1. www.aids2014.org HCV cure: new treatment paradigms for HCV infection Sanjay Bhagani Consultant Physician/Senior Lecturer Royal Free Hospital/UCL London

2. www.aids2014.org HCV/HIV co-infection – ‘shades of grey’

3. www.aids2014.org 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 Weber R, et al. AIDS 2012. Washington USA. Oral presentation THAB0304. Deaths (%) Liver-related disease Cardio -vascular or other heart disease OtherAIDSNon-AIDS malignancies D:A:D Study: Causes of death in n=49,734 HIV-infected patients followed 1999–2011

5. www.aids2014.org HIV/HCV – double-trouble for the liver Chen J Nat Rev Gastroenterol Hep 2014 doi:10.1038/nrgastro.2014.17

6. www.aids2014.org 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. Immune activation Immune dysfunction HIV/HCV Liver disease HIV disease progression Metabolic disorders GI tract Neurologic disease Cardio- vascular Kidney disease Bone disorders CD4 apoptosis Abnormal T-cell responses and cytokine production Cytotoxic T-cell accumulation in liver Impaired CD4 recovery post-HAART Severe immunodeficiency Diabetes mellitus Insulin resistance Microbial translocation Steatosis Fibrosis Cirrhosis End-stage liver disease Liver-related death Global cognitive impairment Cognitive-motor impairment Dementia Peripheral neuropathy Cerebrovascular disease Acute myocardial infarction Opportunistic infections Wasting syndrome Proteinuria Acute renal failure Chronic kidney disease Osteonecrosis Osteoporosis Bone fracture

8. www.aids2014.org A) Overall-Mortality Observation time[days]] 500040003000200010000 Cumulative survival 1,1,9,7,5,3 P<0.0001 Patients with HAART Patients with dual ARvs untreated Patients 6000 Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227 6000500040003000200010000 1,1,9,7,5,3 B) Liver-related-Mortality P<0.018 Patients with HAART Patients with dual ARvs untreated Patients Overall and Liver-related Mortality - effect of HAART Qurishi N et al. Lancet, 2004 Cumulative survival Observation time[days]] Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227

9. www.aids2014.org ‘Hepatotoxcity’ commoner in co- infected patients Vispo, et al. AIDS 2013:27: 1187

10. HCV/HIV SVR24 with pegIFN and RIBAVIRIN 0 25 50 75 100 G1G2/3 Monoinfection APRICOT ACTG RIBAVIC Laguno et al. PRESCO Genotype 1 SVR 14–38% Genotype 3 SVR 44–73% Genotype SVR (%) 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 Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors..PREVIR..ASVIR …UVIR

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

13. ANRS studies TelapreVIH and BocepreVIH in TE HCV GT 1 HIV/HCV co-infected patients 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 TVR BOC SVR24 (%)SVR12 (%)

14. www.aids2014.org ‘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 1. Dieterich D, et al. EACS 2013. PS9/5; 2. Rockstroh J, et al. EACS 2013.PS9/7; 3. Rodriguez-Torres M, et al. ID Week 2013. Poster #714. Follow-up SMV + PR Week 12 3660 SMV + PR (RGT) Follow-up 4872 PR 24  Partial response  Null response  Cirrhotic patients (F4) Genotype 1a/b HCV treatment-naïve  Prior PR relapsers FDV 120 mg + PR PR or follow up (RGT) FDV 240 mg + PR FDV 240 mg + PR PR PR or follow up (RGT) SOF + PR SVR4SVR12SVR24 Follow-up C212 1 STARTVerso4 2 SOF + PR 3 DAA: direct-acting antiviral agents; FDV: faldaprevir; PR: PEG-IFN/RBV; RGT: response guided therapy; SMV: simeprevir Protease inhibitors Nucleoside polymerase inhibitor Genotype 1a/b  Treatment Naïve  Relapse  15% Compensated Cirrhotic patients (F4) Genotype 1-4 HCV treatment-naïve

16. C212: SVR12 by concomitant ART use (ITT population) *0/1 patients; SVR12, sustained virologic response 12 weeks after end of treatment; n/a, not applicable On ART Not on ART 81 70 62 75 87 78 70/93 8/13 7/10 1/2 15/26 7/9 13/1535/43 n/a 0* 58 50 SVR12 (%)

17. www.aids2014.org STARTVerso4: SVR12 overall population 87/123134/185 221/308 Proportion of patients with SVR12 (%)

18. www.aids2014.org Study 1910: SVR12 Rodriguez-Torres M et al. IDWeek 2013, poster 714 100 80 60 40 20 0 HCV RNA <LLOQ (%) 89% 17/19 GT1 1/1 GT2 2/2 GT3 1/1 GT4 LLOQ: lower level of quantification

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

20. PHOTON-1: Virological response Naggie S, et al. CROI 2014. Oral #26. SVR12 (%) TN TE 12 weeks 24 weeks SOF + RBV 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 16/ 17 28/ 42 22/ 24 23/ 26 87/ 114

21. www.aids2014.org C-Worthy Virologic Response ITT Population 29 21 28 29 30 26 29* 27 30 27 30 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. www.aids2014.org  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. ERADICATE - Treatment Response 13/ 13 37/ 37 13/ 13 37/ 37 13/ 13 30/ 30 12/ 12 22/ 22 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– 1. Sulkowski M, 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. 419/ 521 42/ 53 296/ 327 21/ 23 285/ 363 28/ 38 414/ 520 221/ 308 24 or 48 weeks 12 weeks 24 or 48 weeks 12 or 24 weeks SVR12 (%) CirrhosisExcluded12% 3 9% 4 11% 1 6% 2 15% 5 6% 6 5,6 7,8 NOTE: not head-to-head comparisons. 1,2 3,4

24. www.aids2014.org Adjusted a SVR12 (%) HIV Co-infection No (reference) Yes 72.3 85.0 Genotype 1a (reference) 1b 74.2 83.2 FDV dose 120 mg (reference) 240 mg 79.0 78.3 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) -20-15-100101520 12.6 (5.7, 19.5) 9.0 (4.2, 13.8) 30 5 -0.7 (-5.0, 3.6) -5 a Adjusted for IL28B, race, fibrosis stage, baseline HCV RNA, age, baseline GGT and baseline platelet count. Deitrich, APASL 2014, o681

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

27. www.aids2014.org S.Khoo, 15 th Intl. W’shop, 2014

28. www.aids2014.org 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. www.aids2014.org HCV/HIV co-infection – ‘shades of grey’