Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions ...of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination.
We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals UI).
16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46–0·68) and 0·36 (0·28–0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90–1·00) and 0·83 (0·75–1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13–0·32) and 0·35 (0·27–0·39) for 40% coverage, and 0·07 (0·00–0·10) and 0·16 (0·01–0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years).
Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time.
Canadian Institutes of Health Research.
Summary Background In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the ...endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes. Methods 176 464 women aged 20–64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1 214 415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma. Findings The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40–0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46–1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25–0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15–0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 105 (1·1–12·1) and 8·7 per 105 (3·3–18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 105 (7·9–27·0) and 36·0 per 105 (23·2–53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14–0·69) than for squamous-cell carcinoma (0·78, 0·49–1·25). The rate ratio was lowest in women aged 30–34 years (0·36, 0·14–0·94). Interpretation HPV-based screening provides 60–70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years. Funding European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.
Summary Background Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening ...rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening. Methods In this randomised trial, women aged 29–56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131. Findings 22 420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20 106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19 731 in the control group were eligible, of whom 16 750 and 16 743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19 731 in the control group; relative risk 0·73, 95% CI 0·55–0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19 731; 0·29, 0·10–0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20 106; 1·15, 0·92–1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19 286 vs 12 of 19 373; 2·85, 1·47–5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20 106; 1·25, 1·05–1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27–0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57–1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20 106; 0·96, 0·81–1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20 106; 1·08, 0·94–1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29–33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74–1·27; CIN grade 2 or worse in women aged 29–33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81–1·26; CIN grade 3 or worse in women aged 34–56 years: 157 of 16 860 vs 167 of 16 978; 0·95, 0·76–1·18; CIN grade 2 or worse in women aged 34–56 years: 274 of 16 860 vs 248 of 16 978; 1·11, 0·94–1·32). Interpretation Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older. Funding Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).
Summary Background Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation ...in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes. Methods In this randomised controlled non-inferiority trial, we invited women (aged 33–63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0·80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026. Findings We invited 46 001 women to participate, 12 819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 17% of 515 women vs 75 15% of 509 women; relative risk 1·19, 95% CI 0·90–1·57). Referral for colposcopy was more common in the molecular group (284 55% women) than in the cytology group (149 29% women; p<0·0001). Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group (96 days, range 44–101) than in the cytology triage group (158 days, 71–222; p=0·00084). Interpretation DNA methylation analysis of MAL and miR-124-2 genes on HPV-test-positive self-samples is non-inferior to cytology triage in the detection of CIN2 or worse, opening the way to full molecular screening. Funding Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg.
Summary Background 15% of women treated for high-grade cervical intraepithelial neoplasia (CIN grade 2 or 3) develop residual or recurrent CIN grade 2 or 3 or cervical cancer, most of which are ...diagnosed within 2 years of treatment. To gain more insight into the long-term predictive value of different post-treatment strategies, we assessed the long-term cumulative risk of post-treatment CIN grade 2 or 3 or cancer and different follow-up algorithms to identify women at risk of residual or recurrent disease. Methods Women who were included in three studies in the Netherlands and who were treated for CIN grade 2 or 3 between July, 1988, and November, 2004, were followed up by cytology and testing for high-risk human papillomavirus (hrHPV) at 6, 12, and 24 months after treatment, and subsequently received cytological screening every 5 years. The primary endpoint was the cumulative risk of post-treatment CIN grade 2 or higher by December, 2009. We also assessed the cumulative risk of CIN grade 2 or higher in women with three consecutive negative cytological smears and women with negative co-testing with cytology and hrHPV at months 6 and 24. This study is registered in the Dutch trial register, NTR1468. Findings 435 women were included, 76 (17%) of whom developed post-treatment CIN grade 2 or higher, of which 39 were CIN grade 3 or higher. The 5-year risk of developing post-treatment CIN grade 2 or higher was 16·5% (95% CI 13·0–20·7) and the 10-year risk was 18·3% (13·8–24·0). The 5-year risk of developing post-treatment CIN grade 3 or higher was 8·6% (95% CI 6·0–12·1) and the 10-year risk was 9·2% (5·8–14·2). Women with three consecutive negative cytological smears had a CIN grade 2 or higher risk of 2·9% (95% CI 1·2–7·1) in the next 5 years and of 5·2% (2·1–12·4) in the next 10 years. The 5-year risk of CIN grade 3 or higher was 0·7% (95% CI 0·0–3·9) and the 10-year risk was 0·7% (0·0–6·3). Women with negative results for co-testing had a 5-year risk of CIN grade 2 or higher of 1·0% (95% CI 0·2–4·6) and a 10-year risk of 3·6% (1·1–10·7). The 5-year risk of CIN grade 3 or higher was 0·0% (95% CI 0·0–3·0) and the 10-year risk was 0·0% (0·0–5·3). Interpretation The 5-year risk of post-treatment CIN grade 2 or higher in women with three consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24 months was similar to that of women with normal cytology in population-based screening and therefore justifies their return to regular screening. Funding VU University Medical Center, Erasmus University Medical Center, Netherlands.
In many European countries, human papillomavirus (HPV) vaccine uptake among girls has remained below target levels, supporting the scope for vaccination of boys. We aimed to investigate if ...sex-neutral HPV vaccination can be considered cost-effective compared with girls-only vaccination at uptake levels equal to those among girls and under tender-based vaccination costs achieved throughout Europe.
We investigated the cost-effectiveness of sex-neutral HPV vaccination in European tender-based settings. We applied a Bayesian synthesis framework for health economic evaluation to 11 countries (Austria, Belgium, Croatia, Estonia, Italy, Latvia, the Netherlands, Poland, Slovenia, Spain, and Sweden), accommodating country-specific information on key epidemiological and economic parameters, and on current HPV vaccination programmes. We used projections from three independently developed HPV transmission models to tailor region-specific herd effects. The main outcome measures in the comparison of sex-neutral with girls-only vaccination were cancer cases prevented and incremental cost-effectiveness ratios (ICERs), defined as the cost in international dollars (I$) per life-year gained.
The total number of cancer cases to be prevented by vaccinating girls at currently realised vaccine uptake varied from 318 (95% CI 197–405) per cohort of 200 000 preadolescents (100 000 girls plus 100 000 boys) in Croatia (under 20% uptake of the 9-valent vaccine) to 1904 (1741–2101) in Estonia (under 70% uptake of the 9-valent vaccine). Vaccinating boys at equal coverage increased these respective numbers by 168 (95% CI 121–213) in Croatia and 467 (391–587) in Estonia. Sex-neutral vaccination was likely to be cost-effective, with ICERs of sex-neutral compared with girls-only vaccination varying from I$4300 per life-year gained in Latvia (95% credibility interval 3450–5160; 40% uptake) to I$25 720 per life-year gained in Spain (21 380–30 330; 80% uptake). At uniform 80% uptake, a favourable cost-effectiveness profile was retained for most of the countries investigated (Austria, Belgium, Italy, Latvia, the Netherlands, Slovenia, Spain, and Sweden).
Sex-neutral HPV vaccination is economically attractive in European tender-based settings. However, tendering mechanisms need to ensure that vaccination of boys will remain cost-effective at high vaccine uptake rates.
European Commission 7th Framework Programme and WHO.
Abstract This meta-analysis was performed to summarize and compare the diagnostic performance and diagnostic accuracy of radiographic and scintigraphic techniques in the evaluation of patients ...suspected of having aseptically loose acetabular components. Twenty-eight studies, published between January 1975 and October 2004, presented sufficient data for quantitative analysis. The pooled sensitivity and specificity rates for plain radiography were 70% (95% confidence interval CI = 59%-79%) and 80% (95% CI = 73%-86%), respectively; those for subtraction arthrography were 89% (95% CI = 84%-93%) and 76% (95% CI = 68%-82%), respectively; and those for nuclear arthrography were 87% (95% CI = 57%-97%) and 64% (95% CI = 40%-82%), respectively. Finally, bone scintigraphy had a sensitivity of 67% (95% CI = 57%-76%) and a specificity of 75% (95% CI = 64%-83%). We found a significantly higher sensitivity for subtraction arthrography as compared with plain radiography and bone scintigraphy. Therefore, subtraction arthrography is recommended for use as an additional diagnostic technique when plain radiography is found to be inconclusive.
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