Economic Protocol for Mental Health Intervention

Distinction

A UK based randomised control trial (RCT) of a specialised

online cognitive behavioural therapy for depression in a HIV

positive population (HIVCBT): An economic evaluation

Introduction

HIV is associated with a heightened risk of mental health difficulties(1, 2) and depression

has been acknowledged as the most prominent mental health conditions within this

population(3-7). Prevalence of depression within HIV+ populations fall between 0-80%(6)

and has been linked to adverse outcomes including medication non-adherence(8) and

advanced disease development (9). Due to advances in antiretroviral therapy, HIV+

individuals now have a longer life expectancy(10), therefore alleviating depression may

further improve long-term health outcomes within HIV+ populations.

Depression within HIV+ populations has significant cost implications including, increased use

of provision and medical costs(11). In the UK, 12-18% of expenditure in chronic conditions is

allied to mental health problems, currently £8-13 billion(12). Hence, reduced depression

symptomology within chronic conditions may improve cost outcomes.

Cognitive-behavior focused interventions have been found to be effective within HIV+

populations(6). Extensive research demonstrates cognitive behavioural therapies (CBT) to

be successful(13) and cost-effective(14). Computerised CBT, using fewer resources than

traditional (e.g. practitioner time)(15), has emerged due to technological advances, and has

been found to be again both successful (15) and cost-effective within some settings(16, 17).

Computerised CBT may be an alternative or complimentary treatment for depression within

HIV+ populations and thus aid in reducing the cost burden associated with such co-

morbidities. There is a dearth of literature exploring computerised CBT within HIV+

populations, particularly with regards to economic outcomes. A recent protocol outlines a

study investigating the impact of computerised CBT in HIV populations however, no

economic outcomes are to be investigated(18). This protocol will explore the economic

outcomes of a similar type of intervention, adapted for use within a UK HIV population.

This study will be developed within the UK, to inform decision making regarding resource

allocation and treatment options for depression within HIV+ populations and will aim to

inform both the National Institute for Health and Care Excellence (NICE)(19) as well as

patients and healthcare providers. A health and social care (HSC inclusive of National Health

Service) perspective will be adopted to adhere to guidance from NICE (19), informing a cost-

utility analysis (CUA). Additionally, cost-effectiveness analysis (CEA) will be undertaken from

a patient perspective to inform treatment decision making and clinical care for patients and

healthcare providers(20).

An economic evaluation alongside a RCT will be used to assess the costs and outcomes(20)

associated with HIVCBT together with treatment as usual, comparative to treatment as

usual alone (TAU) within a HIV+ population over 12-months. The objectives will be to

compare the effectiveness and cost-effectiveness of the HIVCBT intervention and the TAU

control group, to estimate and assess differences in cost between the HIVCBT and TAU

groups from a HSC and patient perspective, to estimate and explore differences in health

related outcomes between the HIVCBT and TAU groups from a HSC (quality-adjusted life

years; QALY)(21) and patient perspective (Patient health questionnaire measure of

depression; PHQ-9)(22), and to estimate cost-effectiveness at different willingness-to-pay

(WTP) values (20).

Methods

Trial design

An economic evaluation will be conducted alongside a multi-site RCT (individual level) aimed

at exploring the effectiveness and cost-effectiveness of HIVCBT for HIV+ individuals

identified as having depression. An RCT trial design was chosen to maximise the available

information for decision makers(23).

Participants will be recruited from 16 primary care outlets within four UK geographical

counties and will be randomised equally (stratified by geographical location and sex; as

there is a higher proportion HIV+ males comparative to females within the UK)(2) to receive

HIVCBT or TAU. Nine weekly self-led internet-based CBT sessions with a HIV care

component within each session and one face-to-face psychologist-led motivational

interview session at week 4/5, will be included within the HIVCBT intervention. Data will be

collected at baseline, 6 and 12 months. A single-blind study will be conducted as

researchers will be masked from participants’ treatment allocation.

Eligible participants must give consent, be over age 18, be diagnosed as HIV+, be newly

diagnosed as having major depressive disorder (identified by PHQ-9 score ≥10)(22), have

access to a device with internet connection and be fluent in the English language. If

participants were currently suicidal or had been suicidal 6 months prior to the study, or did

not have capacity to consent they were excluded from the trial.

Sample size

A sample size of approximately 100 participants in each trial arm will be used. This figure is

based on exploratory studies of computerised CBT comparative to TAU(16, 18, 24, 25). A

normal distribution was assumed. An estimation was used as a pragmatic RCT, with a

sample size based on economic outcomes (i.e. a net monetary benefit above zero)(26), was

not deemed practical as larger sample sizes are required to detect significant economic

outcomes(27), raising issues regarding feasibility, ethics and funding(20). Furthermore, a

sample size estimate based on the primary clinical outcome (a PHQ-9 score reduced by five

points(22); the estimated minimal clinical relevant difference(28)) was too small and would

not allow for adequate extrapolation of results(29, 30).

Outcomes

As a HSC perspective will be adopted, the QALY, the NICE preferred outcome(19), will be

used as a measure of intervention effectiveness within the CUA. The QALY is a standardized

comparable outcome incorporating quantity and quality of life over time that can be used

across differing settings and disease areas(21).

Based on NICE guidance, the EQ-5D-5L, a standardised health related quality of life

measure(31), will be used to assess utility to inform calculations of the QALY(19). The EQ-

5D-5L measures five health domains (self-care, mobility, usual activities, pain and

discomfort, depression and anxiety) across 5 levels and has been found to be a valid and

sensitive measure of depression(31), and has been shown to be valid within HIV+

populations(32), thus suitable for the current trial. The EQ-5D-5L provides health state

values based on valuations from the general populations (UK)(33), which can be used to

identify deviation in utility value and thus calculate the QALY, which measures the

favorability of differing states of health on a scale of 1; best health state to 0; representing

death(34, 35). Utility value difference at baseline, 6 and 12 months will be used to calculate

the QALY(36).

Depression score (PHQ-9)(22),will be used as the primary clinical outcome for the CEA to

inform a patient perspective. The PHQ-9, scored from 0-27, is a reliable measure sensitive to

varying levels of depression(22).

Resources

Treatment and use of provision for HIV+ individuals is complex and multifaceted(37). As

such, focus groups with both service users and heath care experts, the groups exposed most

to resource use, will be undertaken to identify relevant resources from both a HSC

perspective and a patient perspective. Previous literature will supplement this process(20).

Relevant HSC resources are likely are to include: general practitioner, psychologist, nurses

(either practice based or psychiatric), HIV specialist doctor, social workers, training,

specialised clinic (HIV), accident and emergency, overheads, community care. Relevant

resources from a patient perspective are likely to include: patient out-of-pocket expenditure

(i.e. travel costs) and private treatment (mental health).

Intervention focused resources will be identified using focus groups, inclusive of software

developers, clinical experts and patient groups and will be supplemented by the literature.

Intervention relevant resources are likely to include: development costs (programming and

project management), implementation costs; psychologist, overheads, software support,

maintenance and internet usage(38).

Support and service use information for each participant will be measured using the Client

Service Receipt Inventory (CSRI)(39); a self-report questionnaire completed by participants.

The use of the CSRI is appropriate as the questionnaire is a valid measure of care

component and service usage, thus relevant to the HSC perspective being adopted. The CSRI

will be adapted to include all identified resources from both a HSC and a patient

perspective, and will measure both duration and frequency of resource use (including

intervention use)(39). Due to the complex disease trajectory of HIV, HIV+ groups often use

multiple care outlets and therefore it would not be feasible to conduct record searches for

each healthcare outlet used. The CSRI is therefore the most appropriate measure.(40) The

complexity of HIV may result in difficulty attributing service use, as such, detailed

information will be collected and expert opinion will be used to assess service attribution.

Total costs relating to each perspective (HSC/patient) will be obtained from multiplying

costs (per unit) by the duration and incidence of each service and support use. Publically

available records; Department of Health’s NHS reference costs 2015- 2016(41) and Unit Cost

of Health and Social Care 2016 (PSSRU)(42), will be used to establish HSC services and

alternative service costs inclusive of professionals’ salaries, respectively. Median costs will

be used to obtain average valuations of appropriate overheads and salaries. Patient

expenditure and private services (from a patient perspective) will be based on market

value(20).

Development and execution costs associated with the internet-based intervention will be

obtained from the software developer and costs of development will be apportioned to the

projected software lifespan(38). Internet usage costs will be based on market value. These

costs will be supplemented by incidence and duration data to be obtained from the CSRI to

establish contact time with a psychologist within the intervention. The PSSRU will be used to

obtain psychologists training requirements and per hour contact costs(42) and the

Department of Health’s NHS reference costs 2015- 2016 will be used to obtain costs of

overheads(41).

Economic evaluation

Both CEA and CUA are to be used to assess cost-effectiveness as different outcome

measures of effectiveness based on differing perspectives are to be used. Cost-effectiveness

will be explored by means of comparing additional health improvements (QALY gain in the

CUA and five-point improvement in PHQ-9 score(22, 28) in the CEA) to additional costs.(20)

CEA involves assessing and comparing the costs and outcomes of differing treatment

trajectories (20). A CEA will be undertaken, to assess costs and outcomes in the HIVCBT

group comparative to the TAU group. CEA uses a disease specific (natural) outcome(20)

here, PHQ-9 score(22), and is deemed appropriate in this instance as the CEA is to be

undertaken to inform patient choice regarding treatment of depression within a HIV+

population and thus a measure of clinical effectiveness (i.e. the primary clinical outcome) is

required.

CEA does not however explore opportunity costs in relation to alternative treatments and

therefore to inform decision making bodies’ (i.e. NICE) resource allocation a generic

measure is required(19, 20). Hence, a CUA, based on NICE guidance, will be undertaken

from a HSC perspective(19). CUA aims to determine cost in relation to utilities in trajectories

of treatment action and uses a general health improvement measure (QALY) that can be

used comparatively across different disease areas and settings(21). Here, CUA will be used

to assess the costs associated with gaining a single QALY in the HIVCBT group comparative

to TAU group. This will allow for opportunity costs based on the notion of implementing

treatments to be assessed at differing WTP values(20).

Statistical/sensitivity analysis

All analysis will be completed on an intention to treat basis(43). Differences in cost between

HIVCBT and TAU alone and outcome (QALY and PHQ-9 score) between the trial arms, will be

estimated using multiple regression analysis(44). Potential confounders will be adjusted for

including, baseline characteristics, recruitment site (i.e. to account for clustering effects e.g.

therapist) baseline costs and repeated measures.

Non-parametric bootstrapping (5000 times) will be used to address uncertainty by

establishing 95% confidence intervals for the net monetary benefit approach to establish

cost effectiveness acceptability curves (below)(26, 45, 46). To further address uncertainty,

multiple one-way sensitivity analyses will be undertaken to increasing the robustness of

results. These will explore variations in parameters including differing salaries and training

costs for the psychologist in the intervention, missing data (costs and outcomes) will also be

imputed (using a multiple imputation method) (47) and compared to complete data to

explore the impact of alternative assumptions on cost-effectiveness.

Results

Incremental cost effectiveness ratios (ICER) for the CEA are to be calculated as difference in

mean cost (patient perspective) between the HIVCBT and TAU trial arms divided by the

difference in mean depression score (PHQ-9)(22) between the trial arms to establish cost

per five-point reduction in depression score. The ICER for the CUA are to be calculated as

the difference in mean cost (HSC perspective) between the HIVCBT and TAU trial arms

divided by the difference in mean QALY(21) between the trial arms to establish cost per

additional QALY(20).

CEA

𝐼𝐶𝐸𝑅 = 𝐻𝐼𝑉𝐶𝐵𝑇 𝑐𝑜𝑠𝑡𝑠 (𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑝𝑒𝑟𝑠𝑝𝑒𝑐𝑡𝑖𝑣𝑒) − 𝑇𝐴𝑈 𝑐𝑜𝑠𝑡𝑠 (𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑝𝑒𝑟𝑠𝑝𝑒𝑐𝑡𝑖𝑣𝑒)

𝐻𝐼𝑉𝐶𝐵𝑇 𝑚𝑒𝑎𝑛 𝑃𝐻𝑄9 𝑠𝑐𝑜𝑟𝑒 − 𝑇𝐴𝑈 𝑚𝑒𝑎𝑛 𝑃𝐻𝑄9 𝑠𝑐𝑜𝑟𝑒

CUA

𝐼𝐶𝐸𝑅 = 𝐻𝐼𝑉𝐶𝐵𝑇 𝑐𝑜𝑠𝑡𝑠 (𝐻𝑆𝐶 𝑝𝑒𝑟𝑠𝑝𝑒𝑐𝑡𝑖𝑣𝑒) − 𝑇𝐴𝑈 𝑐𝑜𝑠𝑡𝑠 (𝐻𝑆𝐶 𝑝𝑒𝑟𝑠𝑝𝑒𝑐𝑡𝑖𝑣𝑒)

𝐻𝐼𝑉𝐶𝐵𝑇 𝑚𝑒𝑎𝑛 𝑄𝐴𝐿𝑌 − 𝑇𝐴𝑈 𝑚𝑒𝑎𝑛 𝑄𝐴𝐿𝑌

Cost-effectiveness planes will be formed to establish any dominance as well as explore

uncertainty and variation in estimates of cost-effectiveness using 95% confidence intervals

established from non-parametric bootstrapping(46), (also used to inform the net monetary

benefit approach [NMB]).

The NMB will be used in both the CUA and CEA to combine both costs and outcomes within

a single scale and establish cost-effectiveness. The NMB multiplies willingness-to-pay () by

the difference in outcomes (i.e. mean PHQ-9 score(22) in the CEA and mean QALY in the

CUA) between each trial arm (HIVCBT vs. TAU) and from this total subtracts the difference in

costs between each trial arm (HIVCBT vs. TAU). If the resulting value is greater than zero,

then the intervention will be considered cost-effective(26).

Based on this data, cost-effectiveness acceptability curves (CEAC) can be produced to

provide an overview of value(26) and calculate the likelihood that HIVCBT is cost-effective at

differing WTP values (48). Cost-effective points plotted in the CEAC are derived from the

cost-effectiveness plane (excluding the NE quadrant)(49). WTP values between £0-50,000

will be investigated so to incorporate the ceiling ratio of £20000-30000 recommended by

NICE (19) for a single QALY gain.

Results in context

An economic evaluation of specialised computerised CBT within a HIV+ population has not

been conducted previously. This trial aims to inform patient groups, providers of healthcare

and policy makers. Some considerations should be noted. Based online, HIVCBT has the

potential for extensive implementation and may be a useful alternative or collaborative care

approach for HIV+ individuals using minimal resources(50). However, adaptations may be

required to implement the intervention across cultures.

Ethically it is not deemed as appropriate to deny HIVCBT to the TAU group. Hence, this

group will be offered HIVCBT alongside their TAU at both 6 and 12-month follow-up. Data

will be excluded from the analysis accordingly(51).

While cost-effectiveness will be explored, affordability will not directly be assessed. Budgets

constrain policy makers, and while cost-effective, interventions may be unaffordable.

Further study could incorporate ‘affordability curves’ to provide data on both cost-

effectiveness and affordability to better inform policy makers and other potential

stakeholders(52).

A pragmatic RCT was not undertaken and as such this study will only present estimates of

cost-effectiveness(23, 27). A larger sample size is required to establish confidence in cost-

effectiveness estimates(27). Further research, (e.g. conducting a decision analytic model)

would also allow for the generalisability of the CUA/CEA across differing settings(53).

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