The new Treatments The old problem Dr John F Dillon

Curing one person Curing a population one person at a time

Cirrhosis prevented from antiviral therapy* Living IDUs with cirrhosis ,000 2,000 3, ,000 2,000 3, ,000 2,000 3,000 Decompensated cirrhosis HCC * Excludes those prevented from antiviral therapy prior to 2008 Compensated cirrhosis Uptake of therapy by 225 IDUs per year Uptake of therapy by 1,000 IDUs per year Uptake of therapy by (up to) 2,000 IDUs per year Curing one person Curing a population one person at a time

SVR = Cure SVR rate of 70% Means 7 out of 10 people are cured 100% SVR 3 out of 10 are not cured 0% SVR If we had prediction tools

HCV Therapy 0% 25% 50% 75% 100% Cure rate IFN-α 48 weeks 9% IFN-α 24 weeks 4% IFN/RBV 48 weeks 27% PEG/RBV 48 weeks 45% Triple Rx Protease inhibitor + PEG/RBV 24 weeks 75% PEG/RBV + 2 nd DAA 12 weeks 90% Combo DAA 8-12 weeks No IFN No RGT 95%2015

Genotype 1

Error bars represent 95% confidence intervals GT 1, 4, 5, 6 Treatment-Naïve: SOF+PEG-IFN+RBV x 12 Weeks NEUTRINO Primary Endpoint and Virologic Response  Study met primary endpoint of superiority over historical control rate of 60% ( P <0.001) On treatment 299/327321/325326/327 Week 2Week 4Week 12/EOT Patients with HCV RNA <LLOQ (%) 90 Post-treatment Week /327 Lawitz E, et al. EASL Amsterdam, The Netherlands. Oral #1411 Lawitz E, et al. N Engl J Med Apr 23 [Epub ahead of print]  Relapse accounted for all virologic failures  No S282T mutations observed by population or deep sequencing (1% cutoff) > HCV1/UK/13-05/ABAR/1201c

QUEST-1: Phase 3 trial of Simeprevir + PR in G1 treatment-naive patients 10 Jacobson IM et al, EASL 2013, Amsterdam, #1425 A NS3a PI a replacement for Boceprevir or telaprevir Response Guided Therapy criteria met by 85% SVR in 91% of RGT patients No incremental rash/anemia Hyperbilrubinemia

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

SVR rates of LDV/SOF ± RBV in GT 1 patients 1. Afdhal N, et al. N Engl J Med 2014;370:1889–98; 2. Kowdley K, et al. N Engl J Med 2014;370:1879–88; 3. Afdhal N, et al. N Engl J Med 2014;370:1483–93 Ledipasvir is an investigational agent and not approved for use in HCV by the EMA LDV: ledipasvir; W: weeks ION-1 Treatment-naïve including cirrhotics (N=865) 1 ION-2 Treatment-experienced including cirrhotics (N=440) 3 ION-3 Treatment-naïve non-cirrhotic (N=647) LDV/SOF + RBV 12 Weeks24 Weeks12 Weeks24 Weeks 12 Weeks SVR12 (%) 8 Weeks 107/ / / / / / / / / / / 216 LDV/SOF 8W LDV/SOF 12W LDV/SOF 24W

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 StudyPatientsTreatment RegimenSVR 12 PEARL-II (12 weeks) GT1b treatment- experienced (N=179) AbbVie regimen + RBV (n=88) 97% (85/88) AbbVie regimen only (n=91) 100% (91/91) PEARL-III (12 weeks) GT1b treatment-naive (N=419) AbbVie regimen + RBV (n=210) 99% (209/210) AbbVie regimen only (n=209) 99% (207/209) PEARL-IV (12 weeks) GT1a treatment-naive (N=305) AbbVie regimen + RBV (n=100) 97% (97/100) AbbVie regimen only (n=205) 90% (185/205) TURQUOISE-II (12 & 24 weeks) GT1 treatment-naive and treatment-experienced with compensated cirrhosis (N=380) AbbVie regimen + RBV, 12 weeks (n=208) 92% (191/208) AbbVie regimen + RBV, 24 weeks (n=172) 96% (165/172) SAPPHIRE-I (12 weeks) GT1 treatment-naive (N=631) AbbVie regimen + RBV (n=473) 96% (455/473) SAPPHIRE-II (12 weeks) GT1 treatment-experienced (N=394) AbbVie regimen + RBV (n=297) 96% (286/297)

Genotype 3 The new tough kid on the block

SVR12 Rates Across SOF-Based Studies HCV GT 3 Patients Treatment-Naïve Treatment-Experienced Lawitz E, et al. N Engl J Med May 16;368(20): Zeuzem S, et al. AASLD Washington, DC. #1085. Jacobson IM, et al. N Engl J Med May 16;368(20): Lawitz E, et al. AASLD Washington, DC. Oral #LB-4. Noncirrhotic Cirrhotic 61% 87% 60% SVR12 (%) 89/145 86/92 FUSION SOF RBV 16 wk VALENCE SOF + RBV 24 wk LONESTAR-2 SOF + PegIFN + RBV 12 wk 87/100 14/23 83% 10/12 92% 94% 12/13 25/40 63% 27/45 83% 10/12 68% 21% 61% 34% 0% 20% 40% 60% 80% 100% FISSION SOF + RBV 12 wk VALENCE SOF + RBV 24 wk 13/38 POSITRON SOF + RBV 12 wk 57/84 3/14 HCV GT 3 patients treated with SOF + RBV for 24 weeks or SOF + RBV + PegIFN for 12 weeks achieved high SVR rates regardless of presence of cirrhosis or treatment experience

NS3/NS4A PROTEASE INHIBITORS  BOCEPREVIR  TELAPREVIR  SIMEPREVIR  FALDAPREVIR  VANIPREVIR (MK-7009)  DANOPREVIR  ASUNAPREVIR  ABT-450  MK-5172  SOLAPREVIR  GS-9451

POLYMERASE INHIBITORS (NS5b) NUCLEOSIDE –MERICITABINE NUCLEOTIDE –SOFOSBUVIR –VX-135 NON-NUC’s –ABT-072 –ABT-333 –BI

NS5A COMPLEX INHIBITORS DACLATASVIR ABT-267 LEDIPASVIR MK-8742 ACH-3102 PP-1668

CYCLOPHILIN INHIBITORS ALISPORIVIR TLR7-INHIBITOR GS-9620 NOVEL INTERFERONS LAMBDA-IFN

Future treatment Genotype 1 SVR better than 95% with 2 or 3 oral drugs for 8-12 weeks OR Interferon plus 1 or 2 drugs for 12 weeks Genotype 3 SVR about 90% Interferon plus 2 oral drugs 12 weeks 2 or 3 Oral drugs 24 weeks With Prediction Interferon/ribavirin 16 weeks

So back to treating one person The new treatments are much more expensive SO Get a lot more money? In Scotland there will be some new money Treat a lot less people? Use some of the old treatments in some people. Including a bit of Interferon So what is acceptable

10 YEAR RELATIVE PREVALENCE REDUCTIONS WITH COMBINING OST/NSP/TREATMENT: NO BASELINE COVERAGE OF OST/NSP AND USING DAAs Martin NK, Hickman M, Hutchinson SJ, Goldberg DJ, and Vickerman P. Combination interventions to prevent HCV transmission among people who inject drugs: modelling the impact of antiviral treatment, needle and syringe programmes, and opiate substitution therapy. Clinical Infectious Diseases % chronic prevalence40% chronic prevalence 60% chronic prevalence Large (>40%) reductions in prevalence require treatment in all settings

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