Search strategy

This assessment used two recent systematic reviews by the Belgian Health Care Knowledge Centre, KCE, published in 2015⁽¹⁶⁴⁾ as a basis for our systematic reviews of the clinical literature. Their searches were completed in October 2013. The first search compares the accuracy of HPV testing with cytology as the primary screening test for cervical cancer. The second search considers triaging for women identified as HPV-positive in a primary screening test and is presented in Section 4.2.

The systematic literature search comparing primary HPV testing with cytology

published by KCE in 2015⁽¹⁶⁴⁾ was the latest update in a series of systematic reviews.

The original systematic review was published in 2007.⁽¹⁶⁵⁾ The KCE search of PubMed and EMBASE was updated to the end of January 2016 using the same search strategy. Full details of the search are provided in Appendix 3. The PICOS (Population, Intervention, Comparator, Outcomes, Study design) analysis used to formulate the search is presented in Table 4.1.

The studies included by KCE and the updated search studies were reviewed

according to our inclusion and exclusion criteria. This was carried out independently by two researchers and any disagreements were resolved through discussion. The quality of the included studies (KCE and updated search) was assessed

independently by two researchers. Any disagreements were resolved through discussion, using the quality assessment of diagnostic accuracy studies 2 (QUADAS-2) checklist.⁽¹⁶⁶⁾ Data extraction from all studies (KCE and updated search) was performed independently by two researchers and any disagreements were resolved through discussion.

86 Table 4.1 PICOS analysis for identification of relevant studies for

primary screening with HPV or cytology testing

Population Women aged 18 to 70 participating in a cervical screening programme who were not being followed up for previous cytological abnormalities.

Intervention HPV test, Cytology test (conventional or liquid-based)

Test thresholds (Cytology- ASCUS or worse, HC2 - ≥1pg/ml) Comparator ‘Gold standard’ application of colposcopy and or biopsy on at

least all cytology- and HPV-positive samples

Outcomes Accuracy parameters (sensitivity, specificity, positive predictive value, negative predictive value)

Disease threshold (CIN 2+, CIN 3+)

Study design Observational studies using concomitant cervical cytology and HPV testing

RCTs where women were assigned to either cytology testing, HPV testing or both

Key: ASCUS - Atypical squamous cells of undetermined significance; CIN - cervical intraepithelial neoplasia; HC2 - Hybrid Capture 2 HPV assay; HPV – human papillomavirus; RCT – randomised controlled trial.

Note: The test thresholds for cytology-ASCUS or worse and HC2>=1mg are the standard cut-offs and currently in use in the Irish national cervical screening programme, CervicalCheck.

Note: To reduce the complexity of this chapter and aid in clarity, only accuracy results for sensitivity and specificity are presented.

4.1.2 Results

The following section presents the results from the studies identified as part of the updated systematic search along with the original studies. A synthesis of the evidence is presented in Section 4.1.3. For ease of reading, 95% confidence intervals are referred to as confidence intervals (CI) throughout this chapter.

Eleven additional studies were identified in the extension of the systematic review from October 2013 to January 2016. The original KCE systematic review⁽¹⁶⁴⁾ included 60 studies of which nine were randomized controlled trials (RCTs) and 51 were cross-sectional studies. The updated review contains 71 studies.

In the original systematic review, large variation in the sensitivity in studies conducted in developing countries was observed. The inter-study variation was much lower in studies conducted in industrialised countries and non-significant in studies conducted in China. In industrialised countries, the pooled sensitivity of the Hybrid Capture 2 (HC2) HPV assay (Qiagen) in detecting CIN 2+ was 96% (CI: 95-98%, n=18 studies), and the pooled specificity was 91% (CI: 89-91%, n=18

studies), whereas the pooled sensitivity for detecting CIN 2+ across all locations was

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87 91% (CI 89-93%, n=41 studies) and the pooled specificity was 89% (CI 87-90%, n=41 studies). Given this substantial geographic variation, this HTA will consider studies conducted in industrialised countries.

A large number of different HPV tests are currently available, however, the most commonly used test was the Hybrid Capture 2 (HC2) HPV assay (Qiagen), with a smaller number of studies investigating other HPV tests (Cobas® 4800, PreTectTM HPV Proofer, Aptima®, Amplicor®, Linear array®, qPCR HBRT-H14, HPV 9G DNA chipTM). Apart from the HC2, no test was considered in more than four studies.

Given the large number of studies within the review, to reduce potential variation between studies, this HTA will further restrict the analysis to studies which

considered HC2 only as the HPV test.

Twenty-three of the 71 studies within the review met these additional criteria. The characteristics of these studies are given in Table 4.2. Details of the studies excluded from the review and the reason for their exclusion are provided in Appendix 3.

The included studies comprised 22 cross-sectional studies and one randomised controlled trial (RCT).^(167-189) Of the 23 studies, five were conducted in the UK,^(172-174,

179, 189) three in Germany,(176, 180, 183) three in France,(170, 171, 181) three were multi-country studies across western and eastern Europe^{(177, 188)} and across Canada and the US,⁽¹⁶⁸⁾ two were conducted in Italy,^{(185, 186)} and one each in Norway,⁽¹⁸²⁾ Switzerland,⁽¹⁶⁷⁾ Taiwan,⁽¹⁶⁹⁾ Chile,⁽¹⁷⁵⁾ Japan,⁽¹⁷⁸⁾ Canada⁽¹⁸⁴⁾ and Russia.⁽¹⁸⁷⁾

Seven of the studies compared HPV testing with liquid-based cytology (LBC),(167, 174, 176, 179, 181, 185, 186) 14 compared HPV testing with conventional cytology,(168, 169, 172, 173, 175, 177, 178, 180, 182-184, 187-189) while the remaining two included subgroups comparing HPV testing with both LBC and conventional cytology.^{(170, 171)}

The total sample size in the included studies ranged from to 231⁽¹⁸⁸⁾ to 25,577.⁽¹⁷⁷⁾ The majority of the populations included within the studies are representative of routine screening populations. Two studies,^{(182, 187)} considered populations that potentially had a higher risk of cervical cancer. Nygrad et al.⁽¹⁸²⁾ included women who had previously received an unsatisfactory cytology result, while the study by Shipitsyna et al.⁽¹⁸⁷⁾ included women who were screened while attending routine gynaecological clinics. The two studies by Ronco et al.^{(185, 186)} reported the results of the same study, but the first only included women aged less than 35 years and the second only included women aged over 35 years. In the evidence synthesis section, these two studies were treated as one study, combining the results. The studies by Ronco et al.^{(185, 186)} included two trial arms, one where samples were tested using

88 both HPV testing and LBC, and a second arm which used only conventional cytology;

only results from the first arm of the trial were included in this analysis.

The reported sensitivity of HC2 ranged from 68.8%⁽¹⁶⁸⁾ to 100%(170, 188, 189) for CIN 2+ and 95.2%⁽¹⁷³⁾ to 100%(174, 176, 180, 187, 189) for CIN 3+. This was higher than the reported sensitivity of the cytology tests, which ranged from 34.4%⁽¹⁷⁵⁾ to 100%⁽¹⁸⁵⁾ for CIN 2+ and 38.9%⁽¹⁷⁵⁾ to 100%(185, 187, 189) for CIN 3+. The reported specificity of HC2 ranged from 43.0%⁽¹⁶⁷⁾ to 100%⁽¹⁷⁴⁾ for CIN 2+ and 15.9%⁽¹⁸⁸⁾ to 100%⁽¹⁷⁴⁾ for CIN 3+. The reported specificity of the cytology tests varied widely ranging from 62.0%⁽¹⁸⁴⁾ to 98.7%⁽¹⁷⁵⁾ for CIN 2+, and from 76.6%⁽¹⁸⁸⁾ to 98.6%⁽¹⁷⁵⁾ for CIN 3+.

The prevalence of HPV in screened women varied from 5%(172, 173, 180, 183) to 83%.⁽¹⁸⁸⁾ No relationship was evident between the reported prevalence of HPV in screened women and the resulting sensitivity values. However, studies that reported a high prevalence of HPV had lower specificity values than studies that reported low prevalence of HPV.

The quality of all 23 studies was assessed using the QUADAS-2 checklist (see Table 4.3). Seven studies were assessed as having a low risk of bias across all

domains.(170, 171, 175-177, 179, 183) Five were rated at a higher risk of bias regarding patient selection with either the age range not being representative of routine screening populations(173, 185, 186) or the population likely to be at a higher risk of cervical cancer than the general population.^{(182, 187)} Three were assessed as being at a higher risk of bias regarding the reference standard, where the colposcopists were not blinded to the HPV test results.(169, 172, 181) Two studies were rated at a higher risk of bias regarding the reference standard, flow and timing. Specifically, in Nygard et al.⁽¹⁸²⁾ the baseline outcomes included any additional women diagnosed with CIN 2+ within three years of follow up. The study by Cuzick et al. which was published in 2013⁽¹⁷⁴⁾ did not consider women with normal (negative) cytology who were HPV negative for further investigation. Overall, the quality of the studies was rated as fair to good.

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89 Table 4.2 Characteristics of studies retrieved from industrialised countries comparing the accuracy of HPV testing using HC2 with the accuracy of cytology-based testing as the primary screening test for cervical cancer.

test (s) Outcomes reported

Sensitivity Specificity

HPV test Cytology HPV Test Cytology Bigras

2005⁽¹⁶⁷⁾ Switzerland cross sectional

2008⁽¹⁶⁹⁾ Taiwan cross

sectional (n=10,014)

11% HC2 CC CIN 2+: 85.1% CIN 2+: 81.9% CIN 2+: 89.7% CIN 2+: 98.6%

Clavel

2001⁽¹⁷⁰⁾ France cross

sectional

2003⁽¹⁷¹⁾ France cross

sectional

90

2015⁽¹⁷⁶⁾ Germany cross

sectional

2009⁽¹⁸⁰⁾ Germany cross

sectional (n=16,724)

5% HC2 CC CIN 3+: 100% CIN 3+: 50.0% CIN 3+: 95.2% CIN 3+: 98.3%

Monsonego

2011⁽¹⁸¹⁾ France cross

sectional

2003⁽¹⁸³⁾ Germany cross

sectional

2000⁽¹⁸⁴⁾ Canada cross

sectional (n=407)

45% HC2 CC CIN 2+: 85.0% CIN 2+: 56.0% CIN 2+: 58.0% CIN 2+: 62.0%

Ronco

2006a⁽¹⁸⁵⁾ Italy cross sectional

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91 Ronco

2006b⁽¹⁸⁶⁾ Italy cross sectional

2011⁽¹⁸⁷⁾ Russia concomita

nt testing

Key: AHPV- Aptima® HPV; BD HPV- Becton-Dickinson HPV; CC- conventional cytology; CI- confidence interval; CIN – cervical intraepithelial neoplasia; HBRT-H14-Hybribio Real-time 14 High-risk HPV;HC2 - Hybrid Capture 2 HPV assay; HPV – human papillomavirus; LBC – liquid-based cytology; LSIL- low-grade squamous intraepithelial lesion; RCT- randomised controlled trial.

Note: Studies may have included study arms comparing additional HPV tests, however only HC2 outcomes are shown in the table.

Note: All cytology results presented use the standard threshold of ASCUS+ and all HC2 results presented use the standard threshold of ≥1pg/ml, all extracted data represent the crude values.

92 Table 4.3 Risk of bias appraisal of the included studies of primary screening tests – QUADAS-2

Study Domain 1: Patient Selection

Domain 2: Index Test(s) Domain 3: Reference

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