1. Matt Hickman, Natasha Martin, Peter Vickerman, Hannah Fraser, Zoe Ward
NOT FOR QUOTATION
Model and empirical evidence on the effectiveness of interventions to prevent HCV among people who inject drugs
Thanks for invitation. Welcome respite from post-Brexit Britain.
And I am also very aware that we in Europe are behind the curve in relation to HCV treatment access – with Australia leading the way.
So consider my talk as a little introduction and some justification for your current policy.
Borrowed slides from many people…
Matt Hickman, Natasha Martin, Peter Vickerman, Hannah Fraser, Zoe Ward

2. Acknowledgements & Disclosure/CoI
NIHR Health Protection Research Unit in Evaluation of Interventions
Health Protection Scotland: HCV Action Plan
European Commission Drug Prevention and Information Programme (DIPP) “Treatment as Prevention in Europe: Model Projections [JUST/2013/DPIP/AG/4812]
NIHR (HS&DR) (12/3070/13) - Assessing the impact and cost-effectiveness of NSP
MH received honoraria from Abbvie, MSD, Janssen, Gilead.
The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Collaborators:- Sharon Hutchinson, Vivian Hope, Graham Foster, John Dillon, Sema Mandell, Mary Ramsay, Helen Harris, Ross Harris, Fiona Gordon, Javier Vilar, Matthew Cramp, Stephen Ryder, David Goldberg, Daniela De Angelis, Will Irving, Noel Craine, Marion Lyons, Norah Palmateer, Esther Aspinall, Lucy Platt, Amy Master, Maria Prins, Bernd Schulte, Henrikki Bummer, Viktor Mravcik, Martin Kåberg, Anne Ovrehus, Geert Robaeys, Patrizia Varreiri, Marie Jauffret, Olav Dalgard, Majca Matičič, Hannah Fraser, Zoe Ward, Jason Grebely, Greg Dore, Margaret Hellard, Bristol Drug Project. Silvia Minozzi, Holly Hagan, Clare French, Louisa Degenhardt, Lisa Maher
Further acknowledgements of funding and toehr collaborators

3. http://www. emcdda. europa
HCV is evolving field – so quick ad for recent report from EMCDDA before entirely out of date…

4. EFFECTIVENESS OF NEEDLE/SYRINGE PROGRAMMES AND OPIATE SUBSTITUTION THERAPY IN PREVENTING HCV TRANSMISSION AMONG PEOPLE WHO INJECT DRUGS

5. Impact of current OST exposure (adjusted estimates)
12 studies:
6361 participants
1030 HCV cases
50% reduction in risk of HCV
Little heterogeneity
GRADE: Low Evidence.
Next few slides are our results.
Here you see forest plot for opioid substitution treatment – and we show studies with adjusted estimates only in this slide. This includes twelve observational studies – including over 6300 participants and 1000 HCV incident events. Consistent evidence across geographical areas (Australia, North America, and Europe) – with little heterogeneity that OST reduces HCV transmission by 50%.
Because no trials (and there wont be any as would be unethical now) we have to grade the evidence as low quality – but strong good low quality evidence…

6. Impact of high NSP by region (unadjusted analyses)
7 studies
High heterogeneity (I2=79%)
Weak evidence overall – RR 0.77
In Europe NSP associated with 66% reduction in HCV
Grade: very low evidence
Now to Needle and syringe programmes – evidence is more mixed. Here we show Forest plot for all studies – using unadjusted estimates because didn’t want to drop too many studies.
Overall we find weak evidence – across seven studies – that high coverage NSP High coverage NSP defined either as regular attendance or people receiving sufficient syringes for their injecting frequency reduces HCV transmission by 23%.
There is a great deal of heterogeneity. For studies in Europe which had a more consistent measure of NSP exposure there is evidence that can reduce HCV transmission by 50% or more.

7. Impact of NSP and OST High NSP with OST 4 studies 3356 participants
518 HCV cases Reduced HCV by 71%
moderate heterogeneity
Low NSP with OST
3 studies
3071 participants
449 HCV cases,
Reduced HCV by 24%
GRADE: low evidence
Four studies reported combined exposure to both NSPs and OST – the combination of high coverage NSP and OST reduced HCV by 71% - shown in top forest plot
3 studies also could assess combination of low NSP and OST – and suggested that impact of OST on HCV transmission was reduced in absence of high coverage NSP

8. CAN SCALING UP COVERAGE OF OST & NSP ACHIEVE FURTHER SUBSTANTIAL REDUCTIONS IN HCV AMONG PWID
So natural response advocated by many and recommended in UK and guidelines in Europe and from WHO is that need to scale-up more.
So we projected likely impact of further scaling up OST and NSP – in a scenario like UK – but also in relation to HCV action plan in Scotland.

9. Why HCV treatment is needed for prevention
08 December 2018
Why HCV treatment is needed for prevention
Opioid substation therapy (OST) and needle and syringe programmes (NSP) can reduce HCV prevalence, but unclear whether can lead to substantial reductions
Therefore scaling-up treatment is also needed.
Vickerman et al. Addiction 2012.

10. COMBINATION PREVENTION SCALE-UP: 10 YEAR RELATIVE PREVALENCE REDUCTIONS WITH NO BASELINE COVERAGE OF OST/NSP AND USING DAAs
40% chronic prevalence
Dark red: modest (<20%) impact, high HCV
Orange: ~50% impact
White: >80% impact
>40% reduction requires HCV treatment
OST&NSP increases benefit of HCV treatment
Now this model for a place like UK with 40% chronic HCV projects impact of scaling up HCV treatment with the new DAAs and also OST and hc NSP over ten year period. Projections presented in a sort of heat-tech topography map with x-axis showing impact of increasing coverage of OST/hcNSP and y-axis increasing HCV treatment rates. The lines show % HCV reduction in 10 years with only modest or little effect where graph is dark red, rising to greater impact where orange or near elimination when white. So what is critical is that if want to achieve a substantial reduction in HCV – say >40% in 10 years then need to scale up HCV treatment – cant do it with OST and hcNSP alone. But also as lines are slanted – that as scale up OST/hcNSP require less HCV treatment to achieve different reductions in HCV prevalence – so can use OST/hcNSP in theory to conserve HCV treatments and to increase the prevention benefit of HCV treatment.
Martin NK, Hickman M, Hutchinson SJ, Goldberg DJ, and Vickerman P. C. Clinical Infectious Diseases 2013

11. DAA TREATMENT RATES TO HALVE CHRONIC PREVALENCE IN 10 YRS WITH HARM REDUCTION
Shown here also for populations with 20, 40 or 60% chronic HCV. That the estimated number of treatments required to halve prevalence reduces as scale up OST and NSP. Which matters if want to minimize re-infection and conserve your HCV treatment.
Martin NK, Hickman M, Hutchinson SJ, Goldberg DJ, and Vickerman P. C. Clinical Infectious Diseases 2013

12. CHANGING CLINICAL GUIDELINES & TREATMENT PRIORITISATION
So our recent modelling work considered who should be treated with the new DAA

13. RECOMMENDATIONS ON TREATMENT OF HEPATITIS C 2015
A1: “Further research is very unlikely to change confidence in the estimate of the effect.
B1: “Further research is likely to have an impact on our confidence in the estimate of effect”
HCV treatment guidance is a rapidly evolving area.
In 2014 guidance from European Association Study of the Liver was to prioritise treatment based on severity of disease – starting with people on cirrhosis and then severe disease and people with mild disease depends on individual circumstances but treatment could be delayed. Then in 2015 they recommended also that treatment be given to people with a transmission risk – such as PWID – irrespective of fibrosis/disease stage. They did note though that the evidence supporting the recommendation was moderate/if not downright poor

14. And now in 2016 treatment should be considered without delay for anyone with moderate signs of fibrosis –and for people with onging transmission risk. But now graded A1 “further research unlikely to change intervention effect” – though not sure any new evidence or any empirical evidence of Treatment as Prevention has been presented – waiting for results from Australia…

15. UK willingness-to-pay threshold
ECONOMIC MODELING SUPPORTS TREATMENT FOR PWID AND PRIORITIZATION OF PWID FOR EARLY TREATMENT
Are DAAs cost-effective for PWID?
YES - in UK, Australia, Netherlands
Early DAA treatment for PWID cost-effective compared to delay to cirrhosis1
Who do we prioritize after cirrhotics?
Traditional thinking is most cost-effective to prioritize by disease stage
BUT if include prevention benefits, more cost-effective to prioritize early treatment to PWID regardless of liver disease stage, then to former PWID with moderate disease in 20%/40% chronic prevalence settings1
Early treatment vs delay to cirrhosis
UK willingness-to-pay threshold
Asassumptions.
£1 = 1€ = $1.30
1. Martin NK et al. J Hepatol 2016
2. Scott N et al. J Gastro Hep 2016
3. Van santen DK PLoS ONE 2016

16. MORE COST-EFFECTIVE TO PRIORITIZE EARLY TREATMENT FOR PWID INSTEAD OF BY STAGE IN 20/40% PREV SETTINGS
This slide shows who we should prioritize first for early DAA therapy after we treat those with cirrhosis. Many clinical guidelines would recommend prioritizing those with more advanced liver disease first. Here we can see that in our low and moderate prevalence setting (20% or 40% chronic infection among PWID), from an economic point of view it is best to prioritize treatments first by risk status- first treating PWID regardless of disease stage because of the substantial prevention benefits. Only in a very high prevalence setting is it best to prioritize first by disease stage, treating those with more advanced disease first. This is because of the high rates of reinfection in this setting.
NOTE THAT THIS IS ALSO TESTING HO THAT SHOULD NOT TARGET PWID WITH MILD DISEASE… SAYS RESTRICTING TREATMENT IS UNREASONABLE AND NOT JUSTIFIED/ COST-EFFECTIVE.
NEED OTHER MODELS TO WORK OUT HOW TO USE COMBINATION OF OST/NSP TO ACHIEVE MOST EFFECTIVE/COST-EFFECTIVE STRATEGY FOR PREVENTING HCV…
Not just about HCV treatment, but also about how to allocate resources between treatmetn and harm reduction for overall prevention benefit and also harm reduction key to reducing the risk of reinfection
20% chronic prev among PWID
40% chronic prev among PWID
60% chronic prev among PWID
*£20,000 willingness to pay.
Martin NK et al. J Hepatol 2016: 65(1):17-25.
Economic modeling supports treatment for and prioritization of PWID – essential for achieving elimination targets

17. NUMBER OF NEW INFECTIONS AVERTED PER EARLY TREATMENT
Here we show the projected prevention benefit. So in a population with 20% chronic HCV we would expect for every PWID treated early a further 2 infections would be averted/ and in 40% chronic HCV then for every 1 person treated then a further 1 infection also prevented. But in sites with high chronic HCV then re-infection rates also high reducing prevention benefit – though it is still there…..
20% chronic prev among PWID
40% chronic prev among PWID
60% chronic prev among PWID
Martin NK et al. J Hepatology 2016

18. ARE CURRENT HCV TREATMENT RATES SUFFICIENT TO ACHIEVE A MEASURABLE CHANGE IN HCV TRANSMISSION IN EUROPE?
Now in terms of evidence of treatment as prevention – we need to work out whether sufficient treatment taking place that we can measure any change in transmission.

19. Results 1: % of estimated PWID with chronic infections treated at baseline (2015/16)
Only two sites are treating over 5% of those that are chronically infected at baseline.
Fraser et al, (2017) Journal of Hepatology, In press

20. Results 2: Baseline chronic prevalence
At baseline prevalence varies widely. As shown before, much higher in Finland and Sweden where there is little treatment among PWID than in Czech Republic and Slovenia.
Fraser et al, (2017) Journal of Hepatology, In press

21. Results 2: 10 year impact on chronic prevalence if swop to DAAs
Click 1: In sites with high prevalence and minimal treatment switching to DAAs has little inmpact.
Click 2: In sites with low or decreasing prevalence switching to DAAs has a much greater impact, with projections suggesting it likely to be able to observe a difference in prevalence in 10 years.
$ z-score < 0.5 (unlikely to observe a difference )
+ z-score (may be able to observe a difference )
* z-score (increasingly likely to be able to observe a difference )
# z-score >3 (highly likely to be able to observe a difference )
Fraser et al, (2017) Journal of Hepatology, In press

22. Results 4: Treatment needed per 1000 PWID to reduce HCV to 2 per 100pyrs by 2026
Purple: Number of treatments per 1000 PWID at baseline (2015/16)
Green: Number of treatments needed per 1000 PWID in 2016/17 with current OST and NSP.
Yellow: Number of treatments needed per 1000 PWID in 2016/17 with 80% coverage OST and NSP.
The green shows the number of treatments per 1000 PWID in each site if switching to DAAs only.
In Amsterdam and Slovenia, this is likely to be achieved simply by switching to DAAs and so minimal scale-up is needed.
In Czech Republic scaling-up treatment by 50% is likely to see 2% incidence by 2026.
In all other sites greater scale-up is needed, ranging from 3-17 times current treatment rates in all other sites other than Finland where 200 times current rates are needed.
However, we can see that per 1000 PWID this is actually a similar number of treatments to other sites.
Fraser et al, (2017) Journal of Hepatology, In press

23. Results 4: Treatment needed per 1000 PWID to reduce HCV to 2 per 100pyrs by 2026
Purple: Number of treatments per 1000 PWID at baseline (2015/16)
Green: Number of treatments needed per 1000 PWID in 2016/17 with current OST and NSP.
Yellow: Number of treatments needed per 1000 PWID in 2016/17 with 80% coverage OST and NSP.
Yellow shows treatment needed if OST and NSP also scaled-up to 80% coverage.
Can see that a decrease in the number of treatments is needed.
If we compare to baseline, in Amsterdam and Slovenia no scale-up is needed. In Czech Republic and Belgium minimal scale-up is needed as in over 50% of the runs 2% incidence is already achieved.
In other sites the scale-up needed compared to baseline is less than 5 times for all sites other than Finland, which is 150 times.
What is interesting to note is that the % decrease in the number of treatments needed is 20-80% across all sites if OST and NSP are scaled-up alongside switching to DAAs compared to if not.
Amsterdam 40%, Beglium 80%, CR 30%, Denmark 60%, Finland 20%, France 30%, Hamburg 23%, Norway 60%, Scotland 30%, Slovenia 20% Sweden 40%
Fraser et al, (2017) Journal of Hepatology, In press

24. MORE EXAMPLES – COST-EFFECTIVENESS & COMBINING INTERVENTIONS

25. HCV in Scott County, Indiana
Treatment scale-up to reduce HCV to low levels
Projected number of PWID needing HCV treatment annually
Percentage of infections treated in mid-2016 to mid-2017
Where largest HIV epidemic
Key is how increasing ost/nsp reduces required number of treatments to achieve targets- and in some circumstances makes it possible.
Scale-up = to 50% for both OST/NSP – so moderate to high from low
90% reduction by 2030 possible with no scale-up of harm reduction.
159 treatments per 1000 PWID needed annually (24.9% of infections treated in first year).
Treatments halved (89 treatments, 14.5%) if MAT+SSP scaled-up.
Not possible to decrease prevalence by 90% by 2020.
90% decrease in incidence may be possible (55% of simulations) if MAT and SSP also scaled-up.
90% reduction by 2025 only always possible if MAT+SSP also scaled up.
treatments per 1000 PWID treated annually ( %) to decrease prev/inc.
Again treatments doubled without HR if still possible.
# Only a proportion of parameter sets achieved the target.
* <5% of parameter sets achieved the target.

26. Scenario Analysis Results
08 December December December December December December December December December December December December December December 2018
Scenario Analysis Results
NSP remains cost-effective even when HCV treatment is cheaper
Increasing treatment increases cost-effectiveness of NSP

27. Implications – mixture of evidence
Empirical evidence OST/NSP reduces HCV
NSP & OST highly cost-effective
Models suggest that: OST/NSP avert HCV transmission & increase impact of HCV TasP
Dynamic and Economic Models show that:
HCV treatment scale-up critical for HCV prevention
Early treatment of PWID cost-effective
NSP (and OST) highly cost-effective
Increasing HCV treatment increases NSP CE
No observed evidence (yet) of HCV TasP (in PWID)
Model evidence is clear.
HCV treatment scale-up critical component of HCV prevention in PWID
Have other models which didn’t showy you today that increasing HCV case-finding in PWID is cost-effective.
And likely that early treatment of PWID is cost-effective
But cant wait around for evidence of HCV treatment as prevent to miraculously appear as in most settings treatment rates too low and information on PWID prevalence and HCV prevalence adding uncertainty.
Current treatment rates unlikely to lead to measurable/observable change in HCV transmission
Uncertainty in measuring PWID prevalence & HCV incidence and prevalence in community surveys
Empirical evidence that OST/NSP reduces HCV transmission
Need empirical evidence & TasP also needs to resolve issues with PWID and HCV measurement
HCV TAsP is about reducing HCV transmission in the population - which means we need to measure it – and measure it not just in people treated for HCV but in samples of PWID in the community.
This moves beyond a phase II trial that will monitor SVR and perhaps re-infection rates – which will be important.
And TAsP evaluation will require collection of multiple samples and data sources to address some of the uncertainties –
Not all gloom and doom – scaling up HCV treatment also provides epidemiologists like myself the opportunity to get the numbers right on the number of people who inject drugs – as this is required to determine how many people are treated and because need to combine data on HCV prevalence and prevalence of PWID especially to prepare for phase IV evaluation of implementation studies.
[Phase IV: promoting effective implementation
The purpose of the final phase is to examine the implementation of the intervention into practice, paying particular attention to the rate of uptake, the stability of the intervention, any broadening of subject groups, and the possible existence of adverse effects. As in the case of drug trials, this might be carried out by long term surveillance, although currently there is no established mechanism for funding such activities.]

28. Implications – mixture of evidence
Model projections in Europe suggest treatment scale-up needed to observe change in HCV transmission
Uncertainty in measuring PWID prevalence & HCV incidence and prevalence
Strengthen PH surveillance so can detect change in prevalence & transmission
Promote HCV TasP and OST/NSP scale-up to prevent HCV transmission - EVALUATE
Trials and natural experiments
Model evidence is clear.
HCV treatment scale-up critical component of HCV prevention in PWID
Have other models which didn’t showy you today that increasing HCV case-finding in PWID is cost-effective.
And likely that early treatment of PWID is cost-effective
But cant wait around for evidence of HCV treatment as prevent to miraculously appear as in most settings treatment rates too low and information on PWID prevalence and HCV prevalence adding uncertainty.
Current treatment rates unlikely to lead to measurable/observable change in HCV transmission
Uncertainty in measuring PWID prevalence & HCV incidence and prevalence in community surveys
Empirical evidence that OST/NSP reduces HCV transmission
Need empirical evidence & TasP also needs to resolve issues with PWID and HCV measurement
HCV TAsP is about reducing HCV transmission in the population - which means we need to measure it – and measure it not just in people treated for HCV but in samples of PWID in the community.
This moves beyond a phase II trial that will monitor SVR and perhaps re-infection rates – which will be important.
And TAsP evaluation will require collection of multiple samples and data sources to address some of the uncertainties –
Not all gloom and doom – scaling up HCV treatment also provides epidemiologists like myself the opportunity to get the numbers right on the number of people who inject drugs – as this is required to determine how many people are treated and because need to combine data on HCV prevalence and prevalence of PWID especially to prepare for phase IV evaluation of implementation studies.
[Phase IV: promoting effective implementation
The purpose of the final phase is to examine the implementation of the intervention into practice, paying particular attention to the rate of uptake, the stability of the intervention, any broadening of subject groups, and the possible existence of adverse effects. As in the case of drug trials, this might be carried out by long term surveillance, although currently there is no established mechanism for funding such activities.]