March 1997
WASHINGTON, D.C. – "If we identify a child as being HIV infected we need to intervene immediately, regardless of what the viral load is," said John L. Sullivan, MD, said here at the Fourth Annual Conference on Retroviruses and Opportunistic Infections.
Sullivan discussed the need for early therapy to interrupt transmission of HIV and suppress replication of the virus. Knowing the maternal and infant viral load is of interest to the pediatrician in terms of telling him or her about the biology of the disease, but immediate treatment of the infant should be the focus of the physician's attention, said Sullivan, vice chairman of research, department of pediatrics, University of Massachusetts Medical School. This treatment should take place within the first few weeks of life because the virus is transmitted to the infant during two key periods — in utero or during the intrapartum period.
Sullivan profiled an infant who was infected in utero. The virus could be isolated from the child's peripheral blood mononuclear cells at birth, he said. This infant was ICD P24 positive, 49,000 virions/mL and DNA PCR positive. Over subsequent weeks, the child suffered a burst of viremia and viral load increased dramatically.
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In a child who fits the intrapartum transmission profile, the cord blood is negative, or in the first 24 hours of life the virus cannot be isolated. The RNA is negative and so is the DNA, said Sullivan, who is also a professor of pathology, molecular biology and genetics. If the child is followed, however, all of these become positive within the next several weeks. He gave an example of one infant who was virus negative at birth, but at 4 weeks of age had plasma that showed positive PBMCs, with 2.3 million virions/mL; RNA PCR and DNA PCR were also positive.
"Now the events in between here are not so clear at this point, but we think that somewhere toward the end of the first week is when intrapartum infected patients will begin to become virus positive," he said.
As a member of the executive committee of the Pediatric AIDS Clinical Trials Group (ACTG), Sullivan said the group's goal is to develop and implement combination retroviral protocols in early vertical HIV-1 infection to achieve a 10-year survival with normal immune function. Technology has advanced to the point that an infant can be identified as HIV positive within the first few days of being born. Many laboratories around the country that are connected with ACTG are doing DNA PCRs once or twice a week, Sullivan said. This means that if a pediatrician sends a blood sample to the lab from a baby who is born on Monday, he or she can know by the end of that week whether that baby is infected.
"In addition, we encourage people to follow these babies very closely over the first few weeks of life, so that as soon as you make a diagnosis you have the ability to intercede with a variety of antiretroviral regimens," he said.
It is during these first few weeks of life that the virus is beginning to replicate itself and expand throughout the infant's lymphoreticular system, Sullivan said. This is also the time that the virus is most homogenous. "We also know, from the work of Doug Richman, David Ho and George Shaw, that at that point we have the ability, if one uses a combination of antiretroviral agents, of completely suppressing viral replication," he said.
Sullivan referred to a study by Ann Krivine that showed the RNA levels in infants infected in utero. Within a short period following birth, these infants showed a burst of virus into the hundreds of thousands of copies. She also studied infants who were infected during the intrapartum period and their RNA levels shot up within the first four to six weeks following birth, Sullivan said.
Intervention within these first few weeks is key in treating infected babies. "We know that high level resistance to reverse transcriptease inhibitors and protease inhibitors requires the cumulative acquisition of as many as five or more mutations, and in order for these mutations to occur there must be many rounds of replication," Sullivan said. "So, if one can intervene when the virus population is very homogenous, then one has the ability to suppress prior to these mutations appearing. Combination therapy with three or more antiretroviral agents should be used to achieve complete and durable suppression of viral replication."
One example of therapy which intervened in time to suppress viral replication was a baby who was part of a triple therapy protocol that was presented at the conference by Katherine Luzuriga. In this protocol nevirapine, zidovudine and didanosine were used to treat infants infected during the first two to three months of their lives. One of the infected babies, who had been DNA PCR negative on the ninth day after birth, subsequently became DNA PCR positive, with 290,000 copies of RNA, in the eighth week.
Triple therapy began during the 10th week. Soon after therapy was initiated, the child went from 370,000 copies of RNA to becoming culture and RNA negative. This child, who is now approaching 2 years of age, remains culture negative. Sullivan showed a slide of the child's Western blot, which showed that the infant had become ELISA antibody negative and Western blot negative. And, thus, the child also remains HIV antibody negative.
Another way of interrupting transmission of the virus between mother and child is for the mother to undergo a regimen of antiretroviral therapy before giving birth. A Phase I trial recently completed by the ACTG (ACTG 250) looked at the safety and pharmacokinetics in neonates born to infected mothers. In this study pregnant women were given a single 200 mg oral dose of nevirapine when they came to the hospital in labor. At delivery, which occurred three to seven hours after dosing, the nevirapine had a concentration of 1,240 ng/mL and the cord blood was 1,192 ng/mL. These are more than 100 times the inhibitory concentration for HIV-1. The cord blood to maternal nevirapine ratio was 82%, showing that the drug crosses the placenta very well, Sullivan said.
Whether the various antiretroviral drugs are given to the infected mother during labor or to the exposed baby after birth, the important point is that these therapies should be developed to eliminate vertical transmission. A prompt response on the part of the pediatrician will lead to the ACTG achieving its goal of long-term control of HIV replication.
For more information:
- Sullivan J. Perinatal transmission and early virus replication events in babies. Presented at the Fourth Annual Conference on Retroviruses and Opportunistic Infections. Jan. 22-26. Washington, D.C.
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