Long-term follow-up of ARTISTIC cervical screening trial cohort

Background The National Screening Committee (NSC) based its recommendation that HPV testing should replace cytology in primary cervical screening largely on the 2009 follow-up results of the ARTISTIC trial. The NSC must now decide on screening intervals and triage policy. Options include extending the screening interval up to 10 years for HPV negative women, delaying recall for HPV positive women with normal cytology, as their infections are usually transient, and basing triage on full HPV typing. Methods In the ARTISTIC Trial 24,510 women attending for routine cervical cytology in Greater Manchester in 2001-2003 were recruited. The women were randomly allocated between revealing or concealing their HPV test results and were recalled 3-yearly. After 2009 the women returned to routine cytological screening with recall 3-yearly below age 50 and 5-yearly at age 50-64. We have followed the cohort to 2015 through national cancer registration for CIN3 and cancer and through linkage to the cervical screening call-recall system to obtain lifetime cytology records. Results The analysis included 24,496 women at round 1 and 13,591 at round 2 (30-48 months later). Follow-up via local histology laboratories and national cancer registration identified 505 cases of CIN3+ (including 22 invasive cervical cancers). The cumulative CIN3+ risk 10 years after a negative HPV test (0.31%, 95%CI:0.18-0.49 in the revealed arm) was similar to that 3 years after negative cytology (0.30%, 95%CI:0.23-0.41 in the concealed arm) and fell sharply with age, from 1.1% below 25 (95%CI:0.7%-1.8%) to 0.08% (95%CI:0.03%-0.20%) above 50. The 10 year cumulative CIN3+ risk following a new HPV infection at round 2 was 3.4% (95%CI:2.1-5.4). The highest risks were associated with type-specific persistent infections which overall conferred a 10 year cumulative risk of 20.4% (95%CI:15.6-26.4). Conclusions We found a similar level of protection 10 years after a negative HPV test and 3 years after negative cytology. These data support a considerably longer screening interval after a negative HPV test than after a negative cytology test. About three quarters of women with HPV infection and normal cytology clear their infections within about 3 years. Their risk of CIN3+ within this time is low (1.5%), suggesting that the current policy of annual repeat testing and referral after 2 years may be unnecessarily cautious. Approximately 40% of women who remained HPV positive had cleared their initial infection and acquired a new HPV type. Cumulative CIN3+ risks in women with type-specific persistent infections are about 6 times higher than in women with new infections. Triage strategies based on HPV persistence would therefore reduce unnecessary referral of women with new (and largely transient) infections. HPV assays which identify HPV types 31, 33, 45, 52 and 58 in addition to 16 and 18 could be useful in triage as well as in primary HPV testing. Similar results in recent routine screening suggest our results are generalisable despite changes in cytology and HPV assay methods. We are continuing to follow the ARTISTIC trial cohort into the new era of primary HPV screening. Funding: NHS-HTA programme.