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Analysis of False Negative HIV Tests Based on Oral Fluid in 3 Clinical Trials
Marcel E. Curlin1, Michael T. Martin1, Wanna Leelawiwat2, Roman Gvetadze1, Charles Rose1, Sarika Pattanasin2, Richard Niska1, Timothy Holtz1, Kachit Choopanya3, Janet McNicholl1
1 US Centers for Disease Control and Prevention, Apo, Armed Forces Pacific, United States. 2 Thailand Ministry of Public Health–Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand. 3 Bangkok Tenofovir Study Group, Bangkok, Thailand.
Background: The OraQuick Advance Rapid HIV-1/2 Antibody Test (OraSure, Bethlehem, PA) is a non-invasive, point-of-care, rapid HIV test capable of detecting HIV-specific antibodies in blood and oral fluid. The test is convenient and promises to increase HIV testing in at-risk populations. However, concerns regarding test sensitivity in oral fluid suggest that OraQuick Oral fluid (OQOF) test performance should be further studied before relying on this assay in clinical trials and other contexts where negative predictive value may be lower than in typical clinical settings.
Methods: We examined OQOF performance among all seroconverting participants in the Botswana Tenofovir PrEP Study (TDF2), the Bangkok Tenofovir Study, and the Bangkok Men Who Have Sex With Men Cohort Study, three longitudinal clinical studies conducted in Botswana and Thailand. OQOF screening test results were compared with estimated time of infection determined by enzyme immunoassay and/or nucleic acid amplification tests on stored blood samples. We used generalized estimating equations log-binomial regression to examine the association between FN OQOF test results and participant age and gender, time since infection, viral subtype, plasma viral load (PVL), exposure to antiretroviral drugs, test operator, clinical site, and test lot.
Results: In total, we identified 208 false negative (FN) OQOF test results among 81 of 290 (28%) seroconverters (all studies). Median estimated OQOF reactivity delay time was 98 days (range 14-547 days). FN tests were correlated with testing within 90 days of estimated date of infection, randomization to ARV-based pre-exposure prophylaxis, lower plasma viral loads, individual test operators, and specific testing sites, in one or more studies (p < 0.05). Age, gender, HIV subtype and test kit lot were not associated with FN tests (p > 0.05).
Conclusions: Failure of OQOF to detect HIV-1 infection was frequently observed in these three studies. Factors contributing to FN OQOF test results include recent infection, exposure to antiretroviral agents, low PVL, and operator-related factors. In the context of clinical trials, where a FN test may be more likely than in routine clinical settings, negative screening tests based on oral fluid should be confirmed by laboratory-based tests in blood, and measures should be taken to ensure proper training and ongoing quality assurance.