"The results are the first to provide a baseline on the natural history of HIV blood levels (viral load) in infants and children, and can provide guidance on how to use viral load information to evaluate treatment options for HIV-infected children," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), one of the sponsoring institutes at NIH.
Scientists measured the amount of HIV in the blood of 106 HIV-infected babies from birth up to 5 years of age. The study demonstrated that viral load measurements could be used to predict the severity of disease and suggested that babies with higher viral loads might benefit from antiretroviral treatment. Children with HIV viral loads greater than a 299,000 (median level) virus particles per milliliter (mL) of blood during the first few months of life had a 44 percent probability of progressing to AIDS or death within the first 24 months of life.
For those children with viral loads less than 299,000 (median level) particles/mL, the rate of progression to AIDS or death was only 15 percent. The authors note that although there was no threshold above which all children were rapid progressors, there was a lower threshold below which they saw no progression to overt disease or death. Those infants in the study with viral loads of less than 70,000 particles/mL within the first few months of life did not progress rapidly to AIDS or death within their first 18 months of life.
"The surprise to the investigators," says William T. Shearer, M.D., Ph.D., study chair and professor of pediatrics, microbiology and immunology at Baylor College of Medicine and at Texas Children's Hospital, "was that the very early HIV blood levels may predict the outcome of progression to AIDS in children. Thus, it may be important to determine HIV RNA levels very early in life."
Patients in the study were participants in the Women and Infants Transmission Study (WITS), a multicenter natural history study of HIV-infected pregnant women and their infants. The infants in this study were born between Jan. 8, 1990, and Dec. 3, 1993. Of the 619 children born to HIV-infected mothers in the WITS group during this period, 114 were perinatally infected with HIV. Of these, 106 were available to participate in the study. To measure fluctuations in viral load, investigators collected plasma at birth and at 1, 2, 4, 6, 12, 15 and 18 months of age, and every six months thereafter. They determined viral load using reverse transcription polymerase chain reaction methods to measure amounts of HIV ribonucleic acid (RNA) in stored blood specimens.
All infants in this study were born prior to the closing of the AIDS Clinical Trials Group 076 study, in which the administration of zidovudine during pregnancy, labor and to the newborn for the first 6 weeks of life was shown to decrease significantly risk of HIV transmission. Since March 1994, women have been counseled on the benefits of using zidovudine to prevent HIV perinatal transmission to their infants.
The median viral load for all of the infants in this study was 318,000 particles/mL of blood at 1 month of age and 256,000/mL at 2 months. Viral load levels then slowly declined to a median of 34,000 particles/mL at 24 months of age. The researchers found that infants whose first positive HIV culture was at 48 hours of age or younger showed higher HIV RNA blood levels during their first 2 months of life than those infants whose first positive HIV culture was not until 7 days of age or older. Predictably, infants with rapid disease progression had high peak HIV levels (median 724,000 particles/mL) from birth to 2 months. Infants who did not show rapid progression had lower peak values (219,000 virus particles/mL).
"The dynamics of viral replication in these HIV-infected infants are distinctly different from those observed in infected adults," says Thomas C. Quinn, M.D., senior investigator at NIAID and professor of medicine at Johns Hopkins University. "Following a dramatic rise in viremia during their first month of life, the viral burden remains very high in infants in contrast to the sharp decline usually seen in adults. This persistently high viremia may partially explain the more rapid progression to AIDS observed in infants compared to adults, and further underscore the need for early antiretroviral therapy."
The prospective observational study was conducted at multiple sites by scientists at several collaborating institutions. In addition to Drs. Shearer and Quinn, contributing authors on the article are: Philip La Russa, M.D., Columbia Presbyterian Hospital, N.Y.; Judy F. Lew, M.D., NIAID, Bethesda, Md.; Lynne Mofenson, M.D., National Institute of Child Health and Human Development (NICHD), Bethesda, Md.; Susan Almy, M.S., New England Research Institutes, Watertown, Mass.; Kenneth Rich, M.D., University of Illinois at Chicago; Edward Handelsman, M.D., State University of New York Health Science Center at Brooklyn; Clemente Diaz, M.D., University of Puerto Rico, San Juan; Marcello Pagano, Ph.D., Harvard School of Public Health, Boston; Vincent Smeriglio, Ph.D., National Institute on Drug Abuse (NIDA), Rockville, Md.; and Leslie A. Kalish, D.Sc., New England Research Institutes, Watertown, Mass.
The WITS study is supported by the NIAID, NICHD and NIDA of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies.
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