1. Direct-acting interferon-free therapies and reinfection among people who inject drugs
Associate Professor Jason Grebely
Lisbon Addictions 2017 Conference, 26 October 2017

2. Disclosures
Funding and speaker fees from AbbVie, Bristol-Myers Squibb, Cepheid, Gilead Sciences and Merck

3. HCV treatment and reinfection among active PWID
DAA therapy is effective in people receiving OST and PWID (former/current)
Reinfection will occur following successful DAA therapy in active PWID
What will be required to address HCV reinfection?

4. Defining populations of PWID
Former PWID
Current PWID
Current PWUD
PWID
in OST

5. People receiving OST – phase II/III trials
SVR12 (%)
OBV/PTV/r +
DSV + RBV1
SOF/VEL/VOX4
140
149
4405
4598 66 70
1822
1882 49 51
966
984 47 49
967
1007
269
296
299
316
SOF/LDV
+ RBV2
SOF/VEL3
GZR/ELB5.6
1) Grebely J, ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (FRI-236). 2) Grebely CID ) Grebely CID ) Grebely J, ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (FRI-235). 5) Zeuzem, S. Ann Intern Med ) Dore, GJ Ann Intern Med ) Grebely, Hajarizadeh, and Dore Nature Rev Gastro Hepatology 2017 (In Press).

6. SVR12 among former/recent PWID
Norton
20171
Powis
20175 44 46 89
100 93 98
215
244 60 69 59 72
142
150 88 98
971
1126
Hull
20162
Conway
20163
Bouscaillou
20174
Read
20176
Litwin
20177
Sulkowski
20178
Mazhnaya
20179
1) Norton B, et al. Int J Drug Pol ) Hull M, et al. INHSU ) Conway AASLD ) Bouscaillou EASL ) Powis J. Int J Drug Policy ) Read P. Int J Drug Policy 2017; 7) Litwin AL, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017; 8) Sulkowski M, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, ) Mazhnaya Int J Drug Policy In Press 2017.

7. Lost to follow-up post-treatment
SVR12 (%) 60 69 60 66 59 72 59 65
ITT
mITT
ITT
mITT
1) Powis J. Int J Drug Policy In Press ) Read P. Int J Drug Policy In Press 2017.

8. OST/Recent PWID – The D3FEAT Study
DAA treatment-naïve patients with GT1 chronic HCV infection (F0-4)
People receiving OST or with recent injecting drug use (past six months)
Participants with HIV and decompensated liver disease excluded
Participants received paritaprevir/ritonavir, ombitasvir, dasabuvir (3D) with (G1a) or without ribavirin (G1b) twice-daily using electronic blister packs to monitor adherence
RBV: 1000 or 1200 mg daily according to body weight in 2 divided doses (<75 kg and ≥75 kg, respectively)
3D + RBV, n=87
Week 0
Week 12
Week 24
SVR12
3 yrs
Six-monthly follow-up for reinfection

9. OST/Recent PWID – The D3FEAT Study
57% injecting in past 6 months, 90% G1a, 10% G1b, 8% cirrhosis, DAA-treatment naïve
No virological failures, two viral relapse/reinfection (undergoing sequencing to confirm)
97%
ETR
91%
94%
84/87
79/87
79/84
SVR12: ITT
SVR12: mITT
Conway B, et al. INHSU 2017, New York, United States, September 6-8, 2017

10. Recent PWID – The SIMPLIFY Study
Kirby/UNSW sponsored, international open-label trial
DAA treatment-naïve patients with GT1-6 chronic HCV infection (F0-4)
People with recent injecting drug use (past six months)
Electronic blister packs to monitor adherence
Sofosbuvir/velpatasvir 400/100 mg od, n=103
Week 0
Week 12
Week 24
SVR12
3 yrs
Six-monthly follow-up for reinfection
Grebely J, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (FRI-234)

11. Recent PWID – The SIMPLIFY Study
100% injecting in past 6 months, 35% G1a, 58% G1, 9% cirrhosis, DAA-treatment naïve
No virological failures, no viral relapse, 1 case of reinfection
96%
ETR
94%
99/103
97/103
SVR12
Grebely J, et al. INHSU 2017, New York, United States, September 6-8, 2017

12. Median adherence: 94%
Mean adherence: 89%

13. Cunningham EB, et al In Preparation

14. PREVAIL: Individual vs. DOT vs. group
85% genotype 1a, 27% cirrhosis, 11% treatment-experienced, 14% HIV
98% methadone, 65% with recent drug use in last 6 months
98%
96%
90%
Individual
46/51
50/51
46/48
DOT
Group
Litwin AL, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (PS-130)

15. CHAMPS: HCV treatment uptake
HCV genotype 1, 12% cirrhosis, 25% recent cocaine/heroin use
P=0.11
67%
Usual care (nurse)
83%
76%
24/36
41/54
45/54
UC + incentives
UC + peer support
Sulkowski M, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (SAT-228)

16. CHAMPS: Usual care vs. incentives vs. peer-support
90%
Usual care (nurse)
89%
90%
18/20
33/37
37/41
UC + incentives
UC + peer support
Sulkowski M, et al. ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (SAT-228)

17. Need to move towards simplified models of HCV care
Many programs for HCV treatment are built upon interferon-era
Need to move towards simplification of existing models
Not at the expense of strengthening foundation for drug user health
Modified from John Dillon

18. What is the risk of HCV reinfection following therapy?
Not calculated among people with recent injecting post-therapy

19. HCV reinfection following DAA therapy: C-EDGE CO-STAR
10 reinfections
2.3 reinfections per 100 person years
HCV reinfection following DAA therapy: C-EDGE CO-STAR
Through 6 months follow-up
Through FW12
Through FW24 4
reinfections 5
reinfections 1
reinfection
From ETR Through 24 months of follow-up
10 reinfections
426 person years
2.3 per 100 p-yrs (95% CI: 1.1, 4.3)
From ETR Through 24 months of follow-up (persistence only)
7 reinfections
429 person years
1.6 per 100 p-yrs (95% CI: 0.7, 3.4)
Clearance of reinfection was observed in 3/10 (30%) reinfection cases
Dore GJ, et al. AASLD 2017, Washington, United States

20. HCV reinfection following DAA therapy: C-EDGE CO-STAR
199 participants enrolled in Part B
From the end of treatment through all available follow-up:
74 participants (37%)
reported injecting drug use
Rate of reinfection:
4.2 reinfections / 100 person years
95% CI (1.5, 9.2)
125 participants (63%)
reported NO injecting drug use
0.4 reinfections / 100 person years
95% CI (0.0, 2.3) 4
reinfections 5
reinfections 1
reinfection
Dore GJ, et al. AASLD 2017, Washington, United States

21. Type of injecting drug use/drug use frequency matters
Young J, et al. Clinical Infectious Diseases 2017

22. Specific issues on HCV reinfection for PWID
Acknowledgement: there will be cases of HCV reinfection; if there are no cases, it is not a current PWID population
Harm reduction optimisation (NSP, OST access): HCV reinfection incidence will reflect HCV incidence in the setting
Rapid scale-up: a slow scale-up will create HCV “susceptible” PWID without reduction in viraemic pool
Individual-level strategies: treatment of injecting partners crucial
Access to re-treatment: without stigma and discrimination
Community engagement and partnership: use of peer workers
Razavi H, et al. INHSU Sydney, Australia Grebely J, Hajarizadeh B, and Dore GJ Nature Reviews in Gastroenterology & Hepatology 2017

23. Rapid DAA scale-up is required to limit reinfection
Razavi H, et al. INHSU Sydney, Australia Grebely J, Hajarizadeh B, and Dore GJ Nature Reviews in Gastroenterology & Hepatology 2017

24. Strategies addressing individual-level risk: Bring a friend
“Bring your friends” strategy performed better than the random strategy
Plausible real-world treatment strategy as most people will know their injecting partners
Hellard M, et al. Hepatology 2014

25. Australia – Treatment among PWID
Iversen J, et al. INHSU 2017, New York, United States, September 6-8, 2017

26. Strategies to minimise impact
Discussion re injecting behaviour and injecting partners (consider bring a friend)
Drug dependency management and access to safe injecting equipment (reinfection prevention the same as primary prevention)
Monitor post-SVR via repeat HCV RNA: at least annual (more frequent requires evaluation)
Post-SVR12 detectable HCV RNA = reinfection (but, repeat genotype)
Offer retreatment: standard duration (shorter being evaluated)
Dore GJ

27. Remaining challenges
Further work is needed to address drug user health for PWID
Further simplification of HCV testing and treatment models
One size will not fit all – different settings will require different interventions
Act regionally, but think globally (micro-elimination)
Need to remove disease-stage reimbursement restrictions (double restriction)
Opportunities for DAA therapy simplification (e.g. mild disease, prisons)
Reinfection needs to be acknowledged and accepted

28. Acknowledgements UNSW Sydney Prof. Gregory Dore Dr. Jenny Iversen
Dr. Lisa Maher
A/Prof. Gail Matthews
Dr. Tanya Applegate
Dr. Francois Lamoury
Dr. Marianne Martinello
Ms. Pip Marks
Prof. Andrew Lloyd
Dr. Behzad Hajarizadeh
Dr. Maryam Alavi
Mr. Evan Cunningham
Prof. Carla Treloar
Collaborators
Prof. Margaret Hellard (Australia)