February 1997
NEW YORK — HIV infection doesn't mean what it used to.
Beginning with the dramatic results of the ACTG 076 study, which showed that zidovudine (ZDV) reduced a mother's risk of transmitting HIV to her newborn baby, up to the exciting advances in therapy, HIV infection is not the same disease it was at the beginning of the epidemic. (See related story on page 30.)
"With improved therapy over the last two years, our approach to an HIV-infected individual is changing," said Andrew Wiznia, MD, director of pediatric HIV services, Bronx Lebanon Hospital Center. "This is no longer a chronic, debilitating illness that has to result in death. Those of us in the field are believing that we can turn this illness into something like diabetes; that it is an illness that is present, and if you can control it, you can delay the onset of symptoms and of consequences later on," Wiznia said at the Ninth Annual Infectious Diseases in Children Symposium
"The epidemic of pediatric HIV infection closely mirrors the epidemic of HIV infection in women of childbearing age," Wiznia said. "Women of childbearing age who acquire HIV infection usually acquire their infection or are involved in high-risk activity during their adolescence. The treatment of HIV infection should be the treatment we have used for a number of infectious diseases, and that is prevention. If we can prevent women of childbearing age from becoming infected, we are going to affect the pediatric HIV epidemic."
Prior to the use of ZDV (Retrovir, Glaxo) maternal-infant transmission was approximately 25%, said Wiznia, who is also associate professor of pediatrics, Albert Einstein College of Medicine. Breastfeeding increased the risk by another 5% to 10%.
"The major breakthrough in HIV was in the AIDS Clinical Trial Group 076 study done in 1991," Wiznia said. "It was an attempt to interrupt HIV transmission from an infected women to her baby. It was a best-shot therapy, which means when the study started we did not have a good handle as to when transmission occurred, so therapy was given during the intrapartum period, during the antepartum period, and to the newborn. The placebo group showed a transmission rate of about 25%; in the ZDV-treated group, the transmission rate was about 7%. By using this therapy, ZDV reduced the transmission rate by two-thirds. However, it didn't answer the question: which part of the therapy caused this reduction in transmission?"
The theory was that as an antiviral, ZDV would reduce the mother's viral load and also the baby's risk of exposure. Further analysis of the results of the 076 study, however, suggest that this may not be exactly what happens. Transmission occurred across all levels of viral load, Wiznia said, although the lower levels tended to have reduced transmission.
"The bottom line is even at the lowest level of viremia, there was still transmission. That is the point: there is significant overlap of [viral load] between transmitters and non-transmitters; therefore, [viral load] cannot reliably be used to predict maternal-infant transmission," Wiznia said.
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Four key pieces of information suggest that most infants are getting infected at the time of delivery, not in utero. The first piece came from a retrospective study of twins, Wiznia said. It showed that, in a spontaneous vaginal delivery, the first-born twin was twice as likely as the second twin to be infected with HIV.
The second piece is from polymerase chain reaction (PCR) results. Only a third of HIV-infected infants will have a positive PCR at birth or within the first week of life.
"Maybe the reason for that is very simple: they are being infected during the time we are drawing these blood samples," Wiznia said. "So at 1 or 2 days of life, there is maybe no virus detectable in the blood, but at 4 weeks of life we can find it."
Maternal virology data provides the third piece of information.
"If it was so simple that ZDV lowered viral levels in the mother and that was what was interrupting transmission, then we should have found a line below which there was no transmission," Wiznia said. "We didn't find that."
Finally, prolonged rupture of the membranes increases the risk of transmission from the mother to the baby. Four hours appears to be the line of demarcation; the risk of HIV transmission increases for infants born more than four hours after membranes rupture.
"When you look clinically at HIV-infected children, they fall into two groups: those who progress rapidly, that is about 20% of children, and those who progress slowly, which is about 80% of the population we care for. The thought is that the rapid progressors are acquiring the virus in utero and the slow progressors are getting it at the time of delivery. There are some data that suggest cesarean sections prevent the transmission of virus, but it is retrospective, not prospective, and there is a tremendous amount of bias in that," Wiznia said.
Since publication of the 076 study, the Centers for Disease Control and Prevention (CDC) as well as state health departments have issued guidelines stating that pregnant women infected with HIV should receive ZDV therapy. But how has this translated into everyday practice?
Apparently, not as well as would have been expected. Although the CDC reported that the maternal-infant transmission rate across the country fell about 30% from 1993 to 1994, Wiznia found less dramatic results in the Bronx.
"What happened to the first 49 HIV-infected women to whom we offered ZDV? Of the first 49, 12 refused therapy, 36 said yes," he said. "Of those agreeing to treatment, we found that eight missed their intrapartum doses, four didn't take any antepartum therapy and missed their intrapartum dose. Of the 49 mothers whom we approached, 24 successfully took therapy. When we looked to see what factors were associated with this, it actually surprised us. It didn't have anything to do with whether they previously had an HIV-infected infant or what their CD4 counts were, how long they had been infected, or their race. The factors that caused mothers to reject ZDV therapy was having IV drug use as a risk factor and continued drug use during pregnancy. When we looked at what factors affected adherence to therapy, once again it was drug use.
"HIV infection cannot be looked at solely as HIV infection," Wiznia continued. "It has to be dealt with within the socioeconomic conditions that the epidemic is in. We know that HIV is an epidemic in subpopulations. ... During the period that we were identifying those 49 women, there were 125 women at our hospital who were seropositive when they delivered. So in essence, we were able to treat only 24 of 125 HIV-infected babies to prevent transmission."
Scattered cases have been reported in which HIV-positive infants sero-reverted and were antibody-negative by 4 to 5 years of age, Wiznia said. In a study of 140 children, repeated PCR cultures could detect no latent virus.
"Basically, if the baby is HIV antibody-positive and at 10 months or 12 months of age and becomes antibody negative, which we call sero-reverters, and he is immunologically and clinically normal, you can rest assured that he is probably not HIV-infected," he said.
The symposium was sponsored by Montefiore Medical Center and Infectious Diseases in Children.
For more information:
- Wiznia AA. Pediatric HIV infections: approach to an HIV-infected child. Presented at the Ninth Annual Infectious Disease in Children Symposium. Nov. 24, 1996. New York.
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FDA approved, liquid formulation
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Lamivudine (3TC, Epivir, Glaxo) |
FDA approved, no liquid formulation |
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Nevirapine (Viramune, Boehringer Ingelheim) |
No FDA-approved liquid formulation although studies have been done |
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Stavudine (d4t, Zerit, BMS) |
FDA approved, no liquid formulation |
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Zalcitabine (ddC, Hivid, Roche) |
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ZDV-3TC combo (Glaxo) |
New drug; few pediatric
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Zidovudine (ZDV, Retrovir, Glaxo) |
FDA approved, liquid formulation
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Indinovir (Crixivan, Merck) |
Difficult to put into a liquid
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Ritonavir (Norvir, Abbott) |
FDA provisionally approved
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Saquinavir (Invirase, Hoffmann-LaRoche) |
No liquid formulation |
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