HPV‐mRNA and HPV‐DNA detection in samples taken up to seven years before severe dysplasia of cervix uteri

Abstract

Randomized clinical trials using human papillomavirus (HPV) DNA testing have found increased protection against cervical cancer and HPV-based screening is globally recommended for women ≥30 years of age. HPV-mRNA is a promising alternative target for cervical screening tests, but assessing equivalence requires longitudinal evaluation over at least the length of a screening interval. Our aim is to analyze the longitudinal sensitivity of HPV-mRNA and HPV-DNA in cervical samples taken up to 7 years before severe cervical intraepithelial neoplasia or worse (CIN3+). From a population-based cohort of 95,023 women in Sweden, cervical samples were frozen at -80°C between May 2007 and January 2012. Registry linkages identified that 1,204 of these women had CIN3+ 4 months to 7 years after enrolment. Baseline samples were analyzed for HPV-mRNA (Aptima, Hologic) and for HPV-DNA (Cobas 4800, Roche) and results from both tests obtained for 1,172 women. For both women <30 and ≥ 30 years, HPV-mRNA had similar sensitivity for CIN3+ as HPV-DNA (p = 0.0217 and p = 0.0123 in noninferiority testing for at least 90% relative sensitivity, respectively). Among women ≥30 years, the longitudinal sensitivities for CIN3+ occurring 5-7 years later were comparable [76.3% (95% CI: 65.8%-84.3%) and 82.5% (95% CI: 72.6%-89.4%)] as were the longitudinal negative predictive values for absence of CIN3+ [99.97% (95% CI: 99.95-99.98) and 99.98% (95% CI: 99.96-99.99)], for the HPV-mRNA and HPV-DNA test. In conclusion, HPV-mRNA testing has similar longitudinal sensitivity as HPV-DNA, implying that HPV-mRNA testing can safely be used for cervical screening.

Risk of CIN2 or more severe lesions after negative HPV‐mRNA E6/E7 overexpression assay and after negative HPV‐DNA test: Concurrent cohorts with a 5‐year follow‐up

“…That study also found no significant difference in longitudinal negative predictive value of mRNA and DNA tests. Also a Swedish retrospective study showed similar long term sensitivity for mRNA and DNA assays at least up to 7 years …”

“…Also a Swedish retrospective study showed similar long term sensitivity for mRNA and DNA assays at least up to 7 years. 14 Nevertheless, it is worth to note that the mRNA assay targets a step ahead than HPV-DNA in the natural history of the disease, thus the duration of reassurance following a mRNA negative test can be only lower than, if not equal to, that of a negative DNA test. If the differentiation of productive nononcogenic infections and abortive potentially oncogenic infections occurred very early in the natural history of the infection, the difference in the duration of the protection between the two tests would be very small.…”

“…Such characteristics make the test a promising candidate for primary screening, but data on the long‐term safety after the test are necessary to define a safe interval for rescreening mRNA‐negative women, particularly because the test targets a phase of the viral infection that is by definition downstream the event of infection, that is, the target of HPV‐DNA tests. There are very few studies on the long‐term protective effect of E6/E7 mRNA assay: two small prospective studies suggested higher protection than Pap and similar or slightly lower protection than HPV‐DNA, and one retrospective study showed similar long‐term sensitivity of HPV‐DNA …”

“…There are very few studies on the long-term protective effect of E6/E7 mRNA assay 14,15 : two small prospective studies suggested higher protection than Pap and similar or slightly lower protection than HPV-DNA, 16,17 and one retrospective study showed similar long-term sensitivity of HPV-DNA. 14 In 2011, the Venice screening program started a populationbased pilot study in which women were screened for one round with Aptima E6/E7 mRNA assay. 18 These women were subsequently rescreened after 3 years with HPV-DNA test and followed up for an additional 1.5 years.…”

Early detection and prevention

“…The proposed resource not only will enable the discovery and validation of new biomarkers, but also will be useful for studies on equivalence of new variants of previous tests. An example is a recent validation study where an HPV test based on detection of HPV mRNA was found to have an equivalent performance to tests based on the detection of HPV DNA over a 7-year follow-up (Forslund et al, 2019). The study was based on a large biobank collected more than 7 years ago that had been followed up with registry linkagesand thus did not have to wait prospectively for 7 years to obtain longterm follow-up data.…”