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HCV cure: new treatment paradigms for HCV infection

HCV cure: new treatment paradigms for HCV infection. Sanjay Bhagani Consultant Physician/Senior Lecturer Royal Free Hospital/UCL London. HCV/HIV co-infection – ‘shades of grey’. Outline. Impact of HCV in the HIV-infected patient The importance of treating HCV

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HCV cure: new treatment paradigms for HCV infection

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  1. HCV cure: new treatment paradigms for HCV infection Sanjay Bhagani Consultant Physician/Senior Lecturer Royal Free Hospital/UCL London

  2. HCV/HIV co-infection – ‘shades of grey’

  3. Outline • Impact of HCV in the HIV-infected patient • The importance of treating HCV • PegIFN/ribavirin – a bygone era • DAAs for HCV and HCV/HIV • IFN ‘sparing’ and IFN-free regimens • Is this still a ‘Special Population’? • New Guidelines

  4. D:A:D: Liver-related death is a frequent cause of non-AIDS death in HIV-infected patients D:A:D Study: Causes of death in n=49,734 HIV-infected patients followed 1999–2011 Deaths (%) Non-AIDS malignancies AIDS Cardio-vascular or other heart disease Other Liver-related disease Weber R, et al. AIDS 2012. Washington USA. Oral presentation THAB0304.

  5. HIV/HCV – double-trouble for the liver Chen J Nat Rev GastroenterolHep 2014 doi:10.1038/nrgastro.2014.17

  6. Faster progression even when controlling for alcohol and other co-morbidities Kirk D, et al. Ann Intern Med 2013; 158: 658

  7. HIV/HCV – a contribution to multiple organ dysfunction Adapted from Operskalski EA and Kovacs A. Curr HIV/AIDS Rep 2011;8:12–22. • Global cognitive impairment • Cognitive-motor impairment • Dementia • Peripheral neuropathy Neurologicdisease • Cerebrovascular disease • Acute myocardial infarction Metabolicdisorders • Diabetes mellitus • Insulin resistance Cardio-vascular Immuneactivation • Steatosis • Fibrosis • Cirrhosis • End-stage liver disease • Liver-related death • Opportunistic infections • Wasting syndrome HIV/HCV HIV disease progression Liverdisease Immunedysfunction • Proteinuria • Acute renal failure • Chronic kidneydisease Kidneydisease GI tract • Microbial translocation • CD4 apoptosis • Abnormal T-cell responses and cytokine production • Cytotoxic T-cell accumulation in liver • Impaired CD4 recovery post-HAART • Severe immunodeficiency • Osteonecrosis • Osteoporosis • Bone fracture Bonedisorders

  8. Overall and Liver-related Mortality - effect of HAART A) Overall-Mortality B)Liver-related-Mortality 1,1 1,1 P<0.018 P<0.0001 Patients with HAART Patients with HAART ,9 ,9 Patientswithdual ARvs untreated Patients Cumulative survival Cumulative survival ,7 ,7 ,5 ,5 Patientswithdual ARvs untreated Patients ,3 ,3 6000 0 1000 2000 3000 4000 5000 0 1000 2000 3000 4000 5000 6000 Observation time[days]] Observation time[days]] Patients under observation: HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1 Untreated-group: 137 94 49 37 32 27 Patients under observation: HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1 Untreated-group: 137 94 49 37 32 27 Qurishi N et al. Lancet, 2004

  9. ‘Hepatotoxcity’ commoner in co-infected patients Vispo, et al. AIDS 2013:27: 1187

  10. HCV/HIV SVR24 withpegIFNand RIBAVIRIN Genotype 1SVR 14–38% Genotype 3SVR 44–73% Monoinfection APRICOT ACTG SVR (%) RIBAVIC Laguno et al. PRESCO 100 25 75 0 50 G1 G2/3 Genotype Adapted from: Fried et al, NEJM 2002;347:975-982, Torriani et al, NEJM 2004;351:438-50, Chung R, et al, NEJM 2004;351:451-9 Carrat F, et al, JAMA 2004;292:2839-42, Laguno et al, AIDS 2004;18:F27-F36, Nunez et al, JAIDS 2007;45:439-44

  11. HCV Life Cycle and DAA Targets – drug classes and nomenclature Receptor bindingand endocytosis Transportand release Fusion and uncoating ER lumen Virionassembly (+) RNA ..PREVIR LD LD LD Translation andpolyprotein processing Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen ..ASVIR …UVIR NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  12. HCV Life Cycle and DAA Targets – drugs Receptor bindingand endocytosis Transportand release Telaprevir Boceprevir Faldaprevir Simeprevir ABT 450/r Asunaprevir MK-5172 Fusion and uncoating ER lumen Virionassembly (+) RNA LD LD LD Translation andpolyprotein processing Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5816 Sofosbuvir NS5A* inhibitors *Role in HCV life cycle not well defined Dasabuvir BMS-791325 Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  13. ANRS studies TelapreVIH and BocepreVIH inTE HCV GT 1 HIV/HCV co-infected patients BOC TVR SVR12 (%) SVR24 (%) 1. Cotte L, et al. CROI 2014; Oral #668; 2. Poizot Martin I, et al. CROI 2014. Oral #659. SVR24 in HIV/HCV PEG-IFN/RBV experienced treated with PEG-IFN/RBV + TVR (69) or BOC (64); 4 weeks lead in + 44 weeks standard + 24 additional weeks if HCV RNA at Week 8 >15IU/mL.ATV/r: ritonavir boosted atazanavir; TE: treatment-experienced

  14. ‘Real-life’ experience PegIFN/R + TVR/BOC – pan-European data Rx discontinuation Rx response ITT and OT Neukam K, Munteanu D, et al. CROI 2014

  15. Second generation DAAs + PEG-IFN/RBV in HIV/HCV co-infected patients Protease inhibitors C2121 PR Follow-up • Genotype 1a/b • HCV treatment-naïve • Prior PR relapsers SMV + PR (RGT) PR Follow-up • Partial response • Null response • Cirrhotic patients (F4) SMV + PR PR Follow-up STARTVerso42 FDV 240 mg + PR PR or follow up (RGT) • Genotype 1a/b • Treatment Naïve • Relapse • 15% Compensated Cirrhotic patients (F4) FDV 240 mg + PR PR FDV 120 mg + PR PR or follow up (RGT) Nucleoside polymerase inhibitor SOF + PR3 SOF + PR Follow-up • Genotype 1-4 • HCV treatment-naïve SVR4 SVR12 SVR24 24 12 48 72 36 60 Week DAA: direct-acting antiviral agents; FDV: faldaprevir; PR: PEG-IFN/RBV; RGT: response guided therapy; SMV: simeprevir 1. Dieterich D, et al. EACS 2013. PS9/5; 2. RockstrohJ, et al. EACS 2013 .PS9/7; 3. Rodriguez-Torres M, et al. ID Week 2013. Poster #714.

  16. C212: SVR12 by concomitant ART use(ITT population) On ARTNot on ART 87 81 78 75 70 62 58 50 SVR12 (%) n/a 0* 70/93 1/2 7/9 35/43 13/15 7/10 15/26 8/13 *0/1 patients; SVR12, sustained virologic response 12 weeks after end of treatment; n/a, not applicable

  17. STARTVerso4: SVR12 overall population Proportion of patients with SVR12 (%) 87/123 134/185 221/308

  18. Study 1910: SVR12 100 80 60 40 20 0 89% HCV RNA <LLOQ (%) 17/19 1/1 2/2 1/1 GT1 GT2 GT3 GT4 LLOQ: lower level of quantification Rodriguez-Torres M et al. IDWeek 2013, poster 714

  19. IFN-free DAA regimens in HIV/HCV co-infected patients PHOTON-1 study NaggieS, et al. CROI 2014. Oral #26 C-WORTHY study Sulkowski M, et al. EASL 2014. Oral #63 LDV/SOF STRERADICATE study Osinusi A, et al. EASL 2014. Oral #14

  20. PHOTON-1: Virological response SVR12 (%) • SOF + RBV • 12 weeks • 24 weeks 22/24 16/17 28/42 23/26 87/114 • TN • TE • No HCV resistance (S282T) observed in virological failures (deep sequencing) • HCV breakthrough in 2 patients due to non-adherence to SOF • HIV breakthrough in 2 patients due to non-adherence to ART Naggie S, et al. CROI 2014. Oral #26.

  21. C-Worthy Virologic Response ITT Population 29 29 30 30 29 29 27 30 29 29 27 30 28 29 26 29* Virologic Failures: 1 relapse in +RBV arm; 2 breakthrough and 1 lost to follow up in No RBV arm * One patient has not yet reached FU4

  22. ERADICATE - Treatment Response • The IFN and RBV free regimen of LDV/SOF in HCV/HIV co-infected patients resulted in SVR12 of 100% in ARV untreated patients and SVR4 of 100% in ARV treated patients • LDV/SOF STR was generally well tolerated with no discontinuations • Actively enrolling ION-4 (target of 300 GT 1 and GT 4 HCV/HIV patients). NCT 02073656. 13/13 37/37 13/13 37/37 13/13 30/30 12/12 22/22 10/10 10/10 Osinusi A, EASL, 2014, O14

  23. SVR12 - PEG-IFN/RBV + TVR, SMV, FDV and SOF in HCV GT1 TN patients: HIV+ vs HIV– Cirrhosis 11%1 6%2 12%3 9%4 15%5 6%6 Excluded SVR12 (%) 28/38 285/363 42/53 419/521 221/308 414/520 21/23 296/327 1,2 3,4 7,8 5,6 24 or 48 weeks 24 or 48 weeks 12 weeks 12 or 24 weeks 1. SulkowskiM, et al. AASLD 2012. Oral #54; 2. Janssen Cilag International. INCIVO (Telaprevir), Summary of product characteristics, September 2011; 3. Dieterich D, et al. CROI 2014 Abstract #24; 4. Jacobson I, et al. AASLD 2013. Poster #1122; 5. Dieterich D, et al. APASL 2014. Oral‘#681; 6. Ferenci P, et al. EASL 2013. Abstract #1416; 7. Rodriguez-Torres M, et al. ID week 2013. Poster #714; 8.Lawitz E, et al. APASL 2013. Oral #LB-02. NOTE: not head-to-head comparisons.

  24. Comparisons of SVR12 rates of interest adjusted for important predictors of response across the STARTVerso studies, excluding PI- and EFV-treated patients from STARTVerso4 Adjusted difference in SVR12 (95% CI) 12.6 (5.7, 19.5) 9.0 (4.2, 13.8) -0.7 (-5.0, 3.6) -5 -20 -15 -10 0 10 15 20 5 a Adjusted for IL28B, race, fibrosis stage, baseline HCV RNA, age, baseline GGT and baselineplatelet count. Deitrich, APASL 2014, o681 30

  25. New online EASL HCV recommendations Same treatment regimens can be used in HIV/HCV patients as in patients without HIV infection, as the virological results of therapy are identical (A1) EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

  26. New EASL HCV recommendations – treatment combination options SOF + PEG-IFN/RBV G1, 2, 3, 4, 5, 6 12 weeks SMV + PEG-IFN/RBV G1, 4 12 weeks + RGT 12/36 G4 Daclatasvir + PEG-IFN/RBV 12 weeks + RGT 12 SOF + RBV 12–24 weeks G1, 2, 3, 4 G1, 4 SOF + SMV (± RBV) 12 weeks SOF + daclatasvir (± RBV) G1, 3, 4 12–24 weeks EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

  27. S.Khoo, 15th Intl. W’shop, 2014

  28. Conclusions • The era of DAA based therapy has arrived • IFN-sparing and IFN-free therapy a reality • Responses in HIV+ similar to HIV- • Beware DDIs • Still a ‘Special Population’ – aggressive, multi-system disease, urgent need of Rx • Need for improved cascade of care and access to Rx

  29. HCV/HIV co-infection – ‘shades of grey’

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