The WHO recommends that rapid serological tests can be used to determine HIV exposure in an infant aged younger than 4 months, to determine HIV exposure in infants with signs or symptoms suggestive of HIV infection, to exclude infection in HIV exposed, asymptomatic infants at 9 months of age, and to identify HIV-exposed infants at 9 months of age in need of referral nucleic acid–based testing.[6,7] Infants with a reactive rapid serological test should then undergo nucleic acid–based polymerase chain reaction testing. Our results, however, found that this approach had an unexpectedly low sensitivity (61.7%) and a positive predictive value (42.3%). Although the population included in this study was of unknown HIV exposure, using rapid serological tests as a referral test to nucleic acid–based testing for this population per WHO guidelines would have resulted in missing approximately 38% (36 of 94) of HIV-positive infants due to having a negative rapid serological test. Interestingly, this population of rapid serological test–negative, HIV-positive infants had a median age lower than the rapid serological test–positive, HIV-positive infants, indicating that perhaps they had not yet developed their own anti-HIV antibodies. Age alone, however, could not explain the poor performance of the rapid serological tests or the lack of anti-HIV antibodies because the box plots were significantly overlapping. The sensitivity of rapid serological tests to determine which infants required referral nucleic acid–based testing improved by age; however, the sensitivity remained at or below 80% up to 2 years of age. These results were likely due to the time the infants were infected, which could not be determined within this study.
A recent systematic review and meta-analysis observed better performance of rapid serological tests to determine exposure and HIV infection; however, it is important to note that all studies on this topic were conducted before 2008. Significant progress has been made in the past 10 years in PMTCT, namely the significant increase in mothers receiving lifelong ART for their own health and to reduce transmission (Option B+). Expanded access to better drugs may have accounted for differences between these findings because it is possible that ART, especially when provided soon after infection, can lower viral loads, and thus antigen required to generate a robust antibody response and passive maternal antibody transfer.[14–17] Likewise, the presence of antiretroviral prophylaxis in HIV-positive infants may similarly delay autologous antibody production. Maternal infections occurring late in the third trimester or during breastfeeding could also affect infant rapid serological test performance because infection would have occurred too late to allow for passive maternal antibody transfer. By contrast, however, a recent study in Kenya saw similar results to those presented here. Twenty-three percent (11 of 48) of HIV-positive infants younger than 8 months had a negative rapid serological test.
Interestingly, although it was expected that most, if not all, rapid serological test–negative, HIV-positive infants would have been sick, several healthy yet HIV-positive infants had a negative rapid serological test. Our results and those from the Kenya study, however, suggest that serological testing should not be performed in symptomatic or asymptomatic infants to determine who is in need of referral nucleic acid–based testing. Doing so would unfortunately likely result in 25%–40% of HIV-positive infants being rapid serological test–negative, and thus missed for receiving a critical nucleic acid–based diagnosis and follow-up linkage to ART and care. Alternatively, maternal testing should be emphasized and prioritized as a more reliable mechanism to identify HIV exposure in infants aged younger than 18 months. Known HIV-exposed infants or, on the rare occasion, infants whose exposure status cannot be ascertained through maternal testing should directly receive nucleic acid–based testing for diagnosis.
Although concerns have been raised about the cost of introducing nucleic acid–based testing at age 9 or 12 months instead of serological testing, there have been recent significant decreases in the cost per test for EID. When considering the proportion of HIV-positive infants who would be missed for nucleic acid–based testing, and thus potentially resulting in loss or death, the cost-effectiveness of implementing nucleic acid–based testing for all infants younger than 18 months may be high.[19,20] This is generally due to the testing intervention having a significant impact on life expectancy of such a young population. For example, adding an additional test in the algorithm (at birth) was cost-effective.[19,20] Furthermore, significant investments have been made to expand access to viral load testing of patients on ART essentially dwarfing the small volumes and relatively low costs required to test all HIV exposed, sick, or suspected infants using nucleic acid–based testing instead of serological testing.
Several limitations exist within this study. This study was not designed to determine the performance of serological testing to identify infants in need of referral nucleic acid–based testing in both well, asymptomatic infants compared with sick, symptomatic infants. Because of this, the sample size to observe this phenomenon in well, asymptomatic infants (those presenting at outreach and immunization entry points) was small. It is notable, however, that there were proportionally more false-negative rapid test results in healthy infants compared with those who presented sick. In addition, because we expected serological testing to successfully and consistently identify HIV exposure in infants, we did not conduct rapid serological testing for those presenting to the PMTCT entry point. Furthermore, again because we expected serological testing to successfully and consistently identify HIV exposure in infants, although we provided maternal testing services within the study, maternal test results were not recorded. We were unable, therefore, to determine how many HIV exposed yet uninfected infants were negative by rapid serological test.
These data suggest that the use of rapid serological tests and serological testing should be carefully considered before being used to determine either HIV exposure or infection in infants. As recommended by the WHO, serological assays should not be used in infants aged between 4 and 18 months to determine HIV exposure and instead should be determined through maternal HIV testing whenever possible. Although rapid serological tests are significantly cheaper than nucleic acid–based testing, the focus of PMTCT and EID programs are generally to identify HIV-positive infants in need of antiretroviral treatment. Using rapid serological tests to identify infants in need of a referral nucleic acid–based test would result in a large proportion of significantly vulnerable HIV-positive infants to be missed and sent home without the necessary care and treatment. To improve identification and linkage of HIV-positive infants, nucleic acid–based testing should instead be considered in infants younger than 18 months of age.
The authors gratefully acknowledge the work and dedication of the health care facility staff who were instrumental in conducting this study, the laboratory staff at the Central Public Health Laboratories who conducted the nucleic acid-based testing, the data entry personnel at CHAI, and Meghan Wareham for her support in planning and preparation of this study. The authors also acknowledge the leadership and administration of all the health facilitates where this study was conducted.
J Acquir Immune Defic Syndr. 2018;77(3):331-336. © 2018 Lippincott Williams & Wilkins