An Evaluation Of Two New Low-cost Technologies For Cervical Cancer Screening In Rural China

ObjectivesTo evaluate clinical performance of low-cost high-risk HPV DNA test (careHPV) and high-risk HPV E6oncoprotein test (OncoE6) for detection of cervical precancer and cancer, and investigate the impact factors and the methods of improvement for these new tests, and provide evidence of their implementation in cervical cancer screening programs in rural China.Materials and MethodsThe Low-Cost Molecular Cervical Cancer Screening Study (LCMCCSS) had carried out from October2010to August2012in three rural counties in China. Six screening tests were used to screen the cervical precancer and cancer, which including careHPV testing on self-and clinician-collected specimens (careHPV-S, careHPV-C), hybrid capture2testing on self-and clinician-collected specimens (HC2-S, HC2-C), visual inspection with acetic acid (VIA) and OncoE6. All screen-positive women and approximately10%random sample of screen-negative women were referred to a second VIA and a rigorous colposcopic evaluation that included using a microbiopsy protocol. We also followed up all the screen-positive women and approximately20%random sample of screen-negative women at one year. Firstly, we described the age trends of high-risk human papillomavirus (HR-HPV) infections and E6protein expression, and made explanations for the peak of HR-HPV infection in older women. Secondly, we evaluated the clinical performance (e.g., sensitivity, specificity, positive predictive value, negative predictive value) of careHPV and OncoE6for the detection of cervical intraepithelial neoplasia grade2or worse (CIN2+) and cervical intraepithelial neoplasia grade3or worse (CIN3+), respectively. In the meanwhile, we pooled data from another study called "Screening Technologies to Advance Rapid Testing"(START) and did the receiver operating characteristic (ROC) analysis to compare the performance of each test and find out the optimal cutoff point. Finally, we used the follow-up data to predict the one-year absolute and relative risks of CIN2and CIN3for careHPV and OncoE6; and evaluated the clinical performance of low-cost triage tests for careHPV-positive women. Results1. The age trends of HPV infection and E6expression:The prevalence of HR-HPV, HPV16/18/45and E6were13.1%,2.9%and1.0%in women without CIN2+lesions. There was a peak of19.3%in women aged55-59years for HR-HPV infection. The prevalence of HPV16/18/45and E6increased with the increasing age. One-year clearance rate of HR-HPV decreased with increasing age, however, incidence rate was unrelated to age. Risk factors that associated with HR-HPV infection differed between younger and older women.2. The clinical performance of the two tests in primary cervical cancer screening:The overall performance was better for careHPV on clinician-collected specimens than that on self-collected specimens. The sensitivity for detecting CIN3+was97.0%for both careHPV-C and HC2-C,83.8%for careHPV-S,90.9%for HC2-S,53.5%for OncoE6and50.5%for VIA; and the specificity was86.8%,86.6%,86.5%,83.1%,98.9%and93.4%, respectively. OncoE6had the greatest positive predictive value (PPV) at40.8%for CIN3+compared with the other tests. The sensitivities of the four HPV DNA tests were highly consistency among women with different ages; OncoE6sensitivity increased with increasing age, while VIA sensitivity decreased with increasing age. The sensitivity of OncoE6was higher than that of VIA in women aged45-65years.3. The optimal cutoff point for careHPV:The areas under the ROC curves for careHPV-C were similar to HC2-C (0.954vs.0.948), and better than careHPV-S (0.878). The optimal cutoff points (unit:RLU/CO) for HC2-C, careHPV-C, and careHPV-S to detect CIN3+were1.40,1.74and0.85. Raising the cutoff point of careHPV-C from1.0RLU/CO to2.0RLU/CO could result in non-significantly lower sensitivity but significantly higher specificity. The performance to detect CIN3+was similar in both age groups for each test, but the optimal cutoff point was higher in younger women versus in older women for HPV DNA testing on clinician-collected specimens.4. The management of screen-positive women:careHPV-C with higher viral load (≥10RLU/CO), careHPV16/18/45-C and OncoE6could effectively predict the one-year cumulative risks for CIN3(RR≥50); while careHPV-C negatives had a very low risk (0.1%,95%CI:0.0～0.3) to become CIN3at one year. The sensitivity for detecting CIN3+was88.5%,77.1%,54.2%,63.5%and52.6%for a higher viral load (≥10RLU/CO), careHPV16/18/45, OncoE6, colposcopy and VIA to triage women with careHPV-C positive results; while the specificity was44.7%,76.5%,93.8%,84.4%and86.5%, respectively. OncoE6had the greatest PPV (46.4%) and diagnostic value (OR=17.9) to predict CIN3+lesions. All the tests performed similar in triaging careHPV-S positive women except test of a higher viral load (≥10RLU/CO).Conclusions1. Women aged55-65years also need to be screened for their high positivities of HR-HPV, HPV16/18/45and E6protein. The reasons for the greater HR-HPV prevalence in older versus younger women in rural China may be explained by a cohort effect, higher than expected incidence, and/or poorer clearance at older age.2. careHPV is a suitable test for primary cervical cancer screening in rural China. Sampling methods and testing cutoff points can affect the clinical performance of careHPV test, and testing on clinician-collected specimens performed better than that on self-collected specimens. The optimal cutoff points for careHPV-C and careHPV-S are2.0and1.0in primary cervical cancer screening, and age can affect the optimal cutoff points.3. OncoE6is better than VIA in primary cervical cancer screening, and the sensitivity increased with increasing age. Adding HPV types that are highly prevalent in cervical cancer in China can improve the sensitivity of OncoE6.4. Women who are positive on careHPV-C with higher than10RLU/CO, careHPV16/18/45-C and OncoE6should be treated as high-risk population; while women who are negative on careHPV-C should be treated as low-risk population in cervical cancer screening practice. Different triage strategies for careHPV-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+. The decision for whether and how to triage women should be based on the local resources and policy.