Table 21.

Gaps in knowledge and pertinent research issues and hypotheses regarding the role of screening technologies in secondary cervical cancer prevention.

Key questions	Research and implementation issues
What answers are still needed from the studies of HPV testing in screening?	Is there sufficient buy-in for wide-scale implementation in high-resource settings? Can HPV DNA or RNA testing be implemented cost-effectively in middle- and low-resource settings?
Cotesting versus serial testing: what is the best option for high-resource settings?	Few countries have formally included cotesting (parallel use of HPV plus Pap cytology) in practice guidelines. Can serial testing (HPV followed by Pap triage of HPV positives) attain the same level of safety for guidelines?
If HPV testing is adopted for women ages 30 and older, what screening options should be recommended for younger women?	The technology “neglected” age range of 21–29 years continues to rely on cytology. What types of evidence will be required for increasing the age of screening initiation? Could a compromise solution exist via a single policy of serial testing (HPV followed by Pap triage) beginning at age 25?
Is VIA a solution for low-resource settings, either alone or as triage for low-cost HPV primary screening?	VIA is not as accurate as HPV testing but is easier to deploy. Is it a method that should only be combined with screen-and-treat strategies? What is the value of VIA for the triage of HPV-positive women to improve the effectiveness of screen-and-treat strategies?
Is self-sampling a solution to expand the coverage and bring equity to screening?	HPV testing of self-collected samples could permit reaching remote areas, urban women who are missed by invitations to screen, and women who refuse provider-assisted sampling. Is the balance between lower accuracy and higher coverage acceptable?
Algorithm management versus risk stratification: what is most suitable for guidelines?	Can healthcare providers learn and apply risk stratification via multiple biomarker testing as part of practice guidelines? Does it confer a more personalized level for screening and management? Is it cost-effective?
What is the role of HPV viral load as a clinical tool?	Should HPV testing be based on higher thresholds of viral load for improved specificity? Is the greater complexity of quantitative HPV assays worth the extra cost to be borne in screening?
Is there a role for genotyping in screening or triage?	Genotyping for HPVs 16, 18, and other priority hrHPVs improves the positive predictive value of screening and permits more rational colposcopy referral. Can genotyping become affordable in the near future to be implemented in screening, triage, and surveillance?
What is the role of cytology-based staining for prognostic markers of lesion progression?	Is the accrued accuracy of enhancements in cytology based on the identification of these markers worth the added cost to cytologic triage of HPV positive women? Can it compete with genotyping as a cost-effective strategy?
How should we educate healthcare providers and patients concerning HPV testing results?	Gradual introduction of HPV testing leads to patient anxiety and confusion related to the diversity of guidelines. The change from an oncologic to an STI-detection paradigm in cervical cancer screening requires research on sound educational approaches to demystify the implications of HPV positive results.
What will be the impact of HPV vaccination on screening performance?	As vaccinated young women reach the age of screening, a gradual decrease in lesion prevalence will adversely impact test performance. Which tests will be less likely to be affected? Can guidelines be safely relaxed in HPV-vaccinated populations? Can HPV-based screening be integrated with HPV vaccination strategies for shared resources and improved surveillance?

hrHPV: High-risk human papillomavirus: STI: Sexually-transmitted infection: VIA: Visual inspection with acetic acid.

Reproduced with permission from Franco EL et al. [18].