Advances in the all oral HCV DAA to treat HCV/HIV: No longer a special population? Josep Mallolas Hospital Clínic-University of Barcelona

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1 Advances in the all oral HCV DAA to treat HCV/HIV: No longer a special population? Josep Mallolas Hospital Clínic-University of Barcelona

2 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 2

3 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 3

4 Estimated worldwide numbers of HIV/HCV co-infected individuals HIV 33 million HIV/HCV coinfection up to 10 million HCV million Clausen LN et al. World J Gastroenterol 2014; 20:

5 Prevalence of HCV/HIV co-infection in Europe Prevalence 1960/5957 patients: 33% 1 Center: 20% South: 41% North: 23% East: 47% 1. Rockstroh, JK., et al. Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy. J Infect Dis. 2005; 192: Castro Iglesisas, MA. Epidemiología de la coinfección por VHC y VIH. GH Continuada. enero-febrero Vol. 10 N.º González García, J., et al. Estudio multicéntrico sobre prevalencia de las coinfecciones por virus de hepatitis, indicación de tratamiento de hepatitis crónica C y necesidad de trasplante hepático en pacientes infectados por el VIH en España. Estudio GESIDA 29/02-FIPSE 12185/01Enferm Infecc Microbiol Clin 2005;23(6):

6 Prevalence of HCV-HIV co-infection in Spain HIV 150,000 HCV 450,000 HIV/HCV 50, Encuesta Hospitalaria de pacientes con VIH/sida Ministerio Sanidad. 6

7 Parallel decrease in prevalence if injection drug use and HIV/HCV co-infection in Spain 100 Serial Prevalence, % Year of entry at CoRIS/CoRIS-MD Cachafeiro SP, et al. CID 2009; 48:

8 Changes in patterns of risk behaviors for acquisition of HIV infection in Spain: what is changing? 100 CoRis cohort includijng 7,045 HIV+ patients 80 Risk Category (%) % 68.6% Serrano-Villar S, et al. J Viral Hep 2014; 22:

9 Incidence of acute hep C sexually transmitted is increasing among HIV + MSM HCV incidence in MSM reached 4.1 cases per 100 PY in 2011 (18 fold increase since 1998) Swiss HIV Cohort Study: HCV yearly incidence rate by transmission group* HCV incidence in intravenous drug users (IDU) decreased from 13.9 to 2.2 cases per 100 PY HCV incidence in heterosexuals remained <1 per 100 PY throughout the study period Wandeler G et al. Clin Infect Dis. 2012;55:

10 Incidence of acute hep C sexually transmitted is increasing among HIV + MSM HCV incidence in MSM reached 4.1 cases per 100 PY in 2011 (18 fold increase since 1998) Swiss HIV Cohort Study: HCV yearly incidence rate by transmission group* HCV incidence in intravenous drug users (IDU) decreased from 13.9 to 2.2 cases per 100 PY HCV incidence in heterosexuals remained <1 per 100 PY throughout the study period Wandeler G et al. Clin Infect Dis. 2012;55:

11 Incidence of acute hep C sexually transmitted is increasing among HIV + MSM HCV incidence in MSM reached 4.1 cases per 100 PY in 2011 (18 fold increase since 1998) Swiss HIV Cohort Study: HCV yearly incidence rate by transmission group* HCV incidence in intravenous drug users (IDU) decreased from 13.9 to 2.2 cases per 100 PY HCV incidence in heterosexuals remained <1 per 100 PY throughout the study period Wandeler G et al. Clin Infect Dis. 2012;55:

12 12

13 Diagnosis of acute hepatitis C (AHC) in HIV infected MSM from 2003 to 2014 Number of AHC cases We observed an exponential increase in the incidence of AHC The main route of infection was sexual Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

14 Results (I) January 2003-March 2014 n: 140 cases in 130 patients 126 M (MSM) 1 M (Drug addict) 3 F (1 het, 1 nos, 1 Drug Addict) 8 spontaneous clearance: Rate 5.4% 9 re-infections (1 patient with 3 episodes) Re-infection rate: 7.1% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

15 Results (I) January 2003-March 2014 n: 140 cases in 130 patients 126 M (MSM) 1 M (Drug addict) 3 F (1 het, 1 nos, 1 Drug Addict) 8 spontaneous clearance: Rate 5.4% 9 re-infections (1 patient with 3 episodes) Re-infection rate: 7.1% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

16 Results (I) January 2003-March 2014 n: 140 cases in 130 patients 126 M (MSM) 1 M (Drug addict) 3 F (1 het, 1 nos, 1 Drug Addict) 8 spontaneous clearance: Rate 5.4% 9 re-infections (1 patient with 3 episodes) Re-infection rate: 7.1% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

17 Results (II) Co-infection with other STD (40.8%) : (n: 93 cases) 17 Syphilis 3 Syphilis + LGV 3 Syphilis + Gonococcal urethritis + Chlamydia 5 LGV 3 Gonococcal urethritis +Chlamydia 1 Herpes 1 Inespecific proctitis 5 HIV primary infection SVR: 56% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

18 Results (II) Co-infection with other STD (40.8%) : (n: 93 cases) 17 Syphilis 3 Syphilis + LGV 3 Syphilis + Gonococcal urethritis + Chlamydia 5 LGV 3 Gonococcal urethritis +Chlamydia 1 Herpes 1 Inespecific proctitis 5 HIV primary infection SVR: 56% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

19 Results (II) Co-infection with other STD (40.8%) : (n: 93 cases) 17 Syphilis 3 Syphilis + LGV 3 Syphilis + Gonococcal urethritis + Chlamydia 5 LGV 3 Gonococcal urethritis +Chlamydia 1 Herpes 1 Inespecific proctitis 5 HIV primary infection SVR: 56% Martínez-Rebollar et al. Enferm Infec Microbiol Clin,

20 N=38 SVR: 47% 20

21 Suggest this slide is deleted and the reference placed on subsequent slides Phylogenetic analysis of an epidemic outbreak of acute hepatitis C in HIV-infected patients by massive sequencing Noelia Caro-Pérez (1), María Martínez-Rebollar (2), Josep Gregori (3),(4), Josep Quer (3), Patricia González (1), Martina Gambato (1), Hanna Visser (2), Juan I. Esteban (3), Josep Mallolas (2), Xavier Forns (1), Sofía Pérez-del-Pulgar (1), Montse Laguno (2). Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain (1). Infectious Diseases Unit, Hospital Clínic, IDIBAPS (2). Liver Unit, Vall d'hebron Institut de Recerca-Hospital Universitari Vall ) d'hebron, CIBERehd, Barcelona, (3) Roche Diagnostics SL., Sant Cugat del Vallès, Barcelona, Spain (4) 21

22 Phylogenetic analysis 4d 3a 1b Local controls Coinfected Patients 1a Caro-Pérez N, et al. EASL-ILC 2015; Abstract P

23 Clusters identified by genotype 4d 1a 1b 1 CLUSTER 8 CLUSTERS 5 CLUSTERS Caro-Pérez N, et al. EASL-ILC 2015; Abstract P

24 Genetic distance analysis Genetic distance d A (4d) < d A (1a) p < 2.2e-16 d A (4d) < d A (1b) d A (1b) < d A (1a) Caro-Pérez N, et al. EASL-ILC 2015; Abstract P

25 Hypothetical network of infection in genotype 4d patients p45 p57 p51 03/04/ /10/2013 p16 p62 04/06/ /03/2012 p75 03/11/ /01/2009 p38 04/01/2013 Monitoring common mutations in the quasispecies p4 07/04/2011 p67 27/07/2010 Date of acute hepatitis C diagnosis p17 p29 14/09/ /06/2012 Caro-Pérez N, et al. EASL-ILC 2015; Abstract P

26 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 26

27 HCV/HIV Coinfection: Natural History Considerations Accelerated rates of fibrosis progression Possible weak cellular immune response to HCV antigens HIV-associated immune activation may influence progression of liver disease Activation of hepatic stellate cells HCV-associated proinflammatory cytokines may impact HIV disease HCV coinfection is associated with higher rates of morbidity and mortality related to end-stage liver disease Lower rates of spontaneous HCV clearance in HIV patients Faster progression to cirrhosis and decompensated liver disease HCC occurs at a younger age and associated with shorter survival Lin W, et al. J Infect Dis. 2013;207(suppl 1):S13-S18. Weber R, et al. Arch Intern Med. 2006;166: Ioannou GN, et al. Hepatology. 2013;57: Weber R, et al. HIV Med. 2013;14: Macias J, et al. Clin Infect Dis. 2013;57: Curry MP. J Infect Dis. 2013(suppl 1):S40-S44. Chen TY, et al. Clin Infect Dis. 2009;49:

28 Effect of HIV on HCV Liver Fibrosis Progression Rate 4 Fibrosis Grades (METAVIR Score) HIV+ (n = 122) Matched controls (n = 122) Simulated controls (n = 122) Duration of HCV Infection (years) Increase with CD4 <200/mm 3, ETOH, age Benhamou et al. Hepatology 1999;30:

29 ALIVE Study: HIV, Age, and Severity of HCV-Related Liver Diseases Prospective cohort of HCV-infected IDUs ( ) (n=1176) HIV co-infected (n=394) Baseline and semi-annual elastography Fibrosis was significantly greater in HCV/HIV co-infected versus HCV monoinfection (P<0.001) No cirrhosis (12.9% versus 9.5%) With cirrhosis (19.5% versus 11.0%) Independently associated with increasing age and HIV infection HCV/HIV patients have liver fibrosis similar to HCV mono-infected patients who are nearly 10 years older Predicted FibroScan Score (kpa) Liver Fibrosis and Age: HCV/HIV Versus HCV Infection 9.2 years HCV/HIV HCV Age (years) ALIVE: AIDS Linked to the IntraVenous Experience. Kirk GD, et al. Ann Intern Med. 2013;158:

30 Risk of Liver Decompensation in HCV/HIV Patients With Advanced Fibrosis Retrospective Spanish study (11 tertiary centers ( ) (n=892) HCV treatment-naïve or no SVR Biopsy (n=317) or LSM (n=575) proven advanced fibrosis Liver decompensation rate (events/100 patient-years): Biopsy: 2.3 ( ) LSM: 3.98 ( ) Risk of decompensation increased by baseline fibrosis stage (for both biopsy and LSM) Implications for immediate HCV therapy LSM: liver stiffness measurement. Patients With Decompensation (%) Probability of Decompensation Baseline Fibrosis (biopsy) F3 F4 4% 1% 2% 1 (n=149/168) 13% 3 (n=128/150) 5% Time (years) P=0.023 for trend 23% 5 (n=112/116) 20% 44% >5 (n=81/77) Macias J, et al. Clin Infect Dis. 2013;57:

31 GESIDA HIV/HCV Cohort: HCV Eradication Reduces Liver-Related Outcomes Liver-Related Events Liver Decompensation Patients (%) SVR* Relapse NR Follow-Up (months) Patients (%) SVR* Relapse NR Follow-Up (months) Patients (%) Berenguer J, et al. J Hepatol. 2013;58: HCC Mortality 100 SVR Relapse NR Patients (%) Follow-Up (months) Follow-Up (months) *P<0.05 versus NR and relapse; P<0.05 versus NR. SVR Relapse NR

32 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 32

33 SVR12/24 rates over time in HCV GT1 subjects co-infected with HIV from IFN/RBV to single DAAs ± P/R SVR (%) IFN + RBV PegIFN PegIFN/RBV BOC + P/R TVR + P/R SMV + P/R SOF + P/R SOF + RBV P/R = PegIFN/RBV. Torriani FJ, et al. N Engl J Med 2004; 351: ; Sulkowski M, et al. Lancet Infect Dis 2013; 13: ; Sulkowski M, et al. Ann Intern Med 2013; 159:86 96; Dieterich D, et al. EACS Abstract LBPS9/5; Rodriguez-Torres M, et al. ID Week 2013; Poster 714; Molina JM, et al. AIDS 2014, Abs 105LB. 33

34 SVR12/24 rates over time in HCV GT1 subjects co-infected with HIV from IFN/RBV to single DAAs ± P/R SVR (%) But now we have emerging data with all oral DAAs IFN + RBV PegIFN PegIFN/RBV BOC + P/R TVR + P/R SMV + P/R SOF + P/R SOF + RBV P/R = PegIFN/RBV. Torriani FJ, et al. N Engl J Med 2004; 351: ; Sulkowski M, et al. Lancet Infect Dis 2013; 13: ; Sulkowski M, et al. Ann Intern Med 2013; 159:86 96; Dieterich D, et al. EACS Abstract LBPS9/5; Rodriguez-Torres M, et al. ID Week 2013; Poster 714; Molina JM, et al. AIDS 2014, Abs 105LB. 34

35 PHOTON-2: Sofosbuvir + Ribavirin in GT1-4 HCV Pts Coinfected With HIV Ongoing, nonrandomized, open-label phase III study Stable ART (HIV-1 RNA < 50 copies/ml for 8 wks before enrollment); CD4: > 200 cells/mm3 if ART treated; > 500 cells/mm3 if ART naive 97% on ART: TDF/FTC, 100%; EFV: 25%; ATV/RTV: 17%; DRV/RTV: 21%; RAL: 23%; RPV: 5% 20% of pts with compensated cirrhosis Primary endpoint: SVR12 Wk 12 Wk 24 Tx-naive GT1, 3, 4 Tx-naive GT2 Tx-exp d GT2, 3 Molina JM, et al. AIDS Abstract MOAB0105LB. Sofosbuvir + Ribavirin (n = 200) Sofosbuvir + Ribavirin (n = 19) Sofosbuvir + Ribavirin (n = 55) Sofosbuvir 400 mg QD; weight-based ribavirin 1000 or 1200 mg/day 35

36 PHOTON-2 Study: Overall SVR12 Rates and Virologic Failure % 88% 89% 84% SVR12 (%) Relapse: Breakthrough: 95/112 22/25 94/106 26/31 Genotype 1 Genotype 2 Genotype 3 Genotype 4 14 (13%) 2 (8%) 10 (9%) 5 (16%) (0.9%) 0 HCV treatment-naïve genotypes 1, 3, 4 and HCV treatment-experienced genotypes 2,3: 24 weeks of therapy. HCV treatment-naïve genotypes 2, 3: 12 weeks of therapy. Molina J-M, et al. 20 th IAC. Melbourne, Abstract MOAB0105LB. 36

37 INF-free Regimen: On-treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV-Coinfected Patients: The C-WORTHY Study *HCV G1b only. Grazoprevir (MK-5172) is an NS3/4A PI and Elbasvir (MK-8742), an NS5A inhibitor. *** All patients receiving Raltegravir. Sulkowsky M, Mallolas J, EASLD (London)

38 INF-free Regimen: On-treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV-Coinfected Patients: The C-WORTHY Study Virologic responses (per-protocol population) Sulkowsky M, Mallolas J, EASLD (London)

39 C-EDGE Coinfection: Grazoprevir/Elbasvir for Pts Coinfected With HCV/HIV Multicenter, single-arm, open-label phase III trial Wk 12 HCV treatment-naive pts coinfected with HIV and GT1, 4, or 6 HCV (N = 218) Grazoprevir/Elbasvir (n = 218) Coformulated grazoprevir/elbasvir dosed orally 100/50 mg once daily 66% with GT1a HCV, 60% had HCV RNA > 800,000 IU/mL, 16% cirrhotic Baseline ART Undetectable HIV-1 RNA on ART (%) 96.8 Abacavir containing 21.6 Tenofovir DF containing 75.2 Raltegravir 51.8 Dolutegravir 27.1 Rilpivirine 17.4 Rockstroh JK, et al. EASL Abstract P

40 C-EDGE Coinfection: Key Findings SVR12 (%) n/n = 0 SVR12 With 12 Wks GZR/EBV According to Genotype LTFU or DC* Breakthrough Relapse Reinfection *Unrelated to virologic failure / / / 44 27/ 28 All Pts GT1a GT1b GT4 No subgroup provided an efficacy advantage or disadvantage New NS3, NS5A RAVs detected at failure in 5 of 6 pts who relapsed Short-lived HIV-1 RNA increases occurred in 2 pts on ART during grazoprevir/elbasvir treatment: both resuppressed HIV-1 RNA without change of ART During 12 wks of treatment, no significant changes in CD4+ cell count (n = 207) Grazoprevir/elbasvir well tolerated: no pt discontinued for AEs and no serious treatmentrelated AEs Rockstroh JK, et al. EASL Abstract P

41 TURQUOISE-I: SVR12 rates in HIV/HCV co-infected patients treated with OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV + RBV for 12 or 24 weeks in GT1 treatment-naive and -experienced patients, all with HIV/HCV co-infection HCV GT1, naive or experienced, (N=63)* OBV/PTV/r + DSV + RBV (n=31) OBV/PTV/r + DSV + RBV (n=32) SVR12 (%) Study weeks * Including 6 (19%) patients with cirrhosis (F4) in the 12 week arm and 6 (19%) patients with cirrhosis (F4) in the 24 week arm. DSV = dasabuvir; OBV = ombitasvir; PTV/r = paritaprevir/ritonavir n N weeks 24 weeks OBV/PTV/r + DSV + RBV 2 patients in the 24-week arm had recurrence of HCV believed to be due to re-infection Sulkowski MS, et al. JAMA 2015; 313:

42 TURQUOISE-I: high SVR12 rates in patients receiving either atazanavir or raltegravir Response in patients on HIV ART Reasons for non-response 12 weeks 24 weeks Atazanavir ART: 1 patient withdrew consent SVR12 (%) n N Atazanavir Raltegravir Raltegravir ART: 1 patient in the 12-week arm relapsed 1 patient in the 24-week arm experienced viral breakthrough 2 patients in the 24-week arm had recurrence of HCV believed to be due to re-infection ART = anti-retroviral therapy. Eron JJ, et al. J Int AIDS Soc. 2014; 17(Suppl 3):

43 Time to HCV RNA <25 IU/mL in HCV mono-infected and HIV/HCV co-infected patients and SVR12 by time to HCV RNA Suppression OBV/PTV/r + DSV + RBV Cumulative % HCV Mono-infected HCV/HIV-1 Co-infected <25 IU/mL (LLOQ) Treatment Week SVR12, % Patients Cumulative % <15 IU/mL (LLOD) HCV Mono-infected Treatment Week Week 1 Week 2 Week 4 Week HCV/HIV-1 Co-infected NA Wyles D, et al. CROI Abstract

44 ION-4: LDV/SOF in HCV GT1 or 4 patients with HIV co-infection SVR12 rates Study design: GT1 and 4 with HIV/HCV co-infection* Efficacy results: GT1 and 4 with HIV/HCV co-infection LDV/SOF (N=335) Study 12 weeks SVR12 (%) n N Overall Naive Exp No cirrhosis Cirrhosis * Including 8 (2.4%) patient with GT4 and 67 (20%) patients with cirrhosis. Exp = experienced. Cooper E, et al. EASL-ILC 2015; Poster presentation P

45 ION-4: LDV/SOF Effective Across All Pt Demographic and Disease Subgroups Overall Race HCV Genotype Black Nonblack 1a 1b 4 SVR12, % (95% CI) Statistically significant in multivariate analysis 10 relapses all in black pts No pt with HIV virologic rebound No discontinuation of therapy due to adverse events Baseline HCV RNA (IU/mL) Baseline BMI (kg/m 2 ) IL28B ARV Regimen Baseline CD4 (cells/mm³) < 800, ,000 < CC CT TT TDF/FTC/EFV TDF/FTC + RAL TDF/FTC/RPV < pts experienced increase in creatinine > 0.4 mg/dl 2 completed treatment without change in ART 1 pt changed TDF to new NRTI TDF dose reduced in 1 pt Naggie S, et al. CROI Abstract 152LB. Cooper C et al. EASL Reproduced with permission.

46 ION-4: Resistance Analysis and LDV/SOF Drug Drug Interactions With bpis Deep sequencing at BL identified 67 (20%) pts with NS5A RAVs [1] 63 (94%) of these pts achieved SVR12 In drug drug interaction studies with LDV/SOF and boosted PIs and TFV [2] LDV/SOF increases ATV, RTV, and TFV exposure RAVs in NS5A found in 10/12 pts with virologic failure No S282T mutation in NS5B found in any pt at BL or virologic failure ATV/RTV + TDF/FTC increases LDV DRV/RTV + TDF/FTC decreases SOF Staggered administration did not mitigate interactions but interactions not deemed clinically relevant 1. Naggie S, et al. CROI Abstract 152LB. Cooper C et al. EASL German P, et al. CROI Abstract 82.

47 ALLY-2: SOF + DCV in GT1-6 HCV/HIV- Coinfected Pts Phase III open-label study Non GT1 < 20% in each cohort; compensated cirrhosis < 50% overall; HIV-1 RNA < 50 c/ml and CD in pts on ART; CD4 350 in pts not on ART ART allowed: PI/RTV, NRTIs, NNRTIs, INSTIs, MVC, ENF Primary endpoint: SVR12 in GT1 naive pts treated for 12 wks Wk 8 Wk 12 Treatment-naive pts (N = 151) Treatment-experienced pts (N = 52) SOF 400 mg QD + DCV 30/60/90* mg QD (n = 101) SOF 400 mg QD + DCV 30/60/90* mg QD (n = 50) SOF 400 mg QD + DCV 30/60/90* mg QD (n = 52) Pts followed to Wk 36 *Standard dose of 60 mg adjusted for ART: 30 mg with RTV; 90 mg with NNRTIs except RPV. Wyles DL, et al. CROI Abstract 151LB. EASL Abstract LP01

48 ALLY-2: Virologic Outcomes With SOF + DCV in HIV/HCV-Coinfected Pts High SVR12 rates with 12 wks SOF + DCV SVR12, % n/n = 0 Large decline in SVR rate with shortening to 8 wks 96 GT Overall / 31/ 43/ 98/ 38/ 51/ Wk 8-Wk 12-Wk 12-Wk 8-Wk 12-Wk Naive Exp d Naive Exp d Wyles DL, et al. CROI Abstract 151LB. EASL Abstract LP01. In 12-wk groups analyzed by GT, 100% with SVR12 except GT1a GT1a naive: 96%; exp d: 97% Similar SVR12 rates in pts with or without baseline NS5A RAVs 12 pts with relapse, 10 in 8-wk arm 1 in 8-wk arm had emergent NS5A RAVs No NS5B RAVs at BL or time of failure No discontinuation of therapy due to AEs 10 pts with HIV-1 RNA > 50 at EOT 8 with repeat testing; 7 with suppression without change in ART; 1 with HIV-1 RNA of 59; 2 LTFU 2 with HIV VF = HIV-1 RNA 400 c/ml

49 DACLATASVIR PLUS SOFOSBUVIR WITH OR WITHOUT RIBAVIRIN IN PATIENTS WITH HIV- HCV COINFECTION: INTERIM ANALYSIS OF A FRENCH MULTICENTER COMPASSIONATE USE PROGRAM Hélène Fontaine, Karine Lacombe, Catherine Dhiver et al. EASL 2015 April Vienna Austria

50 Interim analysis of DCV + SOF ± RBV in patients with HIV/HCV co-infection from a French compassionate use program: Baseline characteristics Fontaine H, et al. ILC Abstract LP23 a Includes F3 and F3/F4. b 66 patients had missing data. c 115 patients had missing data. 50

51 Interim analysis of DCV + SOF ± RBV in patients with HIV/HCV co-infection from a French compassionate use program: Efficacy Treatment discontinuations occurred in 14 patients (1.9%) and were related to an adverse event (n=4), death (n=3), patient decision (n=3), contra-indication (n=3) and unknown reason (n=1). Fontaine H, et al. ILC Abstract LP23 51

52 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 52

53 Co-morbidities among HIV/HCV co-infected patients Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV co-infection All cause mortality rate was: 74.1 (70.4 to 77.9) per 1000 person years among veterans with HIV/HCV co-infection 39.8 (36.3 to 43.6) per 1000 person years among veterans with HIV mono-infection Positive predictors of mortality included: Decompensated liver disease (2.33 (1.98 to 2.74)) Coronary artery disease (1.74 (1.32 to 2.28)) Chronic kidney disease (1.62 (1.36 to 1.92)) Anemia (1.58 (1.31 to 1.89)) Erqou S, et al. ISRN Gastroenterol Apr 7;2014: doi: /2014/

54 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV design Open-label Treatment SVR4 SVR12 GT1a OBV/PTV/r + DSV + RBV GT1b OBV/PTV/r + DSV Day 1 Week 12 Week 24 For GT1a: RBV 200 mg QD For GT1b: No RBV Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 54

55 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV efficacy All patients completing treatment to date had virologic response Virologic response has been sustained in all patients who have reached post-treatment weeks 4 and 12 Time-point N Virologic Response (n) Percent End of Treatment Post-treatment Week Post-treatment Week Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 55

56 C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4 or 5 CKD Multicenter, part-randomized, parallel-group, placebo-controlled, phase III trial GT1 HCV-infected pts with stage 4/5 CKD (n = 224) Roth D, et al. EASL Abstract LP02. Wk 12 Randomized period Grazoprevir/Elbasvir (n = 111) Placebo (n = 113) Treatment Follow-up Wk 4 Open-label period Grazoprevir/Elbasvir (n = 113) Follow-up Wk 16 Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group. Treatment arms well matched at baseline Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated cirrhosis 75% and 77% were on hemodialysis; 32% to 36% were diabetic 81% and 82% were CKD stage 5 (egfr < 15 ml/min/1.73 m 2, or on hemodialysis); 18% and 19% were CKD stage 4 (egfr ml/min/1.73 m 2 ) 56

57 C-SURFER: Efficacy Results GZR/EBR 12 wks SVR12 (%) n/n = 0 115/ 116* Modified Full Analysis Set 115/ 122* Full Analysis Set 6/6 Cirrhotic 61/61 GT 1a HCV 54/55 GT 1b HCV 86/87 40/41 On Diabetic hemodialysis Modified analysis set: pts in pharmacokinetic substudy and pts randomized to immediate treatment who received 1 drug dose; excludes pts who died or discontinued where cause not related to study treatment. Full analysis set: all pts receiving 1 drug dose. *1 pt relapsed on each arm. 6 pts in the full analysis set discontinued unrelated to treatment: lost to follow-up (n = 2), n = 1 each for death, noncompliance, withdrawal by subject, and withdrawal by physician (owing to violent behavior). Roth D, et al. EASL Abstract LP02. 57

58 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 58

59 Drug Drug Interactions With ARVs (March 15) 59

60 Drug Drug Interactions With ARVs (March 15) 60

61 Drug Drug Interactions With ARVs (March 15) 61

62 Drug Drug Interactions With ARVs (March 15) 62

63 Drug Drug Interactions With ARVs (March 15) 63

64 But there are resources out there to help (Accessed May 2015). 64

65 HCV in HIV/HCV: No longer a special population? HIV/HCV epidemiology HIV/HCV natural history Treatment HIV/HCV co-infected patients Co-morbidities Drug-drug interactions Treatment guidelines 65

66 AASLD/IDSA Guidance for HIV/HCV Coinfection Same recommendations as in HCV-monoinfected patients, but consider drug drug interactions Need to adjust or withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV Potential for LDV-mediated increase in tenofovir levels, especially if tenofovir used with RTV Avoid LDV if CrCl < 60 ml/min or if receiving tenofovir with RTVboosted PI OMV/PTV/RTV + DSV can be used with raltegravir (and probably dolutegravir), enfuvirtide, tenofovir, emtricitabine, lamivudine, atazanavir SMV can be used with: raltegravir (and probably dolutegravir), rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, abacavir Other interactions at aidsinfo.nih.gov/guidelines, hiv-druginteractions.org AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. 66

67 EASL Recomendations on Treatment of Hepatitis C in

68 EASL Recomendations on Treatment of Hepatitis C in

69 EASL recommendations for treatment prioritisation 69

70 Summary HIV/HCV epidemiology and natural history Treatment Co-morbidities DDIs HIV/HCV coinfection remains a widespread problem associated with high morbidity and mortality Effective treatments are now available to cure the HCV in the great majority of patients including those with HIV/HCV Renal disease is more prevalent in HIV/HCV coinfected patients than uninfected patients but effective HCV treatments are becoming available DDIs are relatively common in HIV/HCV coinfected patients but they are typically manageable and resources are available Updated guidelines state that HIV/HCV co-infection should be treated the same as HCV mono-infection, DDIs should always be appropriately monitored and HIV/HCV coinfected patients should be prioritised for treatment 70