LEVERAGING CANCER MODELS TO EXPLORE THE NATURAL HISTORY OF THE CAUSAL HUMAN PAPILLOMAVIRUS (HPV) INFECTION

Purpose: Clinical trials continue to evaluate the efficacy of vaccines against human papillomavirus (HPV), causally linked to several cancers and genital warts, using surrogate endpoints (e.g. HPV infection, precancer). Although new HPV infections and associated precancer continue to develop over time, the age at which women acquire their “causal” HPV infection that develops into cancer is poorly understood and inherently unobservable, yet critical to the overall effectiveness of vaccination. Our objective was to use a natural history disease simulation model to identify the implied age distribution at which individuals acquire their causal HPV infection in the absence of HPV vaccination or screening in order to help guide the optimal use of both.

Method: We employed a microsimulation model of cervical carcinogenesis to evaluate, for women who go onto develop cancer, the age at which they acquire the causal HPV infection. Model outcomes included the proportion and cumulative number of causal HPV infections by age, stratified by HPV genotype (i.e., HPV-16 vs non-HPV-16 related cancers). Uncertainty in the natural history was captured by the maximum and minimum values across a sample of 50 “good-fitting” parameter sets identified during calibration. 

Result: In the absence of primary (i.e., HPV vaccination) or secondary (i.e., screening) prevention, our model projected that among all cervical cancers, 42% (range: 30-52%) and 57% (range: 47-68%) of women acquired their causal HPV infection by age 20 and 24, respectively. Importantly, the age distribution was contingent on HPV genotype. For example, when we stratified cancers attributed to HPV-16 (a genotype included in the HPV vaccines), we found that nearly 48% (range: 25-82%) of women had already acquired their causal HPV infection by age 20 years. Conversely, the proportion of causal HPV infections acquired by age 20 was reduced to 36% (range: 32-41%) for cancers caused by non-HPV-16 genotypes.

Conclusion: According to our model, nearly half of women who develop invasive cervical cancer related to HPV-16 have already acquired their HPV infection by age 20, suggesting diminishing opportunities to prevent the causal HPV infection as women age. Our model-based explorations can provide important insights into the natural history of the causal HPV infection and can supplement the use of surrogate endpoints in vaccine efficacy studies to effectively guide policy decisions for implementation.