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Value of a catch-up HPV test in women aged 65 and above: A Danish population-based nonrandomized intervention study [1]

['Mette Tranberg', 'University Research Clinic For Cancer Screening', 'Department Of Public Health Programmes', 'Randers Regional Hospital', 'Randers', 'Lone Kjeld Petersen', 'Department Of Obstetrics', 'Gynecology', 'Odense University Hospital', 'Odense']

Date: 2023-07

In the intervention group, a total of 6.5% (95% CI: [6.0, 7.1%]; n = 455) were HPV–positive ( Table 3 ). The HPV prevalence decreased with age from 7.3% (95% CI: [6.3, 8.4%]) at age 65 to 67 to 6.1% (95% CI: [5.4, 6.8%]; p = 0.05) at age 68 to 69. The HPV prevalence was higher in vaginal self-samples (8.0%, 95% CI: [6.9, 9.3%]) compared to clinician-collected cervical samples (5.9%, 95% CI: [5.2, 6.6%]; p < 0.001). Of those HPV–positive, HPV16/18 was found in 25.5% (95% CI: [21.5, 29.7%]) and HPV other types in 74.5% (95% CI: [70.2, 78.4%]) ( Table 3 ). Insufficiently screened women had higher HPV prevalence (11.5%, 95% CI: [8.7, 14.9%]) as compared to sufficiently screened women (6.2%, 95% CI: [5.6, 6.8%]; p < 0.001). Among the 161 women with an HPV–positive self-sample, 99.4% (95% CI: [96.6, 100%]; n = 160) completed follow-up testing at their GP within 180 days, with one woman attending follow-up after 180 days. Of those HPV–positive, 96.4% (n = 439/455) had a record of either cytology (n = 164) or/and histology (n = 275) follow-up during the study period. In the reference group, a total of 4.0% (95% CI: [2.7, 5.7%]; n = 30) were HPV–positive; of whom 46.7% (95% CI: [28.3, 65.7%]) had HPV16/18 detected ( Table 3 ). Among the HPV–positive; 96.7% (n = 29/30) had a record of either cytology (n = 7) or/and histology (n = 22) follow-up during the study period.

Of the 6,965 HPV-tested women in the intervention group; 357 women (5.1%) had histology results registered during follow-up, 275 among HPV–positive and 82 among HPV–negative ( Table 4 ). Of those with histology, 44 (12.3%, 95% CI: [9.1, 16.2%]; n = 44/357) had CIN2+ diagnosed (12 CIN2, 22 CIN3, 6 CIN, and 4 cancers) ( Table 4 ). In the intervention group, the percentage of CIN2+ lesions diagnosed were higher in insufficiently screened (1.4%, 95% CI: [0.5, 2.9%]; p = 0.05; n = 6/443) but not statistically different from the percentage diagnosed among sufficiently screened (0.6%, 95% CI: [0.4, 0.8%]; n = 38/6,522). Among the 743 tested women in the reference group; 75 women (10.1%) had histology results registered and 11 (14.6%, 95% CI: [7.6, 24.7%]; n = 11/75) had CIN2+ diagnosed (3 CIN2, 3 CIN3, 1 CIN, and 4 cancers). The number of CIN3+ lesions diagnosed was significantly higher in the intervention group (2.3 per 1,000 eligible women; 95% CI: [1.5, 3.4]; p < 0.001) as compared to the reference group (0.2 per 1,000 eligible women; 95% CI: [0.1, 0.4]) ( Table 4 ). An even more pronounced tendency was seen for CIN2+ lesions in the intervention group (3.9 per 1,000 eligible women, 95% CI: [2.9, 5.3]; p < 0.001) as compared to the reference group (0.3 per 1,000 eligible women, 95% CI: [0.2, 0.6]). For the harm–benefit ratio, 11.6 (95% CI: [8.5, 15.8]; p = 0.69) and 19.6 (95% CI: [13.2, 29.2]; p = 0.62) colposcopies were performed to detect one CIN2+ and CIN3+, respectively, in the intervention group as compared to 10.1 (95% CI: [5.4, 18.8]) and 15.8 (95% CI: [7.4, 34.0]) colposcopies in the reference group ( Table 4 ).

Discussion

Offering a catch-up HPV test to 65- to 69-year-old women, including the possibility to allow women to choose between a clinician-collected sample or vaginal self-sampling, resulted in an overall uptake of 62.2% and an HPV prevalence of 6.5%. The intervention was associated with a significantly higher CIN2+ detection rate as compared to the reference group (3.9 per versus 0.3 per 1,000 eligible women) and was not associated with a significantly higher number of colposcopies needed to detect one CIN2+ (11.6 versus 10.1, respectively). Whereas clinician-based sampling was the preferred screening modality overall (71.1%), a substantially higher percentage of insufficiently screened women underwent self-sampling than sufficiently screened women (52.1% versus 27.3%).

The screening uptake of 62.2% in the intervention group was substantially higher than the uptakes of 44.0% [37] and 41% to 43.3% [17,38] reported by Danish and Swedish studies targeting women aged 69 and above. The most likely explanations for the improved uptake were the lower age in our study population, providing women the choice between two screening modalities, and using reminders. Although clinician-based sampling was the preferred screening modality, the fact that almost every third woman tested (28.9%) selected self-sampling confirms that providing women the choice is essential and could increase uptake beyond offering clinician-based sampling alone [39]. If follow-up to the cytology test at the GP is poor among HPV–positive self-samplers, the benefit of offering self-sampling could be compromised [20]. In this study, the compliance to follow-up was remarkably high (99%) and was achieved without using an intensive follow-up protocol as used in other studies [20]. Although insufficiently screened women constitute a minority of the female population [10], nevertheless 23% in this study, they are at high risk of cervical cancer and, thus, of particular importance to reach [10,11]. Encouragingly, we observed that the screening uptake by an opt-in self-sampling strategy was almost 2 times higher among insufficiently screened women than among sufficiently screened women (52.1% versus 27.3%). Yet, vaginal self-sampling does not appeal to all women and data from the UK demonstrates that another promising screening modality could be to offer women the opportunity of non-speculum clinician-based sampling at the GP to overcome the pain associated with cervical sampling after menopause [39]. In the intervention group, we found a CIN2+ prevalence of 12.3% among tested women with histology follow-up. This was lower than reported in Danish women aged 69 and above with histology (18%) [16] and in Swedish women aged 56 to 60 with persistent HPV infections (23%) [40], but still higher than the very low CIN2+ prevalence of 0.2% to 1.0% among Swedish women aged 56 and above [41,42]. These differences were probably due to differences in screening strategy (cytology versus HPV) [13], screening history [10], age, and diagnostic strategies [22]. The true CIN2+ prevalence in postmenopausal women is difficult to estimate due to well-known diagnostic challenges resulting in increased risk of missing disease in the cervical canal [22]. A recent Danish study among older screen-positive women demonstrated that more than half of all CIN2+cases detected in the LLETZ specimens were missed by cervical biopsies, suggesting a significant risk of underdiagnosis [22]. Thus, the CIN2+ prevalence strongly depends on the diagnostic strategy and could be underestimated in our study. Ideally, eligible women in all Danish regions should have been individually randomized to the intervention and reference group instead of being allocated to the groups based on their geographical location. Unfortunately, this was not feasible from an organizational point of view [31]. Instead, we used the remaining four Danish regions without an organized HPV screening offer as reference group. For such a comparison to be valid, it is necessary to assume similar cervical cancer incidence rates across regions before the start of this study. This assumption was confirmed by NORDCAN data, showing comparable average age-standardized cervical cancer incidence rates across regions from 2007 to 2016 among women aged 65 and above [43]. Still, indications for cervical sampling in this age group likely differed between the groups. In the reference group, cervical sampling was assumedly performed because of symptoms, e.g., postmenopausal bleeding and thus more severe disease situation which were supported by 36.4% of all CIN2+ cases were cancer as compared to 9.1% in the intervention group. In comparison, women in the intervention group were more likely to be asymptomatic and thus at lower cancer risk. Therefore, comparison with the reference group should be done with caution. Part of the differences in the CIN2+ detection between groups could also be explained by variances in the distribution of age and screening history. Yet, we accounted for this by stratifying the study outcomes for these potential confounders.

In all screening initiatives, it is essential to carefully evaluate the trade-off between benefits and harms. From a population-based perspective, the intervention contributed to a significantly higher detection of CIN2+ and CIN3+ per 1,000 eligible women. Not all CIN3 lesions, and especially CIN2, detected at age 65 and older would have progressed into cancer in the remaining lifespan [7]; thus, the detection and treatment of these precancer lesions could be considered as overtreatment. However, the degree to which CIN2/CIN3 lesions that will progress or spontaneously regress has not been studied in older women [44]. According to Bekos and colleagues [45], the woman’s age has a substantial impact on the natural history of CIN, independent of CIN grade and hrHPV infection. To detect one CIN2+ case in the intervention and reference groups, comparable numbers of colposcopies were required (11.6 versus 10.1, respectively). Still, the estimate of 11.6 in the intervention group was significantly higher than the 5.4 colposcopies (defined by histological samples using LEETZ or biopsy) per CIN2+ case reported in the Danish HPV catch-up study targeting women aged 69 and above [16], suggesting that benefit–harm ratio was less favorable for the younger age group in our study. The amount of potential overdiagnosis was also considerable, as per 1,000 eligible women, 28.0 women had colposcopy performed to exclude the presence of CIN2+ as compared to 1.9 in the reference group. The high number of unnecessary colposcopies was likely influenced by our sensitive and conservative screening triage algorithm; we referred all women with HPV16/18 directly to colposcopy, and at the 12-month repeat screening, we performed co-testing and referred all women with HPV (regardless of genotype) or ASC-US and worse to colposcopy. Direct colposcopy referral of HPV16/18 screen-positive women seemed sensible, as 17% had CIN2+ detected which was within the commonly accepted risk-threshold (10% to 20%) for colposcopy referral in Europe [46]. Still, modification of the triage algorithms is warranted to reduce the number of unnecessary colposcopies and women placed in surveillance cycles of unclear end. In ongoing studies [47], the performance and referral rates of different triage strategies using p16/Ki67 dual stain cytology [48], extended genotyping [49], and DNA host cell methylation [50] are being evaluated.

The key strength of the study was that the intervention was undertaken within a real-world setting of a national screening program, using the same screening invitation protocol and follow-up algorithms that are used routinely in the Danish program. Furthermore, this study included several times as many women as the previous studies exploring the utility of vaginal self-sampling among older women [38,41,44]. The use of individual-level screening data from the nationwide DPDB [28] ensured completeness of the study outcomes and reduced risk of selection and information bias. As 96.4% of the intervention group and 96.7% of the reference group had either cytology or/and histology follow-up after an HPV–positive test result, the impact of loss to follow-up within the study period on the detection of CIN2+/CIN3+ can be expected to be limited. The high compliance to histology follow-up among test-positive women reduced the risk of underestimating the number of colposcopies performed; yet, there was a risk of underestimation as no procedure code exists for colposcopy in the DPDB [28]. Hence, women may have had a colposcopy performed without having histology material sampled. However, the magnitude of this would be expected to be low as national guidelines state that that all women referred for colposcopy should have a minimum of 4 biopsies collected [35]. Although, the study outcomes were stratified by age and screening history, residual confounding from smoking and sexual behavior remain a point of concern. However, the impact of smoking on the detection of CIN2+/CIN3+ was considered limited as one study found no association between screening at older age and risk of cervical cancer when adjusting for smoking [51]. Besides, survey data from younger women [52] found that sexual behavior was only slightly associated with cervical cancer screening participation. Thus, we find it unlikely that this factor substantially confounded the results in this older population.

Our study informs the current debate as to whether women over 65 years of age should be offered a catch-up HPV test if they never had an HPV test. Offering catch-up HPV screening resulted in higher detection of CIN2+ and CIN3+ without significantly increase in the number of colposcopies per detected CIN2+/CIN3+. Furthermore, women with HPV negative screening results in this study will be expected to have an extremely low risk of developing cervical cancer in their remaining life time [14]. Thus, the intervention might be anticipated to yield a greater cervical cancer prevention than no HPV screening intervention. On the other hand, even with the potential risk of underestimation, the rather low CIN2+ prevalence (12.3%) together with the considerable amount of potential overdiagnosis and recognized clinical management issues justify that the choice of the future screening strategy for this older age group should be based on the availability of resources and attitudes to cervical cancer risk in each country [16,22]. As previous screening participation and screening results are key risk markers for cervical cancer at older ages [10,11], one could argue that a satisfactory cost-benefit balance of catch-up HPV interventions would be to only target women aged 65 and above if they have been insufficiently screened instead of targeting all sufficiently screened women who exited the program with normal cytology but never had an HPV test. This differentiated strategy was supported by our intervention data showing significantly higher HPV prevalence as well as a tendency towards higher CIN2+ detection in insufficiently screened as compared to sufficiently screened women. Yet, this differentiated strategy requires up-to-date screening registries, an option not in place everywhere.

In countries with limited resources, collecting an opportunistic cervical cytology sample due to gynecological symptoms seems appropriate from a clinical point of view based on the higher CIN2+ detection per 1,000 tested women in the reference as compared to the intervention group (14.8 versus 6.3 per 1,000 tested, reflecting a per protocol analysis).

Based on this study, vaginal self-sampling might be the optimal screening modality for women aged 65 and above based on its ability to reach older insufficiently screened women and its more favorable cost than clinician-based sampling [21]. Our results may be generalized to countries with comparable organization of the cervical cancer screening program with free-of-charge screening and access to follow-up testing; however, the effect size may depend on the screening history in the included birth cohorts, screening uptake, compliance to follow-up, and especially the diagnostic management of the screen-positive women [22] in each country.

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[1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004253

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