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HCV The Beginning of the end

Dr John F Dillon. HCV The Beginning of the end. HCV Disease Pathway. 20-30%. Acute infection. Spontaneous cure. 70-80%. ??. Chronic Hepatitis. 20-100%!!!. 1- 4%/annum. Hepatocellular carcinoma. Cirrhosis. Modelled prevalent number of HCV infected IDUs in Scotland

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HCV The Beginning of the end

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  1. Dr John F Dillon HCV The Beginning of the end

  2. HCV Disease Pathway 20-30% Acute infection Spontaneous cure 70-80% ?? Chronic Hepatitis 20-100%!!! 1- 4%/annum Hepatocellular carcinoma Cirrhosis

  3. Modelled prevalent number of HCV infected IDUs in Scotland according to stage of HCV disease, 1960-2030 60 Recovered from HCV 50 Cleared HCV from treatment Mild disease 40 Moderate disease Living IDUs (thousands) 2008 30 Cirrhosis 20 10 0 1960 1980 2000 2020 Calendar year Hutchinson et al. Hepatology 2005

  4. Strategic aims of the Scottish Hepatitis C Action Plan Prevent liver failure and HCC • Treat patients with cirrhosis • However, the treatment is less effective • Treat enough patients early in infection • Find them

  5. Modelled number of IDUs with cirrhosis in Scotland by different uptake rates of HCV antiviral therapy, 2008-2030 Uptake of therapy by 1,000 IDUs per year Uptake of therapy by (up to) 2,000 IDUs per year Uptake of therapy by 225 IDUs per year 3,000 3,000 3,000 Living IDUs with cirrhosis 2,000 2,000 2,000 1,000 1,000 1,000 0 0 0 2010 2020 2030 2010 2020 2030 2010 2020 2030 Compensated cirrhosis Decompensated cirrhosis Cirrhosis prevented from antiviral therapy* HCC Hutchinson, SJ. et al 2008 J Hepatol. 48 (Suppl 2):S297 * Excludes those prevented from antiviral therapy prior to 2008

  6. UPTAKE OF TREATMENT In Scotland, 2002-2012: (a) the number of chronic HCV persons commencing a course of therapy each year, and (b) the cumulative number of patients attaining SVR 4000 1000 3000 800 Number treated. Cumulative SVR 600 2000 400 1000 200 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 No persons commencing treatment Cumulative number of known SVR • Key points: • 1052 patients treated in 2012/13 (marginally below the national target of 1,150) • In the last three years, more than 1,000 patients per year commencing treatment in Scotland • The number of persons known to have attained a SVR, now exceeds 3000 McDonald et al. J Viral Hep; in press

  7. (1a) ATTENDANCE AT SPECIALIST SERVICES (1b) UPTAKE OF TREATMENT Proportion attending a specialist clinic within 12 months of diagnosis, by calendar period, in Scotland. Proportion commencing treatment within 12 months of attendance, by calendar period, in Scotland. 50 50 40 40 30 % Treated 30 % Attended 20 20 10 10 0 0 96-98 99-01 02-04 05-07 08-09 08-09 99-01 02-04 05-07 96-98 PERIOD OF DIAGNOSIS PERIOD OF ATTENDANCE Pre phase II Phase II McDonald et al. J Viral Hep; in press

  8. (4) IMPACT OF SVR Liver deaths and instances of first time liver failure among person with Hepatitis C in Scotland, 1998-2011 (I) LIVER DEATHS (II) FIRST-TIME ADMISSION FOR LIVER FAILURE 150 150 Number of admissions Number of deaths 100 100 50 50 0 0 04 00 02 98 06 08 10 98 00 02 04 06 08 10 Year Death Year Admission McDonald et al. J Viral Hep; in press

  9. Estimated uptake of HCV antiviral therapy, by selected country 1Lettmeier et al. J Hepatol. 2008;49(4)528-36 2Volk et al. Hepatology. 2009; 50:1750-1755 3Gidding et al. J GastroenterolHepatol. 2009; 24(10)1648-54

  10. 53.2 50.0 26.8 Liver 10.5 10.0 5.9 Excess risk* Alcohol 7.4 5.0 4.5 2.0 1.3 1.0 0.5 Non-SVR (N=638) SVR (N=560) Non-cirrhotic SVR (N=503) Spontaneous resolved (N=3,690) Excess risk of a liver and an alcohol related hospital episode post treatment (in SVR & non-SVR patients) AND post diagnosis (in spontaneously resolved patients), compared to the general population * Age, sex & year standardised Innes et al. Hepatology, 2011.

  11. HCV treatment the state of the art Feb 2014 • Interferon Based • Tailored to Genotype • Duration 24-48 weeks • Scotland Genotype 1&3 • SVR G1 70%, G3 75%

  12. Boceprevir regimen in G1 HCV-infected patients Boceprevir dose must not be reduced or restarted once stopped STOP • Treatment-naïve without cirrhosis who achieve undetectable HCV RNA at Weeks 8 and 24 PRlead-in PR BOC + PR BOC + PR* • Non-cirrhotic treatment-naïve with detectable HCV RNA at Week 8 but undetectable at Week 24* • Non-cirrhotic relapsers and partial responders BOC + PR HCV RNA If ≥100 IU/mL discontinue all drugs If detectable discontinue all drugs • Null responders • Patients with cirrhosis 24 0 4 8 12 28 28 36 48 Weeks *This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

  13. Telaprevir regimen in G1 HCV-infected patients Telaprevir dose must not be reduced or restarted once stopped • Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (eRVR) STOP PR Telaprevir + PR PR • Non-cirrhotic naïves and relapsers without eRVR • Partial and null responders • Patients with cirrhosis Weeks 0 4 12 24 36 48 HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36:discontinue PR eRVR: extended rapid virologic response Telaprevir EU SmPC

  14. SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone * * PR48 137/363 BOC RGT 233/368 BOC44/PR48 242/366 n/N = *p<0.001 for both boceprevir arms versus PR48 Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206

  15. ADVANCE and ILLUMINATE: SVR rates with telaprevir therapy versus PR alone 72–75* PR48 158/361 T12PR 659/903 n/N = Sherman KE, et al. Hepatology 2010;52(Suppl.):401AJacobson IM, et al. N Engl J Med 2011;364:2405-16; Sherman KE, et al. CROI 2011. Abstract 957 *p<0.001 vs PR48 in ADVANCE (75% versus 44%)

  16. Treating PWID: who do we mean? No Contact/harm reduction Has changed drug habit to get HCV treatment On or off opiate substitution therapy? Needle exchange Methadone/opiate substitution Last injected this morning or last injected 35 years ago!

  17. What is the best pathway to SVR in PWID patients? Therapy will be required to have • SVR rate similar to RCTs to maintain cost-effectiveness • Re-infection low enough not to reduce cost-effectiveness • Wide enough access to make a difference to overall prevalence Options for patients to enter treatment • Enter maintenance programme, treat quickly • Stabilize drug issues first, then treat • Enhancing delivery • Contingency management • Treat the HCV, ignore the drug habit RCTs: randomized control trials

  18. PWID: not a barrier to SVR in OST therapy 80 70 60 50 SVR achieved (%) 40 30 20 10 19/36 12/39 11/31 56/86 33/43* 33/43* 0 G1 Non-G1 Non-IDU Active IDU Ex-IDU Jafferbhoy H, et al. J Viral Hepat. 2012:19(2):112–9 *ex-IDU vs active IDU; P=0.02

  19. The Future

  20. SOF Phase 3 Analysis in Patients with Traditional Negative FactorsVirologic Response: SVR12 in NEUTRINO GT 1,4,5,6 Race (Non-Black vs. Black) Obesity (BMI < vs. ≥ 35 kg/m2) IL28B GT (Non-TT vs. TT) < 35 kg/m2 ≥ 35 kg/m2 Non-TT TT Non-Black Black 100 100 100 91 91 91 90 86 87 80 80 80 60 60 60 SVR12 (%) 40 40 40 20 20 20 44/51 251/276 47/54 248/273 41/45 254/282 0 0 0 Mangia A, et al. AASLD 2013. Washington, DC. #1115

  21. NUC NS5B inhibitor sofosbuvir & Daclatasvir± Ribavirin (geno 1, n =45) Sulkowski M, et al. J Hepatol 2012; 56: S1422

  22. QUEST-1: Phase 3 trial of Simeprevir + PR in G1 treatment-naive patients Response Guided Therapy criteria met by 85% SVR in 91% of RGT patients No incremental rash/anemia Hyperbilrubinemia A NS3a PI a replacement for Boceprevir or telaprevir Jacobson IM et al, EASL 2013, Amsterdam, #1425

  23. AbbVie Phase III Clinical Program Results fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) twice daily

  24. Strategic aims of the Scottish Hepatitis C Action Plan Prevent liver failure and HCC • Treat patients with cirrhosis • However, the treatment is less effective • Treat enough patients early in infection • Find them Prevent infection • Treatment as prevention

  25. CURRENT HCV PREVENTION INTERVENTIONS • In developed country settings, people who inject drugs (PWID) contribute to the majority (>80%) of HCV transmission • Pooled UK evidence for impact of harm reduction on HCV incidence1 • Opiate substitution therapy (OST) or high coverage needle and syringe programmes (NSP) alone reduces an individual’s HCV risk by ~50% • In combination, reduces HCV risk by ~80% • Modelling indicates OST and NSP likely important in preventing very high HCV prevalences in UK, BUT insufficient to reduce HCV to very low levels2 [1] Turner K et al. Addiction 2011; 106:1978-88 [2] Vickerman P et al. Addiction2012;107:1984-1995.

  26. How much treatment for prevention? 100 90 80 70 Annually 60 No scale-up Relative prevalence reduction (%) at 15 years (2027) 50 Scale-up to 10/1,000 PWID 40 Scale-up to 20/1,000 PWID 30 Scale-up to 40/1,000 PWID 20 Scale-up to 80/1,000 PWID 10 0 Edinburgh 25% baseline chronic prevalence Melbourne 50% baseline chronic prevalence Vancouver 65% baseline chronic prevalence Martin NK, et al. J Hepatol 2011;54:1137–44 Bars indicate the mean relative prevalence reductions; whiskers represent the 95% credibility interval for the simualtions

  27. DYNAMIC HCV TRANSMISSION MODEL Non-SVR infected PWID Allow for re-infection Antiviral treatment New PWID Uninfected PWID Chronically infected PWID Spontaneous clearance Cease/die Acutely infected PWID Infection

  28. ADDITIONAL RISK HETEROGENEITY High risk, Off OST • PWID cycle through various risk and intervention states, associated with different risks of HCV acquisition • Allows for examination of targeting strategies High risk, On OST Low risk, Off OST Low risk, On OST Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention among people who inject drugs: modeling treatment scale-up in the age of direct acting antivirals. Hepatology 2013

  29. RESULTS: EDINBURGH IFN-free DAAs Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention among people who inject drugs: modeling treatment scale-up in the age of direct acting antivirals. Hepatology 2013

  30. SENSITIVITY ANALYSIS • Delaying initiation of IFN-free DAA scale-up by 4 yrs reduces impact by over 20% • Less impact seen with shorter injecting duration • Impact not sensitive to changes in assumptions regarding population heterogeneity and treatment targeting (low risk or on OST) because of movement/cycling between risk states Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention among people who inject drugs: modeling treatment scale-up in the age of direct acting antivirals. Hepatology 2013

  31. UK POOLED EVIDENCE FOR IMPACT OF HARM REDUCTION ON HCV INCIDENCE • Survey data pooled from England, Wales and Scotland • Looked at impact of OST and/or exchanging more syringes than you inject (100%NSP) on an individual’s risk of recent infection Turner K et al. Addiction 2011; 106:1978-88

  32. HCV free survival in needle exchanage

  33. NECESSARY DAA TREATMENT RATES TO HALVE CHRONIC PREVALENCE IN 10 YRS WITH HARM REDUCTION Martin NK, et al.. CID 2013

  34. The drug using population in Tayside Tayside 2,500–3,000 in total 2,200 in methadone program • HCV prevalence: 38% • Risk episodes less than 5 per year 7–800 in needle exchange • HCV prevalence: 29% • Harm reduction vs sharp needles • Risk episodes: 30–300 per year • 20% seroconversion at 1 year 300–900 using without service contact • Risk episodes? prevalence? most high risk

  35. How do you find them • Conventional testing with elution step • HCV ab, HIV ab • HCV-PCR & HBsAg • Works where venepuncture difficult

  36. Eradicate HCV Treat 20–40 very active PWIDs per year Recruit from Needle exchange • Bring a friend, mine the vein • Contingency management • Low threshold methadone End-points • Year 2: numbers in treatment and SVR • Year 5, 7 and 10: HCV prevalence • NESI, Needle exchange, entering methadone NESI: Needle Exchange Surveillance Initiative

  37. Eradicate HCV project: an update 6 months into project 28 patients initiated on to treatment 3 drop-outs Adherence good • Contingency management – most popular • Protein drinks and food vouchers Side-effects appear less than conventional treatment pathways • One rash not on DAA 5/6 SVR

  38. Combo DAA Nuc + 2nd DAA 12 wks No IFN No RGT 95-100% Triple Rx Protease inhibitor + PEG/RBV 24 weeks 75% 2011 2013 Success of HCV Therapy • 0 100% HCV a disease that need not kill anyone HCV a disease we can kill in our life time 75% PEG/RBV 48 weeks 45% Cure rate 50% IFN/RBV 48 weeks 27% IFN-α48 weeks 9% IFN-α24 weeks 4% 25% 0% 1985 20yrs 2004

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