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HIV infection remains a public health challenge; HIV testing serving as the gateway to entrance into the HIV care, treatment, and prevention cascade. Whether laboratory evidence of infection is generated by Point of Care test algorithms or highly sophisticated 4th and 5th generation immunoassay/supplemental serological and/or molecular confirmatory algorithms, diagnostic accuracy, correct classification of HIV infection status, is now challenged by the HIV field's most notable advances in the arenas of HIV Prevention and Intervention. Paradigms such as Test and Treat, Treatment as Prevention, Pre-exposure Prophylaxis (PrEP), and Post-exposure Prophylaxis (PEP) reduce viral burden, viral reservoir constitution, the potential for onward HIV transmission, and decrease the risk of serious AIDS related health outcomes. These highly effective strategies however, have also been shown to cause the delay, reduction, or reversal of evolution of serological responses to infection and/or reduce molecular markers to below limits of detection by currently employed assay. Lack of evolution and/or suppression of markers long used by the laboratory to generate evidence confirming or refuting HIV infection can thus lead to misclassification of status. This talk will focus on current HIV testing modalities, challenges of HIV testing under the aforementioned scenarios, presentation of case studies, and considerations for a revised approach.