Scope of the problem 6/2/2015

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1 Interactive Case-Based Presentations and Audience Discussion Arthur Y. Kim, MD Assistant Professor of Medicine Harvard Medical School Director, Viral Hepatitis Clinic Massachusetts General Hospital Boston, Massachusetts Formatted: Chicago, IL: May 19,2015 Learning Objectives After attending this presentation, participants will be able to: Identify drug interactions between antiretrovirals and HCV agents Explain the rationale for antiviral treatment of HCV in HIV-infected individuals Apply recent advances in the treatment of HCV to HIV/HCV-coinfected individuals Slide 2 of 50 Scope of the problem Slide 3 of 50 HIV-1 and HCV share routes of transmission Worldwide burden: HIV 40 million Hepatitis C 180 million Co-infection is common, between 16-33% prevalence in HIVinfected persons Liver disease (largely due to HCV) is 2nd leading cause of death if HIV+ 1

2 A tale of two viruses Slide 4 of 50 Sex > Blood HIV Targets immune cells Years to clinical illness High levels of viremia 10^9 particles/day Low fidelity of reverse transcriptase (RNA-DNA) Frequently mutates 1 cure after BMT Blood > Sex HCV Targets hepatocytes Decades to clinical illness High levels of viremia 10^12 particles/day Low fidelity of RNA-RNA polymerase Frequently mutates >90% Curable Case Slide 5 of 50 Infected via husband who died of AIDS-related complications Insulin-dependent diabetes developed 5 years earlier Hypertension: metoprolol, lisinopril, amlodipine PCOS: ethinyl estradiol / progestin Other meds: ASA 81 mg BMI: 31, no significant EtOH use HIV: Suppressed on TDF/FTC + ritonavir + atazanavir HCV: 1b infection, 12 years ago, bx 1/6 fibrosis, attempted PEG-IFN /, complicated by anemia, requiring transfusion, managed by dose reduction + erythropoeitin Case Slide 6 of 50 Prior HIV regimens: AZT/3TC, AZT/3TC/indinavir, TDF/FTC/EFV, now suppressed on TDF/FTC + ritonavir + atazanavir HCV: 1b infection, 12 years ago biopsy 1/6 fibrosis Laboratory ALT AST TBili 63 U/L 71 U/L 2.2 mg/dl INR 1.1 Platelets 152,000 egfr 62 ml/min/1.73m 2 What would inform a decision to treat? 2

Slide 8 of 50 How do you decide to (re-)stage the degree of liver fibrosis for this patient? 1. No further staging - labs sufficient 2. Routine ultrasound 3. FibroTest 4. Transient elastography 5.

3 Slide 8 of 50 How do you decide to (re-)stage the degree of liver fibrosis for this patient? 1. No further staging - labs sufficient 2. Routine ultrasound 3. FibroTest 4. Transient elastography 5. MR elastography 6. Liver biopsy 7. Other 13% 33% 8% 21% 17% 8% 0% HIV / HCV co-infection is double trouble Slide 9 of 50 Compared to HIV-negative individuals, those with HIV suffer from: 1. Higher rates of persistence (lower rates of spontaneous clearance) 2. Accelerated rate of fibrosis, higher rates of cirrhosis 3. Higher rates of decompensation & higher liverrelated mortality Slide 10 of 50 HIV still associated with higher rates of HCVrelated fibrosis progression HIV+HCV HCV Kirk et al. Ann Intern Med 2013; 158:

to treat with antivirals and achieve cure AASLD/IDSA/IAS-USA HCV Guidance http://hcvguidelines.

4 HIV associated with higher rates of HCV-related liver decompensation, even when on ART Slide 11 of 50 Lo Re V et al. Annals of Internal Medicine 2014 Challenge of HIV/HCV Coinfection: Higher rates of decompensation & higher liver-related mortality Slide 12 of 50 Opportunity to treat with antivirals and achieve cure AASLD/IDSA/IAS-USA HCV Guidance A perfect storm for sexual HCV transmission: HIV+MSM Slide 13 of 50 Bloody practices Semen exposure Other STDs Sex Drugs Crystal methamphentamine Sildenafil Internet HIV Higher levels of virus in plasma and semen Immune deficiency, especially at GI mucosa 4

infection, 12 years ago, bx 1/6 fibrosis, attempted PEG-IFN /, complicated by anemia, requiring

Fibrosure- confounded Ultrasound - mild splenomegaly, present x 10 years Transient elastography -

5 Slide 14 of 50 Case Slide 15 of 50 HIV: Suppressed on TDF/FTC + ritonavir + atazanavir HCV: 1b infection, 12 years ago, bx 1/6 fibrosis, attempted PEG-IFN /, complicated by anemia, requiring transfusion, managed by dose reduction + erythropoeitin, stopped after 6 months for futility Fibrosure- confounded Ultrasound - mild splenomegaly, present x 10 years Transient elastography - 15 kpa Slide 16 of 50 Possible Combinations of HCV treatments Genotypes PEG IFN GT3 10% GT4 4% BOC GT2 9% TLV SMV GS 9451 PTV/r ASV MK 5172 LDV GS 9669 DCV BMS MK 8742 GT1 77% 5

6 SVR Rate SVR12 (ITT) SVR12 (ITT) 6/2/2015 Slide 18 of 50 What would be your choice of antiviral treatment? 1. Simeprevir + sofosbuvir x 24w 2. Simeprevir + sofosbuvir + x 24w 3. Ledipasvir / sofosbuvir FDC x 12w 4. Ledipasvir / sofosbuvir FDC + x 12w 5. Ledipasvir / sofosbuvir FDC x 24w 6. Paritaprevir/r/ombitasvir FDC + dasabuvir x 12w 7. Paritaprevir/r/ombitasvir FDC + dasabuvir + x 12w 8. Paritaprevir/r/ombitasvir FDC + dasabuvir x 24w 63% 5% 26% 5% 0% 0% 0% 0% PEG BOC 67 Slide 19 of 50 HCV versus HIV/HCV, genotype 1 in Clinical Trials Not head to head comparison 63 PEG 75 TLV PEG SMV PEG /521 42/53 40/64 28/38 206/260 13/15 15/23 7/10 9/17 16/28 260/292 17/19 17/25 87/114 0 BOC TLV SMV (Naive) SMV SMV (Partial) SMV (Null) P/R/x12 /Rx24w (Relapser) Poordad F et al, NEJM 2011; 364: vs. Sulkowski et al. Lancet Infect Dis 2013; 13(7): Jacobson I et al, NEJM 2011; 364: vs. Sulkowski et al. Ann Intern Med 2013; 159(2): Antiviral Drugs Advisory Committee Meeting, FDA review, 10/24/13 HCV HIV/HCV C208, C216, C206, C212, HPC3007, Dieterich et al. Clin Infect Disease 2014 (epub ahead of print) Lawitz et al. NEJM 2013 versus Torres-Rodriguez et al., IDSA 2013 Osinusi et al., JAMA 2013;310(8): versus Sulkowski et al. JAMA 2014;312(4): Slide 20 of 50 PEARL-III and IV, 12 week 3D Regimens for GT1 4.8% African- American, ~10% F % African- American, ~18% F / /210 Naive 1b noncirrhotics 3D x12w 3D + x12w 0 Naive 1a noncirrhotics Ferenci et al. NEJM

7 SVR 12 6/2/2015 Regimens in Phase 3 for GT1 Slide 21 of LDV LDV ION-1 and 2: addition did not enhance SVR Cirrhotics (TURQUOISE) 24 weeks 95.9% SVR / / / / / /215 SAPPHIRE-I SAPPHIRE-II TURQUOISE-II ION-1 ION-2 ION-3 Tx-Exp (ION-2) 24 wks LDV/ 108/109 SVR FDA filings LDV/ 2/10/14 3D 4/22/14 no cirrhosis naive no cirrhosis 100% cirrhosis 16% cirrhosis null responder 55% naive 20% cirrhosis Tx-Exp no cirrhosis naive SAPPHIRE-1 Feld et al. NEJM 2014, SAPPHIRE-2 Zeuzem et al. NEJM 2014, ION-1 Afdhal et al. NEJM 4/12/2014, ION-2 Afdhal et al. NEJM 2014; 370(16):1483, ION-3 Kowdley et al. NEJM 4/12/2014. SAPPHIRE/TURQUOISE are 12 week arms only. ION studies are -sparing arms only Event Slide 22 of 50 Adverse Events 3D regimen 12 weeks in SAPPHIRE-1 3D + x 12 weeks (n=473) Placebo (n=217) Discontinuation due to AE 3 (0.6%) 0 Serious AE 10 (2.1%)* Fatigue 164 (34.7%) 45 (28.5%) Headache 156 (33.0%) 42 (26.6%) Nausea 112 (23.7%) 21 (13.3%) Insomnia 66 (14.0%) 12 (7.6%) Asthenia 57 (12.1%) 6 (3.8%) Diarrhea 65 (13.7%) 11 (7.0%) Rash 51 (10.8%) 9 (5.7%) Pruritus 80 (16.9%) 6 (3.8%) Anemia 27 (5.8%)** * 2 were possibly related to 3D by investigator Feld et al. NEJM 2014; Epub ahead of print **no cases of anemia < 8.0 g/dl Slide 23 of 50 Adverse Events LDV/ 12 weeks in ION-1 Event LDV/ x 12 weeks (n=214) LDV LDV+ x 12 weeks (n=217) Discontinuation due to AE 0 0 Serious AE 1 (<1%) 7 (3%) Fatigue 44 (21%) 79 (36%) Headache 53 (25%) 49 (23%) Nausea 24 (11%) 37 (17%) Insomnia 17 (8%) 45 (21%) Asthenia 14 (7%) 23 (11%) Diarrhea 24 (11%) 37 (17%) Rash 16 (7%) 21 (10%) Irritability 11 (5%) 17 (8%) Cough 6 (3%) 21 (10%) Pruritus 11 (5%) 22 (10%) Anemia 0 25 (12%) Afdhal et al. NEJM 2014; Epub ahead of print 7

8 SVR 12 6/2/2015 Extension of therapy beyond 12 weeks may be necessary for GT1a, null responder, cirrhotic Slide 24 of weeks 24 weeks TURQUOISE II 100% cirrhosis /64 14/15 13/13 52/56 11/11 10/10 40/50 39/42 Naive Partial Null Relapse Poordad et al. TURQUOISE - II, EASL 2014 Slide 25 of 50 What would you choose for 1a infection? Non-cirrhotic Cirrhotic Naïve /LDV x 12 weeks /LDV x 12 weeks 3D + x 12 weeks 3D + x 24 weeks SMV/ +/- x 12 weeks SMV/ +/- x 24 weeks Experienced /LDV x 12 weeks /LDV x 24 weeks /LDV+ x 12 weeks 3D + x 12 weeks 3D + x 24 weeks SMV/ +/- x 12 weeks SMV/+/- x 24 weeks Slide 26 of 50 What would you choose for 1b infection? Non-cirrhotic Cirrhotic Naïve /LDV x 12 weeks /LDV x 12 weeks 3D x 12 weeks SMV/ x 12 weeks 3D + x 12 weeks SMV/ x 24 weeks Experienced /LDV x 12 weeks /LDV x 24 weeks /LDV+ x 12 weeks 3D x 12 weeks 3D+ x 12 weeks SMV/+/- x 12 weeks SMV/+/- x 24 weeks 8

9 Slide 28 of 50 Which of these is most problematic with SMV 1. Insulin 2. Metoprolol 3. Lisinopril 4. Amlodipine 5. Ethinyl estradiol / progestin 6. ASA 81 mg 7. TDF/FTC 8. Ritonavir + Atazanavir 78% 17% 6% 0% 0% 0% 0% 0% Slide 29 of 50 Drug-interactions with SMV/ SMV Sofosbuvir Substrate of P-gp and BCRP; potent P-gp inducers may decrease sofosbuvir concentrations Tipranavir, rifampin, St. John s wort induces P-gp at steady state Do not use with amiodarone Simeprevir Mild inhibitor of CYP1A2 and intestinal CYP3A4, inhibits OATP1B1/3 and P-gp Protein bound, biliary elimination Multiple drug interactions (usually a victim, not a perpetrator) From guidelines: Simeprevir should NOT be used with efavirenz, etravirine, nevirapine, cobicistat, or any HIV protease inhibitors. Slide 31 of 50 Which of these is most problematic with 1. Insulin 2. Metoprolol 3. Lisinopril 4. Amlodipine 5. Ethinyl estradiol / progestin 6. ASA 81 mg 7. TDF/FTC 8. Ritonavir + Atazanavir 0% 0% 0% 6% 17% 0% 11% 67%

Ritonavir + Atazanavir - elevated bilirubin 1. 2. 3. 4. 5. 6. 7. 8.

10 Slide 33 of 50 Which of these is most problematic with 1. Insulin 2. Metoprolol 3. Lisinopril 4. Amlodipine - levels rise, may need dose reduction 5. Ethinyl estradiol / progestin - elevated LFTs - avoid 6. ASA 81 mg 7. TDF/FTC 8. Ritonavir + Atazanavir - elevated bilirubin % 0% 0% 0% 0% 0% 0% 0% Slide 34 of 50 Turquoise-1: 3D regimen for HIV/HCV-coinfected patients, GT1 n=63 Sulkowski et al. JAMA 2015 Slide 35 of 50 Turquoise-1: 3D regimen for HIV/HCV-coinfected patients, GT1 n=63 Sulkowski et al. JAMA

% of patients 6/2/2015 TURQUOISE-1 3D+ x 12 or 24 wks in HIV/HCV SVR 12: Treatment naive + PR experienced Slide 36 of 50 100 75 50 25 ITT virologic response rates 100 100 97 97 94 97 94 12-wks 24-wks

29/31 RVR EOTR SVR4 SVR12 High CD4 (median 600s) 5 had blips HIV-1 RNA > 40 copies/ml, all re-suppressed without change or intensification A5329 opening shortly includes RAL and r/drv (QD -> BID)

11 % of patients 6/2/2015 TURQUOISE-1 3D+ x 12 or 24 wks in HIV/HCV SVR 12: Treatment naive + PR experienced Slide 36 of ITT virologic response rates wks 24-wks Mean age 58 ~24% Black 19% cirrhosis n=63 r/atv (n=28) RAL (n=35) No discontinuations 1 withdrew consent 1 breakthrough in nonresponder/cirrhotic 5 >moderate AEs 0 31/31 32/32 30/31 31/32 29/31 31/32 29/31 RVR EOTR SVR4 SVR12 High CD4 (median 600s) 5 had blips HIV-1 RNA > 40 copies/ml, all re-suppressed without change or intensification A5329 opening shortly includes RAL and r/drv (QD -> BID) Sulkowski et al. JAMA D Regimen for HIV/HCV coinfection compatable with HIV protease inhibitors? Slide 37 of 50 PTV/r DRV Ctrough lower ATV Ctrough higher LPV Ctrough higher ABT-450 levels higher with r/atv QPM and r/lpv & levels relatively unaffected Well tolerated, no new safety concerns 207/ /210 Khatri et al. ICAAC September 2014, Washington DC Abstract #038 Recommended no dose adjustment of 3D. Due to higher RTV dose, avoid with r/lpv Slide 38 of 50 Turquoise-1: 3D regimen for HIV/HCV-coinfected patients, GT1 n=63 Eron et al. ICAAC September 2014, Washington DC Abstract #673 11

12 Slide 40 of 50 Which of these is most problematic with 1. Insulin 2. Metoprolol 3. Lisinopril 4. Amlodipine 5. Ethinyl estradiol / progestin 6. ASA 81 mg 7. TDF/FTC 8. Ritonavir + Atazanavir 15% 15% 30% 40% 0% 0% 0% 0% Tenofovir Exposures Slide 41 of 50 NNRTIs Without With LDV/ 1,2 LDV/ 3 RTV-Boosted PIs Without With LDV/ 4-9 LDV/ 10 Range of TFV exposures with available safety data EFV RPV ATR CPA FPV SQV LPV/r ATV DRV ATV DRV * N = * 24 TFV exposures are higher when TDF is coadministered with LDV/ compared to without LDV/ Compared to the range of TFV exposures with available safety data For EFV or RPV: TFV exposures fall within the range 1 For RTV-boosted PIs: TFV exposures partially exceed the range 2 1, Data on File, Gilead Sciences. 2. Hoetelmans RMW, et al. 6 th IWCPHT Quebec City, Canada. Poster # German P, et al. ICPHHT #O6 4. Luber AD, et al. HIV Medicine. 2010;11:193-9 (FPV+RTV) 5. Chittick GE, et al. AAC. 2006; 50(4): (SQV+RTV) 6. Zhu. 9th IWCPHT #023 (ATV+RTV & LPV/r ) * HIV-infected subjects in CASTLE study 7. Kearney B, et al. JAIDS. 2006;43(3): (LPV/r) 10. German P, et al. CROI Agarwala S, et al. 6th IWCPHT #16. (ATV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 2007;64(5): (DRV+RTV) Slide Courtesy of Gilead Sciences LDV/ ERADICATE: Changes in Renal Function Slide 42 of 50 12

ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 43 of 50 Wk 0 Wk 12 Wk 24 N=335 LDV LDV/ SVR12 LDV Phase 3, multicenter, open-label study (NCT02073656) HCV GT 1 or 4 patients in US,

positive, HIV RNA <50 copies/ml; CD4 cell count >100 cells/mm 3 ART regimens included emtricitabine and tenofovir disoproxil fumarate plus efavirenz, raltegravir, or rilpivirine Naggie et al.

13 ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 43 of 50 Wk 0 Wk 12 Wk 24 N=335 LDV LDV/ SVR12 LDV Phase 3, multicenter, open-label study (NCT ) HCV GT 1 or 4 patients in US, Canada, and New Zealand Broad inclusion criteria HCV treatment-naïve or treatment-experienced 20% with compensated cirrhosis Platelets 50,000/mm 3 ; hemoglobin 10 mg/dl, CrCl 60 ml/min HIV-1 positive, HIV RNA <50 copies/ml; CD4 cell count >100 cells/mm 3 ART regimens included emtricitabine and tenofovir disoproxil fumarate plus efavirenz, raltegravir, or rilpivirine Naggie et al. CROI 2015 ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 44 of 50 LDV Naggie et al. CROI 2015 ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 45 of 50 LDV Naggie et al. CROI

ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 46 of 50 LDV Naggie et al.

antiretroviral LDV/, what would you do? 1. Continue regimen, switch if renal monitoring shows change 2. Reduce dose of tenofovir 3. Swap tenofovir for abacavir 4.

Something else 28% 8% 4% 36% 12% 12% 1. 2. 3. 4. 5. 6.

14 ledipasvir + sofosbuvir (FDC) ION-4 for HIV/HCV Slide 46 of 50 LDV Naggie et al. CROI 2015 Slide 48 of 50 HIV: TDF/FTC + ritonavir + atazanavir HCV: 1b infection, 12 years ago, bx 1/6 fibrosis, nonresponder, Fibroscan - 15kPa For antiretroviral LDV/, what would you do? 1. Continue regimen, switch if renal monitoring shows change 2. Reduce dose of tenofovir 3. Swap tenofovir for abacavir 4. Swap ritonavir/atazanavir for raltegravir 5. Both 2 and 3 6. Something else 28% 8% 4% 36% 12% 12% HCV Interactions Summary Slide 49 of 50 LDV LDV/: Key interactions - monitor for potential tenofovir toxicity Particularly with HIV protease inhibitors Care with egfr < 60 ml/min/1.73 m 2, high-risk patients Monitor urine protein, serum BUN/Cr, electrolytes including phosphorus PTV/r 3D regimen: Key interactions - AVOID with efavirenz, rilpivirine, lopinavir/ritonavir Ensure proper ritonavir dosing ACTG 5329 will examine compatibility with boosted darunavir 14

15 Identifying and Managing Interactions (Jen Kiser) Slide 50 of 50 Kiser JJ, Burton JR, Jr, Everson GT. Nature Reviews Gastroenterol Hepatol 2013;10: HCV Drug-Drug Interactions Slide 51 of 50 Requires close attention - develop a systematic approach HIV antiretrovirals Do NOT interrupt therapy Determine need and feasibility for ART switch Factors include prior genotypic testing and ARV history Consult HIV specialist With present cautions and contraindications, majority of patients may require consideration of ARV change 1 HIV suppression remains goal, without compromising future options Monitor adherence, side effects closely during switch Slide 52 of 50 ARV Interaction Score Card Kisergram Simeprevir 1 Sofosbuvir 2 Ledipasvir 3-5 Daclatasvir 6,7 3D 8-10 ATV/r No data No data LDV, ATV a DCV b ABT450 ; ATV DRV/r SIM ; DRV ; DRV LDV, DRV a DCV 3D / ; DRV LPV/r No data No data No data DCV ABT450 ; LPV TPV/r No data No data No data No data No data EFV SIM ; EFV ; EFV LDV ; EFV a DCV b No PK data c RPV SIM ; RPV ; RPV LDV ; RPV No data ABT450 ; RPV ETR No data No data No data No data No data RAL SIM ; RAL ; RAL LDV ; RAL No data 3D ; RAL EVG/cobi No data ; ELV/cobi LDV ; ELV/cobi No data No data DTG No data No data No data No data No data MVC No data No data No data No data No data TDF SIM ; TFV ; TFV LDV ; TFV DCV ; TFV 3D ; TFV a Watch renal function, TFV levels increased, b Decrease DCV dose to 30mg QD with ATV, increase DCV dose to 90mg QD with EFV, c 3D + EFV led to premature study discontinuation due to toxicities 1 Ouwerkerk-Mahadaven S IDWeek 2012, 2 Kirby B AASLD 2012, 3 Harvoni package insert, 4 German P 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy 2014, 5 German P, CROI 2015, 6 Bifano M, et al. Antivir Ther. 2013;18(7):931-40, 7 Eley T HIVDART 2014, 8 Khatri ICAAC 2014, 9 Khatri ICAAC 2014, 10 Viekira Pak package insert Slide Courtesy of J Kiser 15

changed TDF -> abacavir after B*5701 Insurance preference paritaprevir/r/ombitasvir/dasabuvir

16 Case Slide 53 of 50 HIV: TDF/FTC + ritonavir + atazanavir HCV: 1b infection, 12 years ago, bx 1/6 fibrosis, nonresponder, Transient elastography - 15kPa Endoscopy negative for varices egfr = 62 - changed TDF -> abacavir after B*5701 Insurance preference paritaprevir/r/ombitasvir/dasabuvir Changed r/atv -> raltegravir Treatment of HCV Slide 54 of 50 Slide 55 of 50 16

17 Interactive Case-Based Presentations and Audience Discussion Arthur Y. Kim, MD Assistant Professor of Medicine Harvard Medical School Director, Viral Hepatitis Clinic Massachusetts General Hospital Boston, Massachusetts Formatted: Chicago, IL: May 19,

6/2/2015. Interactive Case-Based Presentations and Audience Discussion

6/2/2015. Interactive Case-Based Presentations and Audience Discussion Interactive Case-Based Presentations and Audience Discussion Arthur Y. Kim, MD Assistant Professor of Medicine Harvard Medical School Director, Viral Hepatitis Clinic Massachusetts General Hospital Boston,