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

Transcription

1 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, 17 th May 2018

2 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)

3 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??

4 What have we learned about DAA therapy among PWID?

5 DAA therapy is safe and effective among PWID, even in the realworld

6 Defining populations of PWID Former PWID Current PWID Current PWUD PWID in OST Larney S, et al. Int Journal Drug Policy Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017

7 People receiving OST phase II/III trials 100 OST no OST 94% 96% 94% 97% 96% 98% 96% 96% 96% 98% 92% 95% 80 SVR 12 (%) OBV/PTV/r + DSV + RBV SOF/LDV + RBV SOF/VEL 3 SOF/VEL/VOX 4 GLE/PIB 5 GZR/ELB 6,7 1) Grebely J, et al ILC 2017 (FRI-236). 2) Grebely CID ) Grebely CID ) Grebely J, ILC 2017 (FRI-235). 5) Grebely J, INHSU ) Zeuzem, S. Ann Intern Med ) Dore, GJ Ann Intern Med ) Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017.

8 SVR12 among former/recent PWID % 89% 85% 88% 87% 82% 95% 90% 86% SVR 12 (%) Norton Hull Alimohammadi Bouscaillou Powis Read Litwin Sulkowski Mazhnaya ) Norton B, et al. Int J Drug Pol ) Hull M, et al. INHSU ) Alimohammadi 7 th Canadian HCV Symposium ) Bouscaillou EASL ) Powis J. Int J Drug Policy ) Read P. Int J Drug Policy 2017; 7) Litwin AL, et al. ILC 2017; 8) Sulkowski M, et al. ILC ) Mazhnaya Int J Drug Policy ) Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology 2017.

9 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

10 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 Week 0 Week 12 Sofosbuvir/velpatasvir 400/100 mg od, n=103 Week 24 3 yrs SVR12 Six-monthly follow-up for reinfection Grebely J, et al. The Lancet Gastroenterology & Hepatology 2018

11 Response (%) 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 % 99/103 ETR 94% 97/103 SVR12 Grebely J, et al. The Lancet Gastroenterology & Hepatology 2018

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

13 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

14 Adherent Non-adherent All participants achieved SVR

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

16 SIMPLIFY Drug use during treatment

17 SIMPLIFY - Impact of OST and drug use on SVR

18 We need to acknowledge and accept that HCV reinfection will occur

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

20 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

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

22 HCV testing, linkage to care, treatment Grebely J, Hajarizadeh B, and Dore GJ Nat Rev in Gastroenterology & Hepatology Iversen J, et al. Int J Drug Pol 2017.

23 Global cascade of care for chronic HCV infection Lazarus J, Nat Rev Gastro Hep 2017

24 Innovative strategies to enhance HCV testing and diagnosis are needed

25 The long journey to an HCV diagnosis. Visit #1 Visit #2 Visit #3 Visit #4 Visit #5 Central Lab Central Lab Anti-HCV antibody (Physician) Phlebotomy (Phlebotomist) Antibody test 1-2 weeks Receive diagnosis (Physician) Phlebotomy (Phlebotomist) RNA test 1-2 weeks Receive diagnosis (Physician) Grebely J, Applegate TA, Cunningham P, and Feld JJ Exp Rev Mol Diag 2017

26 Further barriers to HCV testing and diagnosis Poor knowledge and competence of HCV testing among many general practitioners 1-4 Poor knowledge among patients about HCV testing 5-6 Further work is needed to educate patients and providers on HCV testing (e.g. drug and alcohol settings) 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:e ; 3) Gupta L, et al. J Gastroenterol Hepatol. 2006;21: ; 4) Shehab TM, et al. J Viral Hepat. 2001;8: ; 5) Marshall AD, et al. Int J Drug Policy. 2015;26: ; 6) Treloar C, et al. Drug Alcohol Rev. 2012;31:

27 HCV antibody testing with reflex RNA testing Central Lab (%) Order anti-hcv antibody with reflex HCV RNA (Physician) 100% 100% 74% (100% of Ab+) Phlebotomy (Phlebotomist) RNA test 1-2 weeks Receive diagnosis (Physician) 100% 56% 51% (92% of referred) HCV Ab+ Sena Public Health Rep RNA Tested HCV RNA+ HCV RNA+ Referred 1 st appoint

28 HCV antibody testing with reflex RNA testing Central Lab (%) Order anti-hcv antibody with reflex HCV RNA (Physician) 100% 100% 74% (100% of Ab+) Phlebotomy (Phlebotomist) RNA test 1-2 weeks Receive diagnosis (Physician) 100% 56% 51% (92% of referred) HCV Ab+ Sena Public Health Rep RNA Tested HCV RNA+ HCV RNA+ Referred 1 st appoint

29 Advances in diagnostics and point-of-care testing Rapid diagnostic tests Dried blood spot testing Point of care and random access HCV RNA testing Fourati S, et al. INHSU 2017, New York, United States, September 6-8, 2017

30 Rapid HCV antibody testing Central Lab Rapid anti-hcv antibody test (Health care worker) Phlebotomy (Phlebotomist) RNA test 1-2 weeks Receive diagnosis (Physician) Single-center free testing clinic People randomized to interventions for testing of HIV, HBV, and HCV Standard serologybased testing (n=162) Point-of-care rapid testing (n=162) Aware of status 64% (n=104) P< % (n=159) Linked to care 60% P= % Bottero J Open Forum Inf Dis 2017

31 Dried blood spot testing Advantages Dried blood spot sample (Health care worker) Central Lab Antibody test 1-2 weeks Receive diagnosis (Physician) Disadvantages 1) Enhances HCV testing and linkage to care 1) Still requires centralized testing 2) Avoids need for phlebotomy 2) Requires 2 nd 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

32 Dried blood spot testing Advantages Dried blood spot sample (Health care worker) Central Lab Antibody test 1-2 weeks Receive diagnosis (Physician) Disadvantages 1) Enhances HCV testing and linkage to care 1) Still requires centralized testing 2) Avoids need for phlebotomy 2) Requires 2 nd 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

33 Finger-stick testing for HCV RNA detection 60 mins 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 ) McHugh J Clin Micro 2017, Grebely Lancet Gastro Hep 2017, Lamoury Journal of Infectious Diseases 2018

34 Moving to a single-visit hepatitis C diagnosis Grebely J, et al Exp Rev Mol Diag 2017

35 Simplification of existing models of care and interventions is critical

36 What is a model of care? WHERE WHAT WHO HOW

37 Settings, services, and providers Settings Services Providers Sexual health NSP services Primary health care / GPs Drug and alcohol clinics Pharmacies Prisons Community health centres Task-shifting Specialists Drug and alcohol specialist Primary care providers Nurses Pharmacists Peer support workers Others

38 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

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

40 Why is there a drop from diagnosis to DAA therapy? % 73% Why the drop? 52% (71% of Ab+) (%) ,497 1,201 1, ,497 HCV RNA+ Referred 1 st appoint Patel RC Public Health Rep 2016

41 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

42 Traditional referral model of HCV testing and treatment Sexual health Tertiary care hospital Community health centres Drug and alcohol clinics Prisons Primary health care / GPs Needle and syringe programmes Pharmacies

43 Redefining models of HCV testing and linkage to care Need to bring HCV care to the community where patients access services Sexual health Tertiary care hospital Community health centres Drug and alcohol clinics Prisons Primary health care / GPs Needle and syringe programmes Pharmacies

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

45 We have a lot of different models - one size will not fit all HCV testing Peer-delivered outreach HCV testing and counselling 1 Prison-based outreach testing and counselling 2 Patient referral contact tracing programme with monetary incentive for testing 3 Rapid HCV antibody testing at community pop-up/mobile clinics or low threshold settings 4-6 DBS testing 7,8 Integrated on-site testing, counselling and education 9,10 HCV linkage to care Patient navigation and facilitated referral for HCV evaluation Nurse-led pre-treatment assessment in prison with specialist support via telemedicine 14 Non-invasive liver disease assessment using transient elastography with facilitated referral to care 7,15-17 Integrated HCV care in drug & alcohol setting/primary care, including on-site HCV assessment with/without peer support Community-based nurse-led HCV evaluation and liver disease assessment using transient elastography; and subsequent referral to specialist for treatment 24 HCV bridge counsellor employed to provide education, scheduling of specialist appointments, home visits to locate individuals, incentives and transportation 10 Multidisciplinary mobile clinic offering point of care testing, counselling and liver disease assessment using transient elastography 6 HCV treatment uptake Integrated HCV care in drug & alcohol setting/primary care, including on-site HCV assessment with/without peer support 19,20,25 Integrated HCV care and drug use care in primary care, with/without onsite treatment 22,23,26,27 Community-based nurse-led HCV evaluation, including ordering of blood tests and disease assessment using transient elastography; and subsequent referral to specialist for treatment 24 Patient navigation including motivational interviewing and treatment readiness counselling 13 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.

46 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)

47 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

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

49 Is HCV elimination among PWID really feasible?

50 DAA reimbursement restrictions must be removed 17% drug/alcohol use 46% >F2 (advanced disease) 94% specialist prescribing Marshall A, et al. Lancet Gastroenterology and Hepatology 2017

51 The removal of DAA restrictions is starting to occur 29% >F2 (advanced disease) Marshall A, et al. Journal of Hepatology 2018

52 Australia one of the first countries to make access for all public health policy March 2015: PBAC recommends funding of IFN-free DAA regimens ($AUD15,000/ICER) May 2015: Access for all to highly effective HCV treatment a priority Health Minister: Sussan Ley December 2015: $AUD1 billion for HCV treatment over 5 years ( ) a watershed moment

53 Key features and development of DAA program Features Unrestricted DAA access; no cap on treatment numbers; cap on expenditure Risk-sharing arrangement with pharma ( ): 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 (4 th currently, 5 th 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

54 Australian Government-funded DAAs Efficacy 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) 24 weeks 12 weeks 8 weeks 54 Tolerability 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

55 Epidemiology of HCV in Australia: ,000 Australians live with chronic HCV infection Pre-cirrhosis, naive Pre-cirrhosis, experienced Cirrhosis Slide from Gregory Dore

56 Initial DAA uptake encouraging IFN-based IFN-free IFN-free DAA = 61,085 (26% chronic HCV) Hajarizadeh B, et al. J Gastro Hepatol 2016 [updated]

57 DAA treatment numbers have declined DAA initiations/month 57 Kirby Institute 2018

58 HCV treatment in Australia: Prescriber type Gastro ID Other specialist GP Other 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Kirby Institute 2017

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

60 Hepatitis C care cascade: end , , ,000 81% 175, , , ,000 75,000 50,000 25,000 47% 14% of those with chronic HCV at start of 2016 received treatment. Of those treated 93% were cured. - Living with chronic hepatitis C Diagnosed with chronic hepatitis C Hepatitis C RNA tested Received treatment in 2016 Cured in 2016 Kirby Institute, Annual Surveillance Report 2017

61 Key PWID populations for HCV elimination efforts Former PWID N=180,000! with chronic HCV! Current PWID N=38,000 With chronic HCV PWID in OST N=24,000 with chronic HCV Prisoners N=40,000 Chronic HCV 25% N=10,000

62 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

63 The burden of HCV among PWID is considerable 6.1M ( ) PWID are living with HCV infection (39%) Degenhardt L, et al. Lancet Global Health 2017, Grebely, et al. Addiction 2018 Under Review

64 Recent injecting drug use among all people living with HCV infection Globally, people with recent injecting drug use comprise 8.5% (UI ) of all HCV infections North America (30.5%, UI ) Latin America (22.0%, UI ) Eastern Europe (17.9%, UI ) Grebely J, et al. Addiction 2018 Under Review

65 Harm reduction services remain inadequate globally Only 1% of PWID live in countries with high coverage of both NSP and OST Larney S, et al. Lancet Global Health 2017

66 Is global HCV elimination among PWID really feasible? 4 countries account for 51% of burden (Russia, United States, China, and Brazil) Grebely J, et al. Addiction 2018 Under Review

67 Harm reduction services remain inadequate globally Larney S, et al. Lancet Global Health 2017

68 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

69 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

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

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