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Efficacy of zidovudine in preventing HIV transmission from mother to infant
Efficacy of Zidovudine from Mother to Infant
in Preventing
HIV Transmission
James Balsley, MD, PhD, Bethesda, Maryland
I
n 1994, the Pediatric AIDS Clinical Trials Group (ACTG) Protocol 076 study demonstrated that zidovudine reduced the risk of maternal-infant HIV-l transmission by 67%.’ However, the mechanism of zidovudine’s protective effect was unknown. More recently, HIV-1 RNA levels from samples of maternal blood obtained at study entry and delivery have been analyzed.’ These data, summarized below, indicate that the reduction in perinatal HIV transmission due to zidovudine treatment is only partly explained by reduction in maternal HIV-l RNA levels. Therefore, these data provide indirect support for the concept that antiretroviral drugs can be efficacious prophylactic agents.
OVERVIEW OF THE 076 STUDY ACTG Protocol 076 was a randomized, placebocontrolled clinical trial designed to evaluate the efficacy, safety, and tolerance of zidovudine for the prevention of maternal-fetal HIV transmission. This multicenter study was conducted in 59 centers in the United States and France.“’ Eligible patients included HIV-infected pregnant women (14-34-week gestation) who had no antiretroviral treatment during the current pregnancy, baseline CD4+ lymphocyte counts >200 cells/mm’, and no clinical indications for maternal antiretrotiral therapy. Women were stratified according to gestational age and randomized to receive either zidovudine or placebo. The zidovudine regimen consisted of antepartum zidovudine (100 mg orally five times daily) plus intraparturn zidovudine (intravenous loading dose, 2 mg/kg, followed by a continuous infusion (1 mg/kg/hour, until delivery), plus newborn zidovudine syrup (2 mg/ kg every 6 hours for 6 weeks beginning 8-12 hours after birth). The control arm was identical except that placebo was used. The trial began accruing patients early in 1991 and had several ACTG Data and Safety Monitoring Board (DSMB) reviews. In February 1994 the DSMB reviewed the interim analysis and concluded that there was significant evidence of treatment efficacy. The
Am J Med. 1997;102(5B):45-46. From the National Institute of Allergy and lnfecttous Diseases, thesda, Maryland. Requests for reprints should be addressed to James Balsley, Immune, Inc., 35 W. Watkins MIII Road, Galthersburg, Maryland.
‘1997 by Excerpta All rights reserved.
Medica,
Inc.
BeMD, Med
study results were first published in November 1994l and were updated recently.” The estimated risk of transmission was 7.6% in the treatment grloup (95% confidence interval [CI] 4.3-12.3%) and 22.6% in the placebo group (95% CI 17.0-29.0%). The difference in risk was statistically significant (p
VIROLOGIC
DATA
At the initiation of the trial, methods for quantitative measurements of plasma RNA were not widely available. However, maternal plasma was collected at entry, intrapartum, and at 6 months postpartum. Plasma samples were stored at -70” C and retained on site. Subsequently, they were analyzed by each of two methods: a second-generation branched-chain DNA (bDNA) amplification method (Chiron; Emeryville, CA) and a quantitative reverse trans’criptionpolymerase chain reaction (RT-PCR) assay (Amplicar HIV Monitor Test, Roche Molecular Systems; Branchburg, NJ). Results of these studies have been recently published in detail.” The patients included in this study were :relatively healthy women who had early HIV disease. Maternal plasma HIV RNA levels were determined only at study entry and again at the time of delivery. The RNA levels at study entry were generailly IOO100,000 HIV copies/ml. The duration of treatment ranged from several weeks to as long as 24 weeks. Data are not available to evaluate the maximum treatment effect on plasma RNA for i:ndividual women, because interval samples were not available for testing. Using the RT-PCR assay, the median reduction in RNA levels was 0.28 log for those in the zidovudine group and 0.04 log for those in the placebo group.” Transmission of HIV from mother to infant occurred at all levels of maternal RNA load. There was no threshold below which transmission did not occur, although there was a higher risk of transmission from mothers with higher RNA levels. In the placebo group, the transmission rate was 41.7% in the quartile with >15,700 RNA copies/ml using the RT-PCR assay, compared with >7.1% in the quartile with < 1,730 copies/ml.”
MECHANISM
OF ZIDOVUDINE
EFFECT
A logistic-regression model was used to determine the proportion of zidovudine treatment effect, which could be explained by the reduction in maternal HIV ooo2-9343/97/$17.00 PII SOOO2-9343(97)OOD60-0
45
SYMPOSIUM ON HIV POSTEXPOSURE
MANAGEMENT/BALSLEY
RNA levels from study entry to delivery. The change in maternal HIV RNA level accounted for only approximately 16.6% (95% CI 3.9-41.2%) of the zidovudine treatment effect.” What other mechanisms might be operating to explain the treatment benefit? The study was not designed to address this question. Zidovudine freely crosses to the fetus during pregnancy, and the babies are born with levels that are equivalent to the maternal levels. Therefore, the infants have had exposure to zidovudine during most, if not all, of the time that we believe most transmission occurs. It is possible that some of the treatment benefit is due to fetal and/or neonatal prophylaxis. In other words, zidovudine may have prevented infection in some infants who were exposed to maternal virus.
REFERENCES 1. Conner mission
EM, Sperling RS, Gelber of human immunodeficiency
R, et al. Reduction of maternal-infant transvirus type 1 with zidovudine treatment. N
Engl JMed. 1994;331:1173-1180. 2. Sperkng RS, Shapiro DE, Coombs RW, et al. Maternal vrral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med. 1996;335:1621-1629.
DISCUSSION Martin S. Hirsch, MD (Boston, Massachusetts): Did you quantify the amount of maternal HIV that was actually infectious? James Balsley, MD (Bethesda, Maryland): No. We do not know if the viral load reduction measured
46
May 19, 1997
The Amencan
Journal
of Medicrne’”
Volume
102
(58)
by RNA RT-PCR accurately reflects a reduction in infectious virus. Susan Wilburn (Washington, DC): Did you measure compliance with the treatment regimen? Dr. Balsley: We have no detailed information about compliance. Some of the therapy was observed. Obviously, the IV administration during labor was observed, and about 85% of the women received IV medication during labor. The other 15%generally did not receive it, because they delivered on the way to the hospital or delivered so precipitously after arrival that treatment was not possible. We also know that the infants received the medication during the first couple of days in the hospital, because it was administered by the nursing staff. Other than that, we have only patient reports to evaluate ,adherance. Lawrence Corey, MD (Seattle, Washington): I need to react to your comment that 16% of the reduction can be explained by the zidovudine effect. Postexposure prophylaxis of the infant may be important, but it is well recognized that zidovudine’s clinical effect has always been greater than its antiretroviral effect. Dr. Balsley: I tried to make it clear that we think the reduction in maternal RNA can explain 16%and that the rest of the benefit is unexplained. Among the possibilities might be pre- or postexposure prophylaxis. Certainly there are other possibilities, e.g., enhancement of the maternal immune system.
in Preventing
HIV Transmission
James Balsley, MD, PhD, Bethesda, Maryland
I
n 1994, the Pediatric AIDS Clinical Trials Group (ACTG) Protocol 076 study demonstrated that zidovudine reduced the risk of maternal-infant HIV-l transmission by 67%.’ However, the mechanism of zidovudine’s protective effect was unknown. More recently, HIV-1 RNA levels from samples of maternal blood obtained at study entry and delivery have been analyzed.’ These data, summarized below, indicate that the reduction in perinatal HIV transmission due to zidovudine treatment is only partly explained by reduction in maternal HIV-l RNA levels. Therefore, these data provide indirect support for the concept that antiretroviral drugs can be efficacious prophylactic agents.
OVERVIEW OF THE 076 STUDY ACTG Protocol 076 was a randomized, placebocontrolled clinical trial designed to evaluate the efficacy, safety, and tolerance of zidovudine for the prevention of maternal-fetal HIV transmission. This multicenter study was conducted in 59 centers in the United States and France.“’ Eligible patients included HIV-infected pregnant women (14-34-week gestation) who had no antiretroviral treatment during the current pregnancy, baseline CD4+ lymphocyte counts >200 cells/mm’, and no clinical indications for maternal antiretrotiral therapy. Women were stratified according to gestational age and randomized to receive either zidovudine or placebo. The zidovudine regimen consisted of antepartum zidovudine (100 mg orally five times daily) plus intraparturn zidovudine (intravenous loading dose, 2 mg/kg, followed by a continuous infusion (1 mg/kg/hour, until delivery), plus newborn zidovudine syrup (2 mg/ kg every 6 hours for 6 weeks beginning 8-12 hours after birth). The control arm was identical except that placebo was used. The trial began accruing patients early in 1991 and had several ACTG Data and Safety Monitoring Board (DSMB) reviews. In February 1994 the DSMB reviewed the interim analysis and concluded that there was significant evidence of treatment efficacy. The
Am J Med. 1997;102(5B):45-46. From the National Institute of Allergy and lnfecttous Diseases, thesda, Maryland. Requests for reprints should be addressed to James Balsley, Immune, Inc., 35 W. Watkins MIII Road, Galthersburg, Maryland.
‘1997 by Excerpta All rights reserved.
Medica,
Inc.
BeMD, Med
study results were first published in November 1994l and were updated recently.” The estimated risk of transmission was 7.6% in the treatment grloup (95% confidence interval [CI] 4.3-12.3%) and 22.6% in the placebo group (95% CI 17.0-29.0%). The difference in risk was statistically significant (p
VIROLOGIC
DATA
At the initiation of the trial, methods for quantitative measurements of plasma RNA were not widely available. However, maternal plasma was collected at entry, intrapartum, and at 6 months postpartum. Plasma samples were stored at -70” C and retained on site. Subsequently, they were analyzed by each of two methods: a second-generation branched-chain DNA (bDNA) amplification method (Chiron; Emeryville, CA) and a quantitative reverse trans’criptionpolymerase chain reaction (RT-PCR) assay (Amplicar HIV Monitor Test, Roche Molecular Systems; Branchburg, NJ). Results of these studies have been recently published in detail.” The patients included in this study were :relatively healthy women who had early HIV disease. Maternal plasma HIV RNA levels were determined only at study entry and again at the time of delivery. The RNA levels at study entry were generailly IOO100,000 HIV copies/ml. The duration of treatment ranged from several weeks to as long as 24 weeks. Data are not available to evaluate the maximum treatment effect on plasma RNA for i:ndividual women, because interval samples were not available for testing. Using the RT-PCR assay, the median reduction in RNA levels was 0.28 log for those in the zidovudine group and 0.04 log for those in the placebo group.” Transmission of HIV from mother to infant occurred at all levels of maternal RNA load. There was no threshold below which transmission did not occur, although there was a higher risk of transmission from mothers with higher RNA levels. In the placebo group, the transmission rate was 41.7% in the quartile with >15,700 RNA copies/ml using the RT-PCR assay, compared with >7.1% in the quartile with < 1,730 copies/ml.”
MECHANISM
OF ZIDOVUDINE
EFFECT
A logistic-regression model was used to determine the proportion of zidovudine treatment effect, which could be explained by the reduction in maternal HIV ooo2-9343/97/$17.00 PII SOOO2-9343(97)OOD60-0
45
SYMPOSIUM ON HIV POSTEXPOSURE
MANAGEMENT/BALSLEY
RNA levels from study entry to delivery. The change in maternal HIV RNA level accounted for only approximately 16.6% (95% CI 3.9-41.2%) of the zidovudine treatment effect.” What other mechanisms might be operating to explain the treatment benefit? The study was not designed to address this question. Zidovudine freely crosses to the fetus during pregnancy, and the babies are born with levels that are equivalent to the maternal levels. Therefore, the infants have had exposure to zidovudine during most, if not all, of the time that we believe most transmission occurs. It is possible that some of the treatment benefit is due to fetal and/or neonatal prophylaxis. In other words, zidovudine may have prevented infection in some infants who were exposed to maternal virus.
REFERENCES 1. Conner mission
EM, Sperling RS, Gelber of human immunodeficiency
R, et al. Reduction of maternal-infant transvirus type 1 with zidovudine treatment. N
Engl JMed. 1994;331:1173-1180. 2. Sperkng RS, Shapiro DE, Coombs RW, et al. Maternal vrral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med. 1996;335:1621-1629.
DISCUSSION Martin S. Hirsch, MD (Boston, Massachusetts): Did you quantify the amount of maternal HIV that was actually infectious? James Balsley, MD (Bethesda, Maryland): No. We do not know if the viral load reduction measured
46
May 19, 1997
The Amencan
Journal
of Medicrne’”
Volume
102
(58)
by RNA RT-PCR accurately reflects a reduction in infectious virus. Susan Wilburn (Washington, DC): Did you measure compliance with the treatment regimen? Dr. Balsley: We have no detailed information about compliance. Some of the therapy was observed. Obviously, the IV administration during labor was observed, and about 85% of the women received IV medication during labor. The other 15%generally did not receive it, because they delivered on the way to the hospital or delivered so precipitously after arrival that treatment was not possible. We also know that the infants received the medication during the first couple of days in the hospital, because it was administered by the nursing staff. Other than that, we have only patient reports to evaluate ,adherance. Lawrence Corey, MD (Seattle, Washington): I need to react to your comment that 16% of the reduction can be explained by the zidovudine effect. Postexposure prophylaxis of the infant may be important, but it is well recognized that zidovudine’s clinical effect has always been greater than its antiretroviral effect. Dr. Balsley: I tried to make it clear that we think the reduction in maternal RNA can explain 16%and that the rest of the benefit is unexplained. Among the possibilities might be pre- or postexposure prophylaxis. Certainly there are other possibilities, e.g., enhancement of the maternal immune system.