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Prevention of Perinatal HIV Infection: Cause For Optimism

The dramatic reduction in the number of cases of perinatal AIDS in the United States from 1985 to 1997 is an example of a phenomenal public health success. This success is attributable to effective collaboration between dedicated clinical researchers, clinicians, public-health officials, HIV-positive pregnant women, and advocacy organizations. It is also attributable in part to advances in the understanding of the timing and mechanism of perinatal transmission, and to more widespread antepartum HIV counseling and testing. However, the two most significant factors in the decreased risk of perinatal transmission in the U.S. are the widespread use of antiretroviral therapy in pregnancy and the modification of obstetrical practices.

Evidence from both observational and cross-sectional studies suggests that HIV infection can be transmitted from mother to infant during the antepartum, intrapartum, and postpartum period.¹ Most perinatal transmission, however, is believed to occur primarily by ascending infection during the intrapartum period. The strongest predictor of both intrauterine and intrapartum transmission is the maternal viral load.^2,3 The timing and mechanism of transmission have implications for therapeutic strategies that use antiretroviral therapy and the modification of obstetrical practices.

Antiretroviral Regimens

ACTG 076 AZT Regimen

In 1994 the U.S. Public Health Service (USPHS) recommended that all HIV-positive pregnant women be informed of the results of Pediatric AIDS Clinical Trial Group Protocol 076 (ACTG 076).⁴ This protocol evaluated the safety and efficacy of AZT versus placebo in HIV-positive pregnant women with less than 6 months of prior antiretroviral therapy and CD4 counts greater than 200 cells/mm³. Women were randomized to receive either placebo or 500 mg of AZT daily during pregnancy, intravenous AZT during labor, and administration of AZT to their neonate for 6 weeks. The risk of perinatal transmission was significantly lower in the AZT group than in the placebo group (8.3% vs. 25.5%, respectively).⁵ AZT's mechanism of action may be reduction of maternal viral load, inhibition of virus in the mother and fetus, or inhibition of virus in the neonate. Analysis of the ACTG 076 data revealed that, in general, the lower the mother's viral load, the less likely she was to transmit HIV to the neonate. However, lower viral load alone did not entirely account for the difference in transmission rates.⁶

Abbreviated Regimens

Data from observational studies in both the U.S. and the developing world have revealed that shorter antiretroviral regimens than those used in ACTG 076 are effective in reducing the risk of perinatal HIV transmission^7,8,9 A retrospective cohort study from the New York State Pediatric HIV PCR Testing Service revealed that the rate of perinatal HIV transmission among 939 HIV-exposed infants varied, depending on the timing of AZT administration. The study covered a two-year period from 1995 to 1997. The authors found that when treatment was begun in the antepartum period, the transmission rate was 6.1%; when it was begun during the intrapartum period, the transmission rate was 10%; when it was begun within the first 48 hours of life, the transmission rate was 9.3%; and when it was begun three days after delivery or later, the transmission rate was 18.4%. In the absence of treatment, the transmission rate was 26.6%.

Based on these findings, the authors concluded that an abbreviated AZT regimen administered up to 48 hours after delivery was effective in reducing the risk of perinatal HIV transmission.⁷

A randomized, double-blind, placebo-controlled trial of HIV-positive pregnant women at two hospitals in Thailand assessed an abbreviated regimen of AZT 300 mg twice daily, starting at 36 weeks' gestation and AZT 300 mg every 3 hours from the onset of labor to delivery. This treatment resulted in a 50% reduction in the rate of perinatal HIV transmission compared with placebo. All mothers in the trial were provided with infant formula and were encouraged not to breast-feed. The authors reported that 80% of the treatment effect was explained by lowered maternal viral load at time of delivery.⁸

Most recently, a randomized clinical trial in central Africa compared intrapartum and neonatal single-dose nevirapine (200-mg dose at onset of labor with a 2-mg/kg dose for the neonate within 72 hours after birth) with AZT (two 300-mg doses at labor, 300 mg every 3 hours during labor, and 4 mg/kg twice daily for seven days to the infant) among 626 breast-feeding HIV-positive mothers. The rate of transmission in the AZT group was 25.1% versus 13.1% in the nevirapine group.⁹ The results from the nevirapine trial have generated enthusiasm among public-health officials in both the industrialized and the developing world. Nevirapine has characteristics that make it attractive for widespread use in the developing world. To begin with, it is very effective in rapidly reducing viral load. It also has a long half-life (approximately 7 days), and so does not require repeated dosing. Finally, it is inexpensive: The cost of the entire nevirapine regimen per patient in the above-mentioned clinical trial was equivalent to roughly $4 U.S.

Taken together, the data from these clinical trials support the current practice in most U.S. centers of offering an abbreviated course of the ACTG 076 regimen to women who present late for prenatal care, women in active labor who are identified as having received no prenatal care, and women who are identified as HIV positive during the immediate postpartum period. However, these women should be informed that such abbreviated regimens are not as effective as the full ACTG 076 regimen.

Combination Therapy

Administration of the AZT regimen during pregnancy is well established and is offered to many HIV-positive women in the U.S. Since the current clinical approach in treating HIV infection is to use combination antiretroviral therapy to maximally suppress viral load, an increasing number of HIV-positive women enter pregnancy already receiving NRTIs. Moreover, in an effort to maximize maternal health, an increasing number of clinicians are prescribing PI-based antiretroviral therapy to pregnant women. Data on the safety and efficacy of combination therapy during pregnancy are limited. Researchers have reported preliminary data on the pregnancy outcome and perinatal-transmission rate in 178 pregnant women on combination antiretroviral therapy. Most of these women had low or undetectable viral loads. There were no documented cases of perinatal HIV transmission.^10,11,12 The USPHS has issued guidelines on the use of antiretroviral therapy during pregnancy that emphasize the importance of including AZT in any regimen designed to avoid perinatal transmission.

Safety of Antiretrovirals

The safety of using antiretrovirals during pregnancy has not been well characterized. In ACTG 076, the most commonly observed maternal and fetal side effect from AZT therapy was a reversible anemia.⁵ Potential long-term side effects on newborns exposed to AZT include cardiac dysfunction, malignancy, and chromosomal breaks.⁴ ACTG 219 is an ongoing trial that will provide long-term follow-up on infants exposed to AZT. Three reverse transcriptase inhibitors -- efavirenz, AZT, and 3TC -- may be toxic to the fetus. In March 1998, the FDA issued a safety alert regarding efavirenz. In one study, newborn monkeys whose mothers were exposed to this drug suffered abnormalities. Of 13 monkeys exposed to efavirenz, 3 had offspring with birth defects: One monkey had a cleft palate, the second had microphthalmia, and the third had anencephaly. The monkeys in the study received doses proportional to those given to humans.¹³ Efavirenz should therefore not be used during pregnancy.

French investigators recently reported 8 cases of mitochondrial toxicity in children exposed to AZT alone or AZT + 3TC. Two of the children -- both exposed to AZT + 3TC -- had severe neurologic disease and died at ages 13 months and 11 months.¹⁴ (see Research Notes in this issue of ACC). The French report prompted the USPHS to convene a Nucleoside Safety Review Working Group in February 1999. The group reviewed death and autopsy records of children entered into the USPHS databases for possible signs of mitochondrial toxicity. A classification system was used to ascertain possible mitochondrial signs and symptoms. Review of 216 deaths yielded no evidence of fatal mitochondrial toxicity in children exposed to antiretroviral therapy. This review process is ongoing and will be expanded to include living AZT-exposed children. The Working Group emphasizes the importance of long-term follow-up in children exposed to antiretrovirals in utero.¹⁵

Modification of Obstetrical Practices

By modifying obstetrical practices, clinicians can minimize the risk of breaks in the fetal skin that may serve as a portal of viral entry and decrease potential for ascending infection. Obstetrical modifications include avoiding artificial rupture of fetal membranes, fetal scalp electrodes, and operative vaginal delivery. Introduction of these modifications into clinical practice has led to a modest decrease in the rate of perinatal transmission. However, the obstetrical modification with the greatest potential to decrease the rate of perinatal HIV transmission is prophylactic cesarean delivery.

Results from the International Perinatal HIV Group meta-analysis, which assessed the effect of mode of delivery on the risk of transmission, provide persuasive evidence that elective cesarean section -- performed before the rupture of membranes -- is associated with a marked reduction in the rate of HIV transmission. This study included data from 8533 pairs of HIV-positive mothers and their infants, obtained from 10 North American and 5 European studies conducted between 1982 and 1996. The meta-analysis revealed a 50% reduction in the rate of HIV transmission among women undergoing elective cesarean section. Moreover, elective cesarean combined with antiretroviral therapy conferred a greater benefit than either intervention alone. The rate of perinatal transmission was 2% among mothers who underwent elective cesarean section and received antiretroviral therapy, versus 7.3% among mothers on antiretroviral therapy who delivered by other modes. The benefits of elective cesarean section persisted after adjusting for potential confounders, including receipt of antiretroviral therapy, maternal disease state, and infant birth weight.¹⁶

As a result of this meta-analysis, the American College of Obstetrics and Gynecology recently issued a committee opinion supporting prophylactic cesarean section. The opinion recommended that all HIV-positive pregnant women be offered an elective cesarean section at 38 weeks' gestation.¹⁷ However, this recommendation is not fully endorsed by all obstetricians. Stringer and colleagues have called for restraint in the use of prophylactic cesarean section to prevent perinatal transmission.¹⁸ These editorialists point out that the meta-analysis data was based on observational rather than randomized clinical trials. They note that most of the data in the meta-analysis was gathered before the advent of potent combination antiretroviral therapy, including PIs and NNRTIs. The additive benefit of cesarean section and antiretroviral therapy seen in the meta-analysis may not apply to women who achieve undetectable viral loads through treatment with newer, more potent regimens. In addition, they caution that the morbidity for cesarean section in HIV-positive mothers is not well characterized. Stringer and colleagues conclude that elective cesarean section should be reserved for women with high viral loads and for those not receiving antiretroviral therapy.¹⁸

Unregistered HIV-Positive Prenatal Patients

Women who receive no prenatal care are more likely to be HIV-positive. These women represent a population that has not shared in the dramatic decrease in the rate of perinatal HIV transmission. The challenge for clinicians is to diagnose HIV infection in this population in time to provide antiretroviral therapy to both the mother and the neonate. The introduction of rapid HIV antibody testing may afford clinicians the opportunity to test women in labor who have not received prenatal care. Thus, women in labor who test positive could be offered antiretroviral therapy, and treatment could be instituted in the newborn pending the results of the mother's Western blot test. Although the rapid test is attractive, its suitability in clinical settings is unknown.

The CDC will soon begin a multicenter observational study, Mother-Infant Rapid Intervention At Delivery (MIRIAD), to ascertain the feasibility of introducing rapid HIV testing for women in labor who have received little or no prenatal care. The results of this study will provide valuable data on the prospects of reducing the rate of perinatal HIV transmission in this difficult-to-access patient population.

Conclusion

Dramatic clinical success in reducing the rate of perinatal HIV transmission has been achieved in the United States over the past decade. If current trends continue, it is not inconceivable that perinatal transmission can be eliminated in the U.S. However, challenges remain. Researchers need to better characterize the immediate and long-term side effects of antiretroviral therapy in pregnancy, as well as the efficacy of elective cesarean section in women with low or undetectable viral loads receiving antiretroviral therapy. As for clinicians, the most significant challenge is now the detection and treatment of HIV infection in women who receive little or no prenatal care; the development of rapid HIV testing provides one possible solution. We have yet to achieve anything close to the same level of success in the developing world that we have attained in the United States and Western Europe. The new data on the high efficacy and low cost of abbreviated nevirapine therapy provide some cause for hope. However, both research and resources need to be dedicated to narrowing the gap between the low rates of perinatal transmission seen in the developed world and the scourge of perinatal AIDS experienced by the developing world.

— Michael K. Lindsay MD, MPH

Dr. Lindsay is Associate Professor and Director, Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics at Emory University in Atlanta.

Published in Journal Watch HIV/AIDS Clinical Care December 1, 1999

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