Background: Mother-to-child transmission rates have decreased considerably with implementation of Option B+ and Treat All policies, resulting in concern for false positive tests results due to lowering positive predictive values. There is limited guidance on how to interpret low levels of viremia in HIV-exposed infants; therefore, a systematic review, meta-analysis, cost-effectiveness model, and acceptability survey were conducted.
Methods: The systematic review identified 32 studies from 14 countries including data from over 1.3 million HIV-exposed infants. The meta-analysis used a random effects model to calculate true positivity and false positivity across various proposed indeterminate thresholds. Additionally, a decision analysis model of 10,000 HIV-exposed infants was developed to estimate the clinical consequences of implementing an indeterminate range.
Results: The optimal indeterminate range was the equivalent of a cycle threshold of 33 on the Roche COBAS TaqManHIV-1 Qualitative Test v2.0 assay, representing the best trade-off between the proportion of HIV-infected infants who would be incorrectly identified as indeterminate (approximately 8.43%) and the proportion of HIV-uninfected infants who would potentially start treatment unnecessarily (approximately 6.66%) (Table 1). Implementing an indeterminate range was found to be cost-effective across most cycle threshold ranges. Finally, a survey provided to program managers (n=85), health care workers (n=146), and people living with HIV (n=587), established that over 85% of respondents in each group thought the use of an indeterminate range was acceptable in order to prevent unnecessary lifelong treatment.
Conclusions: Implementing an indeterminate range will support more accurate nucleic acid-based early infant diagnosis: it is likely that fewer infants would be put on lifelong treatment unnecessarily as the majority of false positives would fall within the indeterminate range and receive additional testing prior to definitive diagnosis rather than being classified as HIV-infected. Confirmatory testing, retention during the exposure period, and end of exposure testing remain critical.