In Reply We appreciate the opportunity to respond to the letter by Smith et al regarding our recent study.1 In reference to the question and comments posed, the initial adoption of the commercially available tumor tissue–modified viral (TTMV)-human papillomavirus (HPV) DNA test at our institution was sporadic and generally performed ad hoc for patients with HPV-associated cancers either preoperatively or during surveillance. Over time, through multidisciplinary collaboration and the design of the SIRS 2.0 trial,2 testing transitioned to coincide with standard of care surveillance visits in accordance with the National Comprehensive Cancer Network guidelines. As the authors point out, one of the limitations of this nonstandardized collection in our recent work is the difficulty with establishing the potential lead time for recurrence detection.1 Further work is needed with regularly scheduled surveillance testing and clinical examinations and/or imaging studies to help best approximate the lead time benefit of these tests. This can be achieved through retrospective testing of banked specimens from prospective clinical trials as in the recent work by Califano et al3 or through prospective clinical trials. One such clinical trial that is currently underway is NCT04965792, which evaluates circulating tumor HPV DNA testing alongside standard of care surveillance and will report not only recurrence and survival outcomes, but also cost and quality of life measures. We anticipate this study will help elucidate the appropriate protocol for liquid biopsy surveillance testing when it is complete in 2027.