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How does a mRNA HPV test differ from a DNA HPV test?

Several types of HPV testing are available to clinicians. DNA and messenger RNA (mRNA) are the most commonly used. HPV DNA assays tests for the presence of HPV, whereas detection of mRNA identifies transcriptionally active viruses (1-3). Testing for high-risk HPV is more sensitive (high negative predictive value) than cytology for the detection of high-grade squamous intraepithelial lesions (HSIL) (CIN 2 or greater). mRNA testing has a higher specificity while maintaining about the same sensitivity to HPV DNA tests. They identify the mRNA transcripts of the HPV E6/E7 oncoproteins from the 14 high-risk HPV genotypes, which contribute to the development of cervical cancer. In fact, the over-expression of these oncoproteins is associated with a significantly increased risk of CIN and cervical cancer. High-risk HPV DNA testing methods generally provide excellent sensitivity, but the specificity is inadequate (low positive predictive value) as they detect the presence of HPV DNA associated with infection whether in transient or persistent (transforming) states. The resulting positive signals in patients with non-transforming HPV infections that might be followed by unnecessary invasive procedures.

Why is mRNA HPV test more specific?

Most HPV infections are transient and eradicated by the host immune response without increasing the risk of cancer. Studies have showed that 90 percent of HPV infections will be cleared within two years in immunocompetent individuals. A small number of these infections, though, become chronic or persistent. It happens less than 10 percent of the time in the case of HPV infections. This is the fraction that can evade the immune surveillance system and appropriate the host's cells replication machinery, hence becoming a persistent infection. Cellular disruption, proliferation, mutations, and eventual transformation into a neoplastic process may ensue. The HPV oncoproteins E6 and E7 are the culprits in this transformation cascade (4). Accordingly, detection of molecules expressed early in this transformation process will provide more specificity than just identifying markers of the transient infectious agent. Using the same logic, detection of molecules involved downstream in the cascade (like p16) would be more specific, but not sensitive enough to be used as a screening test for premalignant disease. However these remain particularly useful in the diagnostic biopsy workup of HSIL (CIN2+) cases (5).

Do I manage my patients differently based on a positive Aptima® HPV result?

The Aptima HPV test indications are the same as those for DNA-based tests and align with current guidelines in Singapore and Malaysia for cervical cancer screening. The Aptima HPV test is indicated to screen women ≥25 years with ASC-US cytology to determine the need for colposcopy, and to screen women ≥30 years for high-risk HPV types. The Health Promotion Board  (2019) guideline recommends that "only commercial HPV nucleic acid amplification tests that are analytically and clinically validated for primary population-based screening should be used." Aptima HPV test is an example of such test.

Is HPV mRNA testing supported by the local cervical cancer screening guidelines ?

Yes, the guideline (2019) recommends that "only commercial HPV nucleic acid amplification tests that are analytically and clinically validated for primary population-based screening should be used. (6)" Aptima HPV assay is an example of such test.

Why does the Aptima HPV mRNA genotyping assay include HPV type 45?

The Aptima HPV 16, 18/45 genotype assay is the first FDA‐approved HPV genotype test to include HPV Type 45. Recent data suggests that although cervical cancer incidence has decreased since the 1970s, the prevalence of adenocarcinoma cases has risen approximately 32% in the same time frame in the United States (7). Detection of these HPV types as part of reflex testing may help clinicians identify up to 94% of all cervical adenocarcinomas (8). Although HPV genotype 45 is fairly uncommon, identified in only 0.4% of women with normal cytology, data indicates that it is the third most common HPV genotype in invasive cancer globally. The addition of HPV genotype 45 is designed to help identify more women at risk for adenocarcinoma, with minimal impact to colposcopy rates.

How do I collect specimens for Aptima HPV testing?

Cervical specimens collected in ThinPrep™ Pap Test vials containing PreservCyt™ Solution may be tested with the Aptima HPV assay.

How much specimen does Aptima HPV require?

The Assay only requires 1 mL of the specimen from a ThinPrep pap vial, compared to 4 mL for the HC2 assay. A decreased specimen requirement may result in fewer Quantity Not Sufficient (QNS) results for you and your patients.

References

  1. Iftner, Thomas et al. “Longitudinal Clinical Performance of the RNA-Based Aptima Human Papillomavirus (AHPV) Assay in Comparison to the DNA-Based Hybrid Capture 2 HPV Test in Two Consecutive Screening Rounds with a 6-Year Interval in Germany.” Journal of clinical microbiology vol. 57,1 e01177-18. 2 Jan. 2019, doi:10.1128/JCM.01177-18

  2. Weston, Georgie et al. “Use of the Aptima mRNA high-risk human papillomavirus (HR-HPV) assay compared to a DNA HR-HPV assay in the English cervical screening programme: a decision tree model based economic evaluation.” BMJ open vol. 10,3 e031303. 8 Mar. 2020, doi:10.1136/bmjopen-2019-031303

  3. Forslund, Ola et al. “HPV-mRNA and HPV-DNA detection in samples taken up to seven years before severe dysplasia of cervix uteri.” International journal of cancer vol. 144,5 (2019): 1073-1081. doi:10.1002/ijc.31819

  4. Szarewski A, et al. "Comparison of seven tests for high-grade cervical intraepithelial neoplasia in women with abnormal smears: the predictors 2 study." J Clin Microbiol. 2012;55(6):1867-1873.

  5. Darragh T, et al. "The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology". Arch Pathol Lab Med. 2012;136(10):1266-1297.

  6. CervicalScreen Singapore Advisory Committee "Management Guidelines for Cervical Screening and Preinvasive Disease of the Cervix". Available at: https://www.sccps.org/wp-content/uploads/2019/03/CSS-Clinical-Mgt-Guidelines-2019_March-Release.pdf. Accessed June 1, 2022.

  7. Adegoke O, et al. "Cervical cancer trends in the United States: a 35-year population-based analysis." J Woman’s Health. 2012;21(10):1031-1037.

  8. de Sanjose S, et al. "Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study." Lancet Oncol. 2010;11(11):1045-1056.

  9. Arbyn, M et al. “Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening?.” Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases vol. 21,9 (2015): 817-26. doi:10.1016/j.cmi.2015.04.015

  10. Cuzick, J et al. “Comparing the performance of six human papillomavirus tests in a screening population.” British journal of cancer vol. 108,4 (2013): 908-13. doi:10.1038/bjc.2013.22

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