Joseph E. Tota

Epidemiological approaches to evaluate clinical unmasking of HPV ‐associated cervical lesions in the HPV vaccination era

Abstract HPV vaccination reduces the risk of developing HPV‐attributable cancers, including cervical cancer. However, an attenuation of HPV vaccine impact after the implementation of HPV vaccination may occur through clinical unmasking. Clinical unmasking is a distinct and complex phenomenon that arises in the absence of clinical interventions necessary to treat disease caused by high‐risk vaccine‐preventable HPV types (mainly HPV16) allowing uninterrupted progression of non‐vaccine preventable types that are frequently present as co‐infections. Clinical unmasking is distinct from viral unmasking, which is a diagnostic assay artifact, and from HPV type replacement, a theorized biological phenomenon requiring competition between HPV types, which has not yet been documented. All three processes could manifest as an apparent increase in cervical precancer/cancer by non‐HPV vaccine types, resulting in a lower‐than‐anticipated vaccine impact based on projections derived from type attribution studies. Here, we describe these concepts and epidemiological approaches to evaluate clinical unmasking in the post‐vaccination era. We propose a historical and a contemporaneous approach, highlighting key considerations and illustrating the potential outcomes with hypothetical data. Both approaches would have a similar outcome and interpretation: an increased incidence of precancerous lesions (CIN2+) due to non‐vaccine preventable types among vaccinated versus unvaccinated women (historically in the pre‐vaccination era, or contemporaneously) in the long term being indicative of clinical unmasking. Protection afforded by HPV vaccines against high‐grade cervical precancers, irrespective of type, remains considerable. However, carefully designed studies are needed to investigate the potential impact of clinical unmasking and its implications on vaccine effectiveness in the post‐vaccination era.

Defining benchmarks for tolerable risk thresholds in cancer screening: Impact of HPV vaccination on the future of cervical cancer screening

AbstractThe performance of cervical cancer screening will decline as a function of lower disease prevalence—a consequence of successful human papillomavirus (HPV) vaccination. Replacement of cytology with molecular HPV testing as the primary screening test and adoption of risk‐based screening, with less intense screening of vaccinated individuals and initiated at older ages is expected to improve efficiency. However, policy officials may decide to further reduce or eliminate screening as the ratio of benefits to harms continues to decline. To evaluate the level of risk currently tolerated for different cancers in the United States (ie, for which clinical guidelines do not recommend secondary prevention though effective screening methods exist), we used US cancer registry data to compare incidence (2008‐2012) and survival (1988‐2011) associated with different cancers for which organized screening is recommended and not recommended. The most common cancer at ages 70 to 74 years (ie, age group with highest cancer incidence and reasonable life expectancy to consider screening in the US) satisfying Wilson and Jungner's classic screening criteria was vulvar cancer (incidence = 9/100 000 females). In comparison, the incidence of cervical cancer among females 65 years of age (the upper recommended age limit for screening) was 13 cases per 100 000 females (low as a reflection of effective screening), whereas 10‐year survival was 66% (similar to vulvar cancer at 67%). Our approach of defining tolerable risk in cancer screening could help guide future decisions to modify cervical screening programs.