THE INTERPRETATION OF HIV ANTIBODY TESTS IN INFANTS
In 1987 the Centers for Disease Control convened a panel of consultants representing the
American Academy of Pediatrics and eight other disciplines to develop a classification system for
HIV infection in children.1 The CDC reported “Most of the consultants believed that passively
transferred maternal HIV antibody could sometimes persist for up to 15 months” and a positive
test thereafter was considered proof for HIV infection. In 1991 the CDC convened another group
of consultants and three years later reported that maternal HIV antibody “occasionally remains
detectable until 18 months of age. Therefore, standard anti-HIV IgG antibody tests cannot be
used to indicate reliably a child's infection status before 18 months of age”.2
In 1964, using I131 labeled proteins administered to pregnant women near term, Gitlin et al
demonstrated the highly selective passage of maternal plasma proteins across the placenta.3
These include the immunoglobulin class IgG but little if any of the other immunoglobulin classes.
As a result, at the time of delivery mother and baby have nearly identical concentrations of IgG.
Subsequently, the IgG level in the infant falls with “the characteristics of simple exponential
decay”.4 According to Gitlin, “γG in the neonate is degraded at a rate of approximately 2.3% of
the total body γG per day, which is equivalent to a half-life of about 30 days”5 and “maternal IgG
disappears by the age of 9 months”.6
In the Ariel study of mother to child transmission infants were considered HIV infected "if a
peripheral blood sample was positive for HIV-1 by culture and a second sample from a separate
blood drawn was positive by either culture or HIV-1 DNA". "Of the 117 uninfected children
with serological testing done at 1 year of age, 66 (56%) had a positive or indeterminate result".
At 18 months of age 14% of uninfected children tested had a positive or indeterminate antibody
test.7 Thus, between one year and 18 months of age 42% of uninfected children developed a
negative antibody test, that is, three months beyond the time at which all other “maternal IgG
disappears”.
The European Collaborative Study Group monitored the disappearance of HIV seropositivity in
271 children born to HIV seropositive mothers.8 Twenty five percent of the children became
seronegative between birth and nine months of age and an additional 60% between 9 and 22
months. Thus over half these offspring became HIV negative beyond the time at which all other
“maternal IgG disappears”.
Infant seroreversions beyond nine months may be explained by:
1. Selectively slow disappearance of maternal IgG. This would be expected if babies born
to seropositive mothers were to have higher foetal IgG loads necessitating greater time
for metabolic degradation. However, although such mothers may have
hypergammaglobulinaemia this is unlikely to be the case in their infants because (i) the
transfer of IgG across the placenta occurs at a steady state rate consistent with a receptormediated mechanism which is saturable and subject to negative feedback.9, 10 That is,
“when maternal total serum IgG titres reach 15 g/l: cord total IgG titres tend to be lower
than the corresponding maternal values above that concentration”;11 (ii) experimentally,
transplacental transport of hyperimmune serum to HIV is inhibited by preperfusion of the
placenta with intravenous gammaglobulin preparations;9 (iii) the time of seroreversion is
unrelated to maternal or neonatal IgG concentrations;12 (iv) the half life of IgG in
children aged 6 months to 8 years is 20 days compared to 30 days in the newborn.13
Moreover, there are ample data illustrating the opposite is true,14, 15 that is, HIV
seropositive mothers transfer less IgG to their infants. “Both maternal
hypergammaglobulinaemia and maternal HIV infection may contribute to these low
antibody levels at birth and thus lead to early infection in this high-risk population”.15
This is greatly exacerbated by placental malaria infection,11 prematurity and low birth
weight,16-20 factors likely to operate where mother-to-child transmission is considered
prevalent. For example, “Babies born before 22 weeks have severe
agammaglobulinaemia and those born before 34 weeks’ gestation may be expected to
develop agammaglobulinaemia within the first two months of life”.21 Such
circumstances will lead to disappearance of maternal IgG well before 9 months of age.
2. Selectively slower decline in maternal HIV IgG relative to total IgG. However,
researchers from the CDC have “calculated that the half-life of the maternal anti-HIV-1
IgG antibodies is 28-30 days” and that it decays “to background levels by 6 months”,22
that is, at a rate at least as high as total IgG.
3. Maternal HIV IgA obtained via breastfeeding. Given that in the Ariel study no mother
breastfed and in the European Collaborative Study “5% [of infants] were breastfed for
periods from 1 to 30 weeks (median 2.5))”,23 this appears extremely improbable. Also,
if breastmilk IgA were the explanation one would predict no seroreversions before
weaning and all seroreversions after 9 months related to the time of weaning. We have
been unable to find data to test this hypothesis.
Since the these alternatives are either doubtful or unsupported by data it is necessary to consider
two other explanations: (a) infants who serorevert beyond six to nine months of age generate and
subsequently lose their own HIV antibodies. This implies that by unknown means and without
specific antiretroviral treatment at least 60% of infants successfully eliminate HIV; (b) in at least
60% of infants a positive antibody test is caused by non-HIV antibodies. That is, the detection of
such antibodies is unrelated to HIV infection. If 25% of children test positive between birth and
nine months because of maternal antibodies and in 60% the test is non-specific, how certain can
one be that in the remaining 15% of children the test will not also eventually serorevert? Or if the
test remains positive it is a true positive?24-27
Eleni Papadopulos-Eleopulos Biophysicist Department of Medical Physics, Royal Perth Hospital,
Perth, Western Australia 6847
Valendar F. Turner Consultant Emergency Physician Department of Emergency Medicine, Royal
Perth Hospital, Perth, Western Australia 6847
John M Papadimitriou Professor of Pathology University of Western Australia, Perth, Western
Australia 6907
Helman Alfonso Department of Research, Universidad Metropolitana Barranquilla, Colombia
Barry A. P. Page Physicist, Department of Medical Physics, Royal Perth Hospital, Perth, Western
Australia 6847
David Causer Physicist Department of Medical Physics, Royal Perth Hospital, Perth, Western
Australia 6847
Sam Mhlongo Head & Chief Family Practitioner, Family Medicine & Primary Health Care Medical
University of South Africa, 0204, South Africa
Todd Miller Assistant Scientist, Department of Molecular and Cellular Pharmacology University
of Miami School of Medicine, Florida, 33124 United States of America
Christian Fiala Department of Obstetrics and Gynaecology Mulago Hospital, Makarere
University, PO Box 7072, Kampala.
Anthony Brink Advocate of the High Court of South Africa Blue Lagoon Hotel, P O Box 2177
Beacon Bay, 5241 South Africa.
Neville Hodgkinson Science Writer Nuneham Park, Oxford, England OX44 9PG
Manu Kothari Professor of Anatomy Seth Gordhandas Sunderdas Medical College, King Edward
Memorial Hospital, Mumbai, India.
David Crowe President Alberta Reappraising AIDS Society Box 61037, Kensington PO, Calgary,
Alberta, Canada T2N 4S6.
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