A recent article in The New England Journal of Medicine ("Abbreviated Regimens of Zidovudine Prophylaxis and Perinatal Transmission of the Human Immunodeficiency Virus," 329:211, 1409-1414), outlines the results of a retrospective chart review of obstetrical cases in the New York State area. These cases were significant because zidovudine (Retrovir) was given not in the manner prescribed by results of previous clinical trials, but rather in shorter abbreviated courses.
Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 in 1994 established a standard for the treatment for prevention of transmission of HIV from mother to infant. This type of transmission is generally referred to as "vertical" transmission. In this study zidovudine was given in three stages. First, zidovudine was given to the mother orally after fourteen weeks gestation and continued throughout the pregnancy. Giving drug during pregnancy is "antepartum" treatment. Second, zidovudine was given intravenously during delivery ("intrapartum" treatment). Finally, the newborn was given zidovudine orally for six weeks following birth ("postpartum' treatment).
PACTG 076 resulted in a significant reduction of vertical transmission when zidovudine was administered according to the regimen outlined by the study. Without the use of zidovudine, 25.5% of infants were born HIV-infected. The addition of zidovudine lowered the vertical transmission rate to 8.3%. This is a significant reduction and a source of some comfort for many mothers. The drawbacks of this three-part regimen include cost, the fact that many women lack access to prenatal care and the forcible addition of, or change to zidovudine if a mother is to follow the regimen exactly.
Change in the PACTG 076 three-part regimen has been slow for two reasons. First, research about the pharmacokinetics and safety of many of the antiretroviral drugs has not been established. To date, pharmacokinetic studies have been completed only for zidovudine and lamivudine (Epivir). The second impediment to change involves an ethical consideration. Can pregnant women fairly be asked to take a reduced or changed regimen from that of PACTG 076 and risk HIV infection to their newborns? Comparative trials designed to test a different or lesser regimen must ask women to take such a risk—an unacceptable risk in the United States and probably in most of the world.
The study analyzed in The New England Journal of Medicine article avoids the ethical concerns by reviewing charts of women who for one reason or another resorted to a lesser regimen than that outlined in PACTG 076.
In 1995 the New York State Department of Health established a pediatric diagnostic testing service that offers viral load (plasma HIV RNA) testing to infants. The viral load requisition forms require demographic information including information about whether antiretroviral prophylaxis has been administered during the prenatal period, intrapartum period, within 48 hours after birth or from 3 to 42 days of life.
The study reviewed the charts of two groups. The Study Cohort included infants that were 180 days old or younger at the time of collection, where the blood collection and the test results were completed between August 1, 1995 and January 31, 1997. The Validation Sample was a subgroup of the first group. It included infants whose viral load test was submitted from the same facility where they were born and where maternal, neonatal and pediatric medical records were accessible. Forms were sent to the treating physician or head of the clinic to verify the information contained in the requisition forms.
Among the reasons given for the abbreviated zidovudine regimens were the following:
The results of the abbreviated zidovudine regimens were as follow. Among the women receiving zidovudine during the prenatal period the percentage of vertical transmission was 6.1% in the Cohort Study and 5% in the Validation Sample. This result represented the lowest rate of transmission. The highest rate of vertical transmission was among the cases where zidovudine was not administered either to the mother or the infant. In such cases the transmission rates were 26.6% and 25% for the Cohort Study and the Validation Sample, respectively. In addition, the administration of zidovudine after 3 days of birth resulted in equally disappointing rates of transmission. The Cohort Study reported a transmission rate of 18.4%, while the Validation Sample reported a transmission rate of 25% when zidovudine was administered 3 days after birth or later.
Intrapartum treatment with zidovudine and treatment within 48 hours of birth, however, resulted in significant reduction in transmission. When zidovudine was administered intrapartum the transmission rate was reduced to 10% in the Study Cohort and 5.3% in the Validation Sample. When zidovudine was administered within 48 hours of birth, again, the transmission rates were reduced to 9.3% in the Cohort Study and 9.5% in the Validation Sample.
After adjustment for variables such as sex, race or ethnic group, age at viral load test, birth weight and timing of initiation of zidovudine prophylaxis, the results show that not only prenatal treatment, but also intrapartum treatment and treatment within 48 hours of birth are "significantly associated with a reduction in the risk of HIV transmission."
What is the significance of these observations? These results raise practical questions of clinical importance. Can abbreviated courses of zidovudine be effective? Can transmission be avoided if zidovudine is only given to the infant after birth without treatment of the mother? Should an HIV-infected mother be counseled to take zidovudine treatment at the time of delivery even if there has been no previous treatment? These early results of a small study indicate that intrapartum treatment and treatment within 48 hours of birth may be effective ways of preventing vertical transmission.
The results of this study also raise more fundamental questions about the timing of transmission and the role of zidovudine as a prophylactic. Are some children infected at or just before birth? Are other children infected in utero, that is, in the womb? What effect does zidovudine treatment have and when does that effect become therapeutic?
Significant reduction in vertical transmission occurring without prenatal treatment and with only intrapartum treatment and treatment within 48 hours of birth, seems to indicate that a significant percentage of vertical transmission occurs at or just before birth. Other experiences argue in favor of such late transmission. For instance, there have been cases of twins where one twin is HIV-infected and the other is not. Also, the risk of transmission can be associated with the length of time between rupture of membranes and birth.
The authors argue that perhaps the use of zidovudine intrapartum or in the child after birth implies that zidovudine acts not as a barrier against exposure but as a treatment after exposure. Treatment given after exposure to HIV is generally referred to as "post-exposure prophylaxis." This assertion is supported by certain facts. For instance, PACTG 076 treatment with zidovudine reduced maternal HIV titers (levels of virus) only marginally. Without significant reductions of HIV levels in the mother it is unlikely that this reduction alone is responsible for protection of the fetus. Further, health care workers who are exposed accidentally to HIV through needle sticks can similarly reduce their risk of seroconversion through post-exposure prophylaxis.
The certainty of these results is weakened primarily by the small sample sizes of the different groups and by the fact that bias can sometimes be introduced into a study that is retrospective. At the very least this study confirms the results of PACTG 076 and hints strongly at the possibility that shorter courses of zidovudine may provide the necessary intervention to prevent vertical transmission.
In the January 13, 1999 issue of The Journal of the American Medical Association scientists reported on a follow-up, observational study to PACTG 076. The Abstract entitled "Lack of Long-term Effects of In Utero Exposure to Zidovudine Among Uninfected Children Born to HIV-Infected Women" describes a study of infants who had been in the PACTG 076 and had escaped infection with HIV.
In all, 234 uninfected children participated in this study known as PACTG 219. One hundred and twenty-two of the children were from the zidovudine branch of the study, that is, the branch of the study where the mother and child received zidovudine in the three-part regimen described in the above article. The remaining 112 children were from the group that received a placebo instead of zidovudine.
Measurements and observations were made every six months for children younger than 24 months and yearly thereafter, unless otherwise clinically indicated. Parameters measured included physical growth, cognitive and developmental function, immunological function and occurrences of cancer and death. The median age of the children was 4.2 years, with the youngest being 3.2 years old and the oldest being 5.6 years old.
The results indicated that there were no significant differences between children exposed to zidovudine and those who received placebo. Physical growth, cognitive, developmental and immunological functions were all similar and most importantly, no deaths or malignancies had developed. Three children in the zidovudine group had abnormalities that are being followed-up. Two had ophthalmic abnormalities that could not be explained and one child had a mild cardiomyopathy but was clinically asymptomatic.
Zidovudine: generic name for the drug commonly known as AZT.
Intravenously: injected directly into the vein.
Pharmacokinetics: the extent that the body is able to absorb, distribute and eliminate a drug over time.
Comparative trial: a trial in which a drug is compared to another drug or no drug (placebo).
Antiretroviral prophylaxis: administering a drug or drugs that suppress or stop the activity of a retrovirus in the hope that exposure to the retrovirus will not result in infection with that retrovirus.
Placebo: a comparison substance against which experimental drugs are compared. Traditionally a placebo is an inactive substance.
Ophthalmic: of or relating to the eye.
Cardiomyopathy: a disease or disorder of the heart muscle.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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