University of Groningen Economic aspects of public health programmes for infectious disease control Ong, Koh Jun

Economic aspects of public health programmes for infectious disease control

Ong, Koh Jun

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10.33612/diss.98545253

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Ong, K. J. (2019). Economic aspects of public health programmes for infectious disease control: studies on human immunodeficiency virus & human papillomavirus. University of Groningen.

https://doi.org/10.33612/diss.98545253

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ECONOMIC ASPECTS OF PUBLIC HEALTH PROGRAMMES FOR

INFECTIOUS DISEASE CONTROL

Studies on Human Immunodeficiency Virus & Human Papillomavirus

ECONOMIC ASPECTS OF PUBLIC HEALTH PROGRAMMES FOR

INFECTIOUS DISEASE CONTROL

Studies on Human Immunodeficiency Virus & Human Papillomavirus

PhD thesis

to obtain the degree of PhD at the University of Groningen

on the authority of the Rector Magnificus Prof. C. Wijmenga

and in accordance with the decision by the College of Deans This thesis will be defended in public on Monday 21 October 2019 at 12:45 hours

Prof. M.J. Postma Prof. M. Jit

CO-SUPERVISORS

Dr. K. Soldan

Dr. A.J. van Hoek

ASSESSMENT COMMITTEE

Prof. C. Hoebe

Prof. F. Antonanzas Prof. J.C. Wilschut

TABLE OF CONTENTS

Chapter 1 General Introduction 7

Part I Human Immunodeficiency Virus (HIV)

Chapter 2 Economic evaluation of HIV pre-exposure prophylaxis among 21 men-who-have-sex-with-men in England in 2016

Eurosurveillance 2017;22(42)

Chapter 3 HIV care cost in England: a cross-sectional analysis of 41 antiretroviral treatment and the impact of generic introduction

HIV Med (2019), 20: 377-391

Chapter 4 Estimated cost per HIV infection diagnosed through routine 67 HIV testing offered in acute general medical admission units

and general practice settings in England HIV Medicine (2016), 17: 247--254

Part II Human Papillomavirus (HPV)

Chapter 5 Impact and Cost-effectiveness of Selective Human 83 Papillomavirus Vaccination of Men Who Have Sex With Men

CID 2017:64 (1 March)

Chapter 6 Cost Effectiveness of Human Papillomavirus Vaccination for 103 Men Who have Sex with Men; Reviewing the Available Evidence

PharmacoEconomics (2018) 36:929–939

Chapter 7 Systematic review and evidence synthesis of 123 non-cervical human papillomavirus-related disease

health systems costs and quality of life estimates Sex Transm Infect 2019;95:28–35

Chapter 8 Discussion & Concluding Remarks 143

Addendum Summary 155

Samenvatting 160 Acknowledgements 163 Research Institute SHARE 166

General Introduction

chapter 1

9

1

GENERAL INTRODUCTION

OVERVIEW

Payers of healthcare services constantly strive to efficiently use the limited resources they have. This is often done via strategic policy planning activities, which are especially relevant for public health services as they usually cover a wider population. Infectious diseases present one core area for public health activities. This thesis focuses on the use of different economic evaluation methods to inform public health policy decision making related to two sexually transmitted viruses, 1) the human immunodeficiency virus, HIV; and 2) the human papillomavirus, HPV.

THE ROLE OF ECONOMIC EVALUATIONS IN PUBLIC HEALTH

INFECTIOUS DISEASE CONTROL PROGRAMMES

Economic evaluations are vital components of evidence-based decision making, applicable to the assessment of both new and existing public health control programmes. Such evaluations typically consider costs and/or outcomes associated with the interventions, and guide policy decision makers in optimal use of limited resources to achieve both allocative and technical efficiency [1]. The analytical methods in this thesis range from full economic analyses, such as cost-effectiveness analysis, or partial analyses, which only consider either costs or outcomes, for example a cost of illness/disease analysis [2].

PARTIES RESPONSIBLE FOR ADVISING COMMISSIONING DECISIONS

Public health strategies to control transmission require careful consideration of their clinical and economic impact. This requires an understanding of the disease epidemiology and which intervention strategy relating to the local population needs will optimise the limited resources required to implement them, ensuring greatest value for money.

In England, assessment of the clinical and cost-effectiveness of technologies are carried out by either the National Institute for Health and Care Excellence (NICE), or by other expert groups such as the Joint Committee for Vaccination and Immunisation (JCVI), or the Clinical Priorities Advisory Group (CPAG) of National Health Service (NHS) England. NICE typically considers technologies with marketing authorisation for an indication being appraised, with their final appraisal recommendation mandated to be commissioned within 3 months of the decision publication, with certain exemptions such as an affordability challenge. JCVI on the other hand, considers the clinical and economic evidence around immunisation programmes and makes policy recommendations to the Department of Health. CPAG, finally, considers off-label indications, and have historically taken on all evaluations of HIV interventions and haemophilia care.

The methods for economic evaluation of health care technologies generally follow the economic reference case specified by NICE [3], although JCVI and CPAG may adopt their own value assessment protocol to decide whether to recommend funding of a technology. For instance, JCVI has their own code of practice that is similar to the NICE reference case, but adopts their own interpretation of uncertainty based on findings from probabilistic

1

sensitivity analyses [4]Whilst NICE generally accepts a threshold of between £20,000 and _{£30,000 for interventions to be considered cost-effective, JCVI defines a vaccination strategy} to be cost-effective if 90% scenarios fall within £30,000 threshold. CPAG, on the other hand, uses a complex relative prioritisation process to determine which technologies are funded within a defined budget. The process considers both patient benefits and financial impact.

ECONOMIC EVALUATION PERSPECTIVE

Having defined evaluation methodologies allow for standardised assessment of different technologies. Important criteria to define in any economic evaluations include the analytical perspective – typically the commissioner’s perspective i.e. who pays, the time horizon, the clinical pathways of intervention(s) and relevant comparator(s). Whilst Austria, Belgium (outcomes only), the Netherlands and the World Health Organization adopt a societal perspective, which includes consideration such as time off work, other countries including Australia, Canada, England, and Wales take a narrower perspective of cost to the healthcare system and outcomes affecting patients, and occasionally (e.g. NICE in England) the carer’s perspectives [5]. Specifically, the perspective taken in England in terms of cost is usually that of the NHS and personal social services.

COMMISSIONING LANDSCAPE IN ENGLAND

To fully understand the context and potential impact of my analyses, which focused mostly on England, it is important to have an overview of the commissioning landscape in this country. The provision of health services in England, including that of public health, falls under the commissioning responsibility of either the Department of Health, NHS England, or local authorities, depending on the specific technology and disease area. The evaluation perspective corresponds to this commissioning responsibility. In accordance with the Health and Social Care Act 2012, commissioning of public health services in England falls under the responsibility of either the NHS or local authorities. Some of the defined public health functions are commissioned by NHS England, through an annually renewed arrangement with the Secretary of State for Health, under a Public Health functions agreement (Section 7A) [6]. Programmes covered under this commissioning arrangement include, inter alia, vaccination, and certain screening programmes, including cancer screening. Under the same act, local authorities have statutory public health responsibilities, which comprise commissioning of sexual health services, e.g. testing and treatment of sexually transmitted infections (STIs) including HIV testing, and HIV prevention initiatives [7]. HIV treatment, however, remains the commissioning responsibility of NHS England, under its specialised services. Such arrangement means that, depending on the disease area, commissioning responsibilities could rest with either NHS England or local authorities or be jointly commissioned based on prior agreement.

Thus, the assessment of cost-effectiveness of new or existing technologies may be undertaken by the commissioners locally, for instance at a local authority level or at a national

11

1

GENERAL INTRODUCTION

level, as done through the JCVI in their deliberations of value for money of new or alternative national vaccination strategies or occasionally via NHS England’s Clinical Priorities Advisory Group (CPAG) [8].

ROLE OF PUBLIC HEALTH INFECTIOUS DISEASES CONTROL

INTERVENTIONS

Public health infectious diseases interventions generally aim to control infections either through prevention of new infections (i.e. primary prevention) or diagnosis and treatment of cases (i.e. secondary prevention). Such programmes are often designed with the aim of achieving the greatest net value, i.e. considering value to both population’s health and monetary benefits to the commissioner, within budgetary constraints. Sometimes this can be best achieved through high population coverage and occasionally through targeted delivery to a population at greater risk of contracting an infection and/or onward transmission to others. Examples include i) the HIV immediate antiretroviral treatment policy [9], where all newly diagnosed persons are offered antiretroviral treatment immediately regardless of CD4+ count, primarily to reduce onward HIV transmission and secondarily to prevent disease progression; ii) national immunisation programmes such as hepatitis B vaccination that are offered to populations at higher risk of infection e.g. people who inject drugs (PWID) and men who have sex with men (MSM), and more recently to infants and children under 10 years old, born after 1 August 2017 [10]. These policy decisions were guided by their cost-effectiveness evidence. Many countries have their own immunisation schedule that caters to local disease epidemiology.

INFECTIOUS DISEASES & THE POLICY QUESTIONS – HIV & HPV

This thesis focuses on preventive interventions against two viruses that can be transmitted sexually: 1) the human immunodeficiency virus, HIV; and 2) the human papillomavirus, HPV. HIV incidence has remained relatively stable over 2006 to 2015, with some indication of declining in more recent years attributed to existing public health control initiatives [11]. On the other hand, national school-based HPV vaccination programme covers girls only. Further opportunities exist to provide primary and secondary prevention to complement existing public health control interventions in England. Both viral infections usually have long periods where the infected host remain asymptomatic, which increases the probabilities of onward transmission without knowledge of those infected. As such, public health infection control programmes aim to reduce those undiagnosed and prevent new infections. Existing interventions include national HIV screening recommendations for local areas with high diagnosed HIV prevalence, antiretroviral treatment as prevention policy, and the HPV vaccination programme for adolescent girls. This thesis covers three different public health programmes aimed at reducing the incidence of HIV or HPV infections.

1

HIV

_{HIV is transmissible through body fluids, including blood, semen, and breast milk. Persons} infected with HIV may have mild flu-like symptoms during the initial weeks after contracting the virus (acute phase), before becoming asymptomatic for a long period. The virus gradually destroys an infected person’s immune system over many years [12]. In later stages, as the person’s immune system is progressively damaged, they become more likely to get opportunistic infections. The advanced stage of HIV infection is commonly known as AIDS – acquired immune deficiency syndrome. The risk of transmission is highest during the acute and advanced phases of the infection [13].

Laboratory-based serology, as well as point-of-care tests, are used to diagnose HIV [14]. The general testing algorithm is to screen using a test that has high sensitivity and if the result is reactive, to confirm with a different test that has high sensitivity and specificity. For persons diagnosed with HIV, treatment using daily highly active antiretroviral therapy (HAART) reduces viral load and could result in near normal life expectancy [15]. Reductions in viral load mean that those on antiretroviral treatment have substantially reduced risk of transmitting the virus [16]. The current formulation of antiretrovirals requires daily intake for the remaining life of an infected person. There is currently no known cure for HIV.

Over a 10 years period from 2008 to 2017, the annual number of new diagnoses in England has declined, from 6,637 in 2008 to 3,973 in 2017 [11]. During this decade, as treatment and life expectancy continued to improve, the number of persons accessing HIV specialist care in England increased, from 56,353 in 2008 to 85,537 in 2017, with most infections acquired through sex between men or heterosexual contact. Meanwhile, the proportion of those seen in care who received antiretroviral treatment increased from 78% to 98%. The reduction in HIV incidence observed over the past decade has been attributed to increased HIV testing and improved access to antiretroviral treatment [17] [18].

In this thesis, I evaluate two public health strategies for the control of HIV. The first is the introduction of pre-exposure prophylaxis (PrEP). Towards the end of 2014, as evidence on high PrEP efficacy was beginning to emerge and to follow-up on the promising results of the UK PROUD pilot trial [19], I evaluate the introduction of this programme within the NHS. To inform the commissioning decision by NHS England and local authorities around the introduction and costs I focussed on both cost-effectiveness and budgetary impact of the programme. Therefore, the aim of chapter 2 is phrased as: to analyse whether the provision of HIV pre-exposure prophylaxis to persons at higher risk of contracting the virus is cost-effective in England and whether such introduction presents an affordability challenge to the commissioner [20].

As the cost-effectiveness of HIV interventions such as PrEP prevention depends on the life time treatment cost of HIV, I performed a subsequent analysis of the possible change in life time costs of HIV in the changing environment of drugs coming off patent. Consequently, Chapter 3 investigates how this lifetime care cost look like as generics have become available [21].

13

1

GENERAL INTRODUCTION

The second strategy I evaluated to control HIV concerned HIV screening. An important outstanding question for local authorities in England, who are responsible for commissioning of local public health initiatives including HIV prevention, is the optimal setting to deliver screening. Screening could be delivered via local general practice when patients attend clinic for first time, for example, where they have a brief registration check-up, or in hospital settings where patients have their blood withdrawn for testing prior to acute admissions. Thus, I looked at the cost consequence of investing screening in these two settings in Chapter 4 [22], to help local commissioners identify optimal setting for HIV screening based on local HIV prevalence. The cost builds on micro-costing information collected as part of a pilot study, whilst consequence is number of reactive tests.

HPV

HPV is a very common viral infection that is transmitted via skin to skin contact and is generally asymptomatic. There are more than 100 different HPV subtypes; most are not known to be carcinogenic. However, at least a dozen are believed to cause cancer, such as HPV-16, -18, and -33 [23] [24]: these are referred to as “high-risk” (HR) HPV types. Almost all cervical cancers have detectable HR HPV DNA and HR HPV infection is considered a necessary (though not sufficient) cause of all cervical cancers. HR HPV also plays a role in cancers of the vulva, vagina, anus, penis, oropharynx, oral cavity, and larynx. Not all persons infected with HR HPV will progress to cancers later in life.

Of the “low-risk, LR” types, two, HPV-6 and -11, cause the majority of genital warts, a very common symptomatic and troublesome, though not life-threatening, STI.

One of the earliest public health interventions related to HPV in England was the secondary prevention intervention of cervical cancer screening programme aimed at diagnosing and treating cervical pre-cancers and cancers. Diagnosis methods have evolved over time, from cytology testing initially that subsequently used HPV testing as an adjunct to cytology in order to triage cytology borderline results and as a test of cure and moving to HPV primary testing by 2020 [25]. Women who are HPV positive or has high-grade dyskaryosis are referred to colposcopy for further cervical examination [26]. The Papanicolau (pap) smear test was invented in the 1920s but organised call-recall mechanism for universal cervical screening only began in England in 1988. Each year over 2005 and 2014, in women aged between 20 and 64 years, around 175,000 to 200,000 borderline or low-grade abnormalities and ~45,000 high-grade abnormalities or worse have been recorded, with ~2,300 to 2,600 cases of cervical cancer registered for all ages [27]. Although cervical screening has been shown to reduce late stage diagnoses and deaths, screening does not necessarily prevent occurrence of cervical abnormalities in the first instance [28].

Although screening has been successful in reducing risks of cervical disease progression, HPV infection and cervical cancer remained an important public health issue. The remaining disease in countries with effective screening programmes as well as the disease in countries without cervical screening motivated vaccine development as a means of

1

primary prevention. Two HPV vaccines became available around 2006/07 [29] [30], offering _{protection from infections with HPV types 6, 11, 16, and 18 (quadrivalent) or HPV 16 and 18} only (bivalent). England began a national HPV vaccination programme in September 2008, covering girls only, with three-dose vaccination offer for those aged 12-13 years old (plus a catch-up programme to age 18). This followed a JCVI recommendation that was informed by cost-effectiveness analyses that showed when female vaccination coverage was high, adding boys to the vaccination programmes would be unlikely to be cost-effective [31]. The programme used the bivalent vaccine initially, before transitioning to the quadrivalent vaccine. In September 2014, the programme adopted a two-dose schedule for under 15s instead of the originally licenced three-dose schedule [32].

Males having sex with women were expected to gain considerable indirect benefit from the female HPV vaccination programme. However, men would be far less protected if they engage in sex with men. Men who have sex with men represent a high-risk group with ongoing exposure, with higher risk of HIV infection acting as a co-factor for HPV infection and disease progression. In England, the attendance of MSM at genitourinary medicine clinics, also known as sexual health clinics, offered the opportunity to offer HPV vaccination to MSM – ideally at their first attendance. Therefore, in Chapter 5, a previously published heterosexual dynamic cohort model is adapted to consider HPV transmission among MSM, adjusted by HIV status, to inform whether and which strategy of HPV vaccination for MSM could be cost-effective [33].

A related question on the cost-effectiveness of MSM HPV vaccination, having performed a cost-effectiveness model in England, is whether my findings are in agreement with other published work. Hence, a systematic review was conducted to allow for this comparison (Chapter 6) [34].

Finally, with an increasing number of HPV models including non-cervical outcomes, it was necessary to ensure that models used updated and relevant cost and utility estimates. Thus, in Chapter 7 [35], I conduct a systematic review and meta-analysis of the cost and utility of HPV-related non-cervical outcomes so as to better inform economic parameter values input to future HPV models.

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GENERAL INTRODUCTION

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13. Boily, Marie Claude, et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. The Lancet Infectious Diseases. 2 2009. Vol. 9, 2, pp. 118-129. 10.1016/S1473-3099(09)70021-0. 14. Selecting an HIV Test: A Narrative Review for

Clinicians and Researchers. Hurt, Christopher B., et al. 12, s.l. : Lippincott Williams and Wilkins, 1 12 2017, Sexually Transmitted Diseases, Vol. 44, pp. 739-746. 10.1097/OLQ.0000000000000719. 15. May, Margaret T., et al. Impact on life

expectancy of HIV-1 positive individuals of CD4R cell count and viral load response to antiretroviral therapy. AIDS. s.l.  : Lippincott Williams and Wilkins, 2014. Vol. 28, 8, pp. 1193-1202. 10.1097/QAD.0000000000000243.

16. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. Cohen, Myron S, et al. 9, 2016, The New England journal of medicine, Vol. 375, pp. 830-9. 10.1056/NEJMoa1600693. 17. Public Health England. Trends in new HIV

diagnoses and people receiving HIV-related care in the United Kingdom: data to the end of December 2017. Public Health England. London, United Kingdom : s.n., 2018. 18. Guidance, HIV surveillance systems. GOV.

UK. [Online] 2008. https://www.gov.uk/ guidance/hiv-surveillance-systems.

19. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): Effectiveness results from the pilot phase of a pragmatic open-label randomised trial. McCormack, Sheena, et al. 10013, s.l.  : Lancet Publishing Group, 2 1 2016, The Lancet, Vol. 387, pp. 53-60. 10.1016/S0140-6736(15)00056-2. 20. Economic evaluation of HIV pre-exposure

prophylaxis among men-who-have-sex-with-men in England in 2016. Ong, K.J., et al. 42, 2017, Eurosurveillance, Vol. 22. 10.2807/1560-7917.ES.2017.22.42.17-00192. 21. HIV care cost in England: a cross sectional

analysis of antiretroviral treatment and the impact of generic introduction. Ong KJ, et al. 2019, HIV Medicine (in press).

22. Estimated cost per HIV infection diagnosed through routine HIV testing offered in acute general medical admission units and general practice settings in England. Ong, K.J., et al. 4, 2016, HIV Medicine, Vol. 17. 10.1111/hiv.12293. 23. International Agency for Research on Cancer. IARC Monographs Volume 100BHuman Papillomaviruses. International Agency for Research on Cancer, World Health Organization. Lyon, France : s.n., 2018.

24. World Health Organization. Human papillomavirus (HPV) and cervical cancer. Fact Sheets. [Online] 2019. https://www.who. int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer. 25. Public Health England. NHS cervical

screening (CSP) programme. Population screening programmes. [Online] 2019.

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https://www.gov.uk/health-and-social-care/population-screening-programmes-cervical. 26. NHS Cervical Screening Programme

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28. Impact of cervical screening on cervical cancer mortality: Estimation using stage-specific results from a nested case-control study. Landy, Rebecca, et al. 9, s.l. : Nature Publishing Group, 25 10 2016, British Journal of Cancer, Vol. 115, pp. 1140-1146. 10.1038/bjc.2016.290.

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Edmunds, W. John. 7665, 9 8 2008, BMJ, Vol. 337, pp. 331-335. 10.1136/bmj.a769.

32. Public Health England, Department of Health and Social Care and NHS England. Correspondence, HPV vaccination programme: change from 3 to 2 doses. London, United Kingdom: GOV.UK, 2014. https://www.gov.uk/government/ publications/schedule-change-from-3-to-2-doses-in-the-hpv-vaccination-programme. 33. Impact and cost-effectiveness of selective

human papillomavirus vaccination of men who have sex with men. Lin, A., et al. 5, 2017, Clinical Infectious Diseases, Vol. 64. 10.1093/cid/ciw845. 34. Cost Effectiveness of Human Papillomavirus

Vaccination for Men Who have Sex with Men; Reviewing the Available Evidence. Setiawan, D., et al. 2018, Pharmaco Economics. 10.1007/s40273-018-0649-y. 35. Systematic review and evidence synthesis of

non-cervical human papillomavirus-related disease health system costs and quality of life estimates. Ong, Koh Jun, et al. 1, 1 2 2019, Sexually Transmitted Infections, Vol. 95, p. 28. 10.1136/sextrans-2018-053606.

Human Immunodeficiency Virus (HIV)

part 1

Economic evaluation of HIV pre-exposure

prophylaxis among

men-who-have-sex-with-men in England in 2016

Koh Jun Ong¹, Sarika Desai1_{, Nigel Field², Monica Desai¹,} Anthony Nardone1_{, Albert Jan van Hoek}3_{, Owen Noel Gill}1

Eurosurveillance 2017;22(42)

chapter 2

1. _{HIV & STI Department, National Centre for Infectious Disease Surveillance and}

Control (CIDSC), Public Health England, London, United Kingdom

2. _{Research Department of Infection & Population Health, University College}

London, London, United Kingdom

2

ABSTRACT

Clinical effectiveness of pre-exposure prophylaxis (PrEP) for preventing HIV acquisition in men who have sex with men (MSM) at high HIV risk is established. A static decision analytical model was constructed to inform policy prioritisation in England around cost-effectiveness and budgetary impact of a PrEP programme covering 5,000 MSM during an initial high-risk period. National genitourinary medicine clinic surveillance data informed key HIV risk assumptions. Pragmatic large-scale implementation scenarios were explored. At 86% effectiveness, PrEP given to 5,000 MSM at 3.3 per 100 person-years annual HIV incidence, assuming risk compensation (20% HIV incidence increase), averted 118 HIV infections over remaining lifetimes and was cost saving. Lower effectiveness (64%) gave an incremental cost-effectiveness ratio of + GBP 23,500 (EUR 32,000) per quality-adjusted life year (QALY) gained. Investment of GBP 26.9 million (EUR 36.6 million) in year-1 breaks even anywhere from year-23 (86% effectiveness) to year-33 (64% effectiveness). PrEP cost-effectiveness was highly sensitive to year-1 HIV incidence, PrEP adherence/effectiveness, and antiretroviral drug costs. There is much uncertainty around HIV incidence in those given PrEP and adherence/effectiveness, especially under programme scale-up. Substantially reduced PrEP drug costs are needed to give the necessary assurance of cost-effectiveness, and for an affordable public health programme of sufficient size.

INTRODUCTION

In the United Kingdom (UK) new prevention initiatives are needed to reduce the estimated 2,800 incident HIV infections occurring annually in men who have sex with men (MSM) [1]. The UK PROUD study demonstrated that HIV pre-exposure prophylaxis (PrEP) with daily oral antiretroviral (ARV) drug combination tenofovir disoproxil and emtricitabine in addition to standard-of-care risk reduction for MSM at high HIV risk, reduced HIV incidence over the participant follow-up period by 86% (90% confidence interval (CI): 64–96%) [2]. The PROUD data on PrEP effectiveness, supported by the placebo-controlled efficacy data from iPrEX and IPERGAY, showed that PrEP offers a major opportunity to reduce HIV incidence in MSM [3,4]. A PrEP policy was proposed by National Health Service (NHS) England for high HIV risk attendees of the 215 genitourinary medicine (GUM) clinics in England that provide free, confidential, open-access sexual health services [5].

In England, new clinical commissioning policies are prioritised on their effectiveness and value for money [6]. Cost-effectiveness evidence is reviewed, with incremental value for money of competing services scored and compared on the basis of their incremental costs and incremental benefits. In other areas of publically-funded public health prevention programmes (e.g. immunisation), one decision criterion used is a high certainty that the incremental cost-effectiveness ratio (ICER) falls below a recommended threshold, currently GBP 20,000 (EUR 27,210) per quality-adjusted life year (QALY) gained [7,8]. In addition, the affordability of any new service must be ensured based on practical eligibility criteria that are developed to guarantee the service reaches those with greatest need [6].

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ECONOMIC EVALUATION OF HIV PRE-EXPOSURE PROPHYLAXIS AMONG MEN-WHO-HAVE-SEX-WITH-MEN

A static decision analytical model was used to explore the economic implications of a first phase scale-up of a PrEP programme for MSM GUM clinic attendees at high HIV risk, beginning in 2016. The method is valid for a modest scale initial PrEP programme with limited indirect (herd) effect [9], and was chosen for the relatively limited assumptions required, its transparency and ease of interpretation for decision makers, and because of the increasing uncertainties when estimating costs and effects after 5 to 10 years. Moreover, the technique was suitable because the impact on population disease dynamics is likely to be limited in the early years of a PrEP policy given the small numbers protected relative to the total at risk [9].

METHODS

The perspective of a healthcare provider was taken. A 5,000 person-years PrEP coverage level was judged to be reasonable for this initial scale-up period, based on the range suggested by a multidisciplinary, multi-stakeholder group of clinicians, patients, commissioners (budget holders) and public health practitioners [5]. The 4,500–6,500 range was generated after considering the evidence around likely programme roll-out scenarios, the GUM clinic activity dataset (GUMCAD) estimated need, patient-level uptake as informed by community surveys about willingness to take PrEP, and considered potential organisational challenges of delivery across many GUM clinics as well as evidence of PrEP scale-up in other countries [10].

The lifetime HIV risk of 5,000 MSM who began an initial high HIV risk period of one year on PrEP was compared with the lifetime risk of the same group in the absence of PrEP (Figure 1). This required age distribution of MSM at high behavioural risk and estimates of HIV acquisition during the high-risk period of PrEP eligibility, as well as estimates of lifetime HIV acquisition, to account for the residual HIV risk after the high-risk period had passed. PrEP provision to a single high-risk year was modelled at the cohort-level. At the individual-level, should high risk continue beyond the first year, then that individual will form part of a new high-risk cohort in the second year. The ICER for PrEP remains the same for the second cohort as for the previous year’s high-risk cohort.

Data were extracted from GUMCAD [11], a comprehensive, pseudo-anonymised digital download of patient-level data on all sexually transmitted infection (STI) services and diagnoses provided in GUM clinics in England. Each pseudo-anonymised record contains a clinic identifier as well as a local patient number, so data from the same individual attending the same clinic can be linked longitudinally. Estimates of lifetime HIV risk were adjusted to the age-distribution of MSM GUM clinic attendees, using averages for years 2013–14 (see supplementary material [12]).

In the principal scenarios, MSM receiving PrEP were assumed to be prescribed daily tenofovir disoproxil and emtricitabine combined tablet, in accordance with the European Medicines Agency licensed prevention indication [13]. Event-based dosing (i.e. PrEP given before and after sexual exposure) for an average of four tablets used per 7-day period, was explored in sensitivity analyses [4].

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2

Individuals given PrEP will be managed via GUM clinics; for a one year programme, each individual will have five visits to the clinic, at month 0, 1, 3, 6, and 9. The first visit includes assessment of clinical need for PrEP, confirmation of HIV and STI status, and measurement of renal function. Subsequent visits are for monitoring of drug adherence, tolerability, and safety, together with quarterly checking of HIV and STI status [2]. The additional elements of GUM clinic care directly attributable to PrEP were micro-costed (see supplementary material [12]).

Estimating HIV incidence

GUMCAD data on HIV-negative clinic attending MSM for 2009 to 2013 were extracted. Diagnosis or not of any bacterial STI in the previous year was used to indicate recent condomless anal intercourse and to stratify the future risk of being diagnosed with HIV. Those with a bacterial STI in the previous year were labelled ‘high-risk’ and eligible for PrEP, and those without as having ‘medium-risk’ for HIV acquisition [14]. To estimate current HIV incidence in these strata, records were used of MSM with at least one additional documented HIV test between 43 to 365 days after the first HIV test documented in 2012, the most recent year with sufficient data (followed-up to end 2013) for analysis [14]. HIV incidence estimation methodology follows that used in Desai et al. [14].

MSM who did not attend a GUM clinic were assumed to be at ‘low-risk’ [14] (see also supplementary material [12]). To estimate HIV incidence in this stratum, total MSM numbers

Methods

The perspective of a healthcare provider was taken. A

5,000 person-years PrEP coverage level was judged to

be reasonable for this initial scale-up period, based

on the range suggested by a multidisciplinary,

multi-stakeholder group of clinicians, patients,

commission-ers (budget holdcommission-ers) and public health practitioncommission-ers

[5]. The 4,500–6,500 range was generated after

con-sidering the evidence around likely programme roll-out

scenarios, the GUM clinic activity dataset (GUMCAD)

estimated need, patient-level uptake as informed by

community surveys about willingness to take PrEP,

and considered potential organisational challenges of

delivery across many GUM clinics as well as evidence

of PrEP scale-up in other countries [10].

The lifetime HIV risk of 5,000 MSM who began an initial

high HIV risk period of one year on PrEP was compared

with the lifetime risk of the same group in the absence

of PrEP (Figure 1). This required age distribution of MSM

at high behavioural risk and estimates of HIV

acquisi-tion during the high-risk period of PrEP eligibility, as

well as estimates of lifetime HIV acquisition, to account

for the residual HIV risk after the high-risk period had

passed. PrEP provision to a single high-risk year was

modelled at the cohort-level. At the individual-level,

should high risk continue beyond the first year, then

that individual will form part of a new high-risk cohort

in the second year. The ICER for PrEP remains the same

for the second cohort as for the previous year’s

high-risk cohort.

Data were extracted from GUMCAD [11], a

comprehen-sive, pseudo-anonymised digital download of

patient-level data on all sexually transmitted infection (STI)

services and diagnoses provided in GUM clinics in

England. Each pseudo-anonymised record contains

a clinic identifier as well as a local patient number,

so data from the same individual attending the same

clinic can be linked longitudinally. Estimates of lifetime

HIV risk were adjusted to the age-distribution of MSM

GUM clinic attendees, using averages for years 2013–

14 (see supplementary material [12]).

In the principal scenarios, MSM receiving PrEP were

assumed to be prescribed daily tenofovir disoproxil and

emtricitabine combined tablet, in accordance with the

European Medicines Agency licensed prevention

indi-cation [13]. Event-based dosing (i.e. PrEP given before

and after sexual exposure) for an average of four

tab-lets used per 7-day period, was explored in sensitivity

analyses [4].

Figure 1

Decision analytical model structure comparing no-PrEP

with PrEP in 5,000 men who have sex with men at high

HIV riska, England, 2016

Subsequent lifetime HIV negative (4,152) Subsequent lifetime HIV positive (683) Subsequent lifetime HIV negative

(4,152) Year 1 HIV negative

(4,835) Year 1 HIV positive

(165)

No PrEP in Year 1

HIV-PrEP in Year 1

Year 1 HIV positive (86% effectiveness: 28) (64% effectiveness: 71)

Year 1 HIV negative

(86% effectiveness: 137 protected) (64% effectiveness: 94 protected)

Subsequent lifetime HIV positive (86% effectiveness: 19) (64% effectiveness: 13)

Subsequent lifetime HIV negative (86% effectiveness: 118) (64% effectiveness: 81)

Year 1 HIV negative (4,835)

Subsequent lifetime HIV positive (683)

(5,000 HIV negative MSM) (5,000 HIV negative MSM)

MSM: men who have sex with men; PrEP: pre-exposure prophylaxis.

Red and green colours are used to indicate the estimated numbers of HIV-positive or negative MSM respectively, after a defined period (i.e. after the first year of PrEP (year-1) or, for the control group, after year-1 without PrEP, and for the remaining lifetime in both groups).

a _{HIV incidence in Year-1 is 3.3 per 100 person-years and cumulative} lifetime incidence without PrEP is 16.96%.

Figure 2

Impact of year-1 PrEPa on HIV incidence over 10 years for

5,000 MSM at initial high HIV risk, England, 2016–2025

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0 20 40 60 80 100 120 140 160 180 1 2 3 4 5 6 7 8 9 10

New HIV Infections

Weighted HIV Incidence

(per 100 PYs)

Years No HIV-PrEP in Year-1

HIV-PrEP in Year-1, 86% effective + risk compensation HIV-PrEP in Year-1, 64% effective + risk compensation Weighted average annual HIV incidence

HIV risk: 3.3 per 100 PYs

HIV risk: 1.35 per 100 PYs

HIV risk: <1 per 100 PYs

PrEP: pre-exposure prophylaxis; PYs: person-years.

The bars on this chart represent the number of new HIV infections by year: (i) In the absence of PrEP (blue bars); (ii) If PrEP is given in year-1 and assuming 86% effectiveness + risk compensation (turquoise bars); (iii) and if PrEP is given in year-1 and assuming 64% effectiveness + risk compensation (green bars).

Up to age 75 years, there were 848 HIV infections without PrEP, and 730 with PrEP at 86% effectiveness and 767 with PrEP at 64% effectiveness. Slightly more later-HIV infections occur in those given PrEP during year-1 as the MSM protected by PrEP become susceptible on stopping PrEP, albeit at a much lower risk level.

a _{PrEP effectiveness at either 86% or 64%, both with risk} compensation adjustment (see text).

Figure 1. Decision analytical model structure comparing no-PrEP with PrEP in 5,000 men who have sex with men at high HIV riska, England, 2016. MSM: men who have sex with men; PrEP: pre-exposure

prophylaxis. Red and green colours are used to indicate the estimated numbers of HIV-positive or negative MSM respectively, after a defined period (i.e. after the first year of PrEP (year-1) or, for the control group, after year-1 without PrEP, and for the remaining lifetime in both groups). a _{HIV incidence in Year-1}

25

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ECONOMIC EVALUATION OF HIV PRE-EXPOSURE PROPHYLAXIS AMONG MEN-WHO-HAVE-SEX-WITH-MEN

were calculated by combining the male proportion reporting same-sex partnerships in a 2010–12 national survey with 2012 male population estimates [15,16]. Estimated MSM living with HIV (diagnosed and undiagnosed) and GUM attending HIV-negative MSM were subtracted to get the denominator of those at low-risk [1]. Estimated HIV infections that occur in high- and medium-risk MSM were subtracted from the back-calculation estimate of all 2012 HIV infections in MSM to give the numerator for those at low-risk.

MSM eligible for PrEP begin at high-risk and move to medium- or low-risk at a changing probability. Lifetime HIV incidence combined movement between risk strata with estimated stratum-specific HIV incidence. Follow-up of high-risk MSM clinic attendees informed the proportions that stayed high-risk with bacterial STI diagnoses each year, those that became medium-risk who attended a clinic annually without bacterial STI diagnosis, and those without clinic attendance who became low-risk. Allowance was made for any transition from low- or medium-risk back to medium- or high-risk. If in 2013, x% of MSM who began as high-risk in 2009 remained high-risk, y% had become medium-risk, and z% low-risk, and HIV incidence was Η, Μ, and Λ for high, medium, and low-risk respectively, then the weighted average HIV incidence in 2013 was (x%*Η) + (y%*Μ) + (z%*Λ). Similarly calculated weighted HIV incidence averages were used for years 2010, 2011 and 2012. By assuming the same rate of change in risk from 2009 through 2013 and the same HIV incidence by risk stratum, future HIV incidence in 2017 through 2020 was estimated for MSM who began as high-risk in 2016 (PrEP programme year-1). After year-5 in 2020, future annual HIV incidence was interpolated using a constant rate of reduction until it reached Λ, and subsequently kept at Λ until age 75 years, after which risk of HIV acquisition was assumed to be zero. This approach created a declining HIV incidence over time. A slightly higher number remained susceptible in the PrEP group due to their PrEP protection during the first year. Therefore, over the subsequent lifetime to age 75 years, the absolute number of HIV infections each year was slightly greater in the PrEP group compared with the non-PrEP group (Figure 2).

Economic evaluation

A national guide for technology appraisals was followed [7]. PrEP users were assumed not to require HIV post-exposure prophylaxis following sexual exposure (PEPSE). Lifetime HIV infection care cost (excluding ARV costs) were stratified by CD4+ status at diagnosis [7,17]. HIV surveillance data were used to estimate average time to diagnosis once infected, CD4+ count at diagnosis, and rate of CD4+ recovery upon ARV commencement [18] (see also supplementary material [12]). Prompt initiation of ARV treatment following diagnosis was assumed [19].

Drug treatment costs used average 2013–15 NHS England ARV cost [20]. Future costs and QALYs were discounted annually by 3.5% and adjusted to 2014/15 GBP values (EUR values presented in parentheses, using year end 31 December 2015 historical exchange rates of GBP 1 equals EUR 1.3605) [7,21]. Economic parameters are presented in Table 1.

Model outputs included number of new HIV infections and the ICER, as cost per QALY gained, of PrEP compared with no PrEP. Budget impact analyses were presented in present

26

2

2014/15 values and included value added tax (VAT: + 20%) on PrEP drug costs [7]. PrEP service investment time to break-even was calculated as the years to when the cumulative savings from HIV infections averted in year-1 began to exceed PrEP costs in year-1.

Risk compensation

Published evidence suggests increased frequency of condomless anal sex subsequent to PrEP use and increased STI diagnoses [2,22]. Risk compensation would also lead to an increase in HIV exposure. With PrEP scale-up, adherence may reduce and thereby increase HIV transmission. To explore risk compensation, an arbitrary increase of HIV incidence by 20% in those given PrEP was assumed in the principal scenarios. At 64% PrEP effectiveness, for example, annual HIV incidence is (100% – 64%) * Η = 36% * Η, where, Η = HIV incidence in high-risk MSM. If Η is increased by 20% due to risk compensation, then annual HIV incidence becomes (100 – 64%)*(100% + 20%)*Η = 43.2%*Η.

Methods

The perspective of a healthcare provider was taken. A 5,000 person-years PrEP coverage level was judged to be reasonable for this initial scale-up period, based on the range suggested by a multidisciplinary, multi-stakeholder group of clinicians, patients, commission-ers (budget holdcommission-ers) and public health practitioncommission-ers [5]. The 4,500–6,500 range was generated after con-sidering the evidence around likely programme roll-out scenarios, the GUM clinic activity dataset (GUMCAD) estimated need, patient-level uptake as informed by community surveys about willingness to take PrEP, and considered potential organisational challenges of delivery across many GUM clinics as well as evidence of PrEP scale-up in other countries [10].

The lifetime HIV risk of 5,000 MSM who began an initial high HIV risk period of one year on PrEP was compared with the lifetime risk of the same group in the absence of PrEP (Figure 1). This required age distribution of MSM at high behavioural risk and estimates of HIV acquisi-tion during the high-risk period of PrEP eligibility, as well as estimates of lifetime HIV acquisition, to account for the residual HIV risk after the high-risk period had passed. PrEP provision to a single high-risk year was modelled at the cohort-level. At the individual-level, should high risk continue beyond the first year, then that individual will form part of a new high-risk cohort in the second year. The ICER for PrEP remains the same for the second cohort as for the previous year’s high-risk cohort.

Data were extracted from GUMCAD [11], a comprehen-sive, pseudo-anonymised digital download of patient-level data on all sexually transmitted infection (STI) services and diagnoses provided in GUM clinics in England. Each pseudo-anonymised record contains a clinic identifier as well as a local patient number, so data from the same individual attending the same clinic can be linked longitudinally. Estimates of lifetime HIV risk were adjusted to the age-distribution of MSM GUM clinic attendees, using averages for years 2013– 14 (see supplementary material [12]).

In the principal scenarios, MSM receiving PrEP were assumed to be prescribed daily tenofovir disoproxil and emtricitabine combined tablet, in accordance with the European Medicines Agency licensed prevention indi-cation [13]. Event-based dosing (i.e. PrEP given before and after sexual exposure) for an average of four tab-lets used per 7-day period, was explored in sensitivity analyses [4].

Figure 1

Decision analytical model structure comparing no-PrEP with PrEP in 5,000 men who have sex with men at high HIV riska, England, 2016

Subsequent lifetime HIV negative (4,152) Subsequent lifetime HIV positive (683) Subsequent lifetime HIV negative

(4,152) Year 1 HIV negative

(4,835) Year 1 HIV positive

(165)

No PrEP in Year 1

HIV-PrEP in Year 1

Year 1 HIV positive (86% effectiveness: 28) (64% effectiveness: 71)

Year 1 HIV negative

(86% effectiveness: 137 protected) (64% effectiveness: 94 protected)

Subsequent lifetime HIV positive (86% effectiveness: 19) (64% effectiveness: 13)

Subsequent lifetime HIV negative (86% effectiveness: 118) (64% effectiveness: 81)

Year 1 HIV negative (4,835)

Subsequent lifetime HIV positive (683)

(5,000 HIV negative MSM) (5,000 HIV negative MSM)

MSM: men who have sex with men; PrEP: pre-exposure prophylaxis.

Red and green colours are used to indicate the estimated numbers of HIV-positive or negative MSM respectively, after a defined period (i.e. after the first year of PrEP (year-1) or, for the control group, after year-1 without PrEP, and for the remaining lifetime in both groups).

a _{HIV incidence in Year-1 is 3.3 per 100 person-years and cumulative} lifetime incidence without PrEP is 16.96%.

Figure 2

Impact of year-1 PrEPa on HIV incidence over 10 years for 5,000 MSM at initial high HIV risk, England, 2016–2025

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0 20 40 60 80 100 120 140 160 180 1 2 3 4 5 6 7 8 9 10

New HIV Infections

Weighted HIV Incidence

(per 100 PYs)

Years No HIV-PrEP in Year-1

HIV-PrEP in Year-1, 86% effective + risk compensation HIV-PrEP in Year-1, 64% effective + risk compensation Weighted average annual HIV incidence

HIV risk: 3.3 per 100 PYs

HIV risk: 1.35 per 100 PYs

HIV risk: <1 per 100 PYs

PrEP: pre-exposure prophylaxis; PYs: person-years.

The bars on this chart represent the number of new HIV infections by year: (i) In the absence of PrEP (blue bars); (ii) If PrEP is given in year-1 and assuming 86% effectiveness + risk compensation (turquoise bars); (iii) and if PrEP is given in year-1 and assuming 64% effectiveness + risk compensation (green bars).

Up to age 75 years, there were 848 HIV infections without PrEP, and 730 with PrEP at 86% effectiveness and 767 with PrEP at 64% effectiveness. Slightly more later-HIV infections occur in those given PrEP during year-1 as the MSM protected by PrEP become susceptible on stopping PrEP, albeit at a much lower risk level.

a _{PrEP effectiveness at either 86% or 64%, both with risk} compensation adjustment (see text).

Figure 2. Impact of year-1 PrEPa on HIV incidence over 10 years for 5,000 MSM at initial high HIV risk, England, 2016–2025. PrEP: pre-exposure prophylaxis; PYs: person-years. The bars on this chart

represent the number of new HIV infections by year: (i) In the absence of PrEP (blue bars); (ii) If PrEP is given in year-1 and assuming 86% effectiveness + risk compensation (turquoise bars); (iii) and if PrEP is given in year-1 and assuming 64% effectiveness + risk compensation (green bars). Up to age 75 years, there were 848 HIV infections without PrEP, and 730 with PrEP at 86% effectiveness and 767 with PrEP at 64% effectiveness. Slightly more later-HIV infections occur in those given PrEP during year-1 as the MSM protected by PrEP become susceptible on stopping PrEP, albeit at a much lower risk level.

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ECONOMIC EVALUATION OF HIV PRE-EXPOSURE PROPHYLAXIS AMONG MEN-WHO-HAVE-SEX-WITH-MEN

Ta bl e 1 . E co no mic p ar am et er e st im at es us ed in th e tw o p rin cip al s ce na rio s ( pr ov id in g P rE P o r n ot ), a nd v al ue o r r an ge e xp lo re d i n s en si ti vi ty a na ly se s, Eng la nd , 2 01 4/ 15 c os t v alu es Parameter Value

Sensitivity analyses range (min. to max. value of scenarios considered)

Explanator y notes and data source

Disco

unt rate (cost

) 3.5 % 1.5 % – 3.5% [7] Disco

unt rate (QAL

Ys) 3.5 % 1.5 % – 3.5% [7] Costs Annual cost of PrE P drug GBP 4, 331 (EUR 5,892) GBP 43 3 – GBP 4 ,331 (EUR 589 – EU R 5,89 2) Discoun t range: 20% to 90% [32] (last accesse d 5 August 2016); price exclude s VAT and w as directly a pplied to the cost-e ffectiveness analysis Annual cost of PrE P-related GU M tariffs GBP 17 6 (EUR 239) ND [2,3 3], see also suppl ementary mat erial [12 ] PEPSE drug cost a (aver ted in those taking PrE P) GBP 77 2 a (EUR 1,050) per PEPSE course NA [32] (BNF last a ccessed 5 A ugust 201 6); pri ce exclude s VAT and w as directly a pplied to the cost-e ffectiveness analysis PEPSE GUM clinic costs (avert ed in tho se taking PrEP) GBP 25 0 (EUR 340) per PEPSE course NA [33] (adapted to the curren t study) Annual cost of an undiagnosed HIV infecti on GBP 0 (EUR 0) GBP 0 – GBP 2,4 99 (EUR 0 – EUR 3,400) Assumpti on; GBP 2 ,499 b ased on HIV care costs fo r individ uals diagnose d at CD4 + > 200 cells per mm3 no t on ARV tr eatment b [17 ,21] Annual cost of ARV t reatment per HIV-p ositive ind ividual GBP 4, 741 (EUR 6,450) Price reductions fro m 2019: range 0% to 80 % [20] c Annual care cost of HIV + CD4 > 200 cells p er mm 3 GBP 4, 734 (EUR 6,441) ND [17, 21]

2

Ta bl e 1 . ( con tiue d) Parameter Value

Sensitivity analyses range (min. to max. value of scenarios considered)

Explanator y notes and data source

Annual care cost of HIV + CD4 < 200 cells p er mm 3 GBP 7, 479 (EUR 10,175 ) ND [17, 21] Time t o CD4+ re covery from < 200 cells per mm 3 3 mon ths NA Based on analysis of HIV data [18] QALY values Disuti lity betwe en HIV inf ection and diagnosis 0 0 – 0.11 Assumpti on [34] Disu tility associa ted wit h HIV infecti on – pe r annum 0.1 1 0.1 0 – 0.1 3 [34] Util ity values i n UK men aged over 75 years d 0.7 5 NA [35] AR V: a ntir etr ovir al; BNF : B ritish Na tio nal F or mul ar y; GU M: genit our inar y me

dicine; max: maximu

m; min: minimum; NA : not ap plicabl e; ND: not done; NHS: Na tiona l Health S er vic e; N ICE: Th e Na tiona l I nstitut e f or Health a nd C ar e Ex ce llenc e; PEPS E: post -e xposur e pr op hylaxis; P rEP : pr e-exp osur e pr op hy laxis; Q AL Y: qualit y-adjust ed l ife y ear ; V AT : v alue added ta x; UK : Uni ted K ingdo m. a This pr ic e r epr esen ts the highes t possible c ost of cur ren t PE PSE drug r ec omm ended for use b y N HS E ngland (t enof ovir dis opr oxil/em tr ici tabine/r alt eg ra

vir) based on BNF list pr

ic e, e xclud in g VA T f or the cost -eff ec tiv eness anal ysis in ac cor danc e with NI CE M ethods Guide . b Cost e xcludes spe cific HIV -r ela ted c osts such as CD4 + an d v

iral load measur

emen ts , and r esis ta nc e t esting (perso nal communica tion, V C ambiano , D ec ember 2 015). c Pr incip al sc enar io used NHS England r epor ted spend on AR V tr ea tme nt . I n se nsitivit y analy ses , although ac tu al timing of a vailabilit y of gener ic AR Vs f or tr ea tmen t is unk no wn, sensitivi ty ana ly ses e xp lor ed p ot en tial a vailabil ity fr om 201 9. This w as b as ed on the estima te d pa ten t e xpir ation of indiv idual c ompounds of the combina tion AR V tr ea tmen t t enof ovir dis opr oxil/em tr icitabine/e fa vir enz (pr op rietar y name: A tr ip la) b y 20 18 [ 36]. C ombina tion t en of ovir disopr oxil/e m tr icitabin e/efa vir en z is one of the Br iti sh HIV A ssocia tion p ref er red choic e of AR V tr ea tmen t to beg in with in ther ap y-naï ve p atien ts [37]. d W e assumed tha t an H IV -positiv e indivi dual has a lif e-ex pec tanc y of 75 y ears [38]. Giv en tha t the lif e-expec tanc y at bir th f or mal es in England (20 10 t o 201 2 O ffi ce for Na tional S ta tisti cs estima tes) w as 79 y ears , this mean t t ha t an HIV -posi tiv e i

ndividual who dies a

t age 75 years w ould ha ve lost f our y ears of q ualit y of lif e [16]. W e c

ombined this last f

our y ears with the utili ty v alues among UK me n ag ed ab ov e 7 5 y ears (0 .75 per year), which w as obt ained fr om the EQ -5 D utilit y valu es for UK male popula tion, to obtain the Q AL Y losses dur ing th ese final four ye ars of lif e lost consequen t to ear lier dea th s r ela ted t o HIV [35].

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ECONOMIC EVALUATION OF HIV PRE-EXPOSURE PROPHYLAXIS AMONG MEN-WHO-HAVE-SEX-WITH-MEN

Sensitivity analyses

Sensitivity analyses explored plausible ranges of key parameter values (Table 1). Univariate sensitivity analyses were based on cautious choices considered more plausible with substantial scale-up. The scenario with 64% PrEP effectiveness and risk compensation was the preferred benchmark and corresponding ICERs were plotted on a tornado diagram.

Multivariate sensitivity analyses were conducted to illustrate the margin of certainty around whether or not PrEP would remain cost-effective, at different PrEP effectiveness level (Figure 3). Due to the nature of the uncertainties, full probabilistic sensitivity analysis was not possible.

RESULTS

An estimated 466,000 HIV-negative MSM aged between 15 to 75 years-old live in England in 2012, 85,500 (23%) of whom attended GUM clinics during that year. A fifth of the 85,500 (17,400 MSM) had a documented bacterial STI diagnosis i.e. proxy for high risk. Over time, GUMCAD data have shown an increase in the number of HIV-negative MSM GUM attendees, as well as the subset diagnosed with bacterial STI. Thus, the 5,000 person-years PrEP covered 29% of the GUMCAD identified high-risk cohort (who may not represent all high-risk MSM as not all attended GUM clinics [23]), 6% of all HIV-negative MSM GUM attendees, and just 1% of the estimated HIV-negative MSM population in England.

The HIV incidence observed in the high-risk PrEP-eligible stratum was 3.3 per 100 person-years (95% CI: 2.8–4.9 per 100 person-person-years), and 1.5 per 100 person-person-years (95% CI: 1.3–1.8 per 100 person-years) in the medium-risk stratum. In the low-risk MSM stratum the indirectly estimated HIV incidence was 0.3 per 100 person-years (Table 2). The HIV incidence estimates showed that GUM attending MSM had higher HIV risk than non-GUM attending MSM.

Of the 11,742 MSM without diagnosed HIV and with a recent bacterial STI (proxy for high HIV risk), who attended clinic in 2009 (the first of a five year, 2009–2013, longitudinal analysis), only 26% were categorised as high-risk in 2010. This decrease in the proportion of the initial 2009 attendees categorised as high-risk in subsequent years continued through 2011, 2012 and 2013, to 10%, 7% and 5% (see supplementary material [12]). Consequently, there was a large reduction in the weighted average annual HIV incidence for year-2 to year-5 (Figure 2). Interpolating the declining risk behaviour in the cohort and subsequent HIV acquisition forward, the annual HIV incidence reached the lower risk tier of 0.3 per 100 person-years annually by year-9, after which it was kept constant until age 75 years.

Combining the weighted average annual HIV incidence for MSM and the age distribution of MSM clinic attendees in 2013 and 2014, the estimated lifetime HIV incidence to age 75 years in an MSM clinic attendee who began year-1 at high-risk, was 16.96%.

Applying a 20% HIV incidence increase to those given PrEP in year-1, as a risk compensation adjustment, the estimated cumulative HIV incidence to age 75 years was reduced from 16.96% (no PrEP) to 15.4% at 64% PrEP effectiveness, while at 86% effectiveness, it fell to 14.6%.

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www.eurosurveillance.org

effectiveness, England, 2014/15 cost values

44% 64% 86% 96%

10% 20% 30%

Colour coding

Cost saving GBP 0 < ICER < GBP 20,000

(EUR 0 < ICER < EUR 27,210) GBP 20,000 < ICER < GBP 30,000(EUR 27,210 < ICER < EUR 40,815) ICER > GBP 30,000(ICER > EUR 40,815)

1. Year-1 HIV incidence (no risk compensation)

2. Risk compensation in those given PrEP, as percentage increase in HIV incidence

(Year-1 HIV incidence: 3.3 per 100 person-years)

3. Percentage reduction in ARV treatment cost from 2019

(Year-1 HIV incidence: 3.3 per 100 person-years; risk compensation in those given PrEP of 20% HIV incidence increase)

4. Percentage reduction in PrEP BNF annual drug price

(Year-1 HIV incidence: 3.3 per 100 person-years; risk compensation in those given PrEP – 20% HIV incidence increase; 30% reduction in ARV treatment cost after 2019) 9.0 per 100 person-yearsc 5.2 per 100 person-yearsd 2.0 per 100 person-yearse 0% GBP 124,421 (EUR 169,275) GBP 49,762 (EUR 67,701) GBP 66,780 (EUR 90,854) GBP 89,608 (EUR 121,912) GBP 121,837 (EUR 165,759) 0% GBP 4,741 (EUR 6,450) 30% GBP 3,032 (EUR 4,125) GBP 89,608 (EUR 121,912) GBP 98,864 (EUR 134,504) 50% GBP 2,371 (EUR 3,226) 80% GBP 948 (EUR 1,290) 0% GBP 4,331 (EUR 5,892) 21% GBP 3,403f (EUR 4,630) 43% GBP 2,475g (EUR 3,367) 90% GBP 431h (EUR 586) GBP 33,656 (EUR 45,789) -GBP 38,072

(-EUR 51,797) (-EUR 63,066)-GBP 46,355 (-EUR 67,953)-GBP 49,947 (-EUR 69,278)-GBP 50,921

-GBP 4,934 (-EUR 6,713) (-EUR 29,481)-GBP 21,669 GBP 66,260 (EUR 90,147) (-EUR 20,372)-GBP 14,974 -GBP 26,208 (-EUR 35,656) GBP 13,893 (EUR 18,901) (-EUR 11,994)-GBP 8,816 GBP 98,864

(EUR 134,504) (EUR 44,517)GBP 32,721 (EUR 5,494)GBP 4,038 (-EUR 5,090)-GBP 3,741 GBP 114,289

(EUR 155,490) (EUR 65,503)GBP 48,146 (EUR 26,479)GBP 19,463 (EUR 15,896)GBP 11,684 GBP 105,034

(EUR 142,899) (EUR 52,911)GBP 38,891 (EUR 13,888)GBP 10,208 (EUR 3,305)GBP 2,429

GBP 32,721

(EUR 44,517) (EUR 5,494)GBP 4,038 (-EUR 5,090)-GBP 3,741 GBP 23,465

(EUR 31,924) (-EUR 7,099)-GBP 5,218 (-EUR 17,682)-GBP 12,997 GBP 29,582

(EUR 40,246) (-EUR 5,661)-GBP 4,161 (-EUR 17,372)-GBP 12,769

GBP 23,465

(EUR 31,924) (-EUR 7,099)-GBP 5,218 (-EUR 17,682)-GBP 12,997 GBP 18,078

(EUR 24,595) (-EUR 8,488)-GBP 6,239 (-EUR 17,989)-GBP 13,222 GBP 13,296

(EUR 18,089) (-EUR 9,832)-GBP 7,227 (-EUR 18,293)-GBP 13,446 GBP 64,630

(EUR 87,929) (EUR 42,148)GBP 30,980 (EUR 28,275)GBP 20,783

3.3 per 100 person-years

GBP 7,786 (EUR 10,593)

GBP 49,762

(EUR 67,701) (EUR 18,089)GBP 13,296 (EUR 9,832)-GBP 7,227 (EUR 18,293)-GBP 13,446

-GBP 15,572

(-EUR 21,186) (-EUR 39,069)-GBP 28,717 (-EUR 44,490)-GBP 32,701 -GBP 23,010

(-EUR 31,305) (-EUR 50,017)-GBP 36,764 (-EUR 60,548)-GBP 44,504 (-EUR 63,739)-GBP 46,850 PrEP effectivenessb

Parameter combinationsa

BNF: British National Formulary; GUM: genitourinary medicine; GUMCAD: GUM clinic activity dataset; MSM: men who have sex with men; STI: sexually transmitted infection; UK: United Kingdom. a _{First parameter combination (i.e. Year-1 HIV incidence of 3.3 per 100 person-years) assumed within second combination, first and second within third, etc.}

b _{44% was the efficacy level reported in the iPrEx trial; 86% was the UK PROUD trial observed clinical effectiveness level, while 64% and 96% were the lower- and upper-bound 90% confidence intervals reported in} this latter trial [2,3].

c _{Reported HIV incidence in the deferred part (no PrEP, n = 267 MSM) of the PROUD trial [2].}

d _{Estimated HIV incidence in HIV-negative MSM with documented rectal bacterial STI diagnosis in 2012, GUMCAD analysis.} e _{Estimated HIV incidence in all HIV-negative MSM GUM attendees in 2012, GUMCAD analysis.}

f _{21% reduction in PrEP drug price due to 50% event-based dosing i.e. prorated 5.5 tablets per 7-day. This assumed that if an MSM was prescribed event-based dosing, then only four tablets would be dispensed for} every 7-day i.e. 4/7 of the drug cost. Event-based dosing frequency based on the findings reported in the IPERGAY trial [4]. Service provision through GUM clinics remained the same, as frequency of monitoring remained the same.

g _{43% reduction in PrEP drug price due to 100% event-based dosing (four tablets per 7-day).}

h _{90% reduction in PrEP drug price due to fall in current tenofovir disoproxil/emtricitabine price following patent expiry of the PrEP drug used. This is an arbitrary assumption. The future price is dependent on market} competition. The exact timing of when this will happen, however, is uncertain. The patents for tenofovir disoproxil and emtricitabine expired in 2016 and July 2017, respectively. However, Truvada as a combination tablet containing both tenofovir disoproxil/emtricitabine has a supplementary protection certificate (SPC) providing market exclusivity protection until February 2020, although this SPC is being challenged [39].

Figure 3. Multivariate sensitivity of incremental cost-effectiveness ratio (ICER) for different levels of pre-exposure prophylaxis (PrEP) effectiveness, England, 2014/15 cost values. BNF: British National

Formulary; GUM: genitourinary medicine; GUMCAD: GUM clinic activity dataset; MSM: men who have

sex with men; STI: sexually transmitted infection; UK: United Kingdom. a _{First parameter combination}

(i.e. Year-1 HIV incidence of 3.3 per 100 person-years) assumed within second combination, first and

second within third, etc. b _{44% was the efficacy level reported in the iPrEx trial; 86% was the UK PROUD}

trial observed clinical effectiveness level, while 64% and 96% were the lower- and upper-bound 90%

confidence intervals reported in this latter trial [2,3]. c _{Reported HIV incidence in the deferred part}

(no PrEP, n=267 MSM) of the PROUD trial [2]. d _{Estimated HIV incidence in HIV-negative MSM with}

documented rectal bacterial STI diagnosis in 2012, GUMCAD analysis. e _{Estimated HIV incidence in all}

HIV-negative MSM GUM attendees in 2012, GUMCAD analysis. f _{21% reduction in PrEP drug price due to}

50% event-based dosing i.e. prorated 5.5 tablets per 7-day. This assumed that if an MSM was prescribed event-based dosing, then only four tablets would be dispensed for every 7-day i.e. 4/7 of the drug