Case study: the changing IV drug use problem/pattern and what that means to the epidemic

Case study: the changing IV drug use problem/pattern and what that means to the epidemic Mojca Maticic Faculty of Medicine, University of Ljubljana University Medical Centre Ljubljana Slovenia 4th CEE Meeting HCV/HIV: Prague 2018

Disclosure Within the last 36 months: Lecturer: Abbvie, Bayer, Merck, Sandoz Manuscript preparation: Abbvie, Gilead, Merck Travel/accommodational meeting expences: Abbvie, Gilead, Merck No conflict of interest regarding this presentation

Hepatitis C: The first ever curable chronic viral infection in medical history

Hepatitis C: The first ever curable chronic viral infection in medical history Though curable, HCV continues to have a large human, social and economic impact

Global number of deaths continues to rise >400,000 people die each year from HCV-related liver diseases even though HCV is curable >45 deaths every hour >1,095 deaths every day The Boston Consulting Group. Road to Elimination: Barriers and Best Practices in Hepatitis C Management. July 2017.

The natural course of HCV infection with no treatment: It takes >20 years of infection to develop life-threatening conditions 20 40 years + more will die of extrahepatic manifestations For every 100 people infected 75-80 will develop chronic infection 60-70 will develop chronic liver disease 5-20 will develop cirrhosis 1-5 will die of cirrhosis or HCC

Deaths due to HCV-related hepatocellular carcinoma (%) Deaths due to life-threatening conditions of chronic HCV infection after 20-years of follow up Deaths due to HCV-related extrahepatic manifestations (%) NOT cured NOT cured Cured Cured Lee MH et al. J Infect Dis 2012; 2016: 469-77.

Total Viremic Infected (2016) Age distribution of HCV-infected persons in EU in 2015 500,000 450,000 400,000 350,000 300,000 250,000 200,000 150,000 100,000 50,000 - Average age: 54 years The population of HCV-infected has been ageing reaching a critical period for life-threatening conditions to develop Polaris Observatory. Accesses at: http://www.polarisobservatory.com/

PWUD are the driving force of HCV epidemic 80% 60% of new HCV infections of existing HCV infections The Boston Consulting Group. Road to Elimination: Barriers and Best Practices in Hepatitis C Management. July 2017. Accessed 5 July 2018 World Hepatitis Alliance. Available at: http://www.worldhepatitisalliance.org/sites/default/files/resources/documents/holding_governments_accountable_-_civil_society_survey_report.pdf.

Estimated prevalence of injecting drug users by country 15.6 million PWID globally (0.33% of those aged 15 64 years) Degenhardt L et al. Lancet Global Health 2017; 5(12): 1192-207.

Estimated prevalence of injecting drug use by country Europe 15.6 million PWID globally (0.33% of those aged 15 64 years) PWUD Prevalence PWUD N Western 0.34 % 1 million Eastern 1.3 % 3 million Degenhardt L et al. Lancet Global Health 2017; 5(12): 1192-207.

Estimated prevalence of injecting drug use by country Europe 15.6 million PWID globally (0.33% of those aged 15 64 years) PWUD Prevalence PWUD N Western 0.34 % 1 million Eastern 1.3 % 3 million Europe Age >25 y Inject opioids Western 70% 78.3 % Eastern 58% 70% Degenhardt L et al. Lancet Global Health 2017; 5(12): 1192-207.

Estimated anti-hcv prevalence among PWUD by country 15.6 million PWID globally 52.3% anti-hcv positive (= 8.2 million) Degenhardt L et al. Lancet Global Health 2017; 5(12): 1192-207.

Estimated anti-hcv prevalence among PWUD by country 15.6 million PWID globally 52.3% anti-hcv positive (= 8.2 million) Europe Anti-HCV+ prevalence Anti-HCV+ N Western 53 % 0.5 million Eastern 65 % 1.9 million Degenhardt L et al. Lancet Global Health 2017; 5(12): 1192-207.

Anti-HCV seroprevalence among PWUD in Europe 2014-2015 EMCDDA 2017. European Drug Report : Trends and Developments. http://www.emcdda.europa.eu/system/files/publications/4541/tdat17001enn.pdf

What is killing PWID with HCV infection?? Grebely J et al.semin in Liver Dis 2011;31:331-9.

HCV treatment with DAAs EASL 2018 Guidelines

The solution: continuum of services and a cascade-of-care for HCV management WHO Global hepatitis report, 2017. Available at: http://apps.who.int/iris/bitstream/10665/255017/1/who-hiv-2017.06-eng.pdf.

HCV cascade-of-care in PWUD Grebely J, Hajarizadeh B, Dore GJ. Nat Rev Gastroenterol Hepatol 2017; 14: 651-61. Iversen J et al. Int J Drug Pol2017.; 42: 1-6.

Barriers to HCV treatment access in PWUD PRACTITIONER POLICY Lazarus JV, et al. BMC Infect Dis 2014;14(Suppl 6):S16; Grebely J, et al. J Infect Dis 2013;207:S19 25; Harris M, Rhodes T. Harm Reduct J 2013;10:7; Papatheodoridis GV, et al. Liver Int 2014;34:1452 63

Restrictions on access to HCV treatment with DAAs include PWUD in several European countries (N=27) European Liver Patients Association. The 2016 Hep-CORE Report. Brussels: ELPA, 2017.

Barriers to HCV treatment access in PWUD Barriers need to be adressed and solutions need to be found PRACTITIONER POLICY A fundamental dilema: PWUD are difficult to engage in formal healthcare services Lazarus JV, et al. BMC Infect Dis 2014;14(Suppl 6):S16; Grebely J, et al. J Infect Dis 2013;207:S19 25; Harris M, Rhodes T. Harm Reduct J 2013;10:7; Papatheodoridis GV, et al. Liver Int 2014;34:1452 63

A Case study male born in 1971 1991: started iv heroin living with his parents unfinished highschool unemployed (precarious) 1999: entered OST programme (methadone 120 ml qid) tested anti-hcv positive, HCV RNA positive in SLOVENIA

SLOVENIA Anti-HCV positive persons by risk groups (2008-2015) Inhabitants: 2 million 27% 62% Anti-HCV prevalence HCV RNA prevalence N PWUD 0.4% 0.3% 6 8 000 6% Alfaleh FZ, Nugrahini N, Maticic M, et al. J Viral Hep 2015; 22: 42-65. Gregorčič S et al. 3rd CEE Conference on viral hepatitis and HIV, 2017. Poster #13.

SLOVENIA 20 years of policy for HCV management Matičič M et al. Isis 1999; 8: 49-51. Matičič M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Matičič M, Poljak M. Zdrav Vestn 2010: 79. 58-78. National Viral Hepatitis Expert Group. Consensus guidelines for DAA treatment. Ljubljana, December 6, 2017.

SLOVENIA HCV treatment policy National Health Insurance System: treatment for everybody - Nominated specialists (infectologists, hepatologists) - National guidelines Five centers for HCV treatment Historically all the SOC available Direct Acting Antivirals available Indications: 2015/16: F>2 2017: F 2 2018: NO restrictions PWUD: Never contraindicated Matičič M et al. Isis 1999; 8: 49-51. Matičič M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Matičič M, Poljak M. Zdrav Vestn 2010: 79. 58-78. National Viral Hepatitis Expert Group. Consensus guidelines for DAA treatment. Ljubljana, December 6, 2017.

SLOVENIA HCV micro-elimination in 2018: It became feasible in certain high-risk populations Lazarus JV et al. J Hepatol. 2017;67: 665-6. Maticic M et al. EASL ILC 2018. Poster #THU-126.

Percentage of high-risk opioid users receiving drug treatment in European countries EMCDDA 2017. European Drug Report : Trends and Developments. http://www.emcdda.europa.eu/system/files/publications/4541/tdat17001enn.pdf

SLOVENIA 18 Centers for treatment and prevention of drug addiction NIJZ. National Drug Report. 2017 http://www.nijz.si/sites/www.nijz.si/files/publikacije-datoteke/np_2017_zadnja.pdf.

SLOVENIA National healthcare network for HCV management in PWUD INTEGRATED : 18 Centers for treatment and prevention of of drug addiction 5 Centers for treatment of viral hepatitis Maticic M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Maticic M et al. BMC Infect Dis 2014; 14(Suppl 6): 12-3.

SLOVENIA since 2007 An integrated care for HCV treatment n in PWUD involving a multidisciplinary team Councilors: -specially trained nurses Social workers Peers Psychiatrist / psychotherapist Viral hepatitis specialist: Infectologists hepatologists HCV Testing & Treatment & Prevention Other support system: -family -friends -co-workers DT specialists Clinical virologiost Clinical pharmacist Maticic M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Maticic M et al. BMC Infect Dis 2014; 14(Suppl 6): 12-3.

SLOVENIA 2007-2018 National healthcare network for managing HCV in PWUD An integrated approach Maticic M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Maticic M et al. BMC Infect Dis 2014; 14(Suppl 6): 12-3.

SLOVENIA National healthcare network for HCV management in PWUD INTEGRATED : 18 Centers for treatment of drug addiction 5 Centers for treatment of viral hepatitis Maticic M, Kastelic A. Zdrav Vestn 2009; 78: 529-39. Maticic M et al. Suchtmed 2013. 15: 245. Maticic M et al. BMC Infect Dis 2014; 14(Suppl 6): 12-3.

The impact of DAA treatment on prevalence among PWUD a modeling study towards HCV elimination (2016-2026) Frasier H et al. J Hpatol 2018; 68(3):402-11.

A Case study Male, born in 1971, living with his parents, unfinished highschool, unemployed (precarious) 1991: started iv heroin 1999: entered OST programme (methadone 120 ml qid) tested anti-hcv positive, HCV RNA positive vaccinated for hepatitis B motivated for referral to infectologist refuses 2001: referred to infectologist (still in OST programme) fatigue HCV: GT3, ALT 3xUNL, 465 000 IU/mL HCV RNA, liver US normal liver biopsy suggested refuses further referals NO HEALTH PROBLEMS ; does not want to have biopsy! 2004: referred to infectologist (still in OST programme) fatigue HCV: ALT 2xUNL, 165 000 IU/mL HCV RNA PegIFN/RBV suggested (without liver biopsy) refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects! I am fine! Absoultely NO health problems!

A Case study Male, born in 1971, living with his parents, unfinished highschool, unemployed (precarious) 1991: started iv heroin 1999: entered OST programme (methadone 120 ml qid) tested anti-hcv positive, HCV RNA positive vaccinated for hepatitis B motivated for referral to infectologist refuses NO HEALTH PROBLEMS 2001: refered to infectologist (still in OST programme) mild fatigue HCV: GT3, ALT 3xUNL, 465 000 IU/mL HCV RNA, liver US normal liver biopsy suggested refuses further referals 2004: referred to infectologist (still in OST programme) fatigue HCV: ALT 2xUNL, 165 000 IU/mL HCV RNA PegIFN/RBV suggested (without liver biopsy) refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects! I have NO health problems! Do NOT want any biopsy!

A Case study Male, born in 1971, living with his parents, unfinished highschool, unemployed (precarious) 1991: started iv heroin 1999: entered OST programme (methadone 120 ml qid) tested anti-hcv positive, HCV RNA positive vaccinated for hepatitis B motivated for referral to infectologist refuses NO HEALTH PROBLEMS 2001: refered to infectologist (still in OST programme) mild fatigue HCV: GT3, ALT 3xUNL, 465 000 IU/mL HCV RNA, liver US normal liver biopsy suggested refuses further referals NO HEALTH PROBLEMS; does not want liver biopsy 2004: referred to infectologist (still in OST programme) fatigue HCV: ALT 2xUNL, 165 000 IU/mL HCV RNA PegIFN/RBV suggested (without liver biopsy) refuses further referals I have NO health problems! Do NOT want treatment side-effects!

A Case study 2006: refered to infectologist (in detoxication programme) moderate fatigue HCV: ALT nearly normal, 945 000 IU/mL HCV RNA, US slightly enlarged liver PegIFN/RIBA suggested refuses further referals 2011: referred to infectologist (in prison; still in OST programme) extreme fatigue HCV: ALT nearly normal, 1.6 mill. IU/mL HCV RNA, US slightly enlarged liver suggested PegIFN/RBV without liver biopsy refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects!; does not want to have treatment during inprisonment (stigmatisation!) 2015: out of prison; still in OST programme information on DAA tretament option, additional motivation - refuses referals to inf. I have NO health problems! Do NOT want treatment side effects! 2016:still managed in OST programme (Methadone 100 ml qd) Fibroscan inside OST programme (Octobre)

A Case study 2006: referred to infectologist (in detoxication programme) moderate fatigue HCV: ALT nearly normal, 945 000 IU/mL HCV RNA, US slightly enlarged liver PegIFN/RIBA suggested refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects! 2011: referred to infectologist (in prison; still in OST programme) extreme fatigue HCV: ALT nearly normal, 1.6 mill. IU/mL HCV RNA, US slightly enlarged liver PegIFN/RBV suggested without liver biopsy refuses further referals 2015: out of prison; still in OST programme information on DAA tretament option, additional motivation - refuses referals to inf. 2016:still managed in OST programme (Methadone 100 ml qd) Fibroscan inside OST programme (Octobre) Again: NO health problems! Do NOT want treatment side effects and STIGMATISATION!

A Case study 2006: referred to infectologist (in detoxication programme) moderate fatigue HCV: ALT nearly normal, 945 000 IU/mL HCV RNA, US slightly enlarged liver PegIFN/RIBA suggested refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects! 2011: referred to infectologist (in prison; still in OST programme) extreme fatigue HCV: ALT nearly normal, 1.6 mill. IU/mL HCV RNA, US slightly enlarged liver PegIFN/RBV suggested without liver biopsy refuses further referals NO HEALTH PROBLEMS ; does not want to have treatment side effects!; does not want to have treatment during inprisonment (stigmatisation!) 2015: out of prison; still in OST programme information on DAA tretament option, additional motivation refuses referals to infectologist Again: NO health problems!

SLOVENIA Network of Centres for Prevention and Treatment of Drug Addiction Transient elastography introduced in 2016 A transportable Fibroscan - elastography performed in 18 Centers Klesnik M et al. INHSU 2017, New York, September 5-8,2017. Abstract #76.

A Case study 2016: still managed in OST programme (methadone 100 ml qd) severe fatigue Fibroscan offered within OST programme (October) OK, I will do it

A Case study Explanation of the transient elastography result 54.2 kpa http://www.echosenslibrary.com/interpretation-of-liver-stiffness-by-fibroscan-english-vers

Patient reaction after understanding transient elastography result Drug treatment centre Counselling to prevent HCV infection Testing for HCV infection (every 6 12 months) HBV/HAV vaccination Identification of HCV treatment eligible patients Transient elastography on the spot (Fibroscan ) Motivation, assessment Linkage-to-care 54.2 kpa Viral hepatitis centre Medical evaluation/assessment Clinical management Counselling, motivation Treatment (DAAs) Matičič M, Kastelic A. Zdrav Vestn 2009;78:529 39.

A Case study October 2016: immediatelly refered to infectologist still severe fatigue ALT nearly normal, HCV RNA 574 000 IU/mL, AFP negative US: slightly enlarged liver,hiperechogene parenchima, no round lesions Diagnosis: Compensated liver cirrhosis (Child-Pugh A) Co-medications: methadone (no DDI) EXTREMELY MOTIVATED for DAA treatment!!!!! October 2016: introduction of DAAs (sofosbuvir/velpatasvir + RBV, 12 weeks) November 2016 (w4): HCV RNA 57 IU/mL; No treatment AEs January 2017 (w12): HCV RNA negative treatment termination, ETR April 2017 (FU12): HCV RNA negative, AFP negative, US no pathological lesions in liver July 2017 (FU24): HCV RNA negative (SVR24) CURED Refered for FU visits every 6 months (US, AFP)

A Case study Did the story end??? July 2018 (FU70): excellent phisical&psichological condition ALT normal, HCV RNA negative, AFP negative US: slightly enlarged liver, hiperechogene parenchima, two round lesions most probably HCC

A Case study Did the story end??? NO! Fibrosis stage F4: July 2018 (FU70): excellent phisical&psichological condition needs to have FU visits every 6 months (US, AFP) ALT normal, HCV RNA negative, AFP negative US: slightly enlarged liver, hiperechogene parenchima, two round lesions most probably HCC

A Case study January 2018 (FU 48): excellent phisical&psichological condition permanently employed new 28-y old female partner (HCV negative) lives in partner, s appartment attends an IT course (at age of 46) planning to have a child ALT normal, HCV RNA negative, AFP negative US: slightly enlarged liver, hiperechogene parenchima, no round lesions July 2018 (FU70): excellent phisical&psichological condition ALT normal, HCV RNA negative, AFP negative US: slightly enlarged liver, hiperechogene parenchima, two round lesions Hepatocellular carcinoma

What have we learnt from this case study In spite of existing national network for the management of HCV in PWUD that generally yields excellent results, an individual approach is needed to motivate HCV-positive PWUD for linkage-to-care and DAA treatment Results of transient elastograpy, made within OST centers and explained properly may present and excellent motivation for further linkage-to-care and HCV treatment Already existing local facilities and human potenial for diagnosing, linkage-to-care and treatment should be explored and used in an interdisciplinary way

Traditional referral model for HCV testing and treatment Modified from Jphn Dillon. INHSU, September 2018.

Redefining models of HCV testing and linkage-to-care Bring HCV care to the community where patients simply access services Modified from Jphn Dillon. INHSU, September 2018.

The long journey to HCV diagnosis Simplification is needed! Grebely J et al. Exp Rev Mol Diag 2017.

Rapid diagnostic tests needed Point-of-care HCV RNA test: one sep closer to a single-visit diagnosis needs to be more rapid! Real-world performances of HCV RNA quantification: - venepuncture: sensitivity 99%, speificity 96% - modified finger-stick assay: sensitivity 98%, specificity 99% - Xpert HCV VL Fingerstick: sensitivity 100%, specificity 100% McHigh J et al. J Clin Micro 2017. Grebely J et al. Lancet Gasro Hep 2017. Lamcuroury B et al. J Infect Dis 2018.

Simplification of models of care and interventions to access HCV testing and treatment Settings Services Providers Primary healthcare Drug/alcohol clinics N/S programe services STD clinics Pharmacies Community health services Prisons Rapid diagnostic tests Dried blood spot tests Point of care tests Fibroscan One pill a day Specialists General practitioners Addiction therapists Nurses Pharmacists Peers Others Greenman J, et al. J Viral Hepat 2015;22:353 61; Tuaillon E, et al. Hepatology 2010;51:752 8. Bruggman P, Litwin A. Clin Infect Dis 2013;57 (Suppl 2):S56 61; Alavi M, et al. Clin Infect Dis 2014; 57(Suppl2): S62 9; Seidenberg A, et al. BMC Inf Dis 2013; 13: 9; Butler K, et al. J Subst Abuse Treatment 2015;58:90 4; Brunner N, et al. INHSU 2015, Poster #008; Basanta JJA, et al. J Hepatol 2013; 58(Suppl 1):S321.; Dillon JF, et al. HMAP 2016; 1: 2 10. Grebely J et al. Exp Rev Mol Diag 2017.

Simplification of existing models of care to access HCV treatment This is all that we need!!! Modified from Jphn Dillon

A TAKE-HOME MESSAGE One size will not fit all We need multiple models and interventions adapted to specific settings