Early Detection and Diagnosis
Overview of the European and North American studies on HPV testing in primary cervical cancer screening
Article first published online: 3 APR 2006
Copyright © 2006 Wiley-Liss, Inc.
International Journal of Cancer
Volume 119, Issue 5, pages 1095–1101, 1 September 2006
How to Cite
Cuzick, J., Clavel, C., Petry, K.-U., Meijer, C. J.L.M., Hoyer, H., Ratnam, S., Szarewski, A., Birembaut, P., Kulasingam, S., Sasieni, P. and Iftner, T. (2006), Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int. J. Cancer, 119: 1095–1101. doi: 10.1002/ijc.21955
- Issue published online: 5 JUN 2006
- Article first published online: 3 APR 2006
- Manuscript Accepted: 1 FEB 2006
- Manuscript Received: 21 OCT 2005
- EC-grant. Grant Number: QLG4-CJ-2000-1238-HPVCCS
- HPV testing;
- cervical screening;
- primary screening
Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35–49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy. © 2006 Wiley-Liss, Inc.
Currently in Europe and North America, cervical cancer screening is based on exfoliative cytology performed at intervals ranging between 1 and 5 years. Although there has been a marked reduction in incidence and mortality rates of squamous cell carcinoma of the cervix in countries with established cytology screening programmes,1, 2, 3 Sasieni et al. (1996) reported that 47% of women in the UK who developed stage 1B1 or worse invasive cervical cancer before the age of 70 had had an adequate previous screening history.2
The weaknesses in cytology are 3-fold. First, results are dependent on the high quality sample being collected during examination. Second, the test requires the identification of morphological changes within cells, whose interpretation is highly subjective. Last, this method of screening is particularly repetitive, which can lead to a greater number of interpretive errors. False negative cytology has major medical, economic and legal implications, and this is reflected in high malpractice litigation costs in the US associated with misreading cervical smears.
Interest in the use of HPV testing as a screening test is based on the finding that HPV DNA is present in almost all cervical cancers,4 and the availability of easily performed tests, which have demonstrated higher sensitivity for high grade CIN (CIN2+) than that achieved by cytology in several studies. This higher sensitivity offers several potential advantages, including reduced cancer rates and longer screening intervals, but several questions remain concerning the age at which to commence screening and the best way to combine the test with cytology. Here, we have performed an overview based on individual patient data for more than 60,000 women in countries where routine cytology is in place to help clarify the role of HPV testing to provide comparative data against cytology.
Material and methods
This study was restricted to countries in North America and Europe where cervical screening has been in place for several years. Data were available from the United Kingdom, France, Germany, the Netherlands, United States and Canada. The studies included have published their initial results comparing HPV testing to cytology in routine screening.5, 6, 7, 8, 9, 10, 11, 12 However, these results have been reported in different ways, and here we provide a unified analysis including a comparison against cytology, both overall and for different age groups. Because each study used different entry criteria, cytology cutoffs and adjustments for verification bias (see later), our results did not agree exactly with those in the published reports of the individual studies. The main characteristics of each study are shown in Table I. All studies have a similar split-sample study design. They focussed on screening populations mostly aged 30–60, and the Hybrid Capture II (HC-II) test was used in all studies except for those based in the Netherlands and Jena, where consensus PCR with the GP5+/6+ primers was used. Data from the more recent studies in which women are randomised to cytology or HPV testings (with or without cytology) are only just becoming available and are not included. They are less efficient for assessing sensitivity and specificity, but if large enough will be essential for establishing overall effectiveness of programmes. We also have not included studies in the developing counties, where cytology was often not part of routine care and the overall characteristics of both cytology and HPV testing appear to be somewhat poorer, possibly because of other concomitant STIs. These studies have been reviewed by IARC (2005).3 Specific characteristics included for each study are briefly noted later.
|Study||Number screened||Age||Entry Criteria||HPV test||Follow-up procedure||Histology|
|HART (Cuzick et al., 2003)||10,358||30–60||No smear test within the last 3 year, never treated for CIN||HC-II||Immediate colpo if cyto ≥ mild dyskaryosis. Borderline cyto or HPV+ randomised to immediate colpo or HPV and cyto in 6–12 months||Blinded central review|
|German – Tubingen||4,2302||30–87||No abnormal smear in preceding year||HC-II||Immediate colpo if cyto ≥ Pap IIw or HPV+||Blinded central review|
|German – Hannover (Petry et al., 2003)||4,7372|
|Jena (Schneider et al., 2000)||4,761||18–70||No abnormal smear in preceding year||GP 5/6||Referred Colpo and biopsy if abnormality found in colpo, cyto or HPV||Blinded single pathologist any abnormality reviewed by two pathologists|
|Remainder had follow up cyto and colpo at 4–8 months|
|French – Public||8,8582||15–80||No abnormal smear, untreated cervical lesion in last 2 years||HC-II||Immediate colpo for cyto+ results. If neg cyto and HPV+, repeat testing at 6 and 12 months||Two blinded pathologists, discrepancies resolved by third pathologist|
|French – Private (Clavel et al., 2001)||5,2652|
|Seattle (Kulasingam et al., 2002)||4,075||18–50||Routine screening at planned parenthood clinics||MY09-11 (4,075) and HC-II (1,150)||Colpo and biopsy if cyto ≥ ASCUS or HPV+||Single blinded pathologist|
|Only 1,150 with HC-II included||Never treated for CIN||1 in 10 women with cyto neg and HPV neg randomly chosen for colpo|
|Canada-Newfoundland (Ratnam et al., 2000)||2,098||18–69||Routine screening||HC-I (1,440) and HC-II (658)||Cyto ≥ ASCUS or HPV + referred for colpo and biopsy.||Local hospital labs|
|Only 658 with HC-II included||1 in 10 women with cyto neg and HPV neg were randomly chosen for colpo|
|Hammersmith3 (Cuzick et al., 1999)||2,988||35–65||No cytological abnormality in previous 3 years, or treatment for CIN||PCR plus HC-I (1,285) and HC-II (1,703)||Colp if cyto ≥ borderline or HPV(PCR) +||Two blinded pathologists|
|Only 1,703 with HC-II included|
|Netherlands3 (Bulkmans et al., 2004)||21,996||30–60||No abnormal cytology or CIN in last 2 years||GP 5/6||HPV + followed up at 6, 18 and 60 months||Four national labs|
|Italian||23,500 (not included)||25–60||Routine screening||HC-II||Age 35+ Immediate colpo if ≥ ASCUS and/or HPV +||Local pathologist Central review of all CIN2+ and a sample of CIN 1|
|Age <35, immediate colpo if cyto ≥ ACSUS; if cyto neg and HPV+, retest at 12 months and colpo if ≥ASCUS or HPV+|
In the HART study,11 women who were cytology negative and HPV positive, or whose cytology showed borderline changes (regardless of HPV status), were randomised to either immediate colposcopy or 6 monthly surveillance with HPV and cytology (with an exit colposcopy at 1 year).
The most recent study in Germany10 was conducted in two areas, one more rural (Tuebingen) and the other more urban (Hannover). The baseline rates of HPV positivity in these areas were different and these have been split into separate groups for this analysis. Pap IIw or higher was used as the cut-off for cytology positivity. Women who had a positive result for either cytology or HPV were referred for colposcopy.
For an earlier German study in Jena,7 all women received a screening colposcopy (without biopsy), HPV test and cytology. Pap III or higher was used as the cutoff for cytology positivity. If any of these results were abnormal, women were referred for a further colposcopy and biopsy. In addition, follow up cytology and colposcopy at 4–8 months was offered to all women who were initially negative for all 3 tests.
The French study6 offered HPV testing from age 20 and was conducted in Reims. It also had two distinct populations—one group of women who had their screening performed by private gynaecologists and the other who were screened in public hospitals. These two groups had different baseline HPV rates and social class distribution, and were also analysed separately. All women with a cytological abnormality were referred for immediate colposcopy, whereas those who were cytology negative and HPV positive were retested at 6 and 12 months by cytology and HPV. They were referred if either of these tests were positive at either visit.
The Hammersmith study5 enrolled only women above the age of 35. Management was based on the SHARP/PCR system, which used MY09/11 consensus primers. This detection system was found to be suboptimal. A second sample was then retrospectively analysed by the Hybrid Capture method using version 1 for the first 1,440 women and version 2 (HC-II) for the last 1,703 women. HC-II was found to be a very sensitive test, but because management was based on the SHARP results, it was not possible to properly adjust for verification bias as in the other studies, and consequently this study has been used only to evaluate age-specific HPV positivity in this analysis.
A large study based in the Netherlands12 has published initial results. Women with a high-grade cytological abnormality were referred for immediate colpscopy, but follow-up for women who were HPV positive and had low grade or normal cytology has not yet been completed. Therefore, at this stage, it is not possible to evaluate the performance of HPV testing, and so here these data have only been used for evaluating age-specific HPV positivity rates.
In the Seattle study,9 all women entering the study after January, 2000 received a HC-II test, and only these women were included here. Colposcopy and biopsy was performed on those who had had either a positive cytology or HPV test result, as well as on a random sample of women with completely negative results. This study was based at family planning clinics and contained a preponderance of younger women.
The Canadian study,8 like the Hammersmith study, converted to from using HC-I to HC-II during the trial and management was based on HC and cytology results. Only the HC-II part of the study was used in this analysis. All women with an abnormal smear or a HPV positive test result were referred for colposcopy.
A large Italian study has also been completed, but the results are not yet published, and their data are not included in this analysis.
The HC-II results were used in all studies except for Jena and the Netherlands, wherein consensus PCR with GP5+/6+ primers were used. Only the high-risk probe set was used for HC-II, which detects HPV types (16, 18, 31, 33, 35, 39, 45, 51 52, 56, 58, 59 and 68). Previous studies have shown that consensus PCR and HC-II give highly concordant results,13 and we have not separated them for this analysis.
Individual studies have evaluated cytology at different thresholds, but because cytological classification systems differ between countries, comparisons at different thresholds could not be done in this overview. Here, we have dichotomized cytology outcome at the lowest reported degree of abnormality (ASCUS, borderline changes, Pap IIw or equivalent).
Not all patients with abnormal screening results received colposcopy, mostly because of non-compliance. Therefore, not all cases of CIN2+ were identified, and an adjustment for verification bias was needed. Because the proportion of women with both negative cytology and HPV, who received colposcopy is very low, any attempt to adjust for missed disease in this group will lead to unstable results.14 However, any disease in this group of women does not influence the relative sensitivity or specificity of HPV vs. cytology, because the proportional effect is the same in both groups and their ratios are unchanged. Also, it can be seen by reviewing the reports from the individual studies that there are very few high-grade CIN cases found within this group. Thus, we chose to not adjust for the component of verification bias arising from missed cases in this group. As a result, sensitivities are slightly overestimated and specificities very slightly underestimated, both for cytology and for HPV.
Age specific rates were fit by logistic regression, with a spline containing knots at 25, 30, 40, 50 and 60 years. The individual curves for Seattle and Canada were truncated because of a small number of older women and the knots were at 5-year intervals from 25 to 45. For the ‘common shape’ analysis, a single spline was used for all studies combined, but additional indicator variables were included to model ‘shifts’ for each study. The purpose of this model was to more clearly separate the common characteristics of the shape of the age-prevalence curve from area-specific differences in prevalence. A stratified model was used to compute sensitivities and specificities for individual studies and overall, where the weights were the inverse of the stratum specific compliance levels. This approach allows one to adjust for verification bias as discussed earlier, in computing both means and confidence intervals. Thus, the sensitivities and specificities reported here do not agree with naïve estimators based on unadjusted counts, which were sometimes used in the original reports. The 95% confidence intervals, indicated in brackets, were computed by asymptotic methods, as used in sample survey methods. Trend tests were derived from generalised linear models. All calculations were performed by using STATA (Version 8.2).
The age-specific HPV prevalence is shown in Figure 1. Only the Canadian, French, Jena and Seattle studies contribute to the age range 20–30 years. The highest HPV positivity levels are seen at these ages, with a rapid decline after age 25. The French cohort suggests a peak around age 25, whereas for the other studies, rates are highest at age 20 and decline thereafter. The decline continues in all studies until around age 35–40, where they all flatten out at a plateau level. Because this pattern was similar in all studies, to more clearly compare studies, we fitted a model with a common shape for the age prevalence curve. This is shown in Figure 1b, where the curves are constrained to have the same shape, and only group specific differences in odds are fitted. There are clear differences between studies in the level of the plateau. The Seattle estimates of age-specific prevalence are highest, with an estimated rate at age 40 years of 15.6% while rates for Tuebingen and the Netherlands were lowest at 4.5%. The rates in the HART and Hannover studies were similar to each other, both with an estimated rate of 7.1% at 40 years.
HPV sensitivity and specificity
It can be seen from Table II and Figure 2 that HPV testing was consistently very sensitive in all studies, with the sensitivity for CIN2+ and CIN3+ both being 96.1% overall (94.2–97.4% and 93.6–97.6%, respectively). There was no indication of heterogeneity between studies. Also, the sensitivity was unaffected by age. The positivity rate in low-grade lesions (CIN1) was lower, being 80.6% (76.3–84.3%), and again was relatively consistent across populations.
|Study||Performance test||HPV testing (%)||Cytology testing (%)|
|All||Under 35||35–49||50+||Trend test||All||Under 35||35–49||50+||Trend test|
|HART||Sensitivity (CIN3+)||97.1 (69)||100.0 (35)||93.0 (29)||100.0 (5)||p = 0.12||75.9||74.0||78.5||75.1||p = 0.80|
|Sensitivity (CIN2+)||96.8 (90)||100.0 (46)||94.6 (38)||82.7 (6)||p = 0.06||76.7||73.6||80.2||79.4||p = 0.57|
|Specificity (<CIN)||94.0 (9,740)||89.4 (2,068)||94.6 (5,256)||96.9 (2,416)||p < 0.001||96.4||96.2||96.0||97.5||p = 0.01|
|Specificity (<CIN2)||93.4 (9,810)||87.9 (2,098)||94.2 (5,284)||96.6 (2,428)||p < 0.001||95.9||95.1||95.6||97.3||p < 0.001|
|Tuebingen||Sensitivity (CIN3+)||100.0 (13)||100.0 (7)||100.0 (6)||– (0)||–||44.8||42.3||47.9||–||p = 0.84|
|Sensitivity (CIN2+)||100.0 (16)||100.0 (9)||100.0 (7)||– (0)||–||48.9||54.9||40.8||–||p = 0.57|
|Specificity (<CIN)||96.0 (4,165)||94.2 (879)||96.1 (2,237)||97.1 (1,049)||p = 0.001||98.2||98.6||98.4||97.4||p = 0.08|
|Specificity (<CIN2)||95.5 (4,197)||93.6 (887)||95.5 (2,259)||97.0 (1,051)||p < 0.001||98.0||98.4||98.2||97.4||p = 0.14|
|Hannover||Sensitivity (CIN3+)||96.6 (30)||100.0 (9)||94.0 (18)||100.0 (3)||p = 0.52||35.7||20.7||40.6||58.8||p = 0.15|
|Sensitivity (CIN2+)||97.5 (41)||100.0 (14)||95.2 (23)||100.0 (4)||p = 0.41||34.3||13.2||43.7||68.2||p = 0.01|
|Specificity (<CIN)||93.4 (4,562)||91.1 (966)||93.6 (2,773)||95.0 (823)||p = 0.01||96.9||97.9||96.7||96.1||p = 0.06|
|Specificity (<CIN2)||93.0 (4,579)||89.9 (977)||93.5 (2,779)||95.0 (823)||p < 0.001||96.7||97.5||96.6||96.1||p = 0.16|
|Jena||Sensitivity (CIN3+)||93.8 (80)||92.5 (53)||96.2 (26)||100.0 (1)||p = 0.36||22.5||15.1||34.6||100||p = 0.06|
|Sensitivity (CIN2+)||94.7 (113)||93.6 (78)||97.1 (34)||100.0 (1)||p = 0.30||18.6||11.5||32.4||100||p = 0.02|
|Specificity (<CIN)||95.1 (4,528)||93.3 (2,155)||96.6 (1,777)||97.5 (596)||p < 0.001||99.6||99.9||99.3||99.7||p = 0.07|
|Specificity (<CIN2)||94.3 (4,579)||92.0 (2,193)||96.1 (1,789)||97.3 (597)||p < 0.001||99.5||99.8||99.2||99.7||p = 0.17|
|French public||Sensitivity (CIN3+)||98.7 (111)||100.0 (56)||95.2 (32)||100.0 (23)||p = 0.35||64.8||58.6||66.1||80.6||p = 0.07|
|Sensitivity (CIN2+)||98.1 (167)||99.2 (85)||95.4 (58)||100.0 (24)||p = 0.33||62.0||57.5||61.9||81.3||p = 0.10|
|Specificity (<CIN)||85.2 (7,932)||81.5 (3,402)||87.2 (2,929)||89.8 (1,601)||p < 0.001||95.7||94.2||96.7||97.3||p < 0.001|
|Specificity (<CIN2)||84.2 (8,021)||80.3 (3,451)||86.4 (2,954)||88.9 (1,616)||p < 0.001||94.9||92.9||96.3||96.6||p < 0.001|
|French private||Sensitivity (CIN3+)||86.0 (23)||83.5 (14)||88.6 (8)||100.0 (1)||p = 0.44||45.9||53.5||24.0||100.0||p = 0.14|
|Sensitivity (CIN2+)||91.6 (38)||90.2 (23)||92.4 (12)||100.0 (3)||p = 0.52||44.0||50.0||24.3||70.5||p = 0.73|
|Specificity (<CIN)||91.3 (5,063)||88.2 (1,539)||92.6 (1,758)||92.8 (1,766)||p < 0.01||98.3||97.3||98.1||99.3||p < 0.001|
|Specificity (<CIN2)||90.5 (5,108)||86.2 (1,573)||92.1 (1,767)||92.8 (1,768)||p < 0.001||97.8||96.6||97.8||99.3||p < 0.001|
|Seattle||Sensitivity (CIN3+)||96.5 (31)||95.7 (27)||100.0 (4)||– (0)||p = 0.62||60.1||65.2||35.3||–||p = 0.24|
|Sensitivity (CIN2+)||95.7 (55)||96.4 (49)||90.9 (6)||– (0)||p = 0.53||55.9||58.1||40.9||–||p = 0.43|
|Specificity (<CIN)||80.0 (827)||78.8 (746)||92.0 (81)||– (0)||p = 0.03||87.0||86.6||91.0||–||p = 0.76|
|Specificity (<CIN2)||76.5 (868)||75.0 (786)||92.1 (82)||– (0)||p < 0.01||84.2||83.7||89.3||–||p = 0.17|
|Canada||Sensitivity (CIN3+)||87.7 (8)||100.0 (6)||54.6 (2)||– (0)||p = 0.04||60.8||66.4||45.5||–||p = 0.60|
|Sensitivity (CIN2+)||85.0 (14)||100.0 (9)||54.6 (5)||– (0)||p = 0.01||61.0||55.3||72.73||–||p = 0.53|
|Specificity (<CIN)||91.8 (574)||90.6 (399)||94.7 (175)||– (0)||p = 0.13||94.0||93.0||96.1||–||p = 0.20|
|Specificity (<CIN2)||88.5 (591)||86.0 (415)||94.5 (176)||– (0)||p < 0.01||92.9||91.8||95.3||–||p = 0.18|
|Combined||Sensitivity (CIN3+)||96.1 (365)||96.8 (207)||93.7 (125)||100.0 (33)||p = 0.86||55.0||51.6||54.7||79.1||p = 0.01|
|Sensitivity (CIN2+)||96.1 (534)||97.2 (313)||93.9 (183)||97.5 (38)||p = 0.13||53.0||48.7||55.4||79.3||p < 0.001|
|Specificity (<CIN)||91.6 (37,391)||87.4 (12,154)||93.3 (16,986)||94.5 (8,251)||p < 0.001||96.9||95.9||97.1||97.8||p < 0.001|
|Specificity (<CIN2)||90.7 (37,757)||85.8 (12,380)||92.8 (17,090)||94.2 (8,287)||p < 0.001||96.3||94.9||96.8||97.6||p < 0.001|
Specificity (<CIN2) was more variable, and was significantly lower in younger women. A test for heterogeneity across studies was highly significant (p < 0.001) as was a test for trend with age groups (p < 0.001). Overall, the specificity was 90.7% (90.4–91.1%) and ranged from 76.5% (72.8–79.8%) in the mostly young Seattle population to 95.5% (94.7–96.1%) in Tuebingen. The specificity for women with no CIN varied similarly, but was slightly higher overall (91.6%). For women of 35 years and over, specificity was 93.3% (92.9–93.6%) overall and ranged from 87.3% (86.1–88.5%) for the French Public cohort to 96.4% (95.6–97.1%) in Jena. Overall, the positive predictive value of an HPV test for CIN2+ was 15.5% (14.2–16.8%), and was 12.8% (11.2–14.6%) in women 35 years or over and 17.8% (16.0–19.8%) in younger women.
Cytology sensitivity and specificity
Table II and Figure 3 show that the sensitivity of cytology was substantially less than that for HPV testing and varied considerably between studies (p < 0.001 for heterogeneity). The overall sensitivity for CIN2+ was 53.0% (48.6–57.4%), but varied enormously from 18.6% in Jena to 76.7% in the HART study. The sensitivity was substantially better in women over the age of 50 than in younger women (79.3 vs. 59.6%).
The overall specificity for cytology was 96.3% (96.1–96.5%). Overall PPV for cytology was 20.3% (18.3–22.4%). In common with HPV testing, specificity was better in older women (95.9% vs. 97.1% for <35 years vs. 35+ years) and the PPV was higher in younger women (23.2% vs. 17.5% for <35 years vs. 35+ years).
Comparison of HPV testing with cytology
A plot of sensitivity vs. (one minus) specificity is shown in Figure 4. It can be seen that HPV testing is more sensitive than cytology at all ages and in every study. It is also substantially less specific for women under the age of 35 years, but for older women the differences in specificity are quite small.
This overview clearly shows that the performance of HPV testing is similar in different parts of Europe and North America, and that HPV testing is substantially more sensitive but less specific than cytology. The sensitivity of HPV testing was independent of age, but specificity increased with age. The lower specificity of HPV testing in younger women is due to a higher prevalence of transient infections. However, the higher PPV of both HPV testing and cytology in younger women emphasizes the much higher prevalence of CIN2+ lesions in this group. Many of these are also likely to be transient, or at least nonprogressive,15 and further molecular characterization of these lesions may help to clarify which have progressive potential.
It is generally believed that only persistent HPV infections are associated with pre-cancerous lesions.11, 16, 17, 18 Currently, persistence of HPV can be determined only by repeated tests 6–12 months apart. Tests employing HPV E6/E7 mRNA, p16 or other biomarkers may help to distinguish transient from persistent HPV infections, but these still require clinical validation. In order for HPV testing to be cost effective, algorithms are needed to avoid over-referral due to transient infections, especially in younger women. These will have an important impact on the age at which HPV testing can be offered in primary screening, and especially on the management of women found to be HPV positive but cytology negative.
While well-conducted screening programmes based on cytology have undoubtedly led to a large reduction of cervical cancer in some countries, the high variability in sensitivity reported here indicates the need for strict quality control. HPV testing is highly reproducible, more easily monitored, provides an objective test outcome and can easily be automated.
Cytology had a higher PPV than HPV testing, which reduces the costs associated with referral for colposcopy. However, in well-screened populations, its lower sensitivity is associated with a high proportion of cancers occurring in apparently adequately screened women.2 The higher sensitivity of HPV testing also leads to a higher negative predictive value, suggesting that the screening interval can be safely lengthened if HPV testing is used. By doing so, and by employing surveillance for women with HPV positive but cytology negative test results, the impact on overall referral rates of a lower PPV for HPV testing can be minimized. Several studies are underway that are exploring the length of protection afforded by a negative HPV test and the best approach for managing HPV positive, cytology negative women.
The increased sensitivity of HPV testing has led several groups in the United States to recommend its use in conjunction with cytology as a way of safely extending screening intervals.19 However, basic principles suggest that the most appropriate use of the two tests is to perform the most sensitive test first and follow this with the more specific test for those who test positive initially. This suggests that one could offer HPV as the sole primary test and use cytology only as a triage for women who test HPV positive.20 Ongoing trials in Finland,21 the Netherlands, Italy, the United Kingdom and Canada will shed further light on this. Other key issues are the ages at which to start and stop screening and the appropriate interval between screens, which could be age-dependent.
A recent statement from the International Agency for Research on Cancer (IARC) concluded that there is sufficient evidence that HPV testing can reduce the incidence and mortality from cervical cancer and that it is likely to be at least as effective as cytology.3 The English Cervical Screening Advisory Committee has recently accepted the IARC statement (Minutes of Advisory Committee meeting on HPV Testing) and agreed that an HPV test is a valid screening method, which could be used by the national screening program. These statements should be influential in establishing streamlined large-scale demonstration projects employing HPV testing as part of primary screening. Such projects are needed to determine how best to implement this new test and to see if it can reduce invasive cancer rates below those now achieved with cytology-based programmes.
We thank Hannah Evans, Joanna Adams and Shahla Rahman for computing and statistical support for this project, and Eduardo Franco, Laura Koutsky and Achim Schneider for supplying further information from their studies. We also thank additional investigators from the contributing studies for allowing access to their data. We also gratefully acknowledge the participation of over 60,000 women volunteers who have made these projects possible.
Coordination of the overview was facilitated by the European Cervical Cancer Consortium supported by EC-grant-QLG4-CJ-2000-1238-HPVCCS.
- 3IARC. Handbooks of cancer prevention, vol. 10. cervix cancer screening. Lyon: IARC Press, 2005.