We thank Dr. Sun and colleagues for their interest in and thoughtful comments on our article.1 Below, we provide a comprehensive response to the points raised. First, we agree that baseline high-risk human papillomavirus (HR-HPV) positivity represents an intermediate epidemiologic state shaped by upstream determinants of acquisition and early persistence. As noted in the Discussion, unknown infection histories, particularly the duration of HPV infection prior to baseline, may have introduced potential confounding. Nevertheless, this scenario likely reflects real-world conditions more accurately, as individuals in routine screening who test positive for HPV are often unaware of their prior infection status. Additionally, we previously analyzed incident HR-HPV infections in the same cohort, defined as new HPV detections during follow-up among women who were HPV-negative at baseline.2 This analysis revealed consistent type-specific patterns of progression and clearance, with similar relative risk rankings. While such consistency does not fully eliminate the possibility of selection bias, it reinforces the stability of genotype risk ranking across different infection states and provides an evidence base for genotype-stratified clinical management in HPV screening. Cervical lesion attribution has long been a methodological challenge in HPV epidemiological studies. In this study, we applied a rigorous attribution strategy that leverages longitudinal data to identify the dominant persistent genotype. Specifically, when a single HR-HPV DNA type was detected in a lesion, that genotype was considered etiologically linked to the lesion. In cases of multiple HR-HPV infections, causality was assigned if the same HPV type had been detected in the preceding cytological sample. Otherwise, all HR-HPV types detected within the lesion were considered associated with that lesion. This attribution rule has also been adopted in multiple Phase III clinical trials of HPV vaccines, and it minimizes over-attribution to transient co-infections while prioritizing genotypes demonstrating persistence.3 The genotype-specific cervical lesion burden reflects the joint effects of genotype prevalence and progression risk. In our cohort, HPV-52 accounted for the second-highest proportion of total cervical intraepithelial neoplasia grade 2 or greater (CIN2+) cases. However, this finding should be interpreted in the context of the exceptionally high prevalence of HPV-52 in Chinese populations, which was also observed in our cohort. As such, a substantial contribution to the overall CIN2+ burden does not necessarily imply a high infection progression risk, but may instead reflect widespread exposure. This distinction is critical when interpreting genotype-attributable burden and has direct implications for risk-based screening and genotype-specific triage strategies. Finally, regarding the timing of lesion detection, we agree that this approach captures detection dynamics rather than the exact biological onset of CIN2+, which is challenging to ascertain in practice. This limitation is inherent to most similar longitudinal cohorts.4 As explicitly stated in our Methodology, this analytic framework is aligned with cervical cancer screening practices, emphasizing the detection and management of precancerous lesions rather than the full biological course of HPV infection. However, our cohort benefits from a relatively dense, protocolized follow-up schedule that mirrors routine screening pathways, which strengthens the reliability of lesion detection dynamics in a real-world clinical context. Moreover, all participants followed a uniform cytology-triggered referral protocol; the observed type-specific risk profiles accurately capture how these genotypes manifest in routine clinical practice, supporting comparability of genotype-specific risks within this screening pathway. While we recognize the conceptual difference between biological onset and clinical detection, these estimates provide the most direct and pragmatic evidence for optimizing triage. This perspective remains directly relevant to clinical management decisions that follow a positive screening test. In conclusion, while we acknowledge the theoretical limitations regarding the “pure” biological natural history of HPV infection, our findings provide genotype-specific evidence essential for optimizing clinical management of HPV-positive women in China. We fully agree that as vaccination coverage expands, future analytic frameworks will need to evolve. Recent evidence from the same trial cohort highlights divergent shifts in HPV infection profiles between vaccinated and unvaccinated individuals,5 underscoring the need to accelerate the development of optimized cervical cancer screening guidelines in the post-vaccine era. We thank Dr. Sun and colleagues once again for their insightful comments and continued interest in our work. We appreciate the opportunity to further clarify these important aspects of our research. Jiali Quan: Writing – original draft; writing – review and editing. Qi Chen: Writing – original draft; writing – review and editing. Ting Wu: Writing – review and editing; conceptualization. The authors declare that they have no competing interests.
Quan et al. (Sun,) studied this question.