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

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

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?

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

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 2016. 3) Grebely CID 2016. 4) Grebely J, ILC 2017, Amsterdam, The Netherlands, April 19-23rd, 2017 (FRI-235). 5) Zeuzem, S. Ann Intern Med 2015. 6) Dore, GJ Ann Intern Med 2016. 7) Grebely, Hajarizadeh, and Dore Nature Rev Gastro Hepatology 2017 (In Press).

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 2017. 2) Hull M, et al. INHSU 2016. 3) Conway AASLD 2016. 4) Bouscaillou EASL 2017. 5) Powis J. Int J Drug Policy 2017. 6) 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, 2017. 16) Mazhnaya Int J Drug Policy In Press 2017.

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 2017. 2) Read P. Int J Drug Policy In Press 2017.

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

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

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)

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

Median adherence: 94% Mean adherence: 89%

Cunningham EB, et al In Preparation

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)

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)

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)

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

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

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

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

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

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 2015. Grebely J, Hajarizadeh B, and Dore GJ Nature Reviews in Gastroenterology & Hepatology 2017

Rapid DAA scale-up is required to limit reinfection Razavi H, et al. INHSU Sydney, Australia 2015. Grebely J, Hajarizadeh B, and Dore GJ Nature Reviews in Gastroenterology & Hepatology 2017

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

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

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

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

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)