Matti Lehtinen

Controlled trial of cervical cancer screening frequency among human‐papillomavirus‐vaccinated women

Abstract Cervical screening frequency has not been studied in vaccinees. As the major risk factor, oncogenic human papillomavirus (HPV) is declining due to vaccination. We report a trial to assess the effectiveness of cervical screening frequency among women HPV‐vaccinated as early adolescents (NCT02149030). In 2013, 5626 1992‐1995‐born women, who had received three doses of the HPV16/18 vaccine at ages 12–15 between 2007 and 2010 in a community‐randomized vaccination trial (NCT00534638), were allocated at age 22 into high‐intensity cytology‐based cervical screening by even birth date (Arm A1) or into low‐intensity cytology‐based cervical screening by odd birth date (Arm A2). One thousand three hundred thirty‐three women who received HPV16/18 vaccination at age 18 attended a safety of low intensity‐screening arm (Arm A3). Low‐intensity screening, where low‐grade cytological abnormalities were not revealed for 6 years, was compared to the standard high‐intensity screening used in Finland at the time. The prevalence of cytological and HPV findings was calculated at ages 22/25/28. The hazard ratio of histopathologically confirmed immediate cervical cancer precursors (HSIL/CIN2+) among participants was compared between low‐ and high‐intensity screening arms. The overall occurrence of CIN2+ was comparable in Arms A1, 0.70% and A2, 0.66%, with the corresponding hazard ratio at age 28 being 0.97 (95% confidence intervals, 0.50–1.88). By age 28, the occurrence of vaccine‐HPV types 16/18 was reduced up to 88% in the 12‐to‐15 compared to 18‐year‐old HPV‐vaccinated women. In conclusion, the risk of CIN2+ was similar for HPV‐vaccinated women who attended low‐intensity cervical screening compared to high‐intensity screening most likely due to the decline of oncogenic HPVs.

Predicting optimal impact interventions in the post‐ HPV vaccination world

Abstract Prophylactic vaccination is a powerful tool that changes exposure to infections and associated morbidity of preventable diseases. We discuss the impact of pneumococci and human papillomavirus (HPV) vaccination on the population biology of the two micro‐organisms and related public health effects. Data on HPV type‐replacement in communities where vaccine‐covered HPVs are almost eliminated, and interactions of the remaining HPV types on the risk of cervical cancer are reviewed. Results of comprehensive models for European country‐specific conduction of cervical screening among HPV‐vaccinated and unvaccinated women, assuming different HPV‐vaccination coverage and strategies, are discussed in our policy‐oriented review. An acceptable balance of benefits and harms of cervical cancer screening in HPV vaccinated populations requires an understanding of cancer risks in differently vaccinated birth cohorts. Finally, the challenges are complex but can be met if strategies are applied that (i) as fast as possible achieve herd effect and (ii) use a risk‐based design of HPV screening.

Elevated Risk of HPV‐Associated Oropharyngeal Cancers in Husbands of Women With Anogenital Cancer

ABSTRACTIntroductionHuman papillomavirus (HPV) infection is associated with tonsillar and base‐of‐tongue squamous cell carcinomas (TSCC/BOTSCC). We evaluated the relative risk (RR) of TSCC/BOTSCC in the husbands of women with anogenital cancer using the Swedish family database.MethodsThe Swedish family database includes 3.5 million families and 16 million individuals identified since 1932 and linked to cancer data from 1958 to 2015. We explored the RR of TSCC/BOTSCC in husbands of women diagnosed with anogenital (anal, vulvar/vaginal, cervical) cancer or cervical carcinoma in situ (CIS) as compared to husbands of controls.ResultsThe RR of TSCC/BOTSCC in husbands of women with invasive anogenital cancer increased by calendar time and decreasing ages at diagnoses. In 2002–2015, the RR peaked at 5.35 (95% CI 2.21–13.0) in TSCC/BOTSCC cases diagnosed at age < 50 years. In husbands of women with CIS, the RR for TSCC/BOTSCC was 2‐fold irrespective of time period.ConclusionsClustering of increased HPV‐associated invasive cancer risk in spouses appears to be calendar‐time dependent. This introduces a new perspective in cancer science: an increase of familial HPV‐associated cancer risk in spouses.

Low methylation marker levels among human papillomavirus‐vaccinated women with cervical high‐grade squamous intraepithelial lesions

AbstractCervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)‐vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false‐positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case–control study, 9242 women who received the three‐dose HPV16/18‐vaccine at ages 12–15 or 18 in a community‐randomized trial were included. Subsequently, they were re‐randomized for either frequent or infrequent cervical cancer screening trials. Over a 15‐year post‐vaccination follow‐up until 2022, 17 high‐grade squamous intraepithelial lesion (HSIL) and 15 low‐grade (LSIL) cases were identified at the 25‐year screening round, alongside 371 age and community‐matched HPV16/18‐vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host‐cell genes (EPB41L3, FAM19A4, and miR124‐2) was measured, along with HPV‐genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV‐genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host‐cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV‐vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV‐vaccinated women and its implications for management.

Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial

Background Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer. Methods Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002–2005. HPV vaccine cohorts comprised originally 16–17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18–19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts. Findings During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05). Interpretation Vaccination is effective against invasive HPV-positive cancer. Trial registration number NCT00122681, Post-results; NCT00169494, Post-results; NCT00092534, Post-results.

Effectiveness of various human papillomavirus vaccination strategies: A community randomized trial in Finland

AbstractIntroductionWe conducted a community‐randomized trial (NCTBLINDED) in Finland to assess gender‐neutral and girls‐only vaccination strategies with the AS04‐adjuvanted human papillomavirus (HPV)‐16/18 (AS04‐HPV‐16/18)vaccine.MethodsGirls and boys (12−15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04‐HPV‐16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04‐HPV‐16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV‐16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04‐HPV‐16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co‐primary objectives were overall effectiveness following gender‐neutral or girls‐only vaccination.ResultsOf 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: −19.0, 51.1; P = 0.232) with gender‐neutral vaccination. Following girls‐only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04‐HPV‐16/18 vaccine was high in both sexes.ConclusionsThis study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

Assessing the risk of cervical neoplasia in the post‐HPV vaccination era

AbstractThis review is based on the recent EUROGIN scientific session: “Assessing risk of cervical cancer in the post‐vaccination era,” which addressed the demands of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesion (SIL) triage now that the prevalence of vaccine‐targeted oncogenic high‐risk (hr) human papillomaviruses (HPVs) is decreasing. Change in the prevalence distribution of oncogenic HPV types that follows national HPV vaccination programs is setting the stage for loss of positive predictive value of conventional but possibly also new triage modalities. Understanding the contribution of the latter, most notably hypermethylation of cellular and viral genes in a new setting where most oncogenic HPV types are no longer present, requires studies on their performance in vaccinated women with CIN/SIL that are associated with nonvaccine HPV types. Lessons learned from this research may highlight the potential of cervical cells for risk prediction of all women's cancers.

Scientific approaches toward improving cervical cancer elimination strategies

AbstractAt the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender‐neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female‐restricted vaccination is problematic. Extended catch‐up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender‐neutral vaccination, this group can be protected by offering concomitant catch‐up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long‐lasting durability of vaccination‐induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost‐effectiveness modelling suggests that high‐coverage HPV vaccination in multiple population segments will be resource‐saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer.

Cervical Intraepithelial Neoplasm (CIN) in Women (Gardasil) (V501-015)

The primary purpose of the study is to determine if GARDASIL™ (V501) is able to prevent cervical cancer.