We know DAAs work for PWID, now what? Simplifying HCV testing, linkage to care and treatment

Associate Professor Jason Grebely

National Drug & Alcohol Research Centre, Sydney, Australia, 17th May 2018

Disclosures •  Funding and speaker fees from AbbVie, Bristol-Myers Squibb, Cepheid,

Gilead Sciences and Merck

•  This presentation will include the discussion of the investigative use of medical devices (Xpert HCV Viral Load Finger Stick, Cepheid)

Enhancing HCV testing, care and treatment in PWID

•  What have we learned about DAA therapy among PWID?

•  Will HCV reinfection be an issue? •  Testing, diagnosis and linkage to care will be a major barrier to HCV elimination

•  We must simplify our existing models of care and interventions •  “One size will not fit all” – need multiple models and interventions adapted to specific

settings

•  Is HCV elimination among PWID really feasible??

What have we learned about DAA therapy among PWID?

DAA therapy is safe and effective among PWID, even in the “real-world”

Defining populations of PWID

Former PWID

Current PWID

PWID in OST

Current PWUD

Larney S, et al. Int Journal Drug Policy 2015. Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017

94% 94% 96% 96% 96% 92% 96% 97% 98% 96% 98% 95%

0

20

40

60

80

100

OST no OST

SVR

12 (%

)

OBV/PTV/r + DSV + RBV1

SOF/VEL/VOX4

140 149

4405 4598

SOF/LDV + RBV2

66 70

SOF/VEL3 GZR/ELB6,7

1822 1882

49 51

966 984

47 49

967 1007

269 296

299 316

People receiving OST – phase II/III trials

GLE/PIB5

151 157

2055 2099

1) Grebely J, et al ILC 2017 (FRI-236). 2) Grebely CID 2016. 3) Grebely CID 2016. 4) Grebely J, ILC 2017 (FRI-235). 5) Grebely J, INHSU 2017. 6) Zeuzem, S. Ann Intern Med 2015. 7) Dore, GJ Ann Intern Med 2016. 8) Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017.

1) Norton B, et al. Int J Drug Pol 2017. 2) Hull M, et al. INHSU 2016. 3) Alimohammadi 7th Canadian HCV Symposium 2018. 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; 8) Sulkowski M, et al. ILC 2017. 9) Mazhnaya Int J Drug Policy 2017. 10) Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017.

96% 89% 85% 88% 87% 82%

95% 90% 86%

0

20

40

60

80

100

SVR

12 (%

)

Norton 20171

Powis 20175

44 46

Hull 20162

89 100

Alimohammadi 20183

Read 20176

60 69

59 72

Bouscaillou 20174

153 180

215 244

SVR12 among former/recent PWID

Litwin 20177

Sulkowski 20178

142 150

88 98

971 1126

Mazhnaya 20179

Recent PWID – The SIMPLIFY Study (SOF/VEL) •  Investigator-initiated, Kirby/UNSW sponsored, international open-label trial •  19 sites, 7 countries •  Study recruitment conducted through a network of drug and alcohol clinics

(n=1), hospital clinics (n=12), and community clinics (n=2) •  Participants enrolled between April 2016 and October 2016

SIMPLIFY – Study Design

•  DAA treatment-naïve patients with GT1-6 chronic HCV infection (F0-4) •  People with recent injecting drug use (past six months) •  Participants with HIV and decompensated liver disease excluded •  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. The Lancet Gastroenterology & Hepatology 2018

Grebely J, et al. The Lancet Gastroenterology & Hepatology 2018

0 10 20 30 40 50 60 70 80 90

100

Res

pons

e (%

)

96%

ETR 99/103

94%

SVR12

97/103

Recent PWID – The SIMPLIFY Study (SOF/VEL) •  100% injecting in past 6 months, 35% G1a, 58% G3, 9% cirrhosis, DAA-treatment naïve •  No virological failures, no viral relapse, 1 case of reinfection, 4 deaths due to overdose

Adherence among PWID needs to be optimized, but does not impact SVR

Adherence: Median, 94%, Mean, 89% Missed doses •  No missed doses (100% adherent) – 12% •  1-4 missed doses (95-<100% adherent) – 35% •  5-8 missed doses (90-<95% adherent) – 19% •  9-17 missed doses (80-<90% adherent) – 17% •  ≥18 missed doses (<80% adherent) – 17%

Longest episode of non-adherence •  1 day – 43% •  2 days – 18% •  3 days – 3% •  4 days – 9% •  5 days – 2% •  6 days – 3% •  ≥7 days – 11%

Grebely J, et al. Lancet Gastro Hep 2018, Cunningham EB, et al. In Preparation 2018

Adherent Non-adherent

All participants achieved SVR

There is no impact of drug use on SVR during DAA therapy

SIMPLIFY – Drug use during treatment

SIMPLIFY - Impact of OST and drug use on SVR

We need to acknowledge and accept that HCV reinfection will occur

What is the risk of HCV reinfection following therapy?

Not calculated among people

with recent injecting post-

therapy

Specific issues on HCV reinfection for PWID

Razavi H, et al. INHSU Sydney, Australia 2015. Grebely J, Hajarizadeh B, and Dore GJ Nature Reviews in Gastroenterology & Hepatology 2017

•  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

Testing, diagnosis and linkage to care will be a major barrier to HCV elimination

HCV testing, linkage to care, treatment

Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017. Iversen J, et al. Int J Drug Pol 2017.

Global cascade of care for chronic HCV infection - 2015

Lazarus J, Nat Rev Gastro Hep 2017

Innovative strategies to enhance HCV testing and diagnosis are needed

The long journey to an HCV diagnosis….

Grebely J, Applegate TA, Cunningham P, and Feld JJ Exp Rev Mol Diag 2017

Anti-HCV antibody (Physician)

Phlebotomy (Phlebotomist)

Receive diagnosis (Physician)

Central Lab

Antibody test 1-2 weeks

Phlebotomy (Phlebotomist)

Central Lab

RNA test 1-2 weeks

Receive diagnosis (Physician)

Visit #1 Visit #2 Visit #3 Visit #4 Visit #5

Further barriers to HCV testing and diagnosis

1) Grebely J, Applegate TA, Cunningham P, and Feld JJ Exp Rev Mol Diag 2017; 2) Cox J, et al. J Viral Hepat. 2011;18:e332–340; 3) Gupta L, et al. J Gastroenterol Hepatol. 2006;21:694–699; 4) Shehab TM, et al. J Viral Hepat. 2001;8:377–383; 5) Marshall AD, et al. Int J Drug Policy. 2015;26:984–991; 6) Treloar C, et al. Drug Alcohol Rev. 2012;31:918–924.

•  Poor knowledge and competence of HCV testing among many general practitioners1-4

•  Poor knowledge among patients about HCV testing5-6

•  Further work is needed to educate patients and providers on HCV testing (e.g. drug and alcohol settings)

HCV antibody testing with reflex RNA testing

100% 100%

74% (100% of Ab+)

100%

56% 51%

(92% of referred)

0

20

40

60

80

100

(%)

HCV Ab+

Phlebotomy (Phlebotomist)

Receive diagnosis (Physician)

Central Lab

RNA test 1-2 weeks

Order anti-HCV antibody with reflex HCV RNA

(Physician)

RNA Tested HCV RNA+ HCV RNA+ Referred 1st appoint Sena Public Health Rep 2016

326 326 326

241 326

134 241 241 123

241

HCV antibody testing with reflex RNA testing

100% 100%

74% (100% of Ab+)

100%

56% 51%

(92% of referred)

0

20

40

60

80

100

(%)

HCV Ab+

Phlebotomy (Phlebotomist)

Receive diagnosis (Physician)

Central Lab

RNA test 1-2 weeks

Order anti-HCV antibody with reflex HCV RNA

(Physician)

RNA Tested HCV RNA+ HCV RNA+ Referred 1st appoint Sena Public Health Rep 2016

326 326 326

241 326

134 241 241 123

241

Advances in diagnostics and point-of-care testing

Fourati S, et al. INHSU 2017, New York, United States, September 6-8, 2017

Rapid diagnostic tests Dried blood spot testing Point of care and random access

HCV RNA testing

Rapid HCV antibody testing

Bottero J Open Forum Inf Dis 2017

Rapid anti-HCV antibody test

(Health care worker)

Phlebotomy (Phlebotomist)

Receive diagnosis (Physician)

Central Lab

RNA test 1-2 weeks

Standard serology-based testing (n=162)

Point-of-care rapid testing (n=162)

•  Single-center free testing clinic •  People randomized to interventions for testing of HIV, HBV, and HCV

Aware of status 64% (n=104)

98% (n=159)

P<0.001

Linked to care 60%

90%

P=0.04

Dried blood spot testing

Dried blood spot sample

(Health care worker)

Receive diagnosis (Physician)

Central Lab

Antibody test 1-2 weeks

Advantages Disadvantages 1) Enhances HCV testing and linkage to care 1) Still requires centralized testing 2) Avoids need for phlebotomy 2) Requires 2nd visit to get result 3) Enables reflex virological testing 3) Sometimes requires multiple pricks 4) Stable, easy to transport and store 4) May yield a lower HCV RNA titer 5) Can be used for other purposes (e.g. HIV) 6) Collection by peers or community workers

Grebely J, Applegate TA, Cunningham P, and Feld JJ Exp Rev Mol Diag 2017

Dried blood spot testing

Dried blood spot sample

(Health care worker)

Receive diagnosis (Physician)

Central Lab

Antibody test 1-2 weeks

Advantages Disadvantages 1) Enhances HCV testing and linkage to care 1) Still requires centralized testing 2) Avoids need for phlebotomy 2) Requires 2nd visit to get result 3) Enables reflex virological testing 3) Sometimes requires multiple pricks 4) Stable, easy to transport and store 4) May yield a lower HCV RNA titer 5) Can be used for other purposes (e.g. HIV) 6) Collection by peers or community workers

Grebely J, Applegate TA, Cunningham P, and Feld JJ Exp Rev Mol Diag 2017

Finger-stick testing for HCV RNA detection

McHugh J Clin Micro 2017, Grebely Lancet Gastro Hep 2017, Lamoury Journal of Infectious Diseases 2018

•  Relatively easy-to-use point-of-care HCV RNA test – GeneXpert in many LMIC •  Real-world performance for HCV RNA quantification very good

•  Venepuncture HCV Viral Load – Sensitivity – 99%, Sensitivity 96%1 •  Modified finger-stick assay – Sensitivity – 98%, Sensitivity 99%2 •  Xpert® HCV Viral Load Fingerstick - Sensitivity – 100%, Sensitivity 100%3

•  One step closer to a single-visit diagnosis (needs to be more “rapid”)

60 mins

Moving to a single-visit hepatitis C diagnosis

Grebely J, et al Exp Rev Mol Diag 2017

Simplification of existing models of care and interventions is critical

What is a model of care?

WHERE   WHO  WHAT   HOW  

Settings, services, and providers

Drug and alcohol clinics

Primary health care / GPs

Prisons

Community health centres

NSP services

Sexual health

Settings Services Providers

Task-shifting •  Specialists •  Drug and alcohol specialist •  Primary care providers •  Nurses •  Pharmacists •  Peer support workers •  Others

Pharmacies

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 and management

•  Not at the expense of strengthening foundation for other health priorities (e.g. drug and alcohol use)

Modified from John Dillon

“One size will not fit all” – We need multiple models and interventions adapted to specific settings

Why is there a drop from diagnosis to DAA therapy?

Patel RC Public Health Rep 2016

100%

73% 52%

(71% of Ab+)

0

20

40

60

80

100

(%)

1,201 1,497

1,497 938 1,497

HCV RNA+ Referred 1st appoint

Why the drop?

Why do patients who are referred not make it to clinic?

•  Barriers experienced when trying to access services (e.g., limited hours of service, long wait times, and shortage of health care practitioners)

•  Lack of coverage of services

•  Stigma and discrimination from past encounters with the health system •  Distance from tertiary care service

•  Fear of letting down their providers (e.g., missing appointments, forgetting to get blood tests, etc.).

•  HCV is not always the most important priority in people’s lives

Grebely J, et al Journal of the International AIDS Society 2017

Traditional referral model of HCV testing and treatment

Drug and alcohol clinics

Primary health care / GPs

Prisons

Community health centres

Needle and syringe

programmes

Sexual health

Pharmacies

Tertiary care hospital

Redefining models of HCV testing and linkage to care

Drug and alcohol clinics

Primary health care / GPs

Prisons

Community health centres

Needle and syringe

programmes

Sexual health

Pharmacies

Tertiary care hospital

•  Need to bring HCV care to the community where patients access services

Enhancing testing, linkage to care, and treatment in PWID •  Systematic review of interventions to enhance HCV testing, linkage to care or

treatment among PWID

•  10,116 records – 14 studies with comparative interventions included

•  Interventions to enhance HCV testing •  On-site testing with pre-test counselling and education •  Dried-blood spot testing

•  Interventions to enhance linkage to care •  Facilitated referral for HCV

•  Interventions to enhance HCV treatment •  Integrated care for HCV and drug use delivered by a multidisciplinary team (with or without non-

invasive liver disease assessment) Bajis S, et al. International Journal of Drug Policy 2017

We have a lot of different models - one size will not fit all… HCV testing •  Peer-delivered outreach HCV testing and counselling1 •  Prison-based outreach testing and counselling2 •  Patient referral contact tracing programme with monetary incentive for testing3 •  Rapid HCV antibody testing at community pop-up/mobile clinics or low threshold settings4-6 •  DBS testing7,8 •  Integrated on-site testing, counselling and education9,10 HCV linkage to care •  Patient navigation and facilitated referral for HCV evaluation11-13 •  Nurse-led pre-treatment assessment in prison with specialist support via telemedicine14 •  Non-invasive liver disease assessment using transient elastography with facilitated referral to care7,15-17 •  Integrated HCV care in drug & alcohol setting/primary care, including on-site HCV assessment with/without peer support18-23 •  Community-based nurse-led HCV evaluation and liver disease assessment using transient elastography; and subsequent referral to specialist for treatment24 •  HCV bridge counsellor employed to provide education, scheduling of specialist appointments, home visits to locate individuals, incentives and transportation10 •  Multidisciplinary mobile clinic offering point of care testing, counselling and liver disease assessment using transient elastography6 HCV treatment uptake •  Integrated HCV care in drug & alcohol setting/primary care, including on-site HCV assessment with/without peer support19,20,25 •  Integrated HCV care and drug use care in primary care, with/without onsite treatment22,23,26,27 •  Community-based nurse-led HCV evaluation, including ordering of blood tests and disease assessment using transient elastography; and subsequent referral to

specialist for treatment24 •  Patient navigation including motivational interviewing and treatment readiness counselling13

1) Aitken CK, Drug and Alcohol Review 2002; 2) Skipper C, Gut 2003; 3) Brewer DD, Eurosurveillance 2009; 4) Conway B, J Hepatitis 2015; 5) Cosmaro ML, Infection 2011; 6) Remy AJ, U Euro Gastro J 2015; 7) O'Sullivan M, J Hepatology 2015; 8) Tait JM, J Hepatology 2013; 9) Pace CA, J Gen Int Med 2014; 10) Sena AC, Pub Health Rep 2016; 11) Trooskin SB, J Gen Int Med 2015; 12) Islam MM, J Sub Abuse Treat 2012; 13) Ford MM, Clin Inf Dis 2016; 14) Lloyd AR, Clin Inf Dis 2013; 15) Foucher J, J Viral Hep 2009; 16) Marshall A, Int J Drug Pol 2015; 17) Lambert JS, J Hepatology 2016; 18) Alavi M, Clin Infect Dis 2013; 19) Grebely J, Eur J Gastro Hep 2010; 20) Keats J, Int J Drug Pol 2015; 21) Martinez AD, J Viral Hep 2012; 22) Harris KA, J Addict Med 2010; 23) Malnick S, Israel J Psychiatry Rel Sci 2014; 24) Wade AJ, PLOS ONE 2015; 25) Newman AI, Can J Gastro 2013; 26) Seidenberg A, BMC Infect Dis 2013; 27) Woodrell C, J Addict Med2015; 28) Bajis S, et al. Int J of Drug Pol 2017.

How to broaden access to HCV services?

•  Implement HCV care services in settings where people are already accessing other services (e.g. drug treatment clinics, community clinics, prisons, NSPs)

•  Outreach by specialists and/or nurses from tertiary-care hospitals

•  Patient- or peer-navigators to facilitate linkage to care (or between community and hospitals)

•  Education and training of providers in the community to enable broadened prescribing (e.g. drug and alcohol specialists or trained general practitioners)

Task shifting to community-based non-specialist providers •  Three hour education and training •  Overall SVR12 following sofosbuvir/ledipasvir was 87% •  No difference by provider type: NPs, 90%; PCPs, 88%; and specialists, 85%

Kattakuzhy S, et al. Ann Intern Med. 2017

HCV education and training in primary care and D&A settings

http://inhsueducation.org/canada/

Is HCV elimination among PWID really feasible?

DAA reimbursement restrictions must be removed

Marshall A, et al. Lancet Gastroenterology and Hepatology 2017

46% >F2 (advanced disease) 17% drug/alcohol use 94% specialist prescribing

The removal of DAA restrictions is starting to occur

Marshall A, et al. Journal of Hepatology 2018 29% >F2 (advanced disease)

May 2015: “Access for all to highly effective HCV treatment a priority” December 2015: $AUD1 billion for HCV treatment over 5 years (2016-2020) “a watershed moment”

Health Minister: Sussan Ley

March 2015: PBAC recommends funding of IFN-free DAA regimens ($AUD15,000/ICER)

Australia one of the first countries to make “access for all” public health policy

Features •  Unrestricted DAA access; no cap on treatment numbers; cap on expenditure •  Risk-sharing arrangement with pharma (2016-2020): cost/patient AU$10,000 (2016) •  Involvement of non-specialists in DAA prescribing •  Minimal administration for clinicians; minimal co-payment for patients (Euro 4-25/month) Development •  National Hepatitis C Strategies since 2000 (4th currently, 5th soon) •  Bipartisan support and political leadership •  Partnership approach: government, community, clinical, academic reps •  Funding of hepatitis C and drug user community organisations •  General practitioner and addiction medicine clinician education since early 2000s

53

Key features and development of DAA program

Tolerability

Effic

acy

PEG-IFN + RBV + SOF (GT 4-6) SOF/VEL (GT1-6) EBR/GZR (GT1, 4) PrOD + RBV (GT1, 4) SOF/LDV (GT1) SOF + DCV (GT1, 3) SOF + RBV (GT2, 3)

12 weeks

Australian Government-funded DAAs

Gilead Sciences, SOVALDI Australian PI, March 2015; Gilead Sciences, HARVONI Australian PI, June 2016; Bristol-Myers Squibb, DAKLINZA Australian PI, August 2016; AbbVie; VIEKIRA PAK-RBV PI, August 2016,

Merck Sharp & Dohme, ZEPATIER ARTG August 2016; Gilead Sciences, EPCLUSA Australian PI August 2017 54

8 weeks

24 weeks

227,000

Pre-cirrhosis, naive Pre-cirrhosis, experienced Cirrhosis

Australians live with chronic HCV infection

Epidemiology of HCV in Australia: 2015

Slide from Gregory Dore

0

5000

10000

15000

20000

25000

30000

35000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

IFN-based IFN-free

IFN-free DAA = 61,085 (26% chronic HCV)

Initial DAA uptake encouraging

Hajarizadeh B, et al. J Gastro Hepatol 2016 [updated]

57 Kirby Institute 2018

DAA treatment numbers have declined DAA initiations/month

Kirby Institute 2017

Gastro ID Other specialist GP Other

0%  10%  20%  30%  40%  50%  60%  70%  80%  90%  100%  

HCV treatment in Australia: Prescriber type

Australia – Treatment among PWID

Iversen J, et al. INHSU 2017, New York, United States, September 6-8, 2017

81%

47%

-

25,000

50,000

75,000

100,000

125,000

150,000

175,000

200,000

225,000

250,000

Living with chronic hepatitis C

Diagnosed with chronic hepatitis C

Hepatitis C RNA tested

Received treatment in 2016

Cured in 2016

14% of those with chronic HCV at start of 2016 received treatment. Of those treated 93% were cured.

Kirby Institute, Annual Surveillance Report 2017

Hepatitis C care cascade: end 2016

Key PWID populations for HCV elimination efforts

Former PWID N=180,000 !

with chronic HCV!

Current PWID

PWID in OST N=24,000

with chronic HCV

N=38,000 With chronic HCV

Prisoners N=40,000

Chronic HCV 25% N=10,000

Bring HCV testing and treatment to the people…

•  Community health centres

•  Drug treatment services •  Prisons

•  Needle and syringe programmes

•  Supervised consumption facilities

•  Homelessness services •  Hospital in-patient

The burden of HCV among PWID is considerable

Degenhardt L, et al. Lancet Global Health 2017, Grebely, et al. Addiction 2018 Under Review

•  6.1M (3.4-9.2) PWID are living with HCV infection (39%)

Recent injecting drug use among all people living with HCV infection

Grebely J, et al. Addiction 2018 Under Review

•  Globally, people with recent injecting drug use comprise 8.5% (UI 4.6-13.1) of all HCV infections •  North America (30.5%, UI 11.7-56.7) •  Latin America (22.0%, UI 15.3-30.4) •  Eastern Europe (17.9%, UI 8.2-30.9)

Harm reduction services remain inadequate globally

Larney S, et al. Lancet Global Health 2017

Only 1% of PWID live in countries with high coverage of both NSP and OST

Is global HCV elimination among PWID really feasible?

Grebely J, et al. Addiction 2018 Under Review

4 countries account for 51% of burden (Russia, United States, China, and Brazil)

Harm reduction services remain inadequate globally

Larney S, et al. Lancet Global Health 2017

Remaining challenges to enhance HCV care in PWID

•  Implementation of strategies to enhance testing and diagnosis •  Further simplification of testing and treatment

•  Continue to address stigma, discrimination, and HCV awareness •  Continue to engage people in care other than HCV (e.g. drug user

health)

•  One size will not fit all – different settings will require different interventions

Remaining challenges to enhance HCV care in PWID

•  Need to remove disease-stage reimbursement restrictions (double restriction)

•  Task shifting to community-based providers (e.g. drug and alcohol

specialists)

•  Education and training of patients, front-line workers, and providers •  Act regionally, but think globally (micro-elimination)

•  Changes in drug policy to enable expansion of OST and NSP globally

Kirby, UNSW Sydney Prof. Gregory Dore Dr. Evan Cunningham Dr. Tanya Applegate Mr. Francois Lamoury A/Prof. Gail Matthews Dr. Behzad Hajarizadeh Ms. Pip Marks Ms. Sophie Quiene NDARC, UNSW Sydney Prof. Louisa Degenhardt Dr. Sarah Larney Dr. Amy Peacock Dr. Janni Leung Ms. Samantha Colledge Prof. Michael Farrell

Acknowledgements

Collaborators Prof. Matt Hickman Prof. Peter Vickerman Dr. Homie Razavi Ms. Emma Day