Estimation of the individual residual risk of cervical cancer after vaccination with the nonavalent HPV vaccine.

BACKGROUND: The nonavalent HPV (9vHPV) vaccine is indicated for active immunisation of individuals from the age of 9 years against cervical, vulvar, vaginal and anal premalignant lesions and cancers causally related to vaccine HPV high risk types 16, 18, 31, 33, 45, 52 and 58, and to the HPV low risk types 6 and 11, causing genital warts. OBJECTIVE: To estimate the lifetime risk (up to the age of 75 years) for developing cervical cancer after vaccinating a HPV naïve girl (e.g. 9 to 12 years old) with the 9vHPV vaccine in the hypothetical absence of cervical cancer screening. METHODS: We built Monte Carlo simulation models using historical pre-screening age-specific cancer incidence data and current mortality data from Denmark, Finland, Norway, Sweden and the UK. Estimates of genotype contribution fractions and vaccine efficacy were used to estimate the residual lifetime risk after vaccination assuming lifelong protection. RESULTS: We estimated that, in the hypothetical absence of cervical screening and assuming lifelong protection, 9vHPV vaccination reduced the lifetime cervical cancer and mortality risks 7-fold with a residual lifetime cancer risks ranging from 1/572 (UK) to 1/238 (Denmark) and mortality risks ranging from 1/1488 (UK) to 1/851 (Denmark). After decades of repetitive cervical screenings, the lifetime cervical cancer and mortality risks was reduced between 2- and 4-fold depending on the country. CONCLUSION: Our simulations demonstrate how evidence can be generated to support decision-making by individual healthcare seekers regarding cervical cancer prevention.

The whole story: a systematic review of economic evaluations of HPV vaccination including non-cervical HPV-associated diseases.

INTRODUCTION: Many economic evaluations of HPV vaccination have been published, but most have focused on the prevention of cervical disease as a primary health outcome. The cost-effectiveness of vaccination is likely to be underestimated if not all HPV-associated diseases are taken into account. In this review, we assess the influence of non-cervical HPV-associated diseases on the incremental cost-effectiveness ratio (ICER) of preadolescent HPV vaccination. Areas covered: We systematically searched the literature and identified 18 studies that included non-cervical diseases in the estimates of cost-effectiveness of HPV-vaccination. When taking other HPV-related diseases into account compared to not including such other diseases, the mean ICERs were 2.85 times more favorable for girls only vaccination and 3.89 times for gender neutral vaccination. Expert commentary: Including non-cervical diseases in economic evaluations of HPV vaccination programs makes it more likely that the ICER falls beneath accepted cost-effectiveness thresholds and therefore increases the scope for gender neutral vaccination.

An exploration of individual- and population-level impact of the 2-dose HPV vaccination schedule in pre-adolescent girls.

Since 2014, several countries have implemented a 2-dose schedule for Human papillomavirus (HPV) vaccination. Licensure of the 2-dose schedule was based on non-inferiority results from immunobridging studies, comparing the antibody levels of the 2-dose schedule in young girls to those of the 3-dose schedule in young adults. Since licensure, additional data on antibody levels and other aspects of the immune response and clinical effectiveness have become available. This review will discuss the current outcomes on immunogenicity and effectiveness together with an exploration on the population impact of 2-dose schedules from a cost-effectiveness perspective. The 2-dose schedule has important benefits, such as easier logistics, reduced expenditure, potentially higher acceptance and fewer side effects. Policymakers and registration authorities should consider whether these benefits outweigh the likely differences on individual- and population-level impact between the 2- and 3-dose schedules.

Direct benefit of vaccinating boys along with girls against oncogenic human papillomavirus: bayesian evidence synthesis.

OBJECTIVE: To assess the reduction in the vaccine preventable burden of cancer in men if boys are vaccinated along with girls against oncogenic human papillomavirus (HPV). DESIGN: Bayesian evidence synthesis approach used to evaluate the impact of vaccination against HPV types 16 and 18 on the burden of anal, penile, and oropharyngeal carcinomas among heterosexual men and men who have sex with men. The reduced transmission of vaccine-type HPV from vaccination of girls was assumed to lower the risk of HPV associated cancer in all men but not to affect the excess risk of HPV associated cancers among men who have sex with men. SETTING: General population in the Netherlands. INTERVENTION: Inclusion of boys aged 12 into HPV vaccination programmes. MAIN OUTCOME MEASURES: Quality adjusted life years (QALYs) and numbers needed to vaccinate. RESULTS: Before HPV vaccination, 14.9 (95% credible interval 12.2 to 18.1) QALYs per thousand men were lost to vaccine preventable cancers associated with HPV in the Netherlands. This burden would be reduced by 37% (28% to 48%) if the vaccine uptake among girls remains at the current level of 60%. To prevent one additional case of cancer among men, 795 boys (660 to 987) would need to be vaccinated; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2162, 3486, and 1975, respectively. The burden of HPV related cancer in men would be reduced by 66% (53% to 805) if vaccine uptake among girls increases to 90%. In that case, 1735 boys (1240 to 2900) would need to be vaccinated to prevent an additional case; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2593, 29107, and 6484, respectively. CONCLUSIONS: Men will benefit indirectly from vaccination of girls but remain at risk of cancers associated with HPV. The incremental benefit of vaccinating boys when vaccine uptake among girls is high is driven by the prevention of anal carcinomas, which underscores the relevance of HPV prevention efforts for men who have sex with men.

Longitudinal assessment of DNA methylation changes during HPVE6E7-induced immortalization of primary keratinocytes.

High-risk human papillomavirus (hrHPV)-induced immortalization and malignant transformation are accompanied by DNA methylation of host genes. To determine when methylation is established during cell immortalization and whether it is hrHPV-type dependent, DNA methylation was studied in a large panel of HPVE6E7-immortalized keratinocyte cell lines. These cell lines displayed different growth behaviors, i.e., continuous growth versus crisis period prior to immortalization, reflecting differential immortalization capacities of the 7 HPV-types (16/18/31/33/45/66/70) studied. In this study, cells were monitored for hypermethylation of 14 host genes (APC, CADM1, CYGB, FAM19A4, hTERT, mir124-1, mir124-2, mir124-3, MAL, PHACTR3, PRDM14, RASSF1A, ROBO3, and SFRP2) at 4 different stages during immortalization. A significant increase in overall methylation levels was seen with progression through each stage of immortalization. At stage 1 (pre-immortalization), a significant increase in methylation of hTERT, mir124-2, and PRDM14 was already apparent, which continued over time. Methylation of ROBO3 was significantly increased at stage 2 (early immortal), followed by CYGB (stage 3) and FAM19A4, MAL, PHACTR3, and SFRP2 (stage 4). Methylation patterns were mostly growth behavior independent. Yet, hTERT methylation levels were significantly increased in cells that just escaped from crisis. Bisulfite sequencing of hTERT confirmed increased methylation in immortal cells compared to controls, with the transcription core and known repressor sites remaining largely unmethylated. In conclusion, HPV-induced immortalization is associated with a sequential and progressive increase in promoter methylation of a subset of genes, which is mostly independent of the viral immortalization capacity.

Posttreatment assessment of women at risk of developing high-grade cervical disease: proposal for new guidelines based on data from the Netherlands.

OBJECTIVE: Women treated for high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or grade 3 [CIN2/3]) face a significant risk of developing post-treatment disease. Therefore, in most European countries, they are monitored by cytologic testing at 6, 12, and 24 months after treatment. Although testing for high-risk types of the human papillomavirus (hrHPV) in the follow-up seems to be a valuable supplementary method, its use is not yet fully explored. METHODS: Besides reviewing the literature, we completed a long-term follow-up study describing the cumulative risk for CIN2/3 or cancer (CIN2+) of different hrHPV and cytology test results after treatment. CONCLUSIONS: High-risk HPV testing improves the sensitivity to detect posttreatment CIN2/3 (relative sensitivity=1.15, 95% confidence interval [CI]=1.06-1.25), but the highest sensitivity (95%, 95% CI=91%-98%) is reached by performing cotesting (both cytology and hrHPV). The CIN2+ risk after a single negative cotesting result taken 6 months after treatments was similar to the risk after 3 consecutive negative cytologic test results (5-y CIN2+ risk being 3.0% [95% CI=1.5%-6.1%] and 2.9% [95% CI=1.2%-7.1%], respectively). Women who test negative for cotesting at both 6 and 24 months after treatment have a minimal risk of developing CIN3+ in the next 5 years (0.0%, 95% CI=0.0%-3.0%). RECOMMENDATIONS: We propose a new posttreatment surveillance protocol, consisting of combined testing with both cytology and hrHPV at 6 and 24 months after treatment. After 2 negative cotesting results, women should be retested after 5 years.

Arguments in favor of HPV testing for cervical screening and post-treatment CIN2+ monitoring.

Several studies have shown that the human papilloma virus (HPV) test is a more sensitive and objective primary cervical cancer screening tool than cytology. Therefore, conversion of cytology into HPV screening (as is planned in The Netherlands and some other European regions) will result in a better protection against cervical cancer and high-grade precursor lesions. Moreover, offering self-sampling for HPV testing will increase screening attendance by re-attracting former non-attendees. However, triage of HPV positive women is necessary because the specificity of HPV testing is 2-4% lower than of cytology. Several triage strategies have been evaluated, of which two, with cytology testing included, are feasible and were recently recommended. As an alternative for cytology triage, objective, non-morphological disease markers are upcoming and so far have shown promising results. Finally, HPV testing can also contribute to a more efficient monitoring of women treated for high-grade cervical precursor lesions, permitting fewer follow-up visits.

Impact of vaccine protection against multiple HPV types on the cost-effectiveness of cervical screening.

Cross-protection against non-HPV16/18 types and the emergence of broad spectrum vaccines protecting against multiple HPV types will influence the cost-effectiveness of future screening. To assess this influence we used an individual-based simulation model describing the relation between 14 HPV types and cervical disease, allowing the occurrence of multiple type infections. Screening scenarios for vaccinated women were evaluated, firstly for HPV16/18 vaccination with partial cross-protection against HPV 31, 33, 45 and 58 and secondly, for broad spectrum vaccination against 5-13 HPV types. The vaccine-induced incidence reduction of type-specific infection was varied from 0 to 95% in the cross-protection setting and set at 100% in the setting of broad spectrum vaccines. Scenarios of either cytology or HPV DNA screening were considered under varying lifetime number of screening rounds. At a cost-effectiveness threshold of €20,000/QALY, four times HPV DNA screening between 30 and 60 years was the selected scenario in addition to HPV16/18 vaccination, whether or not cross-protection was conferred (€6707 and €9994/QALY, respectively). In the absence of cross-protection, a fifth screening round might be considered (ICER €22,967/QALY). In addition to broad spectrum vaccination, one screen during lifetime was cost-effective up to an 11-valent vaccine. If the vaccine-induced type-specific incidence reduction was lowered to 99%, one screen during lifetime was cost-effective even in addition to 13-valent vaccination. In conclusion, in a cohort of HPV16/18 vaccinated women, four rounds of HPV DNA screening is cost-effective. One screen during lifetime remains cost-effective in addition to broad spectrum vaccination offering protection against many high-risk HPV types.

The clinical benefit and cost-effectiveness of human papillomavirus vaccination for adult women in the Netherlands.

BACKGROUND: The use of human papillomavirus (HPV) vaccines has been universally approved for women from age 12 to 25 years, but those older than 16 years receive no reimbursement for the cost of the vaccine in the Netherlands. Reductions in the vaccine price as well as new insights in the efficacy of HPV vaccines offer renewed arguments to consider HPV vaccination in adult women. We calculated the clinical benefit and cost-effectiveness of vaccinating women aged 17-25 years in 2010. METHODS: The calculations were based on an individual-based simulation model for cervical carcinogenesis, with HPV infection risks obtained from a type-specific HPV transmission model. The indirect protective effect from vaccinating 12 to 16 year-old girls was adjusted for. Cervical screening in the model was incorporated according Dutch screening guidelines, i.e. 7 cytology-based rounds at 5-year intervals from the age of 30. As base-case, we assumed the vaccine to offer full protection against HPV16/18 only if no prior exposure to that type had occurred before vaccination. In sensitivity analyses, we considered partial cross-protection against types 31/33/45/58 and efficacy against all future infections, irrespective of previous or current infection status. RESULTS: In base-case analyses, vaccinating 17 year-olds reduced their lifetime risk of treatment for precancerous lesions from 7.77% to 3.48% and their lifetime cervical cancer risk from 0.52% to 0.24%. These risks were 6.12% and 0.45%, respectively, for a 25 year-old vaccinee. The incremental cost-effectiveness ratio (ICER) for vaccinating 17-25 year-olds was €22,526 per quality-adjusted life-year (QALY) at a vaccine price of €65 per dose, a 50% reduction of the 2010 pharmacy price in the Netherlands. If cross-protection against types 31/33/45/58 was included, the ICER decreased to €14,734 per QALY. Results were robust to efficacy assumptions with respect to previous or current infection status. CONCLUSION: The clinical benefit of HPV vaccination of women up to 25 years moderately depends on cross-protection to non-vaccine types. Refunding the cost of the vaccine to 17-25 year-old women in the Netherlands can be considered cost-effective at anticipated price reductions.

How to screen for cervical cancer after HPV16/18 vaccination in The Netherlands.

In The Netherlands, vaccination against HPV16/18 has been recommended for all 12-year-old girls. Because screening of vaccinated women remains important, we evaluated the model-based cost-effectiveness of cervical cancer screening strategies. We considered cytology and the HPV DNA test as primary screening instrument, varied the number of screening rounds from 7 to 4, and set the screening starting age at 30 and 35 years. Our model predicted reductions in cervical cancer mortality between 60 and 81% (from 199 deaths to 37-79) when adding screening to vaccination (assumptions for vaccination: 95% efficacy, 100% compliance, lifelong protection). Screening 5 times with HPV DNA (euro11,133/QALY) or 7 times with cytology (euro17,627/QALY) were scenarios with comparable costs and effects and incremental cost-effectiveness ratios below the threshold in The Netherlands (euro20,000 per QALY).

HPV16/18 vaccination to prevent cervical cancer in The Netherlands: model-based cost-effectiveness.

We evaluated the cost-effectiveness of HPV16/18 vaccination for girls aged 12 years in The Netherlands in addition to cervical cancer screening. For this purpose, we developed a simulation model that describes the relation between each of the high-risk human papillomavirus (hrHPV) types and cervical disease, allowing the occurrence of multiple type-specific infections. Model parameters were derived from Dutch cohort studies, including a large population-based screening trial, and from the national cervical cancer registry. The model satisfactorily reproduced Dutch data on HPV infection and the presence of cervical lesions. For our base-case scenario in which 85% of the girls aged 12 years were vaccinated against types 16/18 (95% efficacy, lifelong protection), the model predicted a decrease of 60% in the number of cervical cancer cases and cervical cancer deaths indicating that substantial health benefits can be achieved. Health savings were robust against changes in the vaccine efficacy (varied from 85% to 98%) but savings showed a substantial reduction when the efficacy started waning 10 years after vaccination. The discounted costs per quality-adjusted life year (QALY) were euro 19,500/QALY (range euro 11,000 to euro 25,000/QALY) and lied near the cost-effectiveness threshold of euro 20,000/QALY used in The Netherlands. The simulations further showed that vaccination cannot replace screening because vaccination without screening was less effective than screening in preventing cancer in women over 40 years of age. In conclusion, our model results support the implementation of HPV16/18 vaccination in young women in addition to cervical cancer screening.

Optimization of primary and secondary cervical cancer prevention strategies in an era of cervical cancer vaccination: a multi-regional health economic analysis.

With the recent advent of cervical cancer vaccines, many questions relating to the best overall prevention methods for cervical disease are beginning to arise. A Markov model was used across five geographic regions (Canada, The Netherlands, Taiwan, UK, US) to examine the clinical benefits and cost-effectiveness of: (1) vaccination combined with screening, considering changes to screening-related parameters and (2) vaccination combined with screening, considering changes to screening policy. Given the assumptions used in this analysis, adding vaccination to current screening is likely to be cost-effective in the regions studied. When considering vaccination with several plausible changes to screening programmes, locations with the most frequent Papanicolaou smear testing may achieve the most efficiency gains by adopting a less frequent screening interval or incorporating HPV testing into their screening practices. Although it may be beneficial to change screening to maximize efficiency, the most cost-effective strategies for vaccination and screening combinations may not lead to the greatest reductions in cervical cancer; therefore such policy decisions may vary depending on region-specific goals. Finally, new screening paradigms such as primary HPV testing should be considered in future analyses.

Assessing the introduction of universal human papillomavirus vaccination for preadolescent girls in The Netherlands.

A persistent infection with human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. Clinical trials with HPV-vaccines have been very successful in preventing persistent HPV16/18 infections, the two most oncogenic HPV-genotypes. We assessed the introduction of universal HPV-vaccination for preadolescent girls in the Dutch National Immunization Programme. Long-term vaccine efficacy, the need and extent of a catch-up programme for young women, and the impact of vaccination on the cervical cancer screening programme are major unresolved issues. Preliminary conservative estimates (80% vaccine efficacy and no effects on the screening programme, transmission rate, non-cervical cancer incidence, and cross protection) predict an acceptable cost-effectiveness ratio for universal vaccination of preadolescent girls.

Evaluation of cervical screening strategies with adjunct high-risk human papillomavirus testing for women with borderline or mild dyskaryosis.

The management of women with a smear read as borderline/mild dyskaryosis (BMD) found by cervical cancer screening is still under discussion as only few of these cases are associated with high-grade lesions. To determine the optimal screening strategy for these women, a simulation model of cervical cancer development was used that is based on high-risk human papillomavirus (hrHPV) infection. The current strategy of repeat cytological testing at 6 and 18 months after BMD was compared to strategies with adjunct hrHPV testing. Calculations were done for both conventional and liquid-based cytology as the primary screening tool. In comparison to current screening, adjunct hrHPV testing was more effective in preventing cancer and more woman-friendly (reduction in colposcopy referrals with outcome < cervical intraepithelial neoplasia (CIN2) of up to 56% and in repeat smears of 30-100%). In combination with conventional cytology, cost-effective strategies were the ones in which a sample for high-risk human papillomavirus (hrHPV) testing is collected at a return visit within 1 month or in which hrHPV testing is restricted to repeat smears taken at 6 and 18 months. For these strategies, co-collection of samples for hrHPV testing at baseline is not necessary which has organizational and cost advantages. In combination with liquid-based cytology, it was cost-effective to perform a reflex hrHPV test at baseline from the liquid-based specimen. Liquid-based screening was more effective than conventional screening, but annual diagnosis costs were euro5 million higher (population size 16 million). In conclusion, our calculations indicate that implementation of hrHPV testing for the management of women with borderline or mild dyskaryosis (BMD) is feasible both in settings where conventional and liquid-based cytology is current practice.

Overestimation of complication rates in evaluations of Chlamydia trachomatis screening programmes--implications for cost-effectiveness analyses.

BACKGROUND: Cost-effectiveness analyses of screening programmes for asymptomatic Chlamydia trachomatis infection suggest that screening at low prevalences in the population is cost-effective. However, the decision models in these studies are based on assumptions about the risk of complications, which are derived from the literature. Incorrect assumptions may lead to under- or overestimation of the effectiveness of screening. The first objective of this paper is to evaluate the assumptions about the probability of complications after an asymptomatic C. trachomatis infection. The second objective is to calculate alternative rates by using available data on the incidence of complications. METHODS: We identified cost-effectiveness studies via Medline, and evaluated these for the evidence for the quoted probabilities. In addition, the probability of complications was calculated for Amsterdam from available registration data. RESULTS: In the three studies that were identified, the assumptions for the rates of pelvic inflammatory disease (PID) (clinical and subclinical) after C. trachomatis infection varied from 15% to 80%, and for ectopic pregnancy, tubal factor infertility, and chronic pelvic pain after PID from 5-25%, 10-20%, and 18-30%, respectively. The assumptions were based on data from high-risk populations, case-control data, and data not accounting for misdiagnoses. Using data obtained from local registrations, we estimated the probability of a clinical PID (0.43%), ectopic pregnancy (0.07%), and tubal factor infertility (0.02%) for women with a current infection. These estimates were consistently lower than the estimates based on the literature. CONCLUSIONS: We argue that an overestimation of the current complication rates is likely. The effect of overestimation is potentially the greatest in populations with a low prevalence, since the currently assumed cost savings associated with screening may disappear when using more realistic estimates for complications.

Assessment of TGF-beta1-mediated growth inhibition of HPV-16- and HPV-18-transfected foreskin keratinocytes during and following immortalization.

The responsiveness to transforming growth factor-beta1 (TGF-beta1) of two human keratinocyte cell lineages (FK16A and FK18B) generated after transfection with HPV-16 and HPV-18, respectively, was investigated. Both cell lineages revealed loss of heterozygosity (LOH) at 18q and/or 3p associated with the acquisition of the immortal phenotype. These loci harbour genes (TGF-beta receptor II gene at 3p, and Smad2 and Smad4 genes at 18q) encoding products involved in the TGF-beta1 signalling pathway. Mortal and early immortal stages of both cell lineages displayed growth reduction upon exposure to TGF-beta1 concentrations in the range 100 pg/ml to 1 ng/ml. However, the late immortal stages were resistant to TGF-beta1 at concentrations up to 10 ng/ml. TGF-beta1 receptors type I and II were expressed at all stages in both cell lineages. Moreover, mRNA levels of Smad2 and Smad4 genes were nearly constant throughout. TGF-beta1 expression and secretion, which were demonstrated in all analysed stages, may provide selective conditions underlying unresponsiveness to TGF-beta1 upon prolonged monolayer culturing. Thus, LOH at 3p and/or 18q seen during HPV-mediated immortalization of human keratinocytes was not associated with resistance to TGF-beta1-mediated growth inhibition or a marked reduction in TGF- beta1 receptors and mRNA levels of Smad2 or Smad4. Therefore, alternative events are likely to underlie unresponsiveness to TGF- beta1 in late-passage FK16A and FK18B cells.

Do questions on sexual behaviour and the method of sample collection affect participation in a screening programme for asymptomatic Chlamydia trachomatis infections in primary care?

We examined the effect of a questionnaire addressing sexual behaviour on participation in a systematic screening programme for asymptomatic Chlamydia trachomatis infections. Furthermore, we compared participation among persons requested to mail a home-obtained urine sample directly to the laboratory and persons requested to bring a sample to the physician's office. Seven hundred and fifty men and women were randomly assigned to receive a questionnaire with or without intimate questions and to deliver or mail the samples. The inclusion of questions about sexual behaviour did not affect participation among both men and women. Among women there was no difference in participation between delivering or mailing the sample. Among men delivering the sample, participation was 18% (95% confidence interval [CI]: 5-32) lower. This study shows that questions on sexual behaviour can be included in a screening questionnaire without adversely affecting participation. Furthermore, mailing the specimens is the most efficient strategy for men, when screening for C. trachomatis by means of home-obtained urine specimens.

The natural course of asymptomatic Chlamydia trachomatis infections: 45% clearance and no development of clinical PID after one-year follow-up.

The natural course of asymptomatic Chlamydia trachomatis infections in women was studied during one year in a cohort based nested case-control study. Healthy women (n = 744, from four company health services in Amsterdam) with a medical check-up prior to job engagement were included. C. trachomatis-positive women (n = 30, cases) and a randomly selected control group of C. trachomatis-negative women (n = 186, controls) were followed for one year. Urine specimens (at one, six and 12 months) were analysed for the presence of C. trachomatis-DNA and the C. trachomatis-serovars, and questionnaires were filled in. The C. trachomatis prevalence and natural course in relation to demographic and sexual characteristics after one, six and 12 months were studied. The main outcome measures were 1) the prevalence of C. trachomatis using urine specimens; 2) self-reported complaints; 3) clinical symptoms reported to the coordinating physicians. The prevalence of asymptomatic C. trachomatis infections was 4% and there was no correlation with demographic and sexual characteristics. The person/year clearance rate was 44.7% per year. None of the C. trachomatis-positive women developed clinical symptoms or used C. trachomatis specific antibiotic treatment. Women with or without an asymptomatic infection had the same number of self-reported urogenital complaints during follow-up. In persisting infections twice as many C. trachomatis-serovar E infections were detected as compared to clearing infections. Our findings showed that almost half of the asymptomatic C. trachomatis infections in women cleared during one year of follow-up and none developed clinical pelvic inflammatory disease (PID), which is a much lower figure than previously suggested. Therefore these data are important for cost effectiveness calculations in screening programmes for asymptomatic C. trachomatis infections.