Is serological testing for HIV at 18 months of age in children born to HIV-infected mothers still reliable?

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The age of seroreversion, at which maternal antibodies disappear and there is reversion to an HIV-negative status, in HIV-free children born to HIV-1-infected Malawian women increased between 1989 and 2003, according to the findings of a study published in the November 1st edition of the Journal of Acquired Immune Deficiency Syndromes. In light of these findings, the investigators believe that the current policy of HIV serological testing in children of HIV-infected mothers need to be urgently revised.

Serological testing for HIV in children born to HIV-infected mothers is constrained by the persistence of maternal antibodies which results in an HIV-uninfected infant testing positive. On the premise that these antibodies disappear by 18 months of age, the current policy recommends carrying out standard anti-HIV IgG antibody tests to establish an infant’s HIV status at this age.

This policy has been called into question by the observation that in communities with a high prevalence of endemic HIV, maternal HIV antibodies may persist much longer in HIV-exposed HIV-negative children. This is confirmed by the fact that mean time to seroreversion was shorter in studies carried out early in the HIV epidemic than in studies carried out later in non-African children.

Glossary

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

trend

In everyday language, a general movement upwards or downwards (e.g. every year there are more HIV infections). When discussing statistics, a trend often describes an apparent difference between results that is not statistically significant. 

enzyme-linked immunosorbent assay (ELISA)

A diagnostic test in which a signal produced by an enzymatic reaction is used to detect and quantify the amount of a specific substance in a solution. Can be used to detect antibodies to HIV, p24 antigen or other substances.

enzyme

A protein which speeds up a chemical reaction.

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

Although HIV has established itself in Africa with very high prevalence in some countries, there is currently no information about the relationship between community HIV prevalence and time to seroreversion in HIV-free African children born to HIV-infected mothers. In order to address this issue, a team of US and Malawian investigators analysed historical data from three mother-to-child transmission (MTCT) of HIV studies in Malawi.

The three prospective studies were all conducted at the Queen Elizabeth Central Hospital in Blantyre, Malawi, but at different times from 1989-1991 (International Collaborative AIDS Research [ICAR]), from 1993-1996 (HIV Network for Prevention Trials [HIVNET]), and 2000-2003 (nevirapine (NVP)/AZT [NVAZ]). ICAR and HIVNET assessed the risk of MTCT while NVAZ assessed the prophylactic effect of nevirapine and AZT against MTCT of HIV.

Serological testing for HIV antibodies for the three studies was carried out in children aged between twelve and 24 months using various commercial enzyme-linked immunoassays (ELISA) followed by confirmatory Western blot testing on all infants with positive ELISA at or after 18 months of age.

In the ICAR and HIVNET studies neither the mothers nor the children received antiretroviral therapy (ART). In NVAZ all children received short-course antiretroviral prophylaxis and some mothers received single dose NVP prophylaxis during delivery. None of the mothers received ART after delivery.

The proportions of the children seroreverting in the three studies representing the periods 1989-1991, 1993-1996, and 2000-2003 were compared to establish whether a temporal trend existed in seroreversion at 15, 18, and 21 months. Statistical models were used to assess the association of various risk factors and seroreversion. The temporal trend and adjusted odds of seroreversion were compared for children born before 1997 and after 1999.

The analyses included 635 infants from ICAR, 459 from HIVNET, and 1,020 from NVAZ. ELISA was performed by 15 months in 40 -8 7.5 % of the children, by 18 months in 92 -99 % of the children, and by 21-24 months in 97 - 99 % of the children in all three studies.

There was a consistent trend of decrease in the proportion of children seroreverting over time with the highest occurring during 1989 through 1991 and the lowest during 2000 through 2003. Conversely, the proportion of children at 18 months of age with persistent maternal antibodies increased from 0.2 % between 1989 and 1991, 0.5 % between 1993-1996, to 1.9 % between 2000 and 2003. This trend was similar for children aged 15 and 21 months.

Like previous studies in non-African infants, there was no significant association between several risk factors such as gender, gestational age, maternal clinical stage of AIDS, malnutrition, or breast feeding. However, children with a higher birthweight seroreverted earlier.

The findings of Gulia et al. have confirmed that in African children, maternal antibodies persist longer than previously thought in a small but significant number of children born after 1999. Significantly, about 2% of 18 month-old Malawian children were falsely classified as HIV-positive by serological testing.

This study needs to be urgently confirmed in other African countries with a high prevalence of endemic HIV. Current policy guidelines for serological testing for HIV antibodies at 18 months of age must be revised sooner than later.

Reference

Gulia J et al. HIV Seroreversion Time in HIV-1–Uninfected Children Born to HIV-1–Infected Mothers in Malawi. J Acquir Immune Defic Syndr 46: 332–337, 2007.