse transcriptase inhibitor nevirapine (Viramune), a drug which has long been known to achieve high (enough to suppress viral replication) blood levels even after a single dose!
In Kampala, Uganda--a place where many women do not have access to prenatal care, let alone expensive combination regimens--626 pregnant HIV+ women were randomized to receive one of two regimens: Half got a single dose of nevirapine 200 mg, at the onset of labor, and one 2 mg/kg dose was given to the newborn after a few days of life. The other half received oral AZT, begun at labor and continued through delivery, and then administration continued for the baby through the first week of life. Of interest, and potential significance, is the fact that 99% of the mothers breast fed their offspring.
At birth, there was no significant difference in vertical transmission between the nevirapine and AZT groups, but by 6 -- 8 weeks, and increasing at 14 -- 16 weeks, the babies in the nevirapine group had only around half the rate of infection (13.1%) versus 25.1% of the AZT group (p < 0.0006).
Given that this regimen is used right at the time of labor, and costs around $4, the implications for diminishing transmission in developing nations are astounding.
Needless to say, studies showing the results of combining earlier prenatal treatment, perhaps with more expanded use of nevirapine, will be a welcome addition to the HIV and pregnancy armamentarium.
1. "US Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR Morb Mortal Wkly Rep 1998; 47(RR-2):1-30.
2. Mofenson LM, Lambert JS, et al. "Risk factors for perinatal transmission of HIV in women treated with AZT. NEJM 1999; 341:385-393 (8/5/99).
3. Garcia PM, Kalish LA, et al. "Maternal levels of plasma HIV rna and the risk of perinatal transmission. NEJM 1999; 341:394-402 (8/5/99).
4. Read et al. International Perinatal Group. "The mode of delivery and the risk of HIV vertical transmission of HIV--a meta-analysis." NEJM 1999; 340:977-987 (4/1/99).
5. Stringer JS et al. "Prophylactic cesarean delivery for the prevention of perinatal HIV transmission. The case for restraint." JAMA 1999; 281:1946-1949 (5/26/99).
6. Parazzini F et al. European Mode of Delivery Collaboration. "Elective cesarean section vs. vaginal delivery: a randomized clinical trial." Lancet 1999; 353:1035.
7. Guay LA, Musoke P, et al. "Intrapartum and neonatal single-dose nevirapine compared with AZT for prevention of mother-to-child transmission of HIV in Kampala, Uganda: HIVNET 012 randomized trial." Lancet 1999; 354:795-802 (9/4/99)
Mark Katz, MD, is the Regional HIV/AIDS Physician Coordinator for Kaiser Permanente of Southern California.
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