Management of HIV / HCV Coinfection

Advances in HCV 2015 Albany Medical College & Erie County Medical Center Buffalo, New York 24 June 2015 Management of HIV / HCV Coinfection Norbert Bräu, MD, MBA Prof. of Medicine, Icahn School of Medicine at Mount Sinai, New York NY Divisions of Infectious Diseases & Liver Diseases Director, Viral Hepatitis Program, James J Peters VA Medical Center, Bronx NY Bronx VA Medical Center Mount Sinai School of Medicine HIV / HCV coinfection Overview (1)Natural History of HCV Disease in HIV / HCV (2) HCC in HIV (3) Antiviral Therapy with DAAs for HIV / HCV 1

34 years ago 5 June 1981 5 June 1981 2

HIV History 5 June 1981 MMWR: Los Angeles, Pneumocystis carinii pneumonia in 5 homosexual men. 1983 HTLV-III discovered (renamed HIV) 1989 Zidovudine (AZT) first antiretroviral drug 1996 HIV protease inihibitors, beginning of HAART Since 2000 liver disease increasing cause of mortality in HIV0-uinfected patients Effect of HAART on Survival 3

Rising rate of liver-related deaths and of HCC France: Mortalité 2000 & 2005 2000 2005 N ~64,000 78,000 Deaths 964 1,042 Liver deaths: 13.4% 15.4% HCC deaths: 15% 25% p=0.03 Salmon-Ceron D, J Hepatol, April 2009 HCV or HBV within HIV+ pts: HIV and HCV Coinfection Epidemiology HCV strongly depends on mode of transmission of HIV itself: Anti-HCV[+], total 42.5% HBsAg[+], total 6.9% IDU 91 % blood transfusion 71 % sexual transmission 7.1 % N=1,935 Saillour F et al., Brit Med J, 1996 4

Natural History of HCV Infection 100% (100) Acute Infection 25% (25) 75% (75) Resolved Chronic 80% (60) Stable 20% (15) Cirrhosis HIV and Alcohol Slowly Progressive 75% (11) 25% (4) Liver failure, HCC Transplant Death HIV + HCV coinfection Effect of HIV on HCV-related liver disease Does HIV accelerate HCV-induced liver disease? YES, if 5

HIV + HCV coinfection: Liver Fibrosis Progression Rate Fibrosis Grades (METAVR scoring system) 4 3 2 1 HIV positive (n=122) Matched controls (n=122) Simulated controls (n=122) 0 0 10 20 30 40 HCV - infection duration (years) Benhamou Y, Hepatology, Oct 1999 Fibrosis Progression Rate by HIV Viral Load Bräu N, J Hepatol, Jan 2006 6

Fibrosis progression in HIV/HCV coinfeciton - paired liver biopsies - Spain, multicenter: N=135 HIV/HCV with paired Bx (median 3.3 yrs) Factors independently correlated with Fibrosis Progression Rate (FPR) risk ratio 95% CI p HIV RNA undetectable (>70% dur F/U) 0.61 0.39 0.93 0.028 HAART during F/U 0.94 0.72 Baseline necroinflammation 1.77 1.16 2.7 0.009 EOT response to anti-hcv therapy 0.41 0.19 0.88 0.023 Macias J, Hepatology, Oct 2009 HCV Cirrhosis -- Natural History Morbidity and Mortality Cumulative decomp. and HCC(%) 50 40 30 20 10 100 80 60 40 20 Cumulative mortality(%) 0 2 4 6 8 10 Years 0 2 4 6 8 10 Years HCC Cirrhosis Decompensation Fattovich G et al. Gastroenterology. 1997;112:463. 7

Effect of HIV on HCV-related cirrhosis Cumulative incidence of liver failure in HIV/HCV pts. with cirrhosis (N=154) 6.40 cases / 100 person-yrs Est. 3-yr incid. 48 % Est. 5-yr incid. 53 % Pineda JA, Clin Infect Dis, 15 Oct 2009 Effect of HIV on HCV-related end-stage liver disease Shorter survival after decompensation in HIV/HCV vs. HCV (N=1,837) median HIV/HCV 16 mo HCV 48 mo Independent risk factors for death: HIV+, age, MELD score, HE 1 st Sx Pineda JA, Hepatology, Apr 2005 8

HCC in HIV Rising Incidence Andalucia (Spain) 1999 2010 n = 14,300 (2010) HIV / HCV All HIV patients 0.1 0.2 0.5 0.7 1.0 0.9 Merchante N. et al., Clin Infect Dis, Jan 2013 HCC in HIV Rising Prevalence VA System (USA) 1996 2009 n = 24,000 (2009) Ioannou GN. et al., Hepatology, Jan 2013 9

HCC in HIV - Outcome Case Series 2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro Case Series HCC in HIV - Outcome 2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro 2004 n=41 Puoti M et al. (Italy), AIDS 2007 n=63 North American Liver Cancer in HIV Study Group Bräu N et al., J Hepatol 2011 n=102 Berretta M et al. (Italy), Oncologist 10

HCC in HIV - Outcome Case Series 2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro 2004 n=41 Puoti M et al. (Italy), AIDS 2007 n=63 North American Liver Cancer in HIV Study Group Bräu N et al., J Hepatol 2011 n=102 Berretta M et al. (Italy), Oncologist 2012 n=26 Yopp AC et al. (Dallas), Clin Gastroent Hepatol 2012 n=23 Lim C at al. (Paris), JAIDS 2013 n=48 Pavoni M et al. (Bologna, Italy), Dig Liver Dis HCC in HIV - Outcome 1 st Italian HCC in HIV study (2004) Median survival: HIV-pos. (n=41) HIV-neg. (n=701) 5.9 mo 18.0 mo Puoti M et al., AIDS, Nov-2004 11

North American Liver Cancer in HIV Study Group * * ** * * * * * * * * * * * 12 sites (US, Canada) HIV-pos. HCC (n=63) 4 sites HIV-pos. + HIV neg. HCC (n=226) Bräu N et al., J Hepatol, Oct 2007 N American HCC in HIV Study: Survival All Patients At risk HIV[-] 226 64 29 14 7 2 1 median survival: 7.5 mo At risk HIV[+] 63 11 3 1 1 0 0 median survival: 6.9 mo Bräu N et al., J Hepatol, Oct 2007 12

2 nd Italian HCC in HIV study (2011) Median survival: HIV-pos. HIV-neg. 35 mo 59 mo Berretta M et al., Oncologist, 2011 Comparison Survival HIV(+) vs. HIV(-) Median survival N (mo) Study HIV(+) HIV( ) HIV(+) HIV( ) p Italy (2004) 41 701 5.9 18.0 0.045 North America (2007) 63 226 6.9 7.5 0.44 Italy (2011) 104 484 35 59 0.048 Dallas (2012) 26 164 9.6 5.2 0.85 Paris (2012) 23 46 18 26 0.2 Bologna (2013) 48 234 16 30 0.035 13

Liver Cancer in HIV Study Group N=365 as of 05-May-2014 NA n=281 EUR n=59 SA n=24 AUS n=1 Does Screening for HCC in HIV/HCV Patients Improve Survival? Method: N=198 HIV/HCV patients with HCC Diagnosis of HCC via Screening vs. Symptoms Compare: * Staging * Therapy * Survival (adjust for lead-time bias) 14

Screening for HCC in HIV/HCV Patients Patient Characteristics Screened n=117 (59%) Not Screened n=81 (41%) Age (yrs), Mean 52 54 0.082 Female Sex 4% 10% 0.162 Alcohol abuse 30% 50% 0.003 CTP Score: 6.6 7.7 <0.001 P HIV parameters Median CD4+ cells (per mm3) 344 274 0.027 HIV RNA <400 copies/ml 79% 54% <0.001 Fox RK, AASLD, Washington DC, Nov 2013 Screening for HCC in HIV/HCV Patients Tumor Characteristics Screened n=117 Not Screened n=81 Hepatic Lesions Multiple Tumors 42% 58% 0.035 P Median Size Largest Tumor (cm) Portal Vein Thrombosis Extrahepatic Metastases Meets Milan criteria for OLT 3.0 5.2 <0.001 12% 9% 31% 28% 0.001 <0.001 64% 29% <0.001 HCC Tumor Staging Screened n=117 Not Screened n=81 P BCLC Stage, n (%) A B C } Advanced, D } Incurable 44% 17% 27% 11% 7% 20% 43% 30% <0.001 BCLC Stages C and D 39% 73% <0.001 Fox RK, AASLD, Washington DC, Nov 2013 15

Screening for HCC in HIV/HCV Patients HCC Therapy Screened n=117 Unscreened n=81 P Potentially Curative, n (%) Radiofrequency Ablation Percutaneous Ethanol Injection Surgical Resection Liver Transplantation Effective, Non-Curative, n (%) Chemoembolization Sorafenib Sorafenib & Chemoembolization 53 (46%) 19 8 17 9 35 (30%) 28 4 3 10 (12%) 5 2 2 1 17 (21%) 14 3 0 <0.001 No Therapy, n (%) 28 (24%) 54 (67%) Any HCC Therapy 88 (76%) 27 (33%) Fox RK, AASLD, Washington DC, Nov 2013 Screening for HCC in HIV/HCV Patients Survival adjusted for lead-time bias (8.6 mo) Median survival Screened 19.2 mo Unscreened 3.5 mo Fox RK, AASLD, Washington DC, Nov 2013 16

Screening for HCC in HIV/HCV Patients Cox Proportional Hazard Analysis Risk Factor Univariate Hazard Ratio for Death Univar. P Multi- Variable H.R. for death 95% confid. Interval Multi-var. P Effective HCC Therapy 0.13 <0.001 0.21 0.13 0.35 <0.001 HCC Screening 0.22 <0.001 0.38 0.24 0.58 <0.001 BCLC stages A&B vs. C&D 0.36 <0.001 0.58 0.38 0.89 0.012 AFP (per 1000 ng/ml) 1.004 0.061 Alcohol abuse 1.84 0.001 CD4+ cells (per 100/mm 3 ) 0.89 0.014 HIV RNA (per log 10 copies/ml) 1.31 <0.001 Fox RK, AASLD, Washington DC, Nov 2013 Screening for HCC in HIV/HCV Patients Screening over Time 100% 80% 60% 40% 20% p=0.002 52% 49% 77% 0% 1995-2004 2005-2008 2009-2013 Fox RK, AASLD, Washington DC, Nov 2013 17

HIV Viral Load & Natural History of HCC Hypothesis: HIV viremia negatively influences course of HCC In HIV/HCV: More rapid progression of hepatic fibrosis with HIV RNA 400+ Copies/ml Fibrosis Progression Rate by HIV Viral Load in chronic hepatitis C Bräu N, J Hepatol, Jan 2006 18

HIV Viremia: Influence on HCC Survival HIV RNA <400 c/ml n=254 HIV RNA 400+ c/ml n=93 P Age (yrs), Mean 53.8 52.0 0.078 Male Sex 234 (92%) 85 (91%) 0.83 Etiology of HCC Hepatitic C Hepatitis B Non-Viral (NASH, Alcohol) 201 (79%) 49 (19%) 4 (2%) 71 (76%) 21 (23%) 1 (1%) Alcohol Abuse 57 (23%) 36 (41%) 0.001 Platelet count (1000/mm), Mean 146 163 0.16 Child-Pugh Score, Mean 6.6 7.5 <0.001 HCC Diagnosis via Screening 174 (69%) 41 (44%) <0.001 CD4+ Cells (per mm3), Median 347 244 <0.001 0.78 Citti, AASLD 2014, Boston MA HIV Viremia: Influence on HCC Survival Median survival HIV RNA <400 c/ml 19.8 months HIV RNA 400+ c/ml 5.4 months Survival at 1 yr 2 yrs At Risk HIV RNA <400 c/ml 61% 46% HIV RNA 400+ c/ml 36% 27% HIV RNA <400 254 107 60 35 23 10 4 3 2 1 1 HIV RNA 400+ 93 22 13 7 7 4 4 4 3 1 0 Citti, AASLD 2014, Boston MA 19

HIV Viremia: Influence on HCC Survival Factor Multi-Variable Cox Regression Analysis Univar. H.R. for Death Univar. P Multi variable H.R. for Death 95% Conf. Interval Multi var. HCC Diagnosis through Screening 0.23 <0.001 0.35 0.25 0.49 <0.001 BCLC stages A&B vs. C&D 0.38 <0.001 0.58 0.41 0.83 0.003 Alcohol abuse 1.97 <0.001 1.64 1.18 2.28 0.003 Extrahepatic Metastases 2.59 <0.001 1.65 1.13 2.41 0.009 Portal Vein Thrombosis 1.51 <0.001 1.56 1.08 2.24 0.016 Child Pugh score (per unit) 1.26 <0.001 1.15 1.06 1.25 0.001 HIV RNA Level (per log10 cop./ml) 1.33 <0.001 1.16 1.03 1.30 0.013 CD4+ cell Count (per 100/mm3) 0.89 0.001 Platelet Count (per 100,000/mm3) 1.12 0.006 Solitary Liver Tumor 0.67 0.008 Citti, AASLD 2014, Boston MA P Liver Transplantation for HCC in HIV Total Cohort N=367 (100%) Comparison of OLT with other curative therapies: OLT n= 27 (7.4%) Other Curative Therapy n=108 (29.5%) Surgical Resection 51 Radiofrequency Ablation 45 Percutaneous Ethanol Inject. 12 Platt H, AASLD 2014, Boston MA 20

Liver Transplantation for HCC in HIV OLT n=29 Other Curative Rx n=108 Age (yrs), Mean 50.0 53.4 0.060 P Etiology of HCC Chronic Hepatitis C Chronic Hepatitis B Non-Viral (Alcohol, NASH) 21 (78%) 6 (22%) 0 84 (78%) 22 (20%) 2 (2%) 0.77 Excessive Alcohol 6 (22%) 26 (26%) 0.73 Child-Pugh score, Mean 6.8 5.8 0.026 HIV RNA <400 copies/ml 18 (82%) 85 (83%) 0.94 CD4+ Cells (per mm3), Median 322 423 0.36 Hepatic Lesions Mulitple Tumors Size Largest Lesion (cm), Median (Range) AFP level (ng/ml), Median OLT n=27 15 (56%) 3.0 (1.3 5.6) Other Curative Rx n=108 22 (20%) 2.85 (0.5 11) P <0.001 0.98 13.0 44.5 0.022 Extrahepatic metastases 0 7 (6.5%) 0.17 Meets Milan Criteria for OLT 21 (78%) 83 (80%) 0.82 Platt H, AASLD 2014, Boston MA Liver Transplantation for HCC in HIV Survival at: 2 yrs 5 yrs OLT 92% 85% Other Cur. Rx 71% 52% Platt H, AASLD 2014, Boston MA 21

Liver Transplantation for HCC in HIV Survival at: 2 yrs 5 yrs OLT 92% 85% Other Cur. Rx 71% 52% Survival at: 2 yrs 5 yrs OLT 92% 85% Radiofrequ. Abl. 71% 68% Surg. Resection 77% -- Ethanol Inject. 41% -- Platt H, AASLD 2014, Boston MA Other Reports of Transplantation for HCC in HIV Single center, Paris HIV(+) 21 16 OLT HIV(-) 65 58 OLT Survival (76%) (89%) Vibert E et al., Hepatology, Feb 2011 22

HCV Antiviral Therapy in HIV/HCV Coinfection Ledipasvir (NS5a) + sofosbuvir (NA) (Harvoni ) ERADICATE (N=50) GT 1 nv F0-F3 ION-4 (N=355) GT 1 nv/exp 20% cirrh AbbVie 3D + RBV (Viekira Pak ) TURQUOISE-I (part A N=63) GT 1 nv/exp +/- cirrh Daclatasvir (NS5a) + sofosbuvir ALLY-3 (N=203) GT 1-6 nv 13% cirrh Grazoprevir (PI) + elbasvir (NNI) C-EDGE-Coinfection GT-1-4 -6 LDV + SOF in GT1 Treatment Naïve HCV/HIV Coinfection: ERADICATE: Efficacy N = 50 GT1, TN Stable HIV Study Weeks ARV Untreated: LDV/SOF (n = 13) ARV Treated: LDV/SOF (n = 37) 12 24 SVR 12 SVR 12 % Patients with HCV RNA < LLOQ 100% 80% 60% 40% 20% ARV Untreated (n = 13) ARV Treated (n = 37) 100% 100% 100% 100% 100% 100% 100% 100% 100% 97% 97% 97% 0% Week 4 Week 8 EOT SVR4 SVR8 SVR12 Osinusi A, et al. JAMA. 2015 Feb 23. [Epub ahead of print]. 23

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Study Design Wk 0 Wk 12 Wk 24 SVR12 N=335 LDV/SOF Phase 3, multicenter (US, Canada, New Zealand) HCV GT 1 +4, nv/exp, 20% cirrhosis HIV 1 positive, HIV RNA <50 copies/ml; CD4 cell count >100 cells/mm 3 ART regimens included FTC and TDF plus EFV, RAL, or RPV, no PIs Naggie S, et al. NEJM 2015 [in press] LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Efficacy Overall Naïve vs Experienced Cirrhosis Status 100 96 95 97 96 94 80 SVR12 (%) 60 40 20 0 321/335 142/150 179/185 258/268 63/67 LDV/SOF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Naggie S, et al. NEJM 2015 [in press] 24

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Efficacy Overall Naïve vs Experienced Cirrhosis Status 100 96 95 97 96 94 80 SVR12 (%) 60 40 20 0 321/335 142/150 179/185 258/268 63/67 LDV/SOF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Naggie S, et al. NEJM 2015 [in press] LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Safety Patients, n (%) LDV/SOF 12 Weeks N=335 AEs 257 (77) Overall safety Grade 3 4 AE 14 (4) Serious AE 8 (2)* Treatment D/C due to AE 0 Death 1 (<1) Grade 3 4 laboratory abnormality 36 (11) Stable CD4 counts through treatment and follow up phase No patient had confirmed HIV virologic rebound Naggie S, et al. CROI 2015. 25

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Safety Overall safety Patients, n (%) LDV/SOF 12 Weeks N=335 AEs 257 (77) Grade 3 4 AE 14 (4) Serious AE 8 (2)* Treatment D/C due to AE 0 Death 1 (<1) Grade 3 4 laboratory abnormality 36 (11) Stable CD4 counts through treatment and follow up phase No patient had confirmed HIV virologic rebound Naggie S, et al. CROI 2015. LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION 4: Safety Overall safety Patients, n (%) LDV/SOF 12 Weeks N=335 AEs 257 (77) Grade 3 4 AE 14 (4) Serious AE 8 (2)* Treatment D/C due to AE 0 Death 1 (<1) Grade 3 4 laboratory abnormality 36 (11) Patients, n (%) LDV/SOF 12 Weeks N = 335 Headache 83 (25) Fatigue 71 (21) Diarrhea 36 (11) Nausea 33 (10) Arthralgia 22 (7) Upper respiratory tract infection 18 (5) Stable CD4 counts through treatment and follow up phase No patient had confirmed HIV virologic rebound Naggie S, et al. CROI 2015. 26

DCV + SOF for 8vs.12 Weeks in GT 1 6 HIV/HCV Coinfection ALLY 2: Study Design Naive Randomize 2:1 N 101 50 52 DCV 30/60/90 mg + SOF 400 mg QD DCV 30/60/90 mg + SOF 400 mg QD SVR12 * Experienced DCV 30/60/90 mg + SOF 400 mg QD Week 0 8 12 24 Standard DCV dose is 60 mg daily Dose-adjusted for concomitant ARV therapy: 30 mg with ritonavir-boosted PIs, 90 mg with NNRTIs except RPV Wyles D, et al. CROI 2015. DCV + SOF for 8vs.12 Weeks in GT 1 6 HIV/HCV Coinfection ALLY 2: Efficacy GT 1 GT 1 (N = 168) ALLY-2: SVR12 Wyles D, et al. CROI 2015. 27

DCV + SOF for 12 Weeks in GT 1 6 HIV/HCV Coinfection ALLY 2: Efficacy GT 1 4 Wyles D, et al. CROI 2015. DCV + SOF for 12 Weeks in GT 1 6 HIV/HCV Coinfection ALLY 2: Efficacy GT 1 4 Event, n (%) 12-Week Groups N = 153 8-Week Group N = 50 Total Deaths a 0 1 (2) 1 (0.5) Serious AEs b 4 (3) 0 4 (2) AEs leading to discontinuation 0 0 0 Opportunistic infections 0 0 0 Grade 3 or 4 lab abnormalities a INR > 2.0 x ULN 2 (1) 0 2 (1) ALT > 5.0 x ULN 0 0 0 AST > 5.0 x ULN 0 1 (2) 1 (0.5) Total bilirubin > 2.5 x ULN c 7 (5) 1 (2) 8 (4) One death of 52 year-old male with cardiac arrest at posttreatment Week 4 (not related to study therapy). Wyles D, et al. CROI 2015. 28

DCV + SOF for 12 Weeks in GT 1 6 HIV/HCV Coinfection ALLY 2: Efficacy GT 1 4 Event, n (%) 12-Week Groups N = 153 8-Week Group N = 50 Total Deaths a 0 1 (2) 1 (0.5) Serious AEs b 4 (3) 0 4 (2) AEs leading to discontinuation 0 0 0 Opportunistic infections 0 0 0 Grade 3 or 4 lab abnormalities a INR > 2.0 x ULN 2 (1) 0 2 (1) ALT > 5.0 x ULN 0 0 0 AST > 5.0 x ULN 0 1 (2) 1 (0.5) Total bilirubin > 2.5 x ULN c 7 (5) 1 (2) 8 (4) One death of 52 year-old male with cardiac arrest at posttreatment Week 4 (not related to study therapy). Wyles D, et al. CROI 2015. 3D + RBV in GT 1 HCV/HIV Coinfection TURQUOISE I: Study Design Open-label Treatment SVR12 3D + RBV (n = 31) SVR12 3D + RBV (n = 32) Day 1 Week 12 Week 24 Week 36 Key Eligibility Criteria: HCV GT1 infection, HCV treatment naïve or PEG/RBV experienced, Child Pugh A cirrhosis allowed, stable HIV 1 infection on ATV or RAL inclusive ART regimen Sulkowski MS, et al. JAMA. 2015 Feb 23. [Epub ahead of print]. 29

3D + RBV in GT 1 HCV/HIV Coinfection TURQUOISE I: Efficacy 100% 100% 100% 3D + RBV 12-week 97% 97% 3D + RBV 24-week 94% 94% 94% 91% 80% % Patients 60% 40% 20% 0% 31/31 32/32 30/31 31/32 29/31 30/32 29/31 29/32 RVR EOTR SVR4 SVR12 (Week 4) (Week 12 or 24) Sulkowski MS, et al. JAMA. 2015 Feb 23. [Epub ahead of print]. Summary: HIV and Hepatitis Coinfection HIV accelerates HCV liver disease if HIV RNA pos. * Accelerated fibrosis progression * accel. cirrhosis liver failure * accel. liver failure death 30

Summary: HIV and Hepatitis Coinfection HIV accelerates HCV liver disease if HIV RNA pos. * Accelerated fibrosis progression * accel. cirrhosis liver failure * accel. liver failure death HCC is on rise on HIV+ pts. * discrepant data on survival vs. HIV- pts. * HIV viral load correlates with survival * Screening with better survival * High survival with OLT Summary: HIV and Hepatitis Coinfection HIV accelerates HCV liver disease if HIV RNA pos. * Accelerated fibrosis progression * accel. cirrhosis liver failure * accel. liver failure death HCC is on rise on HIV+ pts. * discrepant data on survival vs. HIV- pts. * HIV viral load correlates with survival * Screening with better survival * High survival with OLT High efficacy of DAA combinations in HIV/HCV with good tolerability 31

Thank you for your kind attention 32