PeEP – reasons for caution

I think I disagree with Jim (and Dom)

This is odd. I always agree with Jim, I’ve never yet disagreed with Dom

I may have found something.

It’s HIV PrEP.

This is effective, no doubt. That’s not the issue. It’s an issue of cost effectivness, affordability and ability to stick within a defined set of criteria.
Here are some thoughts

1)

Courts and legal issues

There’s a tussle going on in court about who is responsible for paying for HIV Pre Exposure Prophylaxis
NHSE said – Local govt, as they “do” HIV prevention

The NTional AIDS trust (NAT) have been to court on this, arguing that NHSE should fund it.

Many local authorities seem to be of the view that as this wasn’t part of the original transfer of resource AND this could have been anticipated at the time, that funding should be subject to all the usual criterion should be met and transfer of funding. Plus
The NAT was successful at the High Court in challenging NHS England’s decision that it did not have the legal powers to commission the HIV PrEP.

As always the legal argument is complex with many nuances. There are many points of policy, interpretations of the law and difficult principles. I won’t dwell on those.
The judgement can be accessed here. https://www.judiciary.gov.uk/court/high-court/

https://www.judiciary.gov.uk/judgments/national-aids-trust-v-nhs-england/

It is possible that NHSE will appeal this JR.

Watch that space with interest

2)

There was then a NHSE statement

You may be interested to read NHS England’s statement https://www.england.nhs.uk/2016/08/august-update-on-the-commissioning-and-provision-of-pre-exposure-prophylaxis-prep-for-hiv-prevention/ on the commissioning and provision of PREP,
The ramifications this decision is likely to have in particular for for treatments considered in the Annual Prioritisation process.

Personally, I’d be nervous about NHSE consulting on a very wide definition of “at risk” and then subsequent events in court pushing this back to local govt.

3)

There’s also a draft NHSE commissioning statement

https://www.england.nhs.uk/2016/08/prep-consultation/

Funded in “high risk” groups.
Defined as

“The groups of people considered to be at high risk and covered by this policy are:

High risk Men who have sex with Men (MSM), trans women and trans men who have had anal sex without a condom in the last 3 months and likely to again in the next 3 month
Partners of people living with HIV where they are not known to be on successful HIV treatment. When people with HIV are on effective treatment they have an ‘undetectable’ level of HIV in their body which means they are very unlikely to transmit HIV to others and PrEP adds no benefit. If they do not have an undetectable viral load (i.e. they are not on treatment or have stopped treatment) then PrEP is beneficial.
Heterosexuals assessed to be at similar high risk to MSM

Deciding if someone needs PrEP is based on an assessment by sexual health staff. If PrEP is considered suitable then a HIV test will be done to confirm that person is still HIV-negative. Prescriptions will be for no more than 3 months and people using PrEP will be asked to attend for regular sexual health check-ups (every 3 months) and kidney checks (urine test and occasional blood tests). PrEP does not prevent transmission of other infections and clinics will provide advice about risk reduction including the use of condoms.”

Now…… Call me an old cynic, but ……. You could drive a bus through the policy statement and define that in any number of ways but still be within the policy.
Those with more expertise and closer to the topic will tell me whether the above is consistent with the PROUD study def of high risk.

It’s been a while since I read the detail so Im happy to be corrected there)

5)

Economic appraisal

The cost effectiveness studies are noted in the evidence review paper.

P43 onwards

https://www.engage.england.nhs.uk/consultation/specialised-services/user_uploads/f03x06-evidnc-rev.pdf
Here are the key bits to spare you
a)

Anderson 2009

ICER: Continuous PrEP would cost $47,745/QALY; Intermittent PrEP, taken 50% of time, would cost $6,816/QALY if 90% effective and remain cost-effective if > 46% effective

Conference abstract
b)

Cambiano et al.(2015)

ICER: assuming the cost of antiretroviral drugs [used for PrEP and ART] do not decreases, the cost per QALY gained [compared to the scenario in which PrEP is not introduced] is respectively: £9,500 [1a], £57,100[1b], £39,300 [2], £9,300 [3], cost-saving [4].
c)

Chen 2014

ICER:
[1] base case $160k/QALY (95% uncertainty range: cost saving to $740k);
[2] behavioural disinhibition $320k/QALY ($45k to $1million);
[3] higher adherence $3k/QALY (cost saving to $200k); [4] high baseline HIV prevalence $27k (cost saving to $160k);
[5] high HIV prevalence and high adherence: cost saving (range cost saving to $10k/QALY);
[6] monogamous serodiscordant relationships with partner ART use $280k ($14k to $670k);
[7] 100% condom use $840k (range $230k to $2.5 million)
Noted as a high quality study
Conclusion: cost-effectiveness of PrEP highly dependent on condom use, HIV prevalence, PrEP adherence and degree of behavioural disinhibition.
Comment: This study focuses on a group with a 19% HIV prevalence, substantially higher than among the all MSM in the UK. HIV incidence was not reported. In addition, the cascade of care for people living with HIV in the US is different from the UK. Given the PROUD results, the closest scenario, in terms of efficacy, is the one with 92% efficacy

d)

Desai 2008

ICER:

* base case (50% adherence, 50% efficacy)
ICER $31,972/QALY, daily threshold price above which program ICER>$50k/QALY is $39;

* cost-saving at 70% efficacy, 95% adherence, and the threshold price was $92;

* if efficacy was 50%, adherence 33%, ICER was $81,699, threshold PrEP price was $23;

* ICER is higher if the cost of HIV care is lower
and lower if HIV care cost is higher;

* lower adherence increases ICER;

* across all assumptions and 90% CI for cases
prevented (as predicted by the epidemiological model), PrEP was cost- effective 75% of the time at a threshold of $50k/QALY and 87.5% of the time at threshold of $100k/QALY

Conclusion: authors found PrEP coverage important to the results, that when 2.5% of high-risk MSM were enrolled, PrEP did not prevent enough HIV cases to justify the intervention but when coverage increase to 25% of high- risk MSM, this led to 4-23% reductions in HIV infections (dependent on assumptions about efficacy, mechanism of protection and coverage); assumptions about lifetime HIV treatment costs generally did not affect whether the ICERs were within threshold; if there was a 4.1% increase in sexual partners among those on PrEP and not on PrEP in the base case scenario, it is sufficient to fully offset the no. of infections prevented

Comment: substantial herd protection projected by the model. Maximum effectiveness assumed was 70%.

e)

Drabo 2015

Conference abstract
ICERs relative to status quo: test-and-treat: $21,000 / QALY gained; PrEP: $26,000 / QALY gained;
Testing: $27,500 / QALY gained

f)

Jussola 2012

ICER:
[1] PrEP to 20% MSM, ICER $172k/QALY compared to no PrEP;
[2] giving PrEP to 50% of MSM, ICER: $188k/QALY compared to no PrEP; $216.5k/QALY for 100% MSM coverage compared to no PrEP and $254k/QALY compared to 50% coverage;
[3] PrEP in high-risk MSM only: $52.4k/QALY compared to no PrEP; if only 20% high-risk MSM then ICER $40k/QALY, if 50% high-risk MSM then $44.6k/QALY, both compared to no PrEP

Conclusion: PrEP is costly but if targeted use in high-risk MSM, will be more economically efficient (ICER 20% all MSM $172k/QALY compared to all high- risk MSM (estimated 20% of all MSM) ICER$50k/QALY)(diminishing returns); although PrEP provides good value, it has large budgetary impact, thus affordability is questionable..

I got a bit bored then

Maybe I missed the critical study, and apols if I did. This is w blog not s systematic review.

Summary p67 onwards

Skirts over the fact that it’s hard to make a care this is a cost effective technology?

g)

There are others that I didn’t clock in the NHSE economic review
Ong
Ouellet – The PrEP strategy was cost-saving in all scenarios for undiscounted and 3% discounting rates. At 5% discounting rates, the strategy is largely cost-effective: according to least and most expensive scenarios, incremental cost-effectiveness ratios ranged from $60,311 to $47,407 per quality-adjusted life-year.

http://mobile.aidsmap.com/Provision-of-PrEP-in-the-UK-will-be-cost-effective-for-gay-men-at-high-risk-of-HIV-model-finds/page/2972926

Cost eff of prep in uk

ICER is £9466
Model assumes that PrEP will not be as effective as it was in PROUD study

Decent blog on the Kaiser study here

h)

Hot off the press in late 2017 cambiano et al

NIHR study

oddly paywalled in the journal, nut I’m sure it will be there in full on NIHR website

Methods

In this modelling study and economic evaluation, we calibrated a dynamic, individual-based stochastic model, the HIV Synthesis Model, to multiple data sources (surveillance data provided by Public Health England and data from a large, nationally representative survey, Natsal-3) on HIV among MSM in the UK. We did a probabilistic sensitivity analysis (sampling 22 key parameters) along with a range of univariate sensitivity analyses to evaluate the introduction of a PrEP programme with sexual event-based use of emtricitabine and tenofovir for MSM who had condomless anal sexual intercourse in the previous 3 months, a negative HIV test at baseline, and a negative HIV test in the preceding year. The main model outcomes were the number of HIV infections, quality-adjusted life-years (QALYs), and costs.

Findings

Introduction of such a PrEP programme, with around 4000 MSM initiated on PrEP by the end of the first year and almost 40 000 by the end of the 15th year, would result in a total cost saving (£1·0 billion discounted), avert 25% of HIV infections (42% of which would be directly because of PrEP), and lead to a gain of 40 000 discounted QALYs over an 80-year time horizon. This result was particularly sensitive to the time horizon chosen, the cost of antiretroviral drugs (for treatment and PrEP), and the underlying trend in condomless sex.

Interpretation

This analysis suggests that the introduction of a PrEP programme for MSM in the UK is cost-effective and possibly cost-saving in the long term. A reduction in the cost of antiretroviral drugs (including the drugs used for PrEP) would substantially shorten the time for cost savings to be realised.

The accompanying editorial mages clear the reduction in HIV diagnosis seen in some clinics is due to a combination of increased testing, earlier diagnosis, and immediate initiation onto HIV treatment at diagnosis as well as increased availability of pre-exposure prophylaxis (PrEP) for HIV.

We don’t, I think, know the right mix of ingredients

6)

Other issues that need to be built into future clinical, economic and epi analysis

a)

Obviously the cost effectiveness study has got to factor in the downstream STI costs of folk not using condoms etc..

Whats included in the NHSE evidence review reinforces this.

b)

Drug resistance is a concern – I’m not at all clear how this would be factored in
http://jid.oxfordjournals.org/content/early/2015/01/13/infdis.jiu678.full

http://betablog.org/prep-and-drug-resistance-cause-for-concern/

http://www.huffingtonpost.com/jd-davids/hiv-infection-despite-prep_b_9332986.html

https://www.poz.com/article/prep-fails-gay-man-adhering-daily-truvada-contracts-drugresistant-hiv

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079639/ – report of iPREX

Most of the evidence base I’ve seen reported comes from the Partners PrEP study, which was conducted in Africa, on heterosexual couples, and the HIV negative partner in most cases was the woman (generally, women are more sensible than men and so adhere to meds better). This is a very different population to high risk MSM, and the adherence to treatment was amazing (~97% by self-report and pill count)
By comparison the adherence in iPREX (the only big MSM study I’ve found) was lower – 91% by pill count or below 50% by serum testing (but still pretty high – suspect this will be hard to replicate in a “real-world” rather than self-selecting population – also shows that there are probably a lot of people who will falsely report taking their prophylaxis).

Also there is a theoretical risk in causing resistance to the Truvada drugs because you start someone on prep who is already HIV positive (especially if you only screen them using an antibody test and they are in the window period, where infection is present but the antibody response had not yet been generated).

c)

Other big concern – side effects – in the partners study, higher but not statistically significant rate of renal dysfunction was noted. Same story in iPREX. Also fair amount of nausea in the first four weeks.

Still hard to say if the PREP actually causes resistance (ie giving people prep causes HIV strains to be more likely to become resistant) or just selects for it (ie you only catch it if you are unlucky enough to share bodily fluids with someone who already has a resistant strain)…

c)

Comparator

Still doesn’t negate my initial argument that in condoms another effective and cheaper prevention option is available which also protects against the other resistant STIs (resistant gonorrhoea and syphilis) which are increasing in MSM – arguably it would be irresponsible to provide an option that would have the effect of encouraging people to reduce condom use.
The ‘no PrEP’ comparator would have included use of condoms ? Presumably the incremental effectiveness of PrEP would be less ?

Concluding
So………it’s hard to draw a conclusion its cost effective never mind cost saving…..and to my mind it doesn’t really pass muster against threshold.

I’m also struggling to see how this squares with a commissioning policy principle of commissioning cost effective care…..
Let me be clear, this isn’t an issue of the effectiveness of the intervention. It’s an issue of cost effectiveness, affordability, opportunity cost, and our ability to hold a position set in a commissioning policy.
I cant see a moral case to fund till someone has published a cost eff analysis. Or is HIV a bit like cancer and “special”…….

I hope NICE might publish something definitive on cost effectiveness analysis.
Till then, my own view = it seems pretty much impossible to say that 1) we fund stuff that’s cost effective or cost saving and 2) fund this particular intervention.
We could suspend the requirement for cost effectivness and say this is an effective treatment in preventing HIV thus should be available. That would be one outcome, but would necessitate a judgement that this group are more “special” or “valuable” than other groups we deny finding funding for treatment for. Above my pay grade.
Sorry to be blunt.

Postscript – Other issues to consider

“This is cost saving”A note on ‘invest to save’ proposals

Of pertinence to PrEP if turns out to be ££ saving

https://gregfellpublichealth.wordpress.com/2016/02/28/this-is-cost-savinga-note-on-invest-to-save-proposals/
“But its an effective treatment, you MUST pay for it”. Five considerations

Again of relevance to PrEP

https://gregfellpublichealth.wordpress.com/2016/02/28/but-its-an-effective-treatment-you-must-pay-for-it-five-considerations/

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