The ARTISTIC trial cohort represents the largest population of women in the UK to have undergone routine cervical screening with both LBC and HPV testing. The study population spanned the 20–64 age range of screened women when the trial opened, although the lower age threshold for routine cervical screening in England has since been increased from 20 to 25 years.
Our age-specific HPV positive rates in different grades of cytological abnormality were similar to those in the HART study in which over 10
000 women were screened with conventional cytology and hc2 testing, but our overall HPV prevalence was slightly higher at each age. HPV prevalence in the HART study declined from 14.5% in women aged 30–34 years to 3.8% in women aged 55–59 years (Cuzick et al, 2003
); the corresponding rates in our cohort were 18.5% at 30–34 years and 6% at 55–59 years. Our higher rates may be partly due to regional differences in the UK (2004). The HART study was conducted in five centres across Britain, and the highest HPV prevalence was found in the Manchester area, where 16% of 30–34 year olds were positive for HPV (P Sasieni, personal communication). There may also have been a continuing increase in HPV prevalence in this population. A study conducted in the same area as ARTISTIC between 1988 and 1993 reported HPV prevalence based on MY0911 consensus primer PCR of 18% in women aged 20–24 years declining to 3% in women aged 50–54 years (Peto et al, 2004
). Differences in HPV detection sensitivity may account for part of the disparity, but this doubling of prevalence within 12 years suggests a continuing epidemic rise in HPV prevalence.
Several useful conclusions relevant to the potential role for HPV testing in primary routine screening are suggested by the relationships between age, HPV detection and severity of cytology shown. In women with detectable HPV the prevalence of moderate dyskaryosis is 20- to 30-fold higher than in HPV negative women at all ages, and severe dyskaryosis is increased more than 100-fold. The prevalence of mild dyskaryosis in HPV-positive women is about 10-fold higher than in HPV negative women below age 50 years and more than five-fold higher above age 50 years. Although a great majority (87%) of women aged under 30 years with mild dyskaryosis are HPV positive, this proportion falls to 58% (233/398) at age 30–49 years and to only 28% (18/65) at age 50–64 years suggesting a role for HPV triage. The prevalence of borderline abnormalities in HPV positive women is about twice as high as in HPV-negative women at each age, and although there may be some overcalling by LBC, our results indicate that many borderline abnormalities are not caused by HPV. The prevalence of moderate or severe dyskaryosis in HPV-positive women is 11.6% throughout the premenopausal years suggesting that the natural history of HPV infection may be much the same in premenopausal women irrespective of age, although CIN3 is rarer in HPV-infected women aged 50 years or over. In women aged 30 years or over, our data suggest that the main effect of replacing cytology by HPV testing in primary screening would be the replacement of HPV negative abnormal smears, most of which would be borderline, by a similar number of HPV positive normal smears among women referred for follow-up. For those aged 20–29 years, however, the number who were HR HPV positive was 52% greater than the number with abnormal cytology, suggesting the need for a secondary test prior to colposcopy.
Primary screening with HPV testing in combination with cytology triage has been recommended only in women aged over 30 years (Sasieni and Cuzick, 2002
; Cuzick et al, 2003
), as HPV is so common in younger women. This conclusion seems questionable in the light of our results as high-grade dysplasia is as common among HPV-infected women aged under 30 years as in those age 30–49 years, and much commoner than in women aged over 50 years.
The ARTISTIC trial has also provided the largest collection of HPV typed primary screening cervical samples from the UK. The HPV type may be clinically important as the proportion of hc2 positive women who were infected with HPV16 increased with cytological abnormality, from 14% in those with normal cytology to 55% in those with severe dyskaryosis (). The HPV type might be used to determine whether to refer for colposcopy immediately, repeat the test, or defer any investigation until the next routine screen 3 years later. With the prospect of type 16/18 specific HPV prophylactic vaccines becoming available, data on these types in the screened population is of considerable importance in terms of what proportion of current abnormalities may still occur, notwithstanding a degree of cross protection reported for HPV 45 (Harper et al, 2006
Women are still undergoing repeat cytology and colposcopy as necessary. It is therefore not yet possible to compare the sensitivity and specificity of cytology and HPV testing for detecting CIN2 and CIN3 at entry to the trial, particularly in relation to specific HPV types. As with any quantitative test, the performance of hc2 will depend on the choice of cutoff.
The second round of screening at 3 years began in July 2004 and we anticipate reporting final results at the end of 2007.