Cervical cancer screening programs, unchanged for decades, are now in flux. With different primary and secondary preventive screening choices and management options available, many countries are considering a variety of combinations, and no single “winning strategy” has yet clearly emerged. Because CIN3 and cervical cancer are rare in well-screened populations, the impact on increased disease detection needs to be balanced with the impact on cost, numbers of colposcopies, and morbidity associated with potential overtreatment. The availability of many tested and proven choices for screening allows for designing new screening programs that adapt to specific needs in different healthcare systems; on the other hand, the number and complexity of options maybe confusing to providers and patients with the risk of women potentially being lost to follow up. In a particular practice or geographic setting risk assessment in conjunction with risk modeling and comparative effectiveness research plays a central role in determining the optimal screening and management strategy. Screening strategies will also vary by population and resources of country, most importantly the type of screening program- organized or opportunistic and the uptake of HPV vaccination.  In spite of several notable advances in cervical cancer prevention, most cancer still occurs in the under/ non-screened populations, hence access to screening is key in further decreasing the incidence of cervical cancer. Self-sampling is an emerging methodology aimed largely toward reaching unscreened women. Primary prevention with HPV vaccination will provide the greatest long-term protection against cervical cancer.

The 2012 United States consensus screening and management guidelines were developed using a risk assessment framework originally based on cytology. Balancing harms and benefits of screening was a core principle of these guidelines. In 2014, the FDA approved the Roche cobas test for primary screening based on results of the Athena trial; and interim guidelines were published for management of women screened by primary HPV alone. However cotesting remains the preferred screening option among the 3 approved options of cytology, cotesting and primary HPV screening. Currently there is variable penetration of the guidelines in clinical practice, with estimated 60-70% cotesting, 30-40% cytology with reflex HPV and <1% Primary HPV screening.

The US considerations for prevention of cervical cancer differ from those of other developed countries in that it has an opportunistic screening program in which women’s access to screening and compliance varies considerably, it lacks a school-based HPV vaccination program and cancer registries are not well established at either the federal and state level.  

Primary HPV screening is a very viable screening option, having shown an average of 37% increase in sensitivity compared to cytology in various international trials, and it safely allows lengthening of screening intervals due to its high negative predictive value. Incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV16/18 and cytology can provide a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm).  Specific concerns related to primary HPV testing in the US include- type of HPV test used and its quality control (only 1 test on one liquid collection medium is FDA approved at this time), specimen adequacy (internal control is not specific for epithelial cells), false negatives due to HPV negative cancers, optimal method of triage of HPV non 16/18 + cases, optimal follow up of HPV negative cases, increase in colposcopies due to misunderstanding of management algorithm or if HPV genotyping is not available, overtreatment of younger women since screening will start at 25 years, aspects of the Athena trial (only 3 year follow up limits ability to predict the best long term screening strategy, limited data on women who are persistently HPV 16/18+ and negative on colposcopy, almost 33% of women with HSIL were 25-29 yrs of age, and limited quality control for cytology and colposcopy in trial).  The adoption, implementation and acceptance of Primary HPV testing is currently very low in the USA.

Cotesting provides the highest sensitivity and negative predictive value for HSIL/CIN3, and may provide the highest sensitivity for detection of glandular neoplasia. However the various combinations of screen results and management algorithms for cotesting are complex, and the cost is the highest for a very modest gain in positive predictive value.

The USA will gain further insight from experiences of other developed countries that are transitioning completely to Primary HPV testing and from its own data analysis. In the meanwhile increasing the acceptance and delivery of HPV vaccination, and education of patients and providers on HPV biology and principles of screening and management guidelines is a primary focus of cervical cancer prevention efforts in the United States. As we move toward the future, to choose screening options that are scientifically valid and of high quality, we must remember and reiterate that no screening test is perfect- the very basis of screening requires doing it periodically and repeatedly, whether it is cytology, cotesting primary HPV testing or mammography.