Abstract: We included a total of 40 studies in the review, with more than 140,000 women aged between 20 and 70 years old. Many studies were at low risk of bias. There were a sufficient number of included studies with adequate methodology to perform the following test comparisons: hybrid capture 2 (HC2) (1 pg/mL threshold) versus conventional cytology (CC) (atypical squamous cells of undetermined significance (ASCUS)+ and low-grade squamous intraepithelial lesions (LSIL)+ thresholds) or liquid-based cytology (LBC) (ASCUS+ and LSIL+ thresholds), other high-risk HPV tests versus conventional cytology (ASCUS+ and LSIL+ thresholds) or LBC (ASCUS+ and LSIL+ thresholds). For CIN 2+, pooled sensitivity estimates for HC2, CC and LBC (ASCUS+) were 89.9%, 62.5% and 72.9%, respectively, and pooled specificity estimates were 89.9%, 96.6%, and 90.3%, respectively. The results did not differ by age of women (less than or greater than 30 years old), or in studies with verification bias. Accuracy of HC2 was, however, greater in European countries compared to other countries. The results for the sensitivity of the tests were heterogeneous ranging from 52% to 94% for LBC, and 61% to 100% for HC2. Overall, the quality of the evidence for the sensitivity of the tests was moderate, and high for the specificity. The relative sensitivity of HC2 versus CC for CIN 2+ was 1.52 (95% CI: 1.24 to 1.86) and the relative specificity 0.94 (95% CI: 0.92 to 0.96), and versus LBC for CIN 2+ was 1.18 (95% CI: 1.10 to 1.26) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). The relative sensitivity of HC2 versus CC for CIN 3+ was 1.46 (95% CI: 1.12 to 1.91) and the relative specificity 0.95 (95% CI: 0.93 to 0.97). The relative sensitivity of HC2 versus LBC for CIN 3+ was 1.17 (95% CI: 1.07 to 1.28) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment. Evidence from prospective longitudinal studies is needed to establish the relative clinical implications of these tests.

Plain-language summary: We searched for all relevant studies up to November 2015. Forty studies compared the HPV test to the Pap test on over 140,000 women between 20 to 70 years old who attended for their routine cervical screening. The studies examined which test can detect precancerous cervical changes which are called cervical intraepithelial neoplasias (CIN 2 and CIN 3). There were enough studies with enough women in them to allow us to draw conclusions. However, some of the results from the studies were different from each other. For example, tests were more accurate in studies in Europe than in Asia or Central or South America. Overall, the quality of the evidence was moderate to high. A perfect test would correctly say if a woman has precancerous changes or if a woman does not. But most tests are not perfect. This review found that for every 1000 women screened, around 20 women will have precancerous changes. The HPV test will correctly identify 18 of these women (but will miss 2 women). The Pap test will identify 15 of the women (but will miss 5 women). The women who are missed could develop cervical cancer. For every 1000 women screened, there will be 980 women who will not have precancerous changes. The HPV test will correctly identify 881 women (but 99 women will be incorrectly told that they have a lesion). The Pap test will correctly identify 885 women (but 95 will be incorrectly told that they have a lesion). Women who are incorrectly told that they have a lesion may have their cervix examined or may receive surgery unnecessarily.