Use of an Indeterminate Range in HIV Early Infant Diagnosis: A Systematic Review and Meta-Analysis

Abstract

Background: Expanded access to HIV antiretrovirals has dramatically reduced mother-to-child transmission of HIV. However, there is increasing concern around false-positive HIV test results in perinatally HIV-exposed infants but few insights into the use of indeterminate range to improve infant HIV diagnosis. Methods: A systematic review and meta-analysis was conducted to evaluate the use of an indeterminate range for HIV early infant diagnosis. Published and unpublished studies from 2000 to 2018 were included. Study quality was evaluated using GRADE and QUADAS-2 criteria. A random-effects model compared various indeterminate ranges for identifying true and false positives. Results: The review identified 32 studies with data from over 1.3 million infants across 14 countries published from 2000 to 2018. Indeterminate results accounted for 16.5% of initial non-negative test results, and 76% of indeterminate results were negative on repeat testing. Most results were from Roche tests. In the random-effects model, an indeterminate range using a polymerase chain reaction cycle threshold value of ≥33 captured over 93% of false positives while classifying fewer than 9% of true positives as indeterminate. Conclusions: Without the use of an indeterminate range, over 10% of infants could be incorrectly diagnosed as HIV positive if their initial test results are not confirmed. Use of an indeterminate range appears to lead to substantial improvements in the accuracy of early infant diagnosis testing and supports current recommendations to confirm all initial positive tests.

Assessing the Variability of Cell-Associated HIV DNA Quantification through a Multicenter Collaborative Study

“…Indeterminate PCR results, defined as inconclusive tests, are frequently observed and remain one of the main challenges of EID ( 34 – 38 ). As national programs aiming at preventing mother-to-child transmission are successfully implemented, the positive predictive value of a single diagnostic test will continue to decrease.…”

Indeterminate HIV PCR results within South Africa's early infant diagnosis programme, 2010–2019

“…These recommendations were based on laboratory findings that HIVdetected results with higher cycle threshold (Ct) and lower relative J o u r n a l P r e -p r o o f fluorescence intensity (RFI) values were associated with a poor positive predictive value and irreproducible positive results [4][5]. A similar approach to HIV PCR result verification was adopted by the World Health Organization (WHO) in 2018 as it was estimated >10% of infant HIV results would be incorrectly reported as HIV-positive without such criteria [6,7].…”

Delays in HIV-1 infant polymerase chain reaction testing may leave children without confirmed diagnoses in the Western Cape province, South Africa

“… 20 , 21 During the period covered by this study, indeterminate results were defined as a cycle threshold of ≥ 33, or a relative fluorescence intensity below five. 22 These diagnostic criteria have since been revised, 23 , 24 , 25 , 26 mostly based on collated data, which showed cycle threshold value cut-offs to be the best predictor of reproducible positive results. The cycle threshold value of 33 was shown to most precisely differentiate clear positive from irreproducible cases.…”