Although human papillomavirus (HPV) vaccination has decreased cervical cancer morbidity and mortality, secondary prevention through screening remains an important strategy. A recent report, appearing in JAMA, examined 48-month exit round results of the Human Papillomavirus for Cervical Cancer screening trial (HPV FOCAL), which compared primary HPV testing alone with liquid-based cytology (LBC) screening for prevention of cervical intraepithelial neoplasia (CIN) grade 3 or worse.
Participants in the publicly funded study were 16,347 women from British Columbia aged 25 to 65 who had not had a Pap test in the previous 12 months; were not pregnant, HIV-positive or receiving immunosuppressive therapy; and had no history of CIN2 in the past 5 years. They were recruited from January 2008 to May 2012, with follow-up through December 2016. Randomization was to HPV testing, LBC, or safety groups. However, after January 1, 2011, when the safety group was closed, randomization was changed to HPV testing or LBC.
Patients in the HPV testing group who had negative results were recalled at 48 months for HPV and LBC testing. Those in the LBC group who tested negative were instructed to return at 24 months for repeat testing with LBC in accordance with the cervical cancer screening guidelines in British Columbia.
In the first round of screening, significantly more CIN3 cases were detected in the HPV testing group than in the LBC group (absolute difference in incidence rate 2.67/1000 [95% CI, 0.53 to 4.88]). However, by 48 months, significantly fewer CIN3 cases were detected overall and across all age groups in the HPV testing group compared with LBC (absolute difference in incidence rate -3.22/1000 [95% CI, -5.12 to -1.48]). In terms of cumulative incidence of CIN3, there was no significant difference in disease detection across the groups. However, in the HPV group, the cumulative incidence rate was higher earlier in the trial at 18 months and 42 months compared to the LBC group.
Looking at CIN2, the researchers found significantly more cases in the HPV testing group compared to those in the LBC group in the first round of screening (absolute difference in incidence rate 5.84/1000 [95% CI, 2.70 to 9.07]). But by 48 months, significantly fewer CIN2 cases were detected overall and across all ages in the HPV testing group compared with the LBC group (absolute difference in incidence rate -5.60/1000 [95% CI, -8.21 to -3.13]). Cumulative incidence of CIN2 was higher earlier in the trial at 18 and 42 months compared with the LBC group. Among baseline HPV- or LBC-negative women, rates of CIN2 positivity at 48 months were significantly higher across all age groups in the LBC group compared with those who underwent HPV testing. Cumulative incidence curves showed that women who were HPV-negative at baseline had a significantly lower risk of CIN2 at 48 months compared with cytology-negative women.
Some of the strengths identified for the trial were that it was embedded in a well-established centralized cervical screening program, opportunistic screening not recommended through the trial was minimized by active notification by trial staff, and histopathological assessment was blinded to HPV and cytology results. Identified limitations include an exit intervention that was not the same as the baseline intervention and potential for selection bias.
The authors believe that the findings from this study illustrate that use of primary HPV testing for women undergoing cervical cancer screening resulted in a significantly lower likelihood pf CIN3 at 48 months compared to cytology testing. However more research is necessary to understand long-term clinical outcomes and assess cost-effectiveness.