L’UTILIZZO DEI DAAs NEI CONSUMATORI DI SOSTANZE : EFFICACIA E SICUREZZA

Giorgio Barbarini

Già responsabile Unità Semplice “Diagnosi e terapia delle Malattie Infettive correlate alla Tossicodipendenza” DIPARTIMENTO MALATTIE INFETTIVE E TROPICALI Disclosures

I have received funding in the past 2 years for membership of Advisory Boards, for membership of speaker panels and for support for travel to conferences from the following companies: Abbvie Gilead Sciences April 21, 1989 Seroprevalence of : 150 to 200 Million Worldwide

Eastern Europe 10 M Western Pacific 60 M United States Western Europe 5M 5 M Southeast Asia Highest Prevalence: 30-35 M Egypt-4M Americas (45% adults >40y) 12-15 M Africa 30-40M Australia .2 M

1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. 3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html Hepatitis C is the silent global epidemic of the 21st Century

2015 • ~72 million people with viraemic HCV • ~8.1 million people with HCV-related liver cirrhosis • ~261,000 people with HCV-related HCC • ~7000 HCV-related liver transplants • ~370,000 HCV liver-related deaths Viraemic prevalence 0.0–<0.6% 0.6–<0.8% 0.8–<1.3% 1.3–<2.9% 2.9–<6.7%

Blach S, et al. Lancet Gastroenterol Hepatol 2017;2:161–76; The Polaris Observatory. Hepatitis C. Available at: http://polarisobservatory.org/polaris/hepC.htm (accessed April 2017)

The Lancet Global Health – 23 October, 2017

• Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Louisa Degenhardt et al.

• 179 of 206 countries or territories report IDU (31 new compared to 2008) • 15.6 million PWID worldwide – 17.8% HIV+ ( 2.77 million people ) – 52.3% HCV+ (8.2 million people) – 9% Hepatitis B surface antigen (HBsAg)+ – 83% mainly opioids – 33% mainly stimulants – 58% history of incarceration

Proportion of HCV disease burden attributable to injecting drug use

1990 2013

Mean DALYs 1990 Population Mean DALYs Population attributable 2013 attributable factor factor

Western 376,000 44% 705,000 64% Europe

Eastern 73,000 32% 605,000 68% Europe

Global 2,095,000 23% 7,046,000 38%

Degenhardt L, et al. Lancet Infect Dis 2016;16:1385–98 © 2016 The Authors. Published by Elsevier Ltd. Lifecycle of the

DifferentlyEntry from HIV and HBV:

• HCV replication occursAssembly only in cytoplasm Golgi complex Fusion and Viral RNA uncoating • replication Endoplasmic Viral genome is no archived reticuluminto the NS5B genome ofNS5A infectedReplication cells NS3-NS4A complex ° Nonstructural proteins play RNA a key role in the replication NS4B and assembly of new virions Translation Processing This makes HCV curable!!!!

1. Asselah and Marcellin. Liver Int. 2011;31(suppl 1):68; 2. Scheel and Rice. Nat Med. 2013;19:837. Manns, von Hahn, Nat Rev Drug Discov 2013 Beclabuvir AL-335 Vedroprevir ACH-3422 Radalbuvir AL-516 TegobuvirGS- 9669 IDX- 459 MK- 8876 TMC-055/r Ruzasvir Updated to 2018 September Nearly Everyone With HCV Can Now Be Treated Successfully

• Very high SVR rates; therapies highly tolerable • All-oral therapy for almost every pt

• Treatment generally just 12 wks All-Oral Direct- Therapy Acting Antiviral Current 100 Peginterferon 2013 s 90+ 98+ Standard Ribaviri 2011 80 n 2001 70+ 1998 60 55 1991 42 39 40 34

20 16 6 0 IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ DAA + All–Oral IFN 6Mos 12 6 Mos 12 Mos 12 Mos RBV RBV + RBV ± DAA± Mos 12 Mos DAA PegIFN RBV

Goals obtained by achieving Sustained Virological Response (SVR) ≈ cure

• Reduce necroinflammation • Stop fibrosis progression • Prevent cirrhosis & complications • Prevent hepatocellular carcinoma • Reduce extra-hepatic manifestations • Increase survival • No AE

Eradicate the virus (HCV clearance)

Adapted by Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80. Global Call for HCV Elimination

Vision: “A world where viral hepatitis transmission is stopped and everyone has access to safe, affordable, and effective treatment and care” 2020 target: 3 million HCV treated Feasible by scaling up 6 key interventions to high coverage: Hepatitis B vaccination (including birth dose) Safe injection practices and safe blood 2030 Targets Harm reduction for injecting drug users 90% Diagnosed Safer sex (including condom promotion) 80% Treated Hepatitis B treatment 65% Reduced Mortality

Hepatitis C cure WHO. Towards the elimination of hepatitis B and C by 2030. Draft WHO Global Hepatitis Strategy, 2016-2021. Potential benefits of treatment in PWID : Societal benefits and Individual benefits

• Target therapy to those at greatest risk of transmitting (younger injectors or newer initiates to injecting)

Grebely J, Dore GJ. Antiviral Res 2014;104:62–72

Treatment of HCV in PWID

PWID populations included in clinical trials with DAAs

Lifetime PWID

OST

OST and ongoing drug use Ongoing drug use

▪ PWID populations included in clinical trials with DAAs − Patients on OST (Phase 2 AbbVie trial; ION-1, 2 and 3, ASTRAL-1, 2 and 3) − Patients on stable OST, ongoing injection use permitted (C-EDGE CO-STAR) − Patients on and not on OST with ongoing injection use (SIMPLIFY)

Lalezari J, et al. J Hepatol 2015;63:364–9; Grebely J, et al. Clin Infect Dis 2016;63:1405–11; Grebely J, et al. Clin Infect Dis 2016;63:1479–81;

Dore G, et al. Ann Intern Med 2016;165:625–34; DAA: direct-acting antiviral agent; OST: opioid substitution therapy; Grebely J, et al. EASL 2017; Poster #FRI234 PWID: people who inject drugs

Clinical Symptoms and Well-Being of OST Patients after SOF–Based Regimens: DHC-R ‡ Real-World Impact of SVR12 on PROs and Clinical Symptoms in OST Patients: DHC-R

Clinical Symptoms

1230 24 19 19 No OST: 10 Baseline

8 Week 24 8 7 OST: 6 Baseline

6t

4 4 4 4 Week 24 Percen 4 3 2 2 22 22 22 2 2 2 2 2 1 1 1 1 1 0 0 00 0 0 00 0 0 0 0 0 00 00 0 0 0 00 0 0 0 0

In OST patients, a number of clinical symptoms had decreased compared to baseline, including fatigue, abdominal pain, and depression/depressive mood

26 Christensen S, INHSU 2017, Poster #92 German Hepatitis C – Registry (DHC-R) ‡

Real-World Effectiveness of SOF-Based Regimens in Patients with OST

SVR rate by alcohol consumption (ITT)

P=0.215 P=1.000 P=0.123 P=0.013 P=0.004 93 100 90 88 91 8892 88 84 85 82 ° High SVR rates were achieved in 80 OST and Non-OST patients

60 ° Alcohol consumption had no

SVR (%) SVR 40 impact on SVR12 rates

20 380 42 45 14 335 28 2834 225 3225 267 421 50 53 16 368 34 3055 255 3488 305 0 Yes >40 g/day/men ≤40 g/day/men No Total >30g/day women ≤ 30g/day women SVR rate by cannabis consumption (ITT)

P=0.420 P=0.016 P=0.004 93 100 88 8892 88 83 80 ° SVR rates were comparable in 60 patients with and without OST 40 ° Cannabis consumption had no SVR (%) SVR

20 82 34 3142 233 3325 267 impact on SVR12 rates 93 41 3394 264 3488 305 0 Yes No Total SOF-based therapies resulted in high SVR rates in OST and Non-OST patients. Consumption of alcohol and cannabis had no impact on SVR12

27 Günther, INHSU 2017, Poster #91 TraP HepC: 2-Yr Results From HCV Treatment as Prevention in PWID in Iceland ° Dramatic reduction in community viral load and HCV incidence between 2015-2017 at National Addiction Hospital – 53% reduction in new HCV infections – 72% reduction in HCV PCR positivity among PWID from 43% to 12% SVR12, % Treated Pts (N P = 518) Current IVD use 87 .0033 (last 6 mos) Tyrffingsson T, et al. EASL 2018. Abstract PS-095. Not currently 95 using IVD Homeless 74 .0005 Not homeless 94 Epatite C. Lorenzin: "Nuovi farmaci per tutti, nessuna selezione dei pazienti. Piano nazionale per eradicare la malattia : 80.000 trattati l’anno x 3 anni (1.500.000 E in bilancio).” Criteri AIFA da marzo 2017 Criterio 1: Pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie resettive chirurgiche o loco-regionali non candidabili a trapianto epatico nei quali la malattia epatica sia determinante per la prognosi. Criterio 2: Epatite ricorrente HCV-RNA positiva del fegato trapiantato in paziente stabile clinicamente e con livelli ottimali di immunosoppressione. Criterio 3: Epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B, insufficienza renale). Criterio 4: Epatite cronica con fibrosi METAVIR F3 (o corrispondente Ishack). Criterio 5: In lista per trapianto di fegato con cirrosi MELD <25 e/o con HCC all'interno dei criteri di Milano con la possibilità di una attesa in lista di almeno 2 mesi. Criterio 6: Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo in paziente stabile clinicamente e con livelli ottimali di immunosoppressione. Criterio 7: Epatite cronica con fibrosi METAVIR F2 (o corrispondente Ishack) e/o comorbilità a rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di fegato non virali, diabete mellito in trattamento farmacologico, obesità (body mass index ≥30 kg/m2), emoglobinopatie e coagulopatie congenite]. Criterio 8: Epatite cronica con fibrosi METAVIR F0-F1 (o corrispondente Ishack) e/o comorbilità a rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di fegato non virali, diabete mellito in trattamento farmacologico, obesità (body mass index ≥30 kg/m2), emoglobinopatie e coagulopatie congenite]. Criterio 9: Operatori sanitari infetti. Criterio 10: Epatite cronica o cirrosi epatica in paziente con insufficienza renale cronica in trattamento emodialitico. Criterio 11: Epatite cronica nel paziente in lista d'attesa per trapianto di organo solido (non fegato) o di midollo. ò Regimi terapeutici IFN-free approvati e rimborsati in Italia per la terapia anti HCV

GT

Glecaprevir + Pibrentasvir All

Sofosbuvir + Velpatasvir (± RBV) All

Grazoprevir + Elbasvir (± RBV) 1, 4

Sofosbuvir + Velpatasvir + Voxilaprevir 1

Sofosbuvir + Velpatasvir + Voxilaprevir All EASL 2018 HCV Treatment Guidelines ° Recommendations for treatment-naive patients and patients previously treated with pegIFN/RBV ± SOF or SOF + RBV, ± compensated cirrhosis HCV SOF/VE GLE/PI SOF/VE LDV/SO EBR/GZ OBV/PT Genoty L B L/ VOX F R V/ RTV pe + DSV

1a Yes Yes No* Yes† Yes‡ No 1b Yes Yes No* Yes Yes Yes 2 Yes Yes No* No No No 3 Yesǁ Yes Yes§ No No No 4 Yes Yes No* Yes† Yes# No 5 or 6 Yes Yes No* Yes† No No *Triple combination effective but not needed because double combinations comparably effective. . ‡Tx naive or tx experienced without cirrhosis or with compensated cirrhosis and HCV RNA ≤ 800,000 IU/mL. ǁTx naive or tx experienced without cirrhosis. §Tx naive or tx experienced with compensated cirrhosis. #Treatment naive without cirrhosis or with compensated cirrhosis and HCV RNA ≤ 800,000 IU/mL. EASL HCV Guidelines. 2018. In press.

PWID Population Definitions Marginalized: - Socioeconomic Lifetime PWID - Prisoners - Indigenous

Current PWID

PWID in OST PWID Population Definitions

Past times PWID

Past PWID

PWID in OST Snapshot of PWID

Male Single

Poor quality of life Limited access to healthcare Homeless or living in temporary accommodation Alcohol consumption (shelters, prison) Use of multiple substances Poorly educated (secondary education or less) HIV and/or HBV coinfection ▪ Psychiatric disorders that are common among PWID include: − Anxiety − Bipolar disorder − Depression − Post-traumatic stress − Schizophrenia

SrisBamvita M, Rhodes JM, et al.T. HepatHarm ReductionRes Treat J2014;2014:631481 2013;10:7 ; Profile based on findings of two Canadian studies. PWID: people who inject drugs

Trattamento

HCV RNA + Epatologi-Infettivologi + Ser.D.

Valutazione: Genotipo, Fibroscan (cirrosi/no cirrosi), trattamenti Harm Reduction Program: farmacologici, comorbidità, consumo alcol e/o Training abilità sostanze Kit Riduzione del danno

Presenza criteri Presenza criteri comportamentali clinici e motivazionali

Scelta DAA

Inizio trattamento Compliance (entrambi gli specialisti)

Monitoraggio infettivologico (SVR, comorbidità extraepatiche) Outcome Termine del Trattamento di consumo e comorbidità Controllo virologico a 3 e 6 mesi psichiatriche/comportamentali dall’EOT Follow up Harm Reduction Program: a 3 e 6 mesi Verifica apprendimento/utilizzo misure di Questionario verifica HR riduzione del danno (con specifica scheda di valutazione) 3 e 6 mesi dall’EOT Valutazione QOL a 3 e 6 mesi dall’EOT GESTIONE MULTIDISCIPLINARE INTEGRATA (non solo collaborativa)

LA DECISIONE DI EFFETTUARE IL TRATTAMENTO VIENE ASSUNTA CONGIUNTAMENTE DAL CENTRO SPECIALISTICO E DAL SERD. IL PAZIENTE VIENE TRATTATO NEL SERD, DAGLI OPERATORI DEL SERD DI CONCERTO CON IL CONSULENTE SERD (DOT) IL MONITORAGGIO SUCCESSIVO AL TERMINE DELLA TERAPIA VIENE ESEGUITO PRESSO IL SERD

Reinfection following successful HCV DAA therapy among people with recent injecting drug use: the SIMPLIFY and D3FEAT studies

7th International Symposium on Hepatitis Care in Substance Users Cascais, Portugal19 - 21 September 2018

Evan Cunningham, Grebely J, Dalgard O, Hajarizadeh B, Conway B, Powis J, Bruneau J, Feld JJ, Read P, Cooper C, Amin J, Bruggmann P, Lacombe K, Stedman C, Hellard ME, Marks P, Dunlop A, Quiene S, Moriggia A, Applegate TL, Litwin AH, Matthews GV, and Dore GJ on behalf of the SIMPLIFY and D3FEAT Study Groups “Reinfections are simply an indicator that we are treating the right population. People who become reinfected are not only at risk of HCV infection but likely HCV transmission as well and so treatment among this population is crucial in order to reduce the incidence of new HCV cases. It’s important that reinfection cases are seen in this framework and patients are given access to timely retreatment without any stigma or discrimination.”

A. H . Litwin Medications don’t work in patients who don’t take them - C. Everett Koop, MD The good physician treats the disease ; the best physician treats the patients with the disease

William Osler ORA……. LAVORIAMO INSIEME !!!!!