Thesis Thursday: Koh Jun Ong

On the third Thursday of every month, we speak to a recent graduate about their thesis and their studies. This month’s guest is Dr Koh Jun Ong who has a PhD from the University of Groningen. If you would like to suggest a candidate for an upcoming Thesis Thursday, get in touch.

Title
Economic aspects of public health programmes for infectious disease control: studies on human immunodeficiency virus & human papillomavirus
Supervisors
Maarten Postma, Mark Jit
Repository link
http://hdl.handle.net/11370/0edbcfae-2a0c-4103-9722-fb8086d75cff

Which public health programmes did you consider in your research?

Three public health programmes were considered in the thesis: 1) HIV Pre-Exposure Prophylaxis (PrEP), 2) Human Papillomavirus (HPV) vaccination, and 3) HIV screening to reduce undiagnosed infections in the population.

The first two of the three involved primary infectious disease prevention among men who have sex with men (MSM), and both of these programmes were to be delivered via sexual health clinics in England (commonly known as genitourinary medicine, GUM, clinics).

The third public health infectious disease control programme involved secondary prevention of onward HIV transmission in the general population by encouraging routine HIV screening to reduce undiagnosed HIV, with a view of earlier diagnosis leading to antiretroviral treatment initiation, which will stop HIV transmission with viral suppression.

Was it necessary to develop complex mathematical models?

It depends on the policy research question. A dynamic model was used for the HPV vaccination research question, which captures the ecological externality that vaccination provides by reducing transmission to non-vaccinees. A dynamic model was used because this programme would likely reach a high proportion of MSM who attend GUM clinics in England, and therefore the subsequent knock-on impact of disease transmission in the population was likely to be substantial.

The policy research question was different for PrEP and a static model was more suitable since the objective was to advise NHS England on whether and how such a programme, with relatively small numbers of patients over an initial time-limited period, may represent value for money in England. We first considered a public health control programme, with promising new efficacy data from the 500-person PrEP pilot study (the UK-based PROUD trial) and additional information from per protocol participants in the earlier iPrEx study. The initial consideration was to maintain the preventative effect of a drug that needs to be taken on a daily basis (compared with near one-off HPV vaccination – three doses in total delivered within a year’s time). Regular monitoring of STI and patient’s renal function meant there were clinical service capacity issue to consider, which was likely to limit access initially. Thus, a static model that did not take into account transmission was used.

However, dynamic modelling would be useful to inform policy decisions as PrEP usage expands. Firstly, because it would then be important to capture the indirect effect on infection transmission. Secondly, because when the force of infection begins to fall as incidence declines, dynamic modelling will inform future delivery of a programme that maintains its value. These represent important areas for future research.

Finally, the model designed for the research question on HIV screening was quite straightforward as its aim is primarily to advise local commissioners on financial implications of offering routine screening in their local area, which is dependent on local clinical resources and local disease prevalence.

Did you draw any important conclusions from your literature reviews?

Two literature reviews were conducted: 1) a review on economic parameters i.e. cost and utility estimates for HPV-related outcomes, and 2) a review on published MSM HPV vaccination economic evaluations.

In relation to the first review, most economic models of HPV-related interventions selected economic parameters in a pretty ad hoc way, without reviewing the entirety of the literature. We found substantial variations in cost and utility estimates for all diseases considered in our systematic review, wherever there were more than one publication. These variations in value estimates could result from the differences in cancer site, disease stages, study population, treatment pathway/settings, treatment country and utility elicitation methods used. It would be important for future models to be transparent about parameter sources and assumptions, and to recognise that as patient disease management changes over time, there will be corresponding effects on both cost and utility, necessitating future updates to the estimates. These must be considered when applied to future economic evaluations, to ensure that assumptions are up-to-date and closely reflect the case mix of patients being evaluated.

In relation to the second review, despite limited models, different modelling approaches and assumptions, a general theme from these studies reveal modelling outcomes to be most sensitive to assumptions around vaccine efficacy and price. Future studies could consider synchronising parameter assumptions to test outputs generated by different models.

What can your research tell us about the ‘cost-effective but unaffordable’ paradox?

A key finding and concluding remark of this thesis was that “findings around cost-effectiveness should not be considered independently of budget impact and affordability considerations, as the two are interlinked”. Ultimately, cost-effectiveness is linked to the budget and, in an ideal world, a cost-effectiveness threshold should correspond to the opportunity cost of replacing least cost-effective care at the margin of the whole healthcare budget spend. This willingness to pay threshold should be linked to the amount of budgetary resources an intervention displaces. After all, the concept of opportunity cost in a fixed budget setting means that decisions to invest in something translates to funding being displaced elsewhere.

Since most health economies do not have unlimited resources, even if investment in a new intervention gives high returns and therefore is worthwhile from a value for money perspective, without the necessary resources it cannot always be afforded despite its high return on investment. Having a limited budget means that funding an expensive new intervention may mean moving funding away from existing services, which may be more cost-effective than the new intervention. Hence, the services from which funds are moved from will lose out, and this may leave society worse-off.

A simple analogy may be that buying a property that guarantees return over a defined period is worthwhile, but if I cannot afford it in the first place, is this still an option?

This was clearly demonstrated in the PrEP example, where despite potential to be cost-effective, the high cost of the intervention at list price carried with it a very high budget impact. The size of the population needed to be given PrEP to achieve substantial public health benefits is large, which meant that a public health programme could pose an affordability challenge to the national health care system.

Based on your findings, how might HIV and HPV prevention strategies be made more cost-effective?

Two strategies could influence cost effectiveness: optimizing the population covered and using an appropriate comparator price.

The most obvious way to improve cost-effectiveness is to optimise the population covered. For example, we know that HIV risk, as measured by HIV incidence, is higher among GUM-attending MSM. Therefore, delivering a PrEP programme to this population (at least in the initial phase until the intervention becomes more affordable) will likely result in a higher number of new HIV infections prevented. Similarly, HIV screening offered to areas with high local prevalence would likely give a higher number of new diagnoses.

The other important factor to consider around cost-effectiveness is the comparator price on which the technology appraisal is based. In the chapter on estimating HIV care cost in England, we demonstrated that with imminent availability of generic antiretrovirals, the lifetime care cost for a person living with HIV will reduce substantially. This reduced cost, representing cost of care with existing intervention, should be used as comparator for newer HIV interventions, as they would represent what society will be paying in the absence of the new interventions, allowing corresponding reduced price expectations for new interventions to ensure cost-effectiveness is maintained.

How did you find the experience of completing your thesis by publication?

It was brilliant! I must acknowledge all the contributions from my supervisors and co-authors in making this possible and for the very positive experience of this process. A major advantage of doing a PhD by publication is that the work conducted was regularly peer-reviewed, hence providing an extra check of the robustness of the analyses. And also the fact that these works are out for public consumption almost immediately, making the science available for other researchers to consider and to move the science to the next stage.

Education versus anti-vaxxers: evidence from Europe

Vaccine skepticism and hesitancy – the distrust and skepticism that some members of the public feel for vaccines, as well as for institutions that deliver and encourage vaccination – has emerged as a major threat to world health. Vaccine skepticism is not limited to any particular place; it has been observed across a range of countries, cultures, and levels of prosperity. Vaccine skeptics have made themselves known in Hollywood, led protests in Washington D.C., and lashed out violently against vaccination in Pakistan and Northern Nigeria. Vaccine skepticism has truly gone global.

Vaccine skepticism comes at odds with the proven benefits that vaccines have brought to humanity. The widespread adoption and use of vaccines and antibiotics led to sharp declines in the incidence of, and mortality caused by, infectious diseases. Except for the 1918 global flu epidemic, infectious disease mortality in the United States fell linearly before plateauing in the 1950s, at under one-tenth of the rate seen in 1900.

Vacine hesitancy threatens to reverse years of progress towards reducing measles deaths and ultimately eliminating measles as a threat, as immunization levels in many communities are at or below the 95% level required for herd immunity. In fact, the World Health Organization has seen more cases reported in the first half of 2019 than in any year since 2006. It is clearly time to reappraise vaccine policies and programs.

The role of education

Many people may find it difficult to understand and assess risks and benefits of vaccination, especially in the presence of Wakefield’s fraudulent argument that the MMR vaccine causes autism, while vaccines have been so successful that more people have seen autism than the diseases targeted by the vaccines.

Since one might hope that education can provide both the facts needed to make intelligent decisions about vaccination and the ability to reason, we ask here what is the relation between education and vaccine skepticism.

We use 2017 education data from the United Nations Development Program Human Development Reports, and data on vaccination attitudes from the Vaccine Confidence Project, published in 2016. These data include 28 European countries, with wide ranges in the prevalence of vaccine skepticism (13.5% in the median country did not agree that vaccines were safe, with a range from 4.2% in Portugal, to 51% in France) and years of education (16.4 in the median country, with a range from 12.7 in Azerbaijan to 19.8 in Belgium).

We found a weak (R2 = 0.1847) but statistically significant (p = 0.022) inverse relationship between education level and vaccine skepticism: by country vaccine skepticism decreased by about 2% for each additional year of education.

The relationship between years of schooling and vaccine skepticism, by country.

However, there are significant outliers, consistent with the low coefficient of correlation. For example, among the least educated countries, vaccine skepticism in Bosnia and Herzegovina is 36%, compared with 13% in the less educated Azerbaijan. Vaccine skepticism is 51% in France but 4.2% in Portugal, again despite similar educational levels (16.3 years in Portugal, 16.4 in France). Among the most educated countries, vaccine skepticism was 5.5% in Israel but 14% in the more educated Belgium.

Questions for research

It is clearly important to understand the cultural and other reasons behind the outliers in these data, in order to address the health challenge of vaccine skepticism. Here we offer some speculations and questions for further study.

The European countries with the best systems of education are generally those that were the first to industrialize, reach developed status, and adopt nationwide vaccination programs. As such, their present populations may be very historically removed from the infectious diseases that once plagued the European continent. As such, people in these countries may be less appreciative of the difference that vaccines have made, and more likely to be influenced by anti-vaccine messages.

Another factor to consider may be the politicization of anti-vaccine attitudes. It is possible that vaccine skepticism has become more prevalent simply because more people subscribe to political ideologies that are distrustful of the medical establishment and, more generally, institutions typically associated with their governments. France is again one such country where people are increasingly doubtful of their political institutions and are therefore wary of completely trusting ideas promoted by their government. This is more apparent than ever with the recent yellow vest protests seen across the country.

Distrust is often rooted in real instances of the abuse of public trust by, as well as the failure of, institutions, such as the Tuskegee syphilis trials, the Thalidomide birth defect crisis of the 50s and 60s, as well as unethical pharmaceutical trials that modern drug companies have carried out in developing countries, such the meningitis antibiotic trials that Pfizer carried out in Northern Nigeria during the mid 1990s. Vaccine skeptics have also lobbied for religious exemptions to be upheld in places that were considering their removal due to the resurgence of certain diseases like measles.

A study conducted in Romania concluded that unfavorable information spread by the media regarding vaccines was the lead cause in increasing vaccine skepticism in the country. With one third of the population being skeptical about vaccines, politicians and the reputation of the pharmaceutical industry were also named as reasons people feared vaccines.

In some countries, such as Greece and Romania, medical professionals have often been found to be skeptical of vaccines themselves. These health care workers have expressed concerns regarding the guilt they would feel if patients were to experience negative side effects after receiving vaccines, claiming that certain hepatitis and HPV vaccines have been banned in other countries due to fears of patients developing tumors and autism. These claims are reminiscent of Wakefield’s false and damaging claims that the MMR vaccine caused autism.

Residents of former Yugoslav countries, such as Bosnia and Herzegovina, have attributed lack of vaccine confidence to a discomfort with the relationship between physicians and patients. By evoking the times when the practice of immunization went unquestioned, physicians appear to be advocating the reestablishment of the authoritative power relationship between physicians and patients under socialism.

Given the well-documented strong evidence of the benefits of vaccines, we are left with a communication challenge – how to communicate key scientific facts needed for intelligent decision-making in a respectful, non-threating, non-condescending way.

Credit

Infectious Disease Modelling and Health Economic Evaluation of Vaccines

Who should attend?
People who have an interest in quantitative research, and
who want to learn about infectious disease modelling and
health economic evaluation e.g., health economists,
(bio)statisticians and mathematicians who want to expand
their toolbox, as well as health science professionals and
policy advisors who want to have a deeper understanding
of cost-effectiveness analysis when it is applied to
vaccines.

Programme

  • DAY 1 Introduction to mathematical models for infectious diseases (using R)
  • DAY 2 Inferring model parameters from data (using R)
  • DAY 3 Meta-population and individual-based models (using R)
  • DAY 4 Introduction to health economic evaluation and dealing with uncertainty (using R and MS Excel)
  • DAY 5 Economic evaluation of vaccination programmes, specific issues (using R and MS Excel)

Participants can attend all days or select DAYS 1-3 or 4-5.

Instructors
Prof. Philippe Beutels, Prof. Niel Hens, Prof. Joke Bilcke,
Dr. Pietro Coletti & Dr. Lander Willem
All instructors are researchers of the SIMID group, i.e.
members of the Centre for Health Economics Research
& Modelling Infectious Diseases (CHERMID), Vaccine &
Infectious Disease Institute at the University of Antwerp
and/or of the Center for Statistics, Interuniversity Institute of
Biostatistics and statistical Bioinformatics at Hasselt
University and K.U.Leuven.