Long-term modeling on HPV vaccination: do we really need any more?

Abstract

The human papillomavirus (HPV) is closely related to cervical cancer. In 2007, the EMA approved two vaccines, a bivalent and a quadrivalent one, launched at three-dose schedules and very high prices worldwide. We describe what happened in the EU and what might change in the near future from an economic perspective. HPV vaccination is now established in most EU countries. The main target group of the programs is girls aged 10–14 years. Many western countries used competitive tendering to purchase the two vaccines, achieving considerable savings. The extension to males has been a hotly debated issue. The sex limitation implies that this vaccination cannot by definition achieve a ‘herd immunity’ effect. EMA recently approved a two-dose schedule for both vaccines that should lead to savings, although it is hard to predict how the forthcoming nonavalent vaccine will affect the market situation. Several economic evaluations based on long-term models have been published on the HPV vaccination in the recent years, using official list prices as a baseline. Most of these models can be considered mere exercises in long-term forecasting. Recently, further long-term models have been published with two- and three-dose schedules as alternatives, and the nonavalent vaccine. We wonder what added value they give for public policy purposes.

Keywords:

• bivalent
• forecasting model
• human papillomavirus
• nonavalent
• quadrivalent
• vaccine

The human papillomavirus (HPV) is closely related to cervical cancer (CC), the second most common cancer in women worldwide, with an estimated 530,000 new cases and approximately 270,000 deaths in 2012 [1]. In 2007, the EMA approved two vaccines, one bivalent and one quadrivalent. Both protect against initial infection with HPV types 16 and 18, the most frequently associated with CC; the quadrivalent vaccine against types 6 and 11 too, which cause 90% of genital warts [2]. Although the longest follow-up is only approximately 10 years so far [3], the two vaccines have proved effective. The manufacturers launched the two vaccines at three-dose schedules and very high prices worldwide. Their prices are still considered a major barrier to the diffusion of HPV vaccination in many countries, including the USA [4].

Here, we describe what happened in the EU and what might change in the near future according to an economic perspective. Then we discuss the role played by economic evaluations (EEs) focused on HPV vaccination so far, almost all employing long-term modeling. Finally, we review the latest studies published on the new schedules and the nonavalent vaccine, to discuss whether they really matter for public decision-making.

Historical background

HPV vaccination is now established in most EU countries [5]. The program’s main target group is girls aged 10–14 years; however, the risk of HPV infection persists throughout a woman’s sexual life, so the duration of protection provided by HPV vaccination is critical to assess the overall effectiveness [3]. Financial constraints, mainly the sky-high vaccine prices, seem to be the major hurdle for the remaining European (mostly eastern) countries that have not yet introduced this vaccination.

It is worth noting that many western EU countries used competitive tendering to purchase the two vaccines, achieving considerable savings. For instance, in Italy where awarded prices are known, the HPV vaccine prices per dose have fallen dramatically over the last few years, thanks to regional tenders, by half over 2 years [6] and even sinking to around one-third of the ex-factory prices in the latest tenders in 2013 [7] – the last price awarded in Lombardy (the largest Italian region) was €28.75 per dose [8]. It is a common feeling among experts that there have been similar (if not larger) drops in countries like the UK and Sweden [9], which use national tenders and keep awarded prices confidential. This confirms that prices may fall steeply even when competition is minimal, that is, only two manufacturers producing their own vaccines judged equivalent by health authorities for the prevention of CC.

Future scenario

Since HPV vaccination has been limited to females in most countries so far, the extension to males has been a hotly debated issue [10]. The sex limitation implies that this vaccination cannot by definition achieve a ‘herd immunity’ effect in epidemiology, hence ‘positive externalities’ in an economic perspective [11]. Clearly, female-only vaccination cannot protect men who have sex with men. When considering extension to boys, the potential positive effects on men (prevention of genital warts and HPV-related male cancers) should be considered an additional advantage for the quadrivalent vaccine, so the two vaccines can hardly be considered equivalent. To take this into account, a ‘quality score’ can be added in tender clauses, like in the recent UK tender [12] and in a few regional tenders in Italy [6], so as not to consider only the best price offered.

It is easy to predict that male extension, if adopted, should roughly double expenditure, which would hardly be balanced by additional benefits without any further reduction of the vaccine price since genital warts and HPV-related male cancers are much less burdensome than female CC.

In contrast, an innovation that should very likely lead to savings for healthcare services is the recent approval by EMA of a two-dose schedule for both vaccines [13], while it is still hard to predict how the forthcoming nonavalent vaccine (covering extra 31-33-45-52-58 types) – already approved by the FDA in the USA with a three-dose schedule [14] – will affect the present market situation, mainly depending on its still unknown price at launch.

Economic evaluations

Several EEs have been published on the HPV vaccination in the last few years. The majority were based on long-term Markov models that tried to assess the cost–effectiveness of the two vaccines at three-dose schedules, using official list prices as a baseline. Most EEs were funded by the manufacturers to back the sky-high prices of their two vaccines and almost all concluded in favor of vaccination. As amply debated in three literature reviews [15–17], HPV vaccination seems to be a typical field where EEs built on modeling suffer their greatest limitations in contributing to rational decision-making. Most of these models can be considered mere exercises in long-term forecasting to boost the chances of showing favorable results for vaccination. By projecting short-term clinical evidence into the distant future on the basis of various heterogeneous assumptions and estimates, mainly open to the authors’ discretion and manufacturers’ influence when sponsored, these models are potentially misleading and of scant utility for public policy purposes.

The latest models

Recently, further long-term dynamic models funded by public grants have been built to assess the cost–effectiveness of two- and three-dose schedules as alternatives, and the nonavalent vaccine. To systematically select them, we did a literature search on the international database PubMed (period 2010–2014; search terms ‘HPV vaccine’, ‘cost–effectiveness’ and ‘two doses’ or ‘nonavalent’). We found three articles [13,18,19] and screened them to assess the main features we considered interesting from our viewpoint (Table 1).

Table 1. Main features of recent long-term models including the two-dose schedule and the nonavalent HPV vaccine as alternatives.

Study (year)	Jit (2015) [14]	Laprise (2014) [19]	Drolet (2013) [20]
Journal (IF)	British Medical Journal (16.4)	Vaccine (3.5)	International Journal of Cancer (5.0)
Country	UK	Canada	Canada
Main alternative	Two-dose vs three-dose schedules	Two-dose vs three-dose schedules	HPV9 vs HPV4
Vaccine prices per single dose	HPV4 = £86.50 (€109.23) HPV2 = £80.50 (€101.65)	HPV 4 = HPV 2 = $Can 85 (€57.97^†)	HPV9 = HPV4 = $Can 95 (€64.79^†)
Main conclusion	Two-dose schedules are likely to be the most cost–effective option	Two-dose HPV schedules likely to be cost–effective if protection lasts at least 10 years	The additional cost per dose of the nonavalent vaccine should not exceed US$11 to remain more cost–effective than the quadrivalent vaccine.
Funding	Public grant	Public grant	Public grant

^†Exchange rate 2014.

HPV2: Bivalent; HPV4: Quadrivalent; HPV9: Nonavalent; IF: Impact factor.

The three studies were all published in acknowledged clinical journals and funded by public grants. Two compared the two- and three-dose schedules in Canada [18] and the UK [13], the third the nonavalent to the quadrivalent still in the first setting [19]. Two authors co-signed all three studies and four two of them. All studies used the official list prices for baseline analyses (assuming the nonavalent price equal to the quadrivalent in the second Canadian study) and concluded in favor of the new alternative (two-dose schedule or nonavalent vaccine).

The main goal of the two long-term dynamic models built to assess the cost–effectiveness of two- and three-dose schedules as alternatives was to estimate the economic trade-off between the different duration of protection of the two schemes (presumably longer for the original three dose), and their costs (obviously lower for the recent two dose). Since it is too early to know the precise duration of protection of the 2/3-dose vaccination schemes against HPV, the authors estimated the duration and type of protection while awaiting more accurate data from monitoring both cohorts. As expected, the cost–effectiveness of the two schemes was largely affected by the two vaccine prices. Although the authors of the British model [13] acknowledged that tenders can lead to substantially lower prices and the actual price per dose of the two vaccines is a key determinant of cost–effectiveness analysis, they still used official list prices as a baseline, claiming that awarded prices are kept confidential in the UK; however, this information is essential for deciding whether the obvious reduction in costs from the two-dose scheme is balanced by a shorter duration of protection.

The third model compared the nonavalent vaccine (not yet approved in Canada) with the quadrivalent, assuming the official list price of the latter and three-dose schedules for both vaccines [19]; however, the (inevitably) limited real-world evidence and the three-dose schedule of the nonavalent vaccine can hardly challenge the two-dose bivalent and quadrivalent vaccines at their real prices, and they would become even more advantageous if a single-dose schedule were approved in the future [20,21]. Nevertheless, we expect the manufacturer of the incumbent vaccine (the same as the quadrivalent) to invest further on modeling, to show an acceptable incremental cost–effectiveness and sustain a high price at launch.

Policy implications

According to the rapidly changing scenario and the limitations already evidenced by modeling in this field, we still wonder what added value these long-term exercises will give for public policy purposes, including the most recent ones on the two-dose schedules and the new nonavalent vaccine. Although models try to limit the uncertainty of baseline assumptions, their complexity does not compensate for the lack of important epidemiological information, adding prices as an important source of variation too. While companies seem fully aware of the possibilities of exploiting modeling to seek convenient conclusions, health authorities still need to hone their skills in evaluating the intrinsic limits of long-term models, to avoid unjustified enthusiasm about their results.

Economic theory suggests that EE is a useful decision-making tool when market competition is lacking, which is not the case of HPV vaccination. So, rather than funding models that will be outdated long before their time horizon is reached, we warmly recommend that public authorities invest in finding out sustainable policies in this period of unprecedented economic crisis, when all possible means should be explored to constrain healthcare budgets without a negative impact on health. A first, easy step would be to use the prices from public tenders in countries like Italy, Sweden and the UK as ‘international benchmarks’ for countries with a limited healthcare budget. In this perspective, health economists could help make the potential choices of public health sustainable in practice, promoting competition when possible – like in this field – rather than speculating on unrealistic long-term ‘trade-offs’.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.