HPV Genotyping

Several methods for cervical cancer screening are available. The following 4 methods are the most commonly used approaches in the US:

  • Pap testing (aka cervical cytology) alone
  • Primary HPV testing (without cervical cytology)
  • Co-testing (HPV testing and cervical cytology)
  • Reflex HPV testing (performed when cervical cytology returns positive for ASCUS)

Recommendations vary among major expert groups on which screening approach is best, many of which depend on age. Consider the differences in the recommendations from USPSTF and ACS:

Source: UpToDate (excerpt from larger table)

Interestingly, there are no randomized trials comparing mortality rates among the various screening strategies. One argument for screening that incorporates HPV testing comes from a 2018 USPSTF microsimulation model, which found that screening strategies that included HPV testing (i.e., primary HPV testing or co-testing) were associated with fewer cervical cancer deaths compared with Pap testing alone or reflex HPV testing. Specifically, cervical cancer deaths associated with screening that included HPV testing ranged from 0.23 to 0.29 deaths per 1000 patients versus 0.30 to 0.76 deaths per 1000 patients with screening that included Pap testing. However, a 2018 JAMA meta-analysis (published at the same time as the above model) demonstrated higher false-positive rates with HPV testing in 21-29yo patients, owing to higher rates of transient HPV infection. Together, these findings influenced the USPSTF’s age-based recommendations for cervical cancer screening. 

Digging further into HPV testing is the potential usefulness of genotyping. For instance, our hospital’s laboratory recently transitioned HPV testing (both primary and co-testing) to a new platform that offers automatic genotyping, including results for a High-Risk HPV Genotypes Pool (types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) as well as individual results for HPV16 and HPV18, the most commonly isolated HPV types in cervical cancer.

Why screening with genotyping might be helpful: HPV genotyping in cervical cancer screening can accelerate clinical management, leading to earlier identification and treatment of precancerous lesions and cancer. Specifically, the American Society for Colposcopy and Cervical Pathology recommends immediate colposcopy (instead of 1-year return) in persons with normal cytology and HPV16 and/or 18, and expedited treatment (instead of colposcopy) in persons with high-grade squamous intraepithelial lesion (HSIL) and HPV16. Furthermore, HPV genotyping may be particularly useful in populations with challenges in adhering to longitudinal follow-up.

The unknowns about screening with genotyping: The effects of implementing HPV genotyping into screening programs are largely unknown, and there is no data on cost effectiveness. A 2023 study of average-risk persons aged 30-65 years screened for cervical cancer in the National Breast and Cervical Cancer Early Detection Program (n = 104,991) found that HPV genotyping of HPV-positive persons with normal or HSIL cytology accelerated clinical management in 5.4% of all persons with abnormal screening test results, representing 0.9% of the screened population if management guidelines were followed; HPV genotyping of all of these persons could have accelerated clinical management in an estimated 13.1% of persons with abnormal screening test results, representing 2.2% of the screened population. 

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