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Abstract

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Please cite this paper as: Crosbie EJ. Global human papillomavirus vaccination: can it be cost-effective? BJOG 2012;119:125–128.

Few new developments in gynaecological oncology have the potential to save as many lives as the human papillomavirus (HPV) vaccines Cervarix™ and Gardasil®. These vaccines target HPV 16 and 18, the HPV types responsible for 70% of cervical cancers. Quadrivalent Gardasil® additionally targets HPV 6 and 11, which are low-risk types that cause most genital warts. Both vaccines have been tested in hundreds of thousands of women across the world, and have been found to be safe, immunogenic and highly efficacious against persistent type-specific HPV infection and premalignant disease of the cervix.1 If their full potential were to be realised, figures from the World Health Organisation (WHO) indicate that a 5-year vaccination initiative could prevent one million deaths from cervical cancer.2 Most of these deaths would occur in resource-poor settings, where cancer of the cervix remains the second leading cause of cancer-related death among women. By contrast, in resource-rich countries, where effective cervical screening programmes are in place, cervical cancer has dropped to tenth position on the leader board of cancer-related mortality in women. The successful deployment of HPV vaccines could do much to equilibrate the inconsistencies in global healthcare provision between affluent and impoverished societies.

Whilst the science supports HPV vaccination, policy makers must also consider whether immunisation initiatives offer good value for money. Cost-effectiveness analysis allows epidemiological, clinical and financial data to be amalgamated in a mathematical model that determines the health and economic consequences of various healthcare choices. In this edition of BJOG, cost-effectiveness models have been used to describe the health and economic consequences of HPV vaccination in Japan and Thailand.3,4 Both countries have established screening programmes, but the combination of poor coverage (24% in Japan and 38% in Thailand)2 and unacceptably high loss-to-follow-up rates of screen-positive women have rendered these initiatives a failure, with little impact on cervical cancer rates over recent decades. The models show that HPV vaccination combined with improved screening by cytology (in Japan) or HPV DNA testing (in Thailand) would be a cost-effective way of reducing the incidence of cervical cancer.3,4 In this commentary, the various assumptions made by these and other cost-effectiveness models are explored.

Assumption 1

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Nature of the immune protection afforded by vaccination

Most models assume that HPV vaccines provide complete and lifelong protection against HPV 16/18 infection. This further assumes that the immunised individual is HPV 16/18-naive prior to vaccination, as neither vaccine protects against established infection. To this end, most immunisation schedules vaccinate girls in the pre-adolescent phase, prior to sexual debut. The longevity of immune protection is uncertain, but recent data suggest protection against HPV 16/18 for at least 8.4 years,5 with models predicting sustained protection for 20 years or more.6 These results are based on the strict observance of a 6-month vaccination schedule, but 12 months may be equally acceptable,7 and two doses may be enough.8 HPV-specific serological responses are significantly higher following vaccination than following natural infection, with pre-adolescent girls responding best of all.9 If vaccine-induced protection starts to wane, ‘boosting’ immune responses with further dose(s) of vaccine may be necessary, but this will be expensive and logistically challenging. If short acting, the vaccine may ‘usher’ girls through the risky period of sexual awakening, or simply delay the onset of cancer by 10 years or more. The concern that the vaccines are less immunogenic in girls who are HIV positive is not supported by limited published data.10

Cost-effectiveness models do not consider vaccine-induced cross protection against similar HPV types, which would make vaccination more attractive. Recent WHO data suggest that only 47% of cervical cancers are caused by HPV 16/18 in Japan.2 Efficacy studies have not been powered to assess this, but emerging data indicate cross-protection against premalignant disease of the cervix associated with HPV 31, 33 and 45, and ‘any’ non-vaccine type, following vaccination with Cervarix™.11 In Asia, where HPV types 52 and 58 are over-represented in cervical tumours, a new polyvalent HPV vaccine targeted against seven high-risk (16, 18, 31, 33, 45, 52 and 58) and two low-risk (6, 11)12 HPV types provides hope for the future.

Assumption 2

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Vaccine coverage

If HPV vaccination programmes are to be effective, they must achieve broad coverage. Coverage rates are difficult to predict and extremely variable, depending on the setting. The cost-effectiveness model based in Japan assumed 100% coverage with the vaccine,3 and this is clearly unrealistic. For the Thai model, 80% coverage has been assumed,4 but even this may be difficult to achieve. In its first and second years, the UK-based HPV vaccination programme delivered all three doses of the vaccine to 84% and 76% of eligible girls aged between 12 and 13 years, respectively.13 This success has been attributed to the fact that girls were targeted through schools, the vaccine was free, public acceptability was high, and extensive advertising campaigns were commissioned. The fear that girls from socially deprived backgrounds, at highest risk of cervical cancer but least likely to attend for screening, would be difficult to reach proved unfounded, with 83% and 86% of girls from socially deprived and non-deprived backgrounds receiving the vaccine, respectively.14

But with the exception of Canada, Denmark and Portugal, such high coverage levels have not been seen in other settings. Where vaccines are delivered through community-based programmes, vaccination rates are low. In the USA, just 17.9% and 26.7% of girls aged between 13 and 17 years received all three doses of the vaccine in 2008 and 2009, respectively.15 Cost was the primary barrier to uptake, but ethnicity also played a role, with black girls from socially deprived backgrounds least likely to receive the jab. In the relatively poor state of Mississippi, where the age-adjusted cervical cancer mortality rate is 3.6 per 100 000 women per year, just 15.8% of eligible girls were vaccinated in 2007/2008, compared with 54.7% of those from Rhode Island, a comparatively wealthy state with a cervical cancer mortality rate of 1.8 per 100 000 women per year.16 This mismatch between the need for and access to the vaccine will accentuate the disparities in health between the rich and the poor. Furthermore, vaccination is cost-effective when given to women with poor access to cervical screening, but is relatively cost-inefficient in those who are regularly screened.17

Besides cost, public acceptability and political will are important determinants of uptake: in India, HPV vaccination feasibility studies in Andhra Pradesh and Gujarat were suspended following extreme pressure from scientists and advocacy groups after the alleged vaccine-related deaths of four girls enrolled in the study.18 The vaccine was found to be not accountable for the deaths, but such was the strength of public outrage that the safety concerns raised during the project are being investigated, and renewed efforts to develop ‘home-grown’ vaccines are underway. Without public support, HPV vaccination programmes are bound to fail. Extensive awareness campaigns may be required to encourage participation, and these are expensive. Even so, demonstration projects based in India, Peru, Uganda and Vietnam, have all shown great promise, with coverage rates above 80% when vaccines were delivered via schools.19 Working with communities, developing the infrastructure for immunisation schedules and demonstrating transparency in research are all key to the success of these initiatives.

Assumption 3

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Costs

Whilst cost-effectiveness models have found vaccination programmes to offer good value for money, they cannot determine affordability. In resource-poor settings, the huge financial outlay required to purchase enough vaccine to immunise a full cohort of pre-adolescent girls is prohibitively high. Compared with infant vaccines, HPV vaccines are extremely expensive, and considerable investment from charitable organisations will be needed to fund vaccination initiatives. Both vaccine manufacturers have pledged to provide their vaccines at discounted prices to developing countries, particularly if they ‘bulk buy’ the vaccine for several cohorts of girls.20,21 At heavily discounted prices, global HPV vaccination becomes possible, but if prices subsequently increase, developing countries may be put under considerable pressure to continue with programmes they cannot afford. Variable coverage across successive cohorts of young girls will challenge cervical screening programmes, and the morality of manufacturer-sponsored immunisation initiatives will be called into question. Besides the drug, vaccination costs include developing the infrastructure to achieve widespread coverage, promoting vaccination through advertising and improved screening for the current generation of women for whom death from cervical cancer remains a considerable threat. The WHO, the Alliance for Cervical Cancer Prevention, the Cervical Cancer Action coalition,22 and cost-effectiveness models recommend a comprehensive cervical cancer prevention strategy that combines HPV vaccination with improved screening and treatment for older women. HPV vaccination should be seen as an investment for the future that, by itself, will have little impact on the death toll from cervical cancer over the next few decades. In the current economic climate, however, policy makers may be forced to prioritise the needs of women who are at risk of developing cervical cancer today above those who may go on to develop it in the future. The Global Alliance for Vaccines and Immunisation (GAVI), which subsidises vaccines for low-income countries, is also experiencing acute financial hardship and, despite its pledge, has not yet been able to raise sufficient funds to facilitate HPV vaccination programmes in member countries.23

The need for continued cervical screening in a vaccination era

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Repeated screening by cervical cytology is an excellent test for premalignant disease of the cervix, but its successful implementation at the population level depends on organised call–recall, trained cytologists, high-quality laboratory facilities, rapid access to treatment services for premalignant lesions and low default rates. Such a sophisticated infrastructure is expensive to set up and maintain, and is generally not affordable by many low-income countries. Alternatives to cytology for low-income settings include visual inspection with acetic acid (VIA), and the new careHPV test, which detects 14 high-risk HPV types over a 2.5-hour period, without the need for complicated laboratory equipment or trained staff. The advantage of these two tests is that they allow screen-positive women to be identified and treated immediately, at the same clinic visit. This is enormously beneficial in countries where the major obstacle to cervical screening appears to have been the loss to follow-up of screen-positive women. VIA has shown inconsistency in its performance across different settings, and even within the same setting, where it has variously been shown to reduce or have no effect at all on cervical cancer mortality rates in large prospective trials.24,25 The careHPV test is new on the market and has yet to be fully evaluated, but studies indicate that it detects premalignant disease of the cervix with high sensitivity (90%) and specificity (84%) at an affordable cost.26 Using an HPV test as a primary screening tool is likely to result in over-diagnosis and over-treatment of benign infections that would have resolved spontaneously, but this can be minimised if screening is restricted to older women (>35 years of age). The most cost-effective screening test is likely to be the one that involves the least number of tests per lifetime over the fewest number of visits. In the Thai model, vaccination combined with HPV testing five times per lifetime from 35 years of age reduced the risk of cervical cancer by 70%, and was cost-effective, provided the cost per vaccinated girl was I$200 or less.4 For Japan, boosting cytology coverage to 50% or 80% brought the greatest returns in health, with a 46% and 63% reduction in cervical cancer risk, respectively. Combining screening with vaccination was marginally the most cost-effective strategy examined,3 based on a fixed price per vaccinated girl of 58 000 yen (approximately US$685).

Looking forward

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References

Whilst the specifics of the screening strategies differ according to setting, most cost-effectiveness models have found a combination of vaccination and widespread screening of older women to be a cost-effective way of driving down the incidence of cervical cancer, so long as the vaccine itself is cheap enough. As more data becomes available, models can be refined and certain assumptions clarified, but even the most comprehensive, sophisticated models incorporate assumptions that may never be resolved. Much is still unknown about, for example, the natural history of HPV infection, the pathogenesis of cervical cancer, how high-risk types interact to drive carcinogenesis, whether type replacement is likely to occur and how herd immunity will affect HPV prevalence rates. In the midst of all this uncertainty, governments need to consider evaluations of the health and economic consequences of cervical cancer prevention schemes in order to drive policy change. We have the tools to prevent cervical cancer: the next major challenge is to put these to good use in the populations that need them most.

Disclosure of interests

EJC was paid a small honorarium to serve as an advisor on HPV vaccines for GSK in 2010, and was sponsored by GSK to attend the EUROGIN conference in 2011.

Contribution to authorship

This commentary was written by EJC

Details of ethics approval

Ethics approval was not required.

Funding

EJC is a full-time employee of the University of Manchester. No additional funding was required to complete this commentary.

Acknowledgements

There are no acknowledgements.

References

  1. Top of page
  2. Abstract
  3. Assumption 1
  4. Assumption 2
  5. Assumption 3
  6. The need for continued cervical screening in a vaccination era
  7. Looking forward
  8. References
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