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.

Keywords: HPV; HPV vaccination; cervical cancer; clinical unmasking.

FIGURE 1

Clinical unmasking arises from fewer interventions to treat precancerous lesions and invasive cervical cancer caused by high‐risk HPV types. (A) Among unvaccinated populations, HPV infection by high‐risk HPV types (e.g., HPV16) may progress quickly (compared with other non‐vaccine HPV types, which could be present in coinfection) to precancerous cervical lesions (e.g., CIN2+). Treatment of these lesions via LEEP removes the entire transformation zone, which interrupts progression of non‐vaccine type disease by excising the tissue infected with those types. (B) Vaccinated populations, instead, are protected from infection by high‐risk vaccine preventable types; therefore, less aggressive non‐vaccine preventable types may be clinically unmasked and able to progress uninterrupted to precancerous lesions in the absence of treatment.

FIGURE 2

Historical and contemporaneous epidemiological approaches for evaluating clinical unmasking. An historical approach would compare the absolute incidence of precancerous cervical lesions (CIN2+) by non‐vaccine preventable types among women in the pre‐vaccination era (before the Year 2008) versus the post‐vaccination era (after the Year 2008) whereas a contemporaneous approach would compare incidence rates among unvaccinated (unvax) women versus vaccinated (vax) women. Given the slow progression of non‐vaccine preventable types to precancerous cervical lesions, both approaches would require extended time scales to observe clinical unmasking. Potential sources of bias for the historical approach include secular trends (e.g., possible changes in screening/treatment or sexual behavior over time) and for the contemporaneous approach include differences between vaccinated/unvaccinated women (e.g., differences in risk behavior or screening practices and herd immunity).

FIGURE 3

Natural history of HPV and considerations for evaluating clinical unmasking. Progression of HPV to precancerous cervical lesions and eventually to invasive cervical cancer can take decades after initial infection. Thus, extended time scales will be required to evaluate the potential for clinical unmasking in the post‐vaccination era.