Inge M.C.M. de Kok

Cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands.

BACKGROUND In the Netherlands, low cervical cancer incidence and mortality rates might limit the cost-effectiveness of vaccination against the human papillomavirus (HPV). We examined the effect on cervical cancer incidence and mortality of adding HPV vaccination to the current Dutch cervical cancer screening situation and calculated the cost-effectiveness. METHODS Costs and effects were estimated under favorable assumptions (ie, that HPV vaccination provides lifelong protection against 70% of all cervical cancers, has no side effects, and is administered to all women regardless of their risk of cervical cancer) by using the microsimulation screening analysis (MISCAN) model. The impact of changes in the price of vaccination, number of booster vaccinations, vaccination attendance rate, vaccination efficacy, cervical cancer incidence level, and quality-of-life assumptions was investigated in sensitivity analyses. RESULTS Using the current price of euro118 per vaccine dose and with discounting of costs and effects at an annual rate of 3%, adding HPV vaccination to the current Dutch screening situation had a cost-effectiveness ratio of euro53 500 per quality-adjusted life-year (QALY) gained. The threshold price per vaccine dose at which the cost-effectiveness of vaccination would correspond to an acceptability threshold of euro20 000 per QALY gained was euro40. With the addition of one or more (up to four) booster vaccinations during a lifetime, this threshold price decreased to euro33 for one booster (to euro16 for four boosters). With a doubling of the cervical cancer incidence level, the cost-effectiveness ratio was euro24 400 per QALY gained and the maximum price per dose at threshold of euro20 000 was euro97. All threshold prices were lower under less favorable effectiveness assumptions. CONCLUSIONS In the Netherlands, HPV vaccination is not cost-effective even under favorable assumptions. To become cost-effective, the vaccine price would have to be decreased considerably, depending on the effectiveness of the vaccine.

Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings : cost effectiveness analysis based on a Dutch microsimulation model

Objectives To investigate, using a Dutch model, whether and under what variables framed for other European countries screening for human papillomavirus (HPV) is preferred over cytology screening for cervical cancer, and to calculate the preferred number of examinations over a woman’s lifetime. Design Cost effectiveness analysis based on a Dutch simulation model. Base case analyses investigated the cost effectiveness of more than 1500 different screening policies using the microsimulation model. Subsequently, the policies were compared for five different scenarios that represent different possible scenarios (risk of cervical cancer, previous screening, quality associated test characteristics, costs of testing, and prevalence of HPV). Setting Various European countries. Population Unvaccinated women born between 1939 and 1992. Main outcome measures Optimal screening strategy in terms of incremental cost effectiveness ratios (costs per quality adjusted life years gained) compared with different cost effectiveness thresholds, for two levels of sensitivity and costs of the HPV test. Results Primary HPV screening was the preferred primary test over the age of 30 in many considered scenarios. Primary cytology screening was preferred only in scenarios with low costs of cytology and in scenarios with a high prevalence of HPV in combination with high costs of HPV testing. Conclusions Most European countries should consider switching from primary cytology to HPV screening for cervical cancer. HPV screening must, however, only be implemented in situations where screening is well controlled.

Trends in cervical cancer in the Netherlands until 2007: Has the bottom been reached?

We explored trends in incidence and mortality of cervical cancer by age, stage and morphology, and linked the observed trends to screening activities. Data was retrieved from the Netherlands Cancer Registry during 1989–2007 (incidence) and Statistics Netherlands during 1970–2007 (mortality). Trends were evaluated by calculating the estimated annual percentage change (EAPC). Joinpoint regression analysis was used to detect changes in trends. Cervical intraepithelial neoplasia (CIN) detection rates were calculated by data from “the nationwide network and registry of histo‐ and cytopathology” during 1990–2006. Total age‐adjusted incidence rate (European standardized rate (ESR)) was 7.9 per 100,000 woman years in 2007. During 1989–1998, incidence rates decreased with an EAPC of −1.3% (95% confidence interval (CI) −2.2 to −0.3), during 1998–2001 with −6.7% (95% CI: −16.4 to 4.1), and increased during 2001–2007 with 2.3% (95% CI: 0.4 to 4.2). Total mortality ESR was 1.9 per 100,000 woman years in 2007. Mortality rates decreased during 1970–1994 annually with −4.1% (95% CI: −4.6% to −3.7%), and with −2.6% (95% CI: −3.8% to −1.5%) during 1994–2007. The observed trend in total incidence is similar to the trend in squamous cell carcinomas in age group 35–54 years, suggesting that the observed trends are likely to be associated to changes in the screening program. This is supported by the trend in CINIII detection rates. In conclusion, incidence and mortality overall decreased and leveled off. On top of that there was an extra decrease that was compensated by a following recent increase in incidence, probably resulting from reorganization of the Dutch screening program.

Would the effect of HPV vaccination on non-cervical HPV-positive cancers make the difference for its cost-effectiveness?

Besides cervical cancer, the human papillomavirus (HPV) is found in other cancers and may be preventable with HPV vaccination. However, these other cancers are often not accounted for in cost-effectiveness analyses of HPV vaccination. This study estimates the potential maximum effect on the cost-effectiveness ratio (CER) of HPV vaccination in preventing non-cervical HPV-positive cancers. For the Dutch situation, a mathematical equation was used to estimate the maximum impact if all cancer cases of the penis, vulva/vagina, anus, oral cavity and oro-pharynx with HPV16/18 are prevented, in terms of number of life years gained, savings and improvement in the CER of the vaccination. For other countries and for future developments, we show how the impact on the CER varies depending on the incidence of cervical/non-cervical HPV 16/18-positive cancers, vaccine costs and clinical costs. If in the Netherlands all HPV 16/18-positive cancers are prevented by vaccination in women only, compared to if only HPV 16/18-positive cervical cancer is prevented, the life years gained increase with 14%, the savings increase with 18%, and the CER decreases with 13%. If vaccination prevents HPV-positive cancers in both men and women, these figures increase to 25%, 26% and 21%, respectively. In conclusion, if HPV vaccination fully prevents all non-cervical HPV-positive cancers, this would substantially increase its cost-effectiveness. The impact of the vaccination varies depending on the incidence of cervical/non-cervical HPV16/18-positive cancers, the vaccine costs and clinical costs. Observed combinations of these parameters in different countries show a decrease in the CER between 10% and 31%.

Offering Self-Sampling to Non-Attendees of Organized Primary HPV Screening: When Do Harms Outweigh the Benefits?

Background: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non-attendees. However, effectiveness could decrease if regular attendees “switch” to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits. Methods: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2+ sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage. Results: Without switching, offering self-sampling is (cost-)effective under every studied condition. If the attendance due to self-sampling increases by ≥6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2+ sensitivity and specificity are ≥0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch. Conclusions: Offering self-sampling will gain health effects if the relative CIN2+ sensitivity is ≥0.95, unscreened attendees are recruited, and the total attendance increases by ≥6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program. Impact: Self-sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. Cancer Epidemiol Biomarkers Prev; 24(5); 773–82. ©2014 AACR. See related commentary by Arbyn and Castle, p. 769

Practical implications of differential discounting in cost-effectiveness analyses with varying numbers of cohorts

OBJECTIVE To call attention to the influence of the number of birth-cohorts used in cost-effectiveness analysis (CEA) models on incremental cost-effectiveness ratios (ICERs) under differential discounting. METHODS The consequences of increasing the number of birth-cohorts are demonstrated using a CEA of cervical cancer prevention as an example. The cost-effectiveness of vaccinating 12-year-old girls against the human papillomavirus is estimated with the MISCAN microsimulation screening analysis model for 1, 10, 20, and 30 birth-cohorts. Costs and health effects are discounted with equal rates of 4% and alternatively with differential rates of 4% and 1.5% respectively. The effects of increasing the number of cohorts are shown by comparing the ICERs under equal and differential discounting. RESULTS The ICER decreases as the number of cohorts increases under differential discounting, but not under equal discounting. CONCLUSIONS The variation of ICERs with the number of cohorts under differential discounting prompts questions regarding the appropriate specification of CEA models and interpretation of their results. In particular, it raises concerns that arbitrary variation in study specification leads to arbitrary variation in results. Such variations could lead to erroneous policy decisions. These findings are relevant to CEA guidance authorities, CEA practitioners, and decision makers. Our results do not imply a problem with differential discounting per se, yet they highlight the need for practical guidance for its use.

Harms of cervical cancer screening in the United States and the Netherlands

We studied harms related to cervical cancer screening and management of screen‐positive women in the United States (US) and the Netherlands. We utilized data from four US integrated health care systems (SEARCH), the US National Health Interview Survey, New Mexico state, the Netherlands national histopathology registry, and included studies on adverse health effects of cervical screening. We compared the number of Papanicolaou (Pap) smear tests, abnormal test results, punch biopsies, treatments, health problems (anxiety, pain, bleeding and discharge) and preterm births associated with excisional treatments. Results were age‐standardized to the 2007 US population. Based on SEARCH, an estimated 36 million Pap tests were performed in 2007 for 91 million US women aged 21–65 years, leading to 2.3 million abnormal Pap tests, 1.5 million punch biopsies, 0.3 million treatments for precancerous lesions, 5 thousand preterm births and over 8 million health problems. Under the Netherlands screening practice, fewer Pap tests (58%), abnormal test results (64%), punch biopsies (75%), treatment procedures (40%), preterm births (60%) and health problems (63%) would have occurred. The SEARCH data did not differ much from other US data for 2007 or from more recent data up to 2013. Thus compared to the less intensive screening practice in the Netherlands, US practice of cervical cancer screening may have resulted in two‐ to threefold higher harms, while the effects on cervical cancer incidence and mortality are similar. The results are also of high relevance in making recommendations for HPV screening. Systematic collection of harms data is needed for monitoring and for better incorporation of harms in making screening recommendations.

Cervical Cancer Screening in Partly HPV Vaccinated Cohorts - A Cost-Effectiveness Analysis.

Background Vaccination against the oncogenic human papillomavirus (HPV) types 16 and 18 will reduce the prevalence of these types, thereby also reducing cervical cancer risk in unvaccinated women. This (measurable) herd effect will be limited at first, but is expected to increase over time. At a certain herd immunity level, tailoring screening to vaccination status may no longer be worth the additional effort. Moreover, uniform screening may be the only viable option. We therefore investigated at what level of herd immunity it is cost-effective to also reduce screening intensity in unvaccinated women. Methods We used the MISCAN-Cervix model to determine the optimal screening strategy for a pre-vaccination population and for vaccinated women (~80% decreased risk), assuming a willingness-to-pay of €50,000 per quality-adjusted life year gained. We considered HPV testing, cytology testing and co-testing and varied the start age of screening, the screening interval and the number of lifetime screens. We then calculated the incremental cost-effectiveness ratio (ICER) of screening unvaccinated women with the strategy optimized to the pre-vaccination population as compared to with the strategy optimized to vaccinated women, assuming different herd immunity levels. Results Primary HPV screening with cytology triage was the optimal strategy, with 8 lifetime screens for the pre-vaccination population and 3 for vaccinated women. The ICER of screening unvaccinated women 8 times instead of 3 was €28,085 in the absence of herd immunity. At around 50% herd immunity, the ICER reached €50,000. Conclusion From a herd immunity level of 50% onwards, screening intensity based on the pre-vaccination risk level becomes cost-ineffective for unvaccinated women. Reducing the screening intensity of uniform screening may then be considered.

How many cervical cancer cases can potentially be prevented using a more sensitive screening test at young age

The human papilloma virus (HPV) DNA test has higher sensitivity than cytology for cervical cancer screening. Therefore, cervical cancer cases that are missed by cytology could potentially be identified if we use primary HPV testing. Studies showed that HPV screening is the preferred primary test at age 35 and over. Given the high prevalence of harmless HPV infections, the use of HPV testing at younger age is less obvious. The number of cancers in young age is often mentioned to indicate the possible benefits of a more sensitive test. We actually estimated the proportion of those cases that is potentially preventable in The Netherlands by the use of a more sensitive screen‐test at the first screening age 30, given that the more sensitive test is used at age 35 and over. We analysed the screening history of women diagnosed with cervical cancer in the period 2004 to March 2009, using data from the Dutch National Pathology Registry. Only 15–30% (two to four cases per 100,000 women) of the cases was preceded by negative cytology under age 35 and therefore could have been prevented by a more sensitive test at age 30. The lower the screening coverage and the shorter the screening interval in those screened at young age, the smaller the gain of a more sensitive test. So, as long as the current screening pattern is not changed, the majority of the cervical cancer cases at young age would still occur even when applying a more sensitive test at the younger ages.

The Role of Acquired Immunity in the Spread of Human Papillomavirus (HPV): Explorations with a Microsimulation Model

Background Knowledge of the natural history of human papillomavirus (HPV), in particular the role of immunity, is crucial in estimating the (cost-) effectiveness of HPV vaccination and cervical cancer screening strategies, because naturally acquired immunity after clearing an infection may already protect part of the risk population against new HPV infections. Methods We used STDSIM, an established stochastic microsimulation model, quantified to the Netherlands. We explored different assumptions regarding the natural history of HPV-16 and HPV-18, and estimated the transmission probabilities and durations of acquired immunity necessary to reproduce age-specific prevalence. Results A model without acquired immunity cannot reproduce the age-specific patterns of HPV. Also, it is necessary to assume a high degree of individual variation in the duration of infection and acquired immunity. According to the model estimates, on average 20% of women are immune for HPV-16 and 15% for HPV-18. After an HPV-16 infection, 50% are immune for less than 1 year, whereas 20% exceed 30 years. For HPV-18, up to 12% of the individuals are immune for less than 1 year, and about 50% over 30 years. Almost half of all women will never acquire HPV-16 or HPV-18. Conclusions Acquired immunity likely plays a major role in HPV epidemiology, but its duration shows substantial variation. Combined with the lifetime risk, this explains to a large extent why many women will never develop cervical cancer.