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Universal vaccination with the quadrivalent HPV vaccine in Austria: impact on virus circulation, public health and cost–effectiveness analysis Expert Rev. Pharmacoecon. Outcomes Res. 14(2), 269–281 (2014)
Xavier Bresse*1, Christoph Goergen1, Bernhard Prager1,2 and Elmar Joura3 1
Sanofi Pasteur MSD, Lyon, France Sanofi Pasteur MSD, Austria 3 Department of Gynaecology and Obstetrics, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria *Author for correspondence: Tel.: +33 437 284 571 Fax: +33 437 284 443 [email protected] 2
The International Agency for Research on Cancer acknowledges that HPV is a human carcinogen affecting both sexes. This study aimed to evaluate the public health impact of universal HPV vaccination in Austria, to assess its cost–effectiveness and to estimate the HPV prevalence reduction over time. Vaccinating 65% of 9-year-old boys and girls in Austria would result in a 70% decrease in HPV infections in both males and females, hereby avoiding 9500 cases of genital warts annually and 431 HPV 16/18-related cancers in males and females. This strategy would be cost effective with base case analysis of e26,701/quality-adjusted life year (QALY) gained for cervical cancer only, e15,820/QALY also including vaginal/vulvar cancers and genital warts, and e10,033/QALY also considering anal, oropharyngeal and penile cancers, with an incremental cost–effectiveness ratio ranging from e2500 to e21,000/QALY in sensitivity analyses. HPV circulation would be controlled hereby preventing subsequent HPVrelated cancers. KEYWORDS: Austria . cost–effectiveness . HPV . papillomavirus . public health . universal vaccination
Human papillomavirus, or HPV, infection is known to be associated with a number of conditions including vaginal, vulvar and cervical cancers in females, penile cancer and genital warts in males and some head and neck cancers as well as anal cancers in both genders [1–4]. Recently, an Australian study also reported a link between HPV and esophageal squamous cell carcinoma with a threefold higher risk of developing esophageal squamous cell carcinoma after HPV infection [5]. HPV vaccines have been licensed for use in females and vaccination programs have been initially introduced in many countries to prevent HPV 16/18-related cervical cancer and HPV 6/11-related genital warts. However, recent studies indicate that the quadrivalent HPV vaccine (Gardasil) also prevent infection with HPV 6, 11, 16 and 18 and the development of related external genital lesions in males 16–26 years of age [6]. Although the quadrivalent vaccine is efficient in preventing HPV-related diseases in informahealthcare.com
10.1586/14737167.2014.881253
men, questions concerning the most relevant target population and vaccination cost–effectiveness are still debated. In October 2011, the US Advisory Committee on Immunization Practices recommended routine use of quadrivalent HPV vaccine in males aged 11 or 12 years and also vaccination for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series [7]. This recommendation was based on Grading of Recommendations, Assessment, Development and Evaluation method [8] and factors considered in determining this recommendation included balance between benefits and harms, evidence type, values and preferences and health economic analysis. In Canada, the National Advisory Committee on Immunization (NACI) determined in January 2012 that there was good (Grade A) evidence to recommend the use of Gardasil in males between 9 and 26 years of age for the
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prevention of anal intraepithelial neoplasia Grades 1, 2 and 3, anal cancer and anogenital warts. The NACI also recommended Gardasil (NACI recommendation Grade B, i.e., fair evidence) for the prevention of penile, perianal and perineal intraepithelial neoplasias and associated cancers. Moreover, HPV quadrivalent vaccination is also recommended in males who have sex with males (MSM) ‡9 years of age (NACI recommendation Grade A) [9]. In Australia, the national school-based HPV Vaccination Program, provided through the National Immunisation Program, has been extended to include males. Since February 2013, males and females aged 12–13 years receive the HPV vaccine at school and males aged 14–15 years also receive the vaccine as part of a catch-up program [10]. In most European countries, HPV vaccination is recommended and funded only for girls, not for boys. Austria was the first country that initially recommended HPV vaccination for girls and for boys. In their 2013 vaccination plan, the Austrian health authorities stated that vaccinating both men and women was indeed important for stopping the circulating infections and for achieving herd immunity. Therefore, they recommend vaccination for children who are not yet sexually active (9–12 years). Recent epidemiological data from Austria indicate that more than 60% of cervical intraepithelial neoplasia (CIN) 2/3 lesions (immediate precursor lesions of cervical cancer) are associated with HPV 16 and/or 18 [11]. Other data report a total of about 600 cancers annually related to HPV 16/18, 30% of them among males [12]. Moreover, about 13,300 genitals warts related to HPV 6/11 are observed every year in both genders. Several factors including local disease burden, vaccine efficacy, vaccine safety, cost–effectiveness, and also social and ethical factors need to be taken into account during decision-making around the introduction of population-based vaccination programs [13]. In addition to epidemiological and cost–effectiveness issues, using a health technology assessment approach taking into account biotechnological, organizational, social, legal and bioethical considerations was shown to be a useful strategy in the evaluation process of introducing new vaccines [14]. The aim of our study was to evaluate the public health impact of universal HPV vaccination in Austria in terms of reduction of HPV prevalence and incidence of HPV-related diseases over time, and to assess whether such vaccination was cost-effective.
quadrivalent HPV vaccination program in girls and boys aged 9 years in Austria (FIGURE 1). We assumed that all quadrivalent HPV vaccination strategies evaluated would be combined with current cervical cancer screening and HPV disease management practices in Austria. In an old Austrian consensus paper on economic evaluation [16], both costs and outcomes were suggested to be discounted at 5% in the base case analysis, and authors reported that preventive measures should not be disadvantaged compared with curative ones, suggesting that European discount rates of 3% should be applied. In this study, base case analysis was conducted using a 3% discount rate for both costs and benefits.
Method
Vaccination
Objectives of the research
A vaccine uptake of 65% for both genders and an overall compliance rate of 80% were used in the model. Vaccine efficacy parameters are presented in TABLE 1.
The purpose of this study was to assess the impact on prevalence of HPV 16/18 infections, on public health in terms of HPV 16/18-related cancers avoided as well as the economic consequences of vaccinating one cohort of 9-year-old girls and boys with the quadrivalent 6/11/16/18 vaccine in Austria, from the perspective of the payer. Study design & vaccination strategies
A previously developed and published mathematical model [15] was adapted to the Austrian setting to evaluate the impact of a 270
Input parameters
Natural history parameters used were previously described and reported by Elbasha and Dasbach [15]. Demographic data & sexual behavior patterns
Population data and life table by age group were retrieved from Statistik Austria 2011. The total population in Austria on 31 December 2010 was estimated to be 8,420,900 people [17]. A constant population size was assumed. Because data regarding sexual Austrian behavior patterns are sparse, UK data were integrated into the model (Additional file). The proportion of population in each sexual activity group (low, medium and high, defined as 0–1, 2–4 and more than 5 sexual partners per year) and the average number of opposite sexual partners were obtained from the UK National Survey of Sexual Attitudes and Lifestyles II [18]. In order to provide comparability of our research with other published works, parameters used by other authors, dealing with the topic of HPV vaccination in Austria and its cost–effectiveness, were reviewed. By literature research we could identify papers by Kundi [19] and Zechmeister et al. [20], which used the same sources and values for sexual behavior data in their calculations as we did. Cervical cancer screening
The annual cervical cancer screening rates were extracted from a report by Ludwig Boltzmann Institut [21]. Another putative source [22] was identified, where almost same age groups and similar values for the screening rate were mentioned. However, due to currentness of data, the report by Zechmeister was preferred.
Disease & treatment patterns
Regarding epidemiological data, incidental cases (TABLE 2) of cervical cancer in Austria were retrieved from Statistik Austria [23]. Since data on HPV-related cancer incidence rates were not available for Austria, the proportion was measured based on the methods and results of the epidemiological report by Hartwig et al. [24]. Thus, natural history parameters were based on international data Expert Rev. Pharmacoecon. Outcomes Res. 14(2), (2014)
Impact of HPV vaccination in Austria
n
s sio
gr e
Reactivation or reinfection Clearance
d
re
Clearance
Reactivation of reinfection
Los so fi
and were the same as in the original Recovered with model [24]. Regarding measurements of the seroconversion Clea amount of genital warts cases in Austria, ity (Z) ran n u ce m age- and sex-specific incidence rates were m extracted from a German research by Kraut et al. [25] and were applied accordingly to age groups to Austrian population figures [26]. Figures describing performed hysterectomies in Austria could be retrieved from the Austrian setting by Statistik Austria [12]. Progression For mortality data, with respect to Infection Susceptible Infected Disease mortality rates of HPV-related diseases, (X) (Y) (C) several sources were identified based on Regression Austrian or German settings. Cervical cancer mortality rates by stage (local, regional, distant) and age were retrieved from a German source by Schobert et al. [27] as no appropriate data from the Austrian setting could be identified. Further on, due to the lack of informaan tion, these data were also applied as ce n a r proxy measures for vaginal and vulvar Recovered, no Cle a seroconversion cancer mortality rates. For anal cancer (ZS) mortality rates, the German Robert Koch report [28] was chosen as the most Figure 1. Simplified schematic diagram of compartments for unvaccinated indiappropriate replacement for representing viduals encompassing human papillomavirus infection and disease state transiAustrian circumstances. Figures for the tions. A susceptible host in compartment (X) may be infected with a given HPV type mortality rate of patients suffering from and move to compartment (Z) if s/he seroconverts or (ZS) if s/he does not seroconvert. penile cancer were based on data proPersons in compartments (Z) move back to the susceptible host compartment (X) when their immunity wanes. Infected persons can develop disease and may progress though vided by Statistik Austria 2011 for the several health states (compartments C). Persons with disease can regress to normal with year 2010 [29]. or without human papillomavirus infection. Those regressing to normal with infection In order to receive a HPV-related mormove to compartment (Y), whereas those regressing without human papillomavirus tality rate of head and neck cancers, we infection and with seroconversion can move to compartment (Z) and without seroconfirst retrieved a general mortality rate version to compartment (ZS). Adapted from [15]. from the Robert Koch Institute report dealing with figures from oral cavity and pharynx [28]. Afterwards, we applied a reduction of 64% which taken for diagnostic measures which can be compared to cost– was developed by Fakhry et al. [30] by comparing mortality effectiveness analyses of HPV vaccinations. When dealing with costs for cervical intraepithelial neoplasia rates of HPV-positive and negative oropharyngeal and laryngeal cancer patients. This was done because it is now generally and for vaginal intraepithelial neoplasia estimations from Geraccepted that the tumor HPV status is the single greatest deter- man reports [38,39] were again included as there was no alternaminant of survival for patients with local-regionally advanced tive available which was based on the Austrian setting. In case of genital warts in women, treatment costs were oropharyngeal cancer [31–35]. retrieved from a German study dealing with cost–effectiveness of HPV-vaccination in girls [27]. It was aimed to find sexEconomic parameters Despite the importance of indirect costs in the overall eco- specific treatments costs for genital warts in men as well, but nomic burden of cancer, this study focused on direct medical no appropriate data for a comparable setting could be identicosts. Cost data for non-cervical cancers were not available for fied. Therefore, it was necessary to apply the data from Austria. Hence, similar to Jit et al. [36] and Brisson et al. [37], Schobert et al. [27] to the male population as well. Costs are at we used the relative cost of each non-cervical cancer to those 2012 prices or inflated according to the gross domestic product for cervical cancer and applied these relative costs to the Aus- deflator by the Organisation for Economic Co-operation and trian cost of cervical cancer [20]. Vaccination costs (about e120 Development (OECD) [40]. Depending on the year of publicaper dose, administration costs included) were taken from offi- tion, prices presented in TABLE 3 were deflated by using informacial sources. For providing benchmark of our work, values were tion provided by OECD [40]. While prices from the year ion ress eg dr an
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Table 1. Vaccine efficacy assumptions. Gender
Male
HPV genotype
6
11
Female
[6]
16
18
41.1
62.1
6
[13]
11
16
18
76
96.3
98.8
98.4
98.8
98.4
97.9
100
VIN
100
100
VaIN
100
100
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Against transient infection (%) Anal, cervical, head/neck, penile, vaginal and vulvar disease Genital warts and RRP disease
49
57
76.1
76.1
Against persistent infection (%) Anal and head/neck diseases
78.7
96
Cervical, vaginal and vulvar disease Penile disease
78.7
96
Against individual infection (%) CIN
100
Genital warts
84.3
90.9
98.9
100
100
In the absence of data at the time of the analysis, efficacy for 1 and 2 doses assumed to be 23 and 45% of efficacy of the full 3 doses, respectively (as done in the original model from Elbasha and Dasbach [15]). Efficacy against genital infection in males is assumed to prevent from transmission of genital infections to females, and vice versa. CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus; RRP: Recurrent respiratory papillomatosis; VaIN: Vaginal intraepithelial neoplasia; VIN: Vulvar intraepithelial neoplasia.
2011 or 2012 remained the same in our calculations, prices from 2009 were adjusted to financial circumstances of the year 2010, as this is currently the latest year for deflators published by OECD (prices from 2009 were multiplied with the Austrian deflation index of 1.035811569 [value of 2010/value of 2009] as OECD states that e96.542656 in 2009 reached the value of e100 in 2010 in Austria). German age-specific utilities were used. In the absence of Austrian-specific utilities, qualityadjusted life year (QALY) weights were retrieved from
international literature (TABLE 3). Impact of HPV-related cancers was accounted for in survivors by applying a utility score of 0.76 [15]. Model calibration
The predictive validity of the model was evaluated by comparing model results with epidemiologic data reported in the literature. We evaluated our model predictions against the following outcomes: genital warts incidence, incidences of cervical, vaginal,
Table 2. Dynamic transmission model calibration inputs, targets and results. Carcinoma type
Cases per year (n)
Prevalence of HPV+ cases (%)
Proportion of HPV 6/11/16/18-related cases (%)
HPV 6/11/ 16/18-related cases (n)
Range of acceptability (±10%)
Model prediction (cases [n])
Ref.
Cervical
380
100.0
76.2
290
(261–319)
294
[2,23]
Vaginal
37
70.0
61.3
17
(15–18)
11
[2,20]
Vulvar
147
40.4
36.6
22
(20–25)
9
[2,20]
Penile
58
46.7
73.6
20
(18–22)
22
[2,20]
Anal (female)
80
85.0
78.6
58
(53–64)
57
[2,20]
Anal cancer (males)
34
85.0
78.6
26
(24–29)
28
[2,20]
OSCC (females)
68
39.7
89.5
26
(23–29)
25
[2,4]
OSCC (males)
329
39.7
89.5
125
(112–137)
117
[2,4]
Genital warts (females)
8473
90
90
7626
(6863–8388)
7353
[22]
Genital warts (males)
6320
90
90
5688
(4830–5903)
5438
[22]
HPV: Human papillomavirus; OSCC: Oropharyngeal squamous cell carcinoma.
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Table 3. Overview of considered HPV-related direct medical costs and utilities. Medical cost
Base case (e)†
Screening (PAP smear) and office visit
28
Colposcopy
8.3
[15]
Biopsy
24.9
[15]
Vaccine per dose
110
[15]
Administration per dose
10.3
[15]
Cervical cancer, stage I
17,128 [100%]
0.76
[13,15]
Cervical cancer, stage II–III
27,681–28,599 [100%]
0.67
[13,15]
Cervical cancer, stage IV
29,201 [100%]
0.48
[13,15]
Vulvar/vaginal cancer, stage I
14,901 [87%]
0.65/0.59
[35,76]
Vulvar/vaginal cancer, stage II–III
24,081–25,067 [87%]
0.65/0.59
[35,76]
Vulva/vaginal cancer, stage IV
25,405 [87%]
0.48
[13,35]
Penile cancer, stage I
12,160 [71%]
0.79
[13,35]
Penile cancer, stage II
19,653–20,305 [71%]
0.67
[13,35]
Penile cancer, stage III
20,732 [71%]
0.48
[13,35]
Anal cancer, stage I
17,469 [102%]
0.57
[35,76]
Anal cancer, stage II–III
28,234–29,171 [102%]
0.57
[35,76]
Anal cancer, stage IV
29,784 [102%]
0.48
[13,35]
OSCC, stage I
20,553 [120%]
0.76
[13,35]
OSCC, stage II–III
33,216–34,319 [120%]
0.58
[35,76]
OSCC, stage IV
35,041 [120%]
0.48
[13,35]
Genital warts (men)
550
0.91
[13,24]
Genital warts (women)
550
0.91
[13,24]
CIN1
348
0.862
[37,77]
CIN2/3
1551
0.822
[37,77]
VaIN, 1 surgery
881
[36]
VaIN, >1 surgery
2605
[36]
Utility
Ref. [14,15]
†
Relative costs versus cervical cancer are indicated within square brackets. CIN: Cervical intraepithelial neoplasia; OSCC: Oropharyngeal squamous cell carcinoma; PAP smear: Papanicolaou smear; VaIN: Vaginal intraepithelial neoplasia.
vulvar, anal, penile, oropharyngeal squamous cell carcinoma cancer and death due to each of these cancers. Model predictions are described in TABLE 2. Data used were taken from Austrian studies or mainly from European studies which based calculations for Austria on figures from the Austrian National Cancer Registry. Prevalence of genotypes was retrieved from international literature as presented in TABLE 2.
rate of 65%, and an 80% compliance rate between each dose received. Univariate sensitivity analyses were conducted to handle uncertainty related to cost of diseases, vaccination coverage rates assumed, vaccine’s duration of protection, discount rates, vaccine price and QALYs. Sensitivity analysis wes restricted to parameters previously shown to be key drivers of outcomes. Results
Base case & sensitivity analysis
Calibration (internal validity)
We followed international and Austrian guidelines and adopted the payer’s perspective for the base case analysis. For the base case analysis, we calculated discounted and undiscounted life years gained, QALYs and costs for the ‘screening only strategy’ as well as for the vaccination strategy, assuming a vaccination coverage
Overall, as reported in TABLE 2, the model predicted within 10% error for all HPV-related cancers and genital warts except vulvar and vaginal cancer, except for very low burden of those cancers. For mortality, the model predicted within a 10% error window all HPV-related cancer death, with a constant
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cost–effectiveness ratio (ICER) of e10,033/QALY gained versus the current situation. The detailed ICER are presented in TABLE 4. As already demonstrated in many different settings, the quadrivalent vaccine has a better economic profile than the bivalent vaccine, through the prevention of HPV 6/11-related cases of genital warts [36,41]. In the Austrian setting, it is expected that among all healthcare costs avoided over 100 years, 54% would be by the prevention of HPV 6/11-related diseases.
0.0
Reduction in prevalence (%)
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-10.0 Among females
-20.0
Among males
-30.0
No vaccination -40.0 -50.0 -60.0
Sensitivity analyses
-70.0 -80.0 -90.0 -100.0
0
10
20
30
40
50
60
70
80
90
100
Years
Figure 2. Estimated reduction of HPV 16/18-related infection prevalence among females and males over 100 years.
underestimation. The model predicted lower cervical cancer incidence and mortality among older cohorts than currently observed cross-sectionally. This differential may be attributed to a cohort effect, whereby, current cohorts of older women would be expected to have higher cervical cancer incidence and mortality than future cohorts of older women. Despite some differences and the fact that predictions are underestimated, the calibration was considered acceptable. Virus circulation
The estimated reduction of the prevalence of HPV 16/18related infection among females and males over 100 years is depicted in FIGURE 2. Uninterrupted reduction in HPV 16/18related HPV infection was found, stabilizing 50 and 80 years after vaccine introduction among males and females, respectively. The decrease in HPV prevalence was slightly slower in females than males but this decrease reached a higher level in females (-78%) compared with males (-70%). Public health impact
The public health impact of universal vaccination compared with current practice is shown in FIGURE 3A for females and FIGURE 3B for males. In a steady-state situation (at 100 years), HPV-related cancer burden could be reduced annually by 71% in men, hereby avoiding 121 cancer cases (91 oropharyngeal, 19 anal and 11 penile cancer cases). Similarly, the cancer burden could be reduced by 75% in women, hereby avoiding 310 cancer cases (among which 217 cervical cancers) compared with the current situation. This reduction was observed for all cancers assessed. Economic impact & cost–effectiveness
Vaccinating one cohort of Austrian boys and girls aged 9 under base case assumptions would lead to an incremental 274
Results from sensitivity analysis are presented in FIGURES 4 and 5. Discount rates were defined as the rate at which monetary and non-monetary benefits in the future are brought back to the present. As expected, the most influential factor is discount rates (FIGURE 4). Whatever the parameter that varied, universal vaccination of one cohort of boys and girls aged 9 remained very cost-effective compared with a strategy with no vaccination, ranging from e2530 to e21,075/QALY gained. Although vaccination coverage rate has only little impact on cost–effectiveness, it may have an impact on the reduction of infections over time. FIGURE 5 indicates that the reduction in HPV 16/18 prevalence increases with vaccination coverage with a faster reduction with increasing uptake. Over 100 years, the reduction of HPV 16/18 prevalence among both males and females is about 20% higher with vaccination coverage of 80% compared with coverage of 50% only. No probabilistic sensitivity analysis has been performed, in line with best practice recommendations from the International Society for Pharmacoeconomics and Outcomes Research – Society for Medical Decision Making (ISPOR–SMDM) Modeling Good Research Practices Task Force Working Group [42]. Discussion
Our study shows that a publicly funded universal (i.e., gender neutral) HPV vaccination is highly cost-effective. Moreover, the analysis shows that with a vaccination coverage rate of 65%, virus circulation could be controlled, and that the HPV-related cancer burden could be reduced by 73% in men and 75% in women. Anogenital warts would be reduced by 71% in both men and women. Although vaccination coverage rate has only little impact on cost–effectiveness, it may have an impact on the reduction of infections over time. No probabilistic sensitivity analysis has been performed, in line with best practice recommendations from ISPOR–SMDM Modeling Good Research Practices Task Force Working Group [42]. Improving vaccination uptake has no real impact on cost–effectiveness, meaning that additional costs are offset by additional benefits, but making all efforts to increase vaccination coverage could allow adequately control virus circulation. Since the introduction of HPV vaccination program worldwide, science has evolved and now the International Agency for Research on Cancer acknowledges a causal link between HPV infection and occurrence of several cancers [43], with associated unmet medical and public health needs [44,45]. In contrast to Expert Rev. Pharmacoecon. Outcomes Res. 14(2), (2014)
Impact of HPV vaccination in Austria
A
B 180
Anal cancers
400
160
58 17 22
Cases (n)
350
Vaginal cancers
140
300
Vulvar cancer Cervical cancers
250 200 150
290 7 14 54 73
100 50
Cases (n)
Oropharynx cancers 26
450
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Oropharynx cancers Anal cancers Penile cancers
120
125
100 80 60 40
26
34
20
20
7 9
No vaccination
Universal vaccination
0
0 No vaccination
Universal vaccination
Figure 3. Annual number of HPV 16/18-related carcinoma cases among males and females when considering a vaccination strategy of boys and girls aged 9 years of age versus no vaccination. (A) Annual number of HPV 16/18-related carcinoma cases among females according to vaccination strategy. (B) Annual number of HPV 16/18-related carcinoma cases among males according to vaccination strategy.
cervical cancer, there is indeed no routine screening for any of the other HPV-related cancers (including anal and oropharyngeal). These cancers are often diagnosed at a late stage and associated with high mortality and morbidity, specifically related to long-term effects after treatment. Current treatments are mutilating, traumatizing to the patients and associated with high acute and long-term toxicity and handicapping side effects [46–49]. Cancer survivors will require prolonged support from health and social services, including rehabilitation and socialization [50,51]. These aspects were not considered in the present health economic analysis, thus underestimating the value of vaccination. A universal vaccination program is the most efficient and equitable public health intervention and is a matter of right to best protection, equal access and gender equity. Universal vaccination programs are less confusing for the public and healthcare providers and targeting all subjects facilitates the understanding, acceptability and implementation of the program. HPV is easily transmitted both between and by men and women [52]. Therefore, both populations suffer from HPV diseases and should be entitled to the same rights to directly benefit from HPV vaccination [53]. Targeting both boys and girls in a universal HPV vaccination program would share the responsibility for prevention across both boys and girls, helping to de-sexualize the vaccination and avoid any stigma around a girl-only vaccination. This in turn would ease the burden on women and reduce the socio-cultural barriers to HPV vaccination, thereby increasing acceptability and ultimately uptake [54,55]. A study conducted in the USA reported substantial socioeconomic disparities in cervical cancer incidence and mortality with persistence over time, despite decreasing incidence and mortality rates [56]. Other authors suggested that inclusion of boys in HPV vaccination programs could be able to increase equity between socio-demographic groups differing by their risk factors for HPV infection [57]. However, as stated informahealthcare.com
by the European CDC, different baseline assumptions, as well as different choices for the modeling, have generated wide discrepancies in the cost–effectiveness estimates for vaccinating boys [45]. The major strengths of our study based on a previously published model [15] include: adequate calibration based on Austrian incidence data and prevalence data issued from an international meta-analysis [2], use of conservative assumptions such as an underestimated cervical cancer target, and analysis based on a payer perspective. Moreover, our results are in line with previously published similar studies [58]. However, our study suffers from some limitations. First of all, the increased incidence of oropharyngeal squamous cell carcinomas [59,60], anal [61] and penile [62] cancers observed over the past decades in Denmark, Sweden and the UK [63] are not taken into account. Such an increase might also be present in Table 4. Cost–effectiveness analysis of vaccinating girls and boys compared with no vaccination. HPV 6/11/16/18 disease included
Cumulative ICER in e/QALY†
Cervical
26,701
Vaginal
26,279
Vulvar
25,567
Genital warts
15,820
Anal
13,850
OSCC
10,136
Penile
10,033
Text in bold only includes diseases that are consistent with the quadrivalent HPV vaccine license. † ICER includes all diseases in the preceding rows (if applicable). HPV: Human papillomavirus; ICER: Incremental cost–effectiveness ratio; OSCC: Oropharyngeal squamous cell carcinoma; QALY: Quality-adjusted life year.
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€2530
Annual discount rates (0%/5%)
€21,075 €10,033
Duration of protection (lifetime/20 years)
€8202
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Vaccine price (±15%)
Range
Costs of diseases (±50%) Vaccine uptake (±15%)
-5000
0
€12,200
€9041
€11,012
€9248
€10,869
€9982
Compliance (100%/50%) -10,000
€11,787
€10,033
No utilities (LYG)
€19,590
5000
10,000
€11,351 15,000
20,000
25,000
30,000
ICER (€/QALY)
Figure 4. Tornado diagram of the univariate sensitivity analysis. QALY: Quality-adjusted life year.
Austria, hereby underestimating the potential epidemiological benefits among boys, and thus increasing the ICER. Moreover, HPV-related costs of diseases are underestimated and cannot always be correctly evaluated. These include conizations and subsequent impact on fertility, intensive care costs for preterm delivered neonates, functional and psychological sequelae of treatment resulting in disruption of social and family interactions, impaired quality of life and potential incapacity to return to work [64–72], prolonged support from health and social services, including rehabilitation and socialization [50,51,66,71,72], anal incontinence or – as highlighted by European CDC [45] – the cost of the psychological impact of HPV-related morbidities, such as condylomata. Another possible limitation is that we used separate and independent models for each HPV-type/disease combination. This was based on the assumption that HPV types have independent natural histories with no interaction between them. If there are significant competing risks (e.g., cross-immunity between HPV types or effects of treatment on prevalence of other types and associated disease), our estimates of the cost–effectiveness ratios of vaccination programs may be inaccurate. Moreover, the analysis is conducted over 100 years with a constant vaccine price and calibration regarding death is weak, resulting in a possible underestimation of the ICER. The impact of future price reductions in tenders or a 2-dose schedule was not evaluated. Finally, our model focused on heterosexual transmission of HPV and did not incorporate transmission between homosexuals and heterosexuals, or MSM. Most published cost–effectiveness evaluations do not include potential savings from prevented premature birth cases following conization in younger life years. This may be attributable to the fact that disease models have early on focused on 276
direct disease benefit, not taking the full potential of HPV vaccines into account. Soergel et al. found that cost reductions of neonatal mortality and morbidity may be sufficient to make HPV vaccines cost effective [73]. For reasons of better comparability, we also excluded this potential cost savings from premature deliveries as well as the rare recurrent respiratory papillomatosis. Economic and social considerations associated with male vaccination have been discussed previously [74–77] and results on gender-neutral HPV vaccination cost–effectiveness are heterogeneous. Some studies have shown that adding male vaccination to female-only vaccination became more cost effective when all HPV-associated health outcomes were included in the model and when vaccine coverage of females was low (e.g., 3-dose vaccine coverage 21 years was approximately twoto four-times that of vaccinating males aged
Research Report
Universal vaccination with the quadrivalent HPV vaccine in Austria: impact on virus circulation, public health and cost–effectiveness analysis Expert Rev. Pharmacoecon. Outcomes Res. 14(2), 269–281 (2014)
Xavier Bresse*1, Christoph Goergen1, Bernhard Prager1,2 and Elmar Joura3 1
Sanofi Pasteur MSD, Lyon, France Sanofi Pasteur MSD, Austria 3 Department of Gynaecology and Obstetrics, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria *Author for correspondence: Tel.: +33 437 284 571 Fax: +33 437 284 443 [email protected] 2
The International Agency for Research on Cancer acknowledges that HPV is a human carcinogen affecting both sexes. This study aimed to evaluate the public health impact of universal HPV vaccination in Austria, to assess its cost–effectiveness and to estimate the HPV prevalence reduction over time. Vaccinating 65% of 9-year-old boys and girls in Austria would result in a 70% decrease in HPV infections in both males and females, hereby avoiding 9500 cases of genital warts annually and 431 HPV 16/18-related cancers in males and females. This strategy would be cost effective with base case analysis of e26,701/quality-adjusted life year (QALY) gained for cervical cancer only, e15,820/QALY also including vaginal/vulvar cancers and genital warts, and e10,033/QALY also considering anal, oropharyngeal and penile cancers, with an incremental cost–effectiveness ratio ranging from e2500 to e21,000/QALY in sensitivity analyses. HPV circulation would be controlled hereby preventing subsequent HPVrelated cancers. KEYWORDS: Austria . cost–effectiveness . HPV . papillomavirus . public health . universal vaccination
Human papillomavirus, or HPV, infection is known to be associated with a number of conditions including vaginal, vulvar and cervical cancers in females, penile cancer and genital warts in males and some head and neck cancers as well as anal cancers in both genders [1–4]. Recently, an Australian study also reported a link between HPV and esophageal squamous cell carcinoma with a threefold higher risk of developing esophageal squamous cell carcinoma after HPV infection [5]. HPV vaccines have been licensed for use in females and vaccination programs have been initially introduced in many countries to prevent HPV 16/18-related cervical cancer and HPV 6/11-related genital warts. However, recent studies indicate that the quadrivalent HPV vaccine (Gardasil) also prevent infection with HPV 6, 11, 16 and 18 and the development of related external genital lesions in males 16–26 years of age [6]. Although the quadrivalent vaccine is efficient in preventing HPV-related diseases in informahealthcare.com
10.1586/14737167.2014.881253
men, questions concerning the most relevant target population and vaccination cost–effectiveness are still debated. In October 2011, the US Advisory Committee on Immunization Practices recommended routine use of quadrivalent HPV vaccine in males aged 11 or 12 years and also vaccination for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series [7]. This recommendation was based on Grading of Recommendations, Assessment, Development and Evaluation method [8] and factors considered in determining this recommendation included balance between benefits and harms, evidence type, values and preferences and health economic analysis. In Canada, the National Advisory Committee on Immunization (NACI) determined in January 2012 that there was good (Grade A) evidence to recommend the use of Gardasil in males between 9 and 26 years of age for the
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prevention of anal intraepithelial neoplasia Grades 1, 2 and 3, anal cancer and anogenital warts. The NACI also recommended Gardasil (NACI recommendation Grade B, i.e., fair evidence) for the prevention of penile, perianal and perineal intraepithelial neoplasias and associated cancers. Moreover, HPV quadrivalent vaccination is also recommended in males who have sex with males (MSM) ‡9 years of age (NACI recommendation Grade A) [9]. In Australia, the national school-based HPV Vaccination Program, provided through the National Immunisation Program, has been extended to include males. Since February 2013, males and females aged 12–13 years receive the HPV vaccine at school and males aged 14–15 years also receive the vaccine as part of a catch-up program [10]. In most European countries, HPV vaccination is recommended and funded only for girls, not for boys. Austria was the first country that initially recommended HPV vaccination for girls and for boys. In their 2013 vaccination plan, the Austrian health authorities stated that vaccinating both men and women was indeed important for stopping the circulating infections and for achieving herd immunity. Therefore, they recommend vaccination for children who are not yet sexually active (9–12 years). Recent epidemiological data from Austria indicate that more than 60% of cervical intraepithelial neoplasia (CIN) 2/3 lesions (immediate precursor lesions of cervical cancer) are associated with HPV 16 and/or 18 [11]. Other data report a total of about 600 cancers annually related to HPV 16/18, 30% of them among males [12]. Moreover, about 13,300 genitals warts related to HPV 6/11 are observed every year in both genders. Several factors including local disease burden, vaccine efficacy, vaccine safety, cost–effectiveness, and also social and ethical factors need to be taken into account during decision-making around the introduction of population-based vaccination programs [13]. In addition to epidemiological and cost–effectiveness issues, using a health technology assessment approach taking into account biotechnological, organizational, social, legal and bioethical considerations was shown to be a useful strategy in the evaluation process of introducing new vaccines [14]. The aim of our study was to evaluate the public health impact of universal HPV vaccination in Austria in terms of reduction of HPV prevalence and incidence of HPV-related diseases over time, and to assess whether such vaccination was cost-effective.
quadrivalent HPV vaccination program in girls and boys aged 9 years in Austria (FIGURE 1). We assumed that all quadrivalent HPV vaccination strategies evaluated would be combined with current cervical cancer screening and HPV disease management practices in Austria. In an old Austrian consensus paper on economic evaluation [16], both costs and outcomes were suggested to be discounted at 5% in the base case analysis, and authors reported that preventive measures should not be disadvantaged compared with curative ones, suggesting that European discount rates of 3% should be applied. In this study, base case analysis was conducted using a 3% discount rate for both costs and benefits.
Method
Vaccination
Objectives of the research
A vaccine uptake of 65% for both genders and an overall compliance rate of 80% were used in the model. Vaccine efficacy parameters are presented in TABLE 1.
The purpose of this study was to assess the impact on prevalence of HPV 16/18 infections, on public health in terms of HPV 16/18-related cancers avoided as well as the economic consequences of vaccinating one cohort of 9-year-old girls and boys with the quadrivalent 6/11/16/18 vaccine in Austria, from the perspective of the payer. Study design & vaccination strategies
A previously developed and published mathematical model [15] was adapted to the Austrian setting to evaluate the impact of a 270
Input parameters
Natural history parameters used were previously described and reported by Elbasha and Dasbach [15]. Demographic data & sexual behavior patterns
Population data and life table by age group were retrieved from Statistik Austria 2011. The total population in Austria on 31 December 2010 was estimated to be 8,420,900 people [17]. A constant population size was assumed. Because data regarding sexual Austrian behavior patterns are sparse, UK data were integrated into the model (Additional file). The proportion of population in each sexual activity group (low, medium and high, defined as 0–1, 2–4 and more than 5 sexual partners per year) and the average number of opposite sexual partners were obtained from the UK National Survey of Sexual Attitudes and Lifestyles II [18]. In order to provide comparability of our research with other published works, parameters used by other authors, dealing with the topic of HPV vaccination in Austria and its cost–effectiveness, were reviewed. By literature research we could identify papers by Kundi [19] and Zechmeister et al. [20], which used the same sources and values for sexual behavior data in their calculations as we did. Cervical cancer screening
The annual cervical cancer screening rates were extracted from a report by Ludwig Boltzmann Institut [21]. Another putative source [22] was identified, where almost same age groups and similar values for the screening rate were mentioned. However, due to currentness of data, the report by Zechmeister was preferred.
Disease & treatment patterns
Regarding epidemiological data, incidental cases (TABLE 2) of cervical cancer in Austria were retrieved from Statistik Austria [23]. Since data on HPV-related cancer incidence rates were not available for Austria, the proportion was measured based on the methods and results of the epidemiological report by Hartwig et al. [24]. Thus, natural history parameters were based on international data Expert Rev. Pharmacoecon. Outcomes Res. 14(2), (2014)
Impact of HPV vaccination in Austria
n
s sio
gr e
Reactivation or reinfection Clearance
d
re
Clearance
Reactivation of reinfection
Los so fi
and were the same as in the original Recovered with model [24]. Regarding measurements of the seroconversion Clea amount of genital warts cases in Austria, ity (Z) ran n u ce m age- and sex-specific incidence rates were m extracted from a German research by Kraut et al. [25] and were applied accordingly to age groups to Austrian population figures [26]. Figures describing performed hysterectomies in Austria could be retrieved from the Austrian setting by Statistik Austria [12]. Progression For mortality data, with respect to Infection Susceptible Infected Disease mortality rates of HPV-related diseases, (X) (Y) (C) several sources were identified based on Regression Austrian or German settings. Cervical cancer mortality rates by stage (local, regional, distant) and age were retrieved from a German source by Schobert et al. [27] as no appropriate data from the Austrian setting could be identified. Further on, due to the lack of informaan tion, these data were also applied as ce n a r proxy measures for vaginal and vulvar Recovered, no Cle a seroconversion cancer mortality rates. For anal cancer (ZS) mortality rates, the German Robert Koch report [28] was chosen as the most Figure 1. Simplified schematic diagram of compartments for unvaccinated indiappropriate replacement for representing viduals encompassing human papillomavirus infection and disease state transiAustrian circumstances. Figures for the tions. A susceptible host in compartment (X) may be infected with a given HPV type mortality rate of patients suffering from and move to compartment (Z) if s/he seroconverts or (ZS) if s/he does not seroconvert. penile cancer were based on data proPersons in compartments (Z) move back to the susceptible host compartment (X) when their immunity wanes. Infected persons can develop disease and may progress though vided by Statistik Austria 2011 for the several health states (compartments C). Persons with disease can regress to normal with year 2010 [29]. or without human papillomavirus infection. Those regressing to normal with infection In order to receive a HPV-related mormove to compartment (Y), whereas those regressing without human papillomavirus tality rate of head and neck cancers, we infection and with seroconversion can move to compartment (Z) and without seroconfirst retrieved a general mortality rate version to compartment (ZS). Adapted from [15]. from the Robert Koch Institute report dealing with figures from oral cavity and pharynx [28]. Afterwards, we applied a reduction of 64% which taken for diagnostic measures which can be compared to cost– was developed by Fakhry et al. [30] by comparing mortality effectiveness analyses of HPV vaccinations. When dealing with costs for cervical intraepithelial neoplasia rates of HPV-positive and negative oropharyngeal and laryngeal cancer patients. This was done because it is now generally and for vaginal intraepithelial neoplasia estimations from Geraccepted that the tumor HPV status is the single greatest deter- man reports [38,39] were again included as there was no alternaminant of survival for patients with local-regionally advanced tive available which was based on the Austrian setting. In case of genital warts in women, treatment costs were oropharyngeal cancer [31–35]. retrieved from a German study dealing with cost–effectiveness of HPV-vaccination in girls [27]. It was aimed to find sexEconomic parameters Despite the importance of indirect costs in the overall eco- specific treatments costs for genital warts in men as well, but nomic burden of cancer, this study focused on direct medical no appropriate data for a comparable setting could be identicosts. Cost data for non-cervical cancers were not available for fied. Therefore, it was necessary to apply the data from Austria. Hence, similar to Jit et al. [36] and Brisson et al. [37], Schobert et al. [27] to the male population as well. Costs are at we used the relative cost of each non-cervical cancer to those 2012 prices or inflated according to the gross domestic product for cervical cancer and applied these relative costs to the Aus- deflator by the Organisation for Economic Co-operation and trian cost of cervical cancer [20]. Vaccination costs (about e120 Development (OECD) [40]. Depending on the year of publicaper dose, administration costs included) were taken from offi- tion, prices presented in TABLE 3 were deflated by using informacial sources. For providing benchmark of our work, values were tion provided by OECD [40]. While prices from the year ion ress eg dr an
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Table 1. Vaccine efficacy assumptions. Gender
Male
HPV genotype
6
11
Female
[6]
16
18
41.1
62.1
6
[13]
11
16
18
76
96.3
98.8
98.4
98.8
98.4
97.9
100
VIN
100
100
VaIN
100
100
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Against transient infection (%) Anal, cervical, head/neck, penile, vaginal and vulvar disease Genital warts and RRP disease
49
57
76.1
76.1
Against persistent infection (%) Anal and head/neck diseases
78.7
96
Cervical, vaginal and vulvar disease Penile disease
78.7
96
Against individual infection (%) CIN
100
Genital warts
84.3
90.9
98.9
100
100
In the absence of data at the time of the analysis, efficacy for 1 and 2 doses assumed to be 23 and 45% of efficacy of the full 3 doses, respectively (as done in the original model from Elbasha and Dasbach [15]). Efficacy against genital infection in males is assumed to prevent from transmission of genital infections to females, and vice versa. CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus; RRP: Recurrent respiratory papillomatosis; VaIN: Vaginal intraepithelial neoplasia; VIN: Vulvar intraepithelial neoplasia.
2011 or 2012 remained the same in our calculations, prices from 2009 were adjusted to financial circumstances of the year 2010, as this is currently the latest year for deflators published by OECD (prices from 2009 were multiplied with the Austrian deflation index of 1.035811569 [value of 2010/value of 2009] as OECD states that e96.542656 in 2009 reached the value of e100 in 2010 in Austria). German age-specific utilities were used. In the absence of Austrian-specific utilities, qualityadjusted life year (QALY) weights were retrieved from
international literature (TABLE 3). Impact of HPV-related cancers was accounted for in survivors by applying a utility score of 0.76 [15]. Model calibration
The predictive validity of the model was evaluated by comparing model results with epidemiologic data reported in the literature. We evaluated our model predictions against the following outcomes: genital warts incidence, incidences of cervical, vaginal,
Table 2. Dynamic transmission model calibration inputs, targets and results. Carcinoma type
Cases per year (n)
Prevalence of HPV+ cases (%)
Proportion of HPV 6/11/16/18-related cases (%)
HPV 6/11/ 16/18-related cases (n)
Range of acceptability (±10%)
Model prediction (cases [n])
Ref.
Cervical
380
100.0
76.2
290
(261–319)
294
[2,23]
Vaginal
37
70.0
61.3
17
(15–18)
11
[2,20]
Vulvar
147
40.4
36.6
22
(20–25)
9
[2,20]
Penile
58
46.7
73.6
20
(18–22)
22
[2,20]
Anal (female)
80
85.0
78.6
58
(53–64)
57
[2,20]
Anal cancer (males)
34
85.0
78.6
26
(24–29)
28
[2,20]
OSCC (females)
68
39.7
89.5
26
(23–29)
25
[2,4]
OSCC (males)
329
39.7
89.5
125
(112–137)
117
[2,4]
Genital warts (females)
8473
90
90
7626
(6863–8388)
7353
[22]
Genital warts (males)
6320
90
90
5688
(4830–5903)
5438
[22]
HPV: Human papillomavirus; OSCC: Oropharyngeal squamous cell carcinoma.
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Table 3. Overview of considered HPV-related direct medical costs and utilities. Medical cost
Base case (e)†
Screening (PAP smear) and office visit
28
Colposcopy
8.3
[15]
Biopsy
24.9
[15]
Vaccine per dose
110
[15]
Administration per dose
10.3
[15]
Cervical cancer, stage I
17,128 [100%]
0.76
[13,15]
Cervical cancer, stage II–III
27,681–28,599 [100%]
0.67
[13,15]
Cervical cancer, stage IV
29,201 [100%]
0.48
[13,15]
Vulvar/vaginal cancer, stage I
14,901 [87%]
0.65/0.59
[35,76]
Vulvar/vaginal cancer, stage II–III
24,081–25,067 [87%]
0.65/0.59
[35,76]
Vulva/vaginal cancer, stage IV
25,405 [87%]
0.48
[13,35]
Penile cancer, stage I
12,160 [71%]
0.79
[13,35]
Penile cancer, stage II
19,653–20,305 [71%]
0.67
[13,35]
Penile cancer, stage III
20,732 [71%]
0.48
[13,35]
Anal cancer, stage I
17,469 [102%]
0.57
[35,76]
Anal cancer, stage II–III
28,234–29,171 [102%]
0.57
[35,76]
Anal cancer, stage IV
29,784 [102%]
0.48
[13,35]
OSCC, stage I
20,553 [120%]
0.76
[13,35]
OSCC, stage II–III
33,216–34,319 [120%]
0.58
[35,76]
OSCC, stage IV
35,041 [120%]
0.48
[13,35]
Genital warts (men)
550
0.91
[13,24]
Genital warts (women)
550
0.91
[13,24]
CIN1
348
0.862
[37,77]
CIN2/3
1551
0.822
[37,77]
VaIN, 1 surgery
881
[36]
VaIN, >1 surgery
2605
[36]
Utility
Ref. [14,15]
†
Relative costs versus cervical cancer are indicated within square brackets. CIN: Cervical intraepithelial neoplasia; OSCC: Oropharyngeal squamous cell carcinoma; PAP smear: Papanicolaou smear; VaIN: Vaginal intraepithelial neoplasia.
vulvar, anal, penile, oropharyngeal squamous cell carcinoma cancer and death due to each of these cancers. Model predictions are described in TABLE 2. Data used were taken from Austrian studies or mainly from European studies which based calculations for Austria on figures from the Austrian National Cancer Registry. Prevalence of genotypes was retrieved from international literature as presented in TABLE 2.
rate of 65%, and an 80% compliance rate between each dose received. Univariate sensitivity analyses were conducted to handle uncertainty related to cost of diseases, vaccination coverage rates assumed, vaccine’s duration of protection, discount rates, vaccine price and QALYs. Sensitivity analysis wes restricted to parameters previously shown to be key drivers of outcomes. Results
Base case & sensitivity analysis
Calibration (internal validity)
We followed international and Austrian guidelines and adopted the payer’s perspective for the base case analysis. For the base case analysis, we calculated discounted and undiscounted life years gained, QALYs and costs for the ‘screening only strategy’ as well as for the vaccination strategy, assuming a vaccination coverage
Overall, as reported in TABLE 2, the model predicted within 10% error for all HPV-related cancers and genital warts except vulvar and vaginal cancer, except for very low burden of those cancers. For mortality, the model predicted within a 10% error window all HPV-related cancer death, with a constant
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cost–effectiveness ratio (ICER) of e10,033/QALY gained versus the current situation. The detailed ICER are presented in TABLE 4. As already demonstrated in many different settings, the quadrivalent vaccine has a better economic profile than the bivalent vaccine, through the prevention of HPV 6/11-related cases of genital warts [36,41]. In the Austrian setting, it is expected that among all healthcare costs avoided over 100 years, 54% would be by the prevention of HPV 6/11-related diseases.
0.0
Reduction in prevalence (%)
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-10.0 Among females
-20.0
Among males
-30.0
No vaccination -40.0 -50.0 -60.0
Sensitivity analyses
-70.0 -80.0 -90.0 -100.0
0
10
20
30
40
50
60
70
80
90
100
Years
Figure 2. Estimated reduction of HPV 16/18-related infection prevalence among females and males over 100 years.
underestimation. The model predicted lower cervical cancer incidence and mortality among older cohorts than currently observed cross-sectionally. This differential may be attributed to a cohort effect, whereby, current cohorts of older women would be expected to have higher cervical cancer incidence and mortality than future cohorts of older women. Despite some differences and the fact that predictions are underestimated, the calibration was considered acceptable. Virus circulation
The estimated reduction of the prevalence of HPV 16/18related infection among females and males over 100 years is depicted in FIGURE 2. Uninterrupted reduction in HPV 16/18related HPV infection was found, stabilizing 50 and 80 years after vaccine introduction among males and females, respectively. The decrease in HPV prevalence was slightly slower in females than males but this decrease reached a higher level in females (-78%) compared with males (-70%). Public health impact
The public health impact of universal vaccination compared with current practice is shown in FIGURE 3A for females and FIGURE 3B for males. In a steady-state situation (at 100 years), HPV-related cancer burden could be reduced annually by 71% in men, hereby avoiding 121 cancer cases (91 oropharyngeal, 19 anal and 11 penile cancer cases). Similarly, the cancer burden could be reduced by 75% in women, hereby avoiding 310 cancer cases (among which 217 cervical cancers) compared with the current situation. This reduction was observed for all cancers assessed. Economic impact & cost–effectiveness
Vaccinating one cohort of Austrian boys and girls aged 9 under base case assumptions would lead to an incremental 274
Results from sensitivity analysis are presented in FIGURES 4 and 5. Discount rates were defined as the rate at which monetary and non-monetary benefits in the future are brought back to the present. As expected, the most influential factor is discount rates (FIGURE 4). Whatever the parameter that varied, universal vaccination of one cohort of boys and girls aged 9 remained very cost-effective compared with a strategy with no vaccination, ranging from e2530 to e21,075/QALY gained. Although vaccination coverage rate has only little impact on cost–effectiveness, it may have an impact on the reduction of infections over time. FIGURE 5 indicates that the reduction in HPV 16/18 prevalence increases with vaccination coverage with a faster reduction with increasing uptake. Over 100 years, the reduction of HPV 16/18 prevalence among both males and females is about 20% higher with vaccination coverage of 80% compared with coverage of 50% only. No probabilistic sensitivity analysis has been performed, in line with best practice recommendations from the International Society for Pharmacoeconomics and Outcomes Research – Society for Medical Decision Making (ISPOR–SMDM) Modeling Good Research Practices Task Force Working Group [42]. Discussion
Our study shows that a publicly funded universal (i.e., gender neutral) HPV vaccination is highly cost-effective. Moreover, the analysis shows that with a vaccination coverage rate of 65%, virus circulation could be controlled, and that the HPV-related cancer burden could be reduced by 73% in men and 75% in women. Anogenital warts would be reduced by 71% in both men and women. Although vaccination coverage rate has only little impact on cost–effectiveness, it may have an impact on the reduction of infections over time. No probabilistic sensitivity analysis has been performed, in line with best practice recommendations from ISPOR–SMDM Modeling Good Research Practices Task Force Working Group [42]. Improving vaccination uptake has no real impact on cost–effectiveness, meaning that additional costs are offset by additional benefits, but making all efforts to increase vaccination coverage could allow adequately control virus circulation. Since the introduction of HPV vaccination program worldwide, science has evolved and now the International Agency for Research on Cancer acknowledges a causal link between HPV infection and occurrence of several cancers [43], with associated unmet medical and public health needs [44,45]. In contrast to Expert Rev. Pharmacoecon. Outcomes Res. 14(2), (2014)
Impact of HPV vaccination in Austria
A
B 180
Anal cancers
400
160
58 17 22
Cases (n)
350
Vaginal cancers
140
300
Vulvar cancer Cervical cancers
250 200 150
290 7 14 54 73
100 50
Cases (n)
Oropharynx cancers 26
450
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Oropharynx cancers Anal cancers Penile cancers
120
125
100 80 60 40
26
34
20
20
7 9
No vaccination
Universal vaccination
0
0 No vaccination
Universal vaccination
Figure 3. Annual number of HPV 16/18-related carcinoma cases among males and females when considering a vaccination strategy of boys and girls aged 9 years of age versus no vaccination. (A) Annual number of HPV 16/18-related carcinoma cases among females according to vaccination strategy. (B) Annual number of HPV 16/18-related carcinoma cases among males according to vaccination strategy.
cervical cancer, there is indeed no routine screening for any of the other HPV-related cancers (including anal and oropharyngeal). These cancers are often diagnosed at a late stage and associated with high mortality and morbidity, specifically related to long-term effects after treatment. Current treatments are mutilating, traumatizing to the patients and associated with high acute and long-term toxicity and handicapping side effects [46–49]. Cancer survivors will require prolonged support from health and social services, including rehabilitation and socialization [50,51]. These aspects were not considered in the present health economic analysis, thus underestimating the value of vaccination. A universal vaccination program is the most efficient and equitable public health intervention and is a matter of right to best protection, equal access and gender equity. Universal vaccination programs are less confusing for the public and healthcare providers and targeting all subjects facilitates the understanding, acceptability and implementation of the program. HPV is easily transmitted both between and by men and women [52]. Therefore, both populations suffer from HPV diseases and should be entitled to the same rights to directly benefit from HPV vaccination [53]. Targeting both boys and girls in a universal HPV vaccination program would share the responsibility for prevention across both boys and girls, helping to de-sexualize the vaccination and avoid any stigma around a girl-only vaccination. This in turn would ease the burden on women and reduce the socio-cultural barriers to HPV vaccination, thereby increasing acceptability and ultimately uptake [54,55]. A study conducted in the USA reported substantial socioeconomic disparities in cervical cancer incidence and mortality with persistence over time, despite decreasing incidence and mortality rates [56]. Other authors suggested that inclusion of boys in HPV vaccination programs could be able to increase equity between socio-demographic groups differing by their risk factors for HPV infection [57]. However, as stated informahealthcare.com
by the European CDC, different baseline assumptions, as well as different choices for the modeling, have generated wide discrepancies in the cost–effectiveness estimates for vaccinating boys [45]. The major strengths of our study based on a previously published model [15] include: adequate calibration based on Austrian incidence data and prevalence data issued from an international meta-analysis [2], use of conservative assumptions such as an underestimated cervical cancer target, and analysis based on a payer perspective. Moreover, our results are in line with previously published similar studies [58]. However, our study suffers from some limitations. First of all, the increased incidence of oropharyngeal squamous cell carcinomas [59,60], anal [61] and penile [62] cancers observed over the past decades in Denmark, Sweden and the UK [63] are not taken into account. Such an increase might also be present in Table 4. Cost–effectiveness analysis of vaccinating girls and boys compared with no vaccination. HPV 6/11/16/18 disease included
Cumulative ICER in e/QALY†
Cervical
26,701
Vaginal
26,279
Vulvar
25,567
Genital warts
15,820
Anal
13,850
OSCC
10,136
Penile
10,033
Text in bold only includes diseases that are consistent with the quadrivalent HPV vaccine license. † ICER includes all diseases in the preceding rows (if applicable). HPV: Human papillomavirus; ICER: Incremental cost–effectiveness ratio; OSCC: Oropharyngeal squamous cell carcinoma; QALY: Quality-adjusted life year.
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€2530
Annual discount rates (0%/5%)
€21,075 €10,033
Duration of protection (lifetime/20 years)
€8202
Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by University of Queensland on 10/12/14 For personal use only.
Vaccine price (±15%)
Range
Costs of diseases (±50%) Vaccine uptake (±15%)
-5000
0
€12,200
€9041
€11,012
€9248
€10,869
€9982
Compliance (100%/50%) -10,000
€11,787
€10,033
No utilities (LYG)
€19,590
5000
10,000
€11,351 15,000
20,000
25,000
30,000
ICER (€/QALY)
Figure 4. Tornado diagram of the univariate sensitivity analysis. QALY: Quality-adjusted life year.
Austria, hereby underestimating the potential epidemiological benefits among boys, and thus increasing the ICER. Moreover, HPV-related costs of diseases are underestimated and cannot always be correctly evaluated. These include conizations and subsequent impact on fertility, intensive care costs for preterm delivered neonates, functional and psychological sequelae of treatment resulting in disruption of social and family interactions, impaired quality of life and potential incapacity to return to work [64–72], prolonged support from health and social services, including rehabilitation and socialization [50,51,66,71,72], anal incontinence or – as highlighted by European CDC [45] – the cost of the psychological impact of HPV-related morbidities, such as condylomata. Another possible limitation is that we used separate and independent models for each HPV-type/disease combination. This was based on the assumption that HPV types have independent natural histories with no interaction between them. If there are significant competing risks (e.g., cross-immunity between HPV types or effects of treatment on prevalence of other types and associated disease), our estimates of the cost–effectiveness ratios of vaccination programs may be inaccurate. Moreover, the analysis is conducted over 100 years with a constant vaccine price and calibration regarding death is weak, resulting in a possible underestimation of the ICER. The impact of future price reductions in tenders or a 2-dose schedule was not evaluated. Finally, our model focused on heterosexual transmission of HPV and did not incorporate transmission between homosexuals and heterosexuals, or MSM. Most published cost–effectiveness evaluations do not include potential savings from prevented premature birth cases following conization in younger life years. This may be attributable to the fact that disease models have early on focused on 276
direct disease benefit, not taking the full potential of HPV vaccines into account. Soergel et al. found that cost reductions of neonatal mortality and morbidity may be sufficient to make HPV vaccines cost effective [73]. For reasons of better comparability, we also excluded this potential cost savings from premature deliveries as well as the rare recurrent respiratory papillomatosis. Economic and social considerations associated with male vaccination have been discussed previously [74–77] and results on gender-neutral HPV vaccination cost–effectiveness are heterogeneous. Some studies have shown that adding male vaccination to female-only vaccination became more cost effective when all HPV-associated health outcomes were included in the model and when vaccine coverage of females was low (e.g., 3-dose vaccine coverage 21 years was approximately twoto four-times that of vaccinating males aged
