8/11/2014 HIV/HCV CO-INFECTION: RECENT ADVANCES AND NEW OPPORTUNITIES HISTORY NEVER LOOKS LIKE HISTORY WHEN YOU ARE LIVING THROUGH IT.

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1 HIV/HCV CO-INFECTION: RECENT ADVANCES AND NEW OPPORTUNITIES Jacob Langness, PharmD, BCPS Clinical Pharmacy Specialist HIV and Hepatology HISTORY NEVER LOOKS LIKE HISTORY WHEN YOU ARE LIVING THROUGH IT John W. Gardner Objectives Review pathogenesis, transmission, and epidemiology of HIV/HCV Coinfection Review approved agents and learn current recommendations for treatment of chronic HCV in a patient living with HIV Discuss future treatment options for coinfected patients, including future medications in the investigational pipeline and estimated approval timelines 1

2 Challenging Patient Groups Patients with cirrhosis HCV genotype 3 infection Patients nonresponsive to DAA regimens HIV Co-infection BRIEF BACKGROUND IN HEPATITIS C Epidemiology of Hepatitis C Estimated million people worldwide living with Hepatitis C (HCV) approximately 3% of the world population Approximately 50% undiagnosed with infection Leading cause of liver transplantation in America From 2010 to 2020: Cirrhosis, hepatic decompensation, and hepatocellular carcinoma are expected to double Liver-related deaths are expected to triple CDC 2

3 HCV-Related Cirrhosis HCV Treatment Cascade (data in millions) Americans with Chronic HCV Diagnosed Referred to Care 0.3 Treated 0.18 SVR (Holmberg et al., Hepatitis C in the US N Engl J Med 2013; 368: ) OMG! 10 Average HCV Patients 3

4 Patients With Liver Complications (%) 8/11/2014 For Every 100 people with HCV People Still Require Treatment. Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis 100 No SVR SVR Mos Pts at Risk, n Bruno S, et al. Hepatology. 2007;45:

5 13 Location of Replication Leads to Cure Slide adopted from Kiser, J. HCV HIV HIV and HCV Co-Infection Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HCV/HIV-coinfected patients HIV accelerates the natural course of hepatitis C [1] Higher HCV viral loads in Coinfection Has not been associated with increased fibrosis Successful HIV suppression can slow fibrosis progression but not back to the rate in HCV monoinfection [2] [1] Rockstroh JK, et al. Am J Gastroenterol. 1996;91: [2] Graham CS, et al. Clin Infect Dis. 2001;33:

6 HCV Coinfection vs Monoinfection: Cumulative Incidence of Decompensation 10-year hepatic decompensation risk 83% higher in coinfected patients Adjusted HR 1.83 (95% CI: ) 0.2 HIV/HCV coinfected HCV monoinfected Yrs to Hepatic Decompensation Lo Re V, et al. IAC Abstract WEAB0102. P <.001 HIV/HCV epidemiology National-wide, approximately 25% of HIV+ patients are coinfected with HCV [1] UCH IDGP Clinic: ~14% Less IVDU, Less urban As many as 80% of HIV+ patients who inject drugs are coinfected with HCV [1] Route of transmission can affect sequence of infection IVDU: Generally contract HCV then HIV MSM: Generally contract HIV then HCV [2] All patients with HIV infection should be tested for HCV HIV+ patients are at 4.1x higher risk to acquire HCV as HIV- patients [3] [1] CDC. HIV and viral hepatitis. May [2] Kum AY, Chung RT. Gastroenterology. 2009; 137(3):795. [3] Yaphe S, et al. Sex Transm Infect. 2012;88: Transmission of HCV Multiple factors associated with HCV transmission in HIV+ patients Unprotected receptive anal intercourse Online casual sexual partners Sex at sex venues Older age Syphilis Recreational drug use Drinking > 13 alcoholic drinks per week 6

7 HIV/HCV Challenges 1. Progression of Liver Disease 1. Progression to cirrhosis risk 3-fold higher in coinfected vs HCV-monoinfected patients [1] 2. Relative risk of decompensated liver disease 6-fold higher in coinfected vs HCV-monoinfected patients [2] 3. Risk of liver cancer is 8x higher in HIV patients than general public [3] 4. Progression of HCV infection to cirrhosis is 8 years faster in Coinfected patients than HCV mono-infected patients [4] 2. Comorbidities of population 1. Substance Abuse 2. Mental Health 3. HTN, DMII, CVD, etc 3. Drug-Drug Interactions especially HIV medications [1] DHHS Antiretroviral Guidelines for Adults and Adolescents. [2] Naggie S, et al. Gastroenterology. 2012;142: [3] Patel P, et al. Ann Intern Med. 2008;148(10):728. [4] Brau N, et al. J Hepatol. 2007;47(4):527 Risks and Consequences of Deferring Therapy in HIV/HCV-Coinfected Patients Accelerated rate of HCV-related hepatic fibrosis progression in coinfected patients with increasing immune deficiency Coinfected patients have reduced access to liver transplantation and reduced survival HCV Life Cycle and DAA Targets Receptor binding and endocytosis Translation and polyprotein processing Fusion and uncoating (+) RNA ER lumen LD Transport and release ER lumen LD Virion assembly NS3/4 protease inhibitors Membranous web NS5A* inhibitors LD NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Block replication complex formation, assembly Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:

8 The Good News 100 PegIFN DAAs Standard IFN 1991 RBV IFN 6 mos 16 IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos PegIFN/ RBV/ DAA Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. DAA + RBV PegIFN Determinants of Successful HIV ART and HCV DAAs? Clinician experience Communication skills Multidisciplinary team Replication rate (Viral load) Mutation rate (Resistance) Tropism Latent HIV reservoirs Clinician Virus Drug Patient Potency Pharmacokinetics (dosage schedule) Tolerability Toxicity Convenience Resistance Adherence Access to care Access to medication Life situation Disease stage Slide Adapted from Clinical Care Options : Hepatitis What Are the Key Elements of an Ideal HCV Regimen? Highly Effective Safe and Tolerable Pan-Genotypic Easy Dosing, All Oral Few Drug-Drug Interactions 8

9 Priorities: A Balancing Act Cost Simplicity Shortest Duration Efficacy Overview of DAAs C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Serine Protease Protease Cofactor RNAdependent HCV Replicase RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex Drugs Boceprevir Telaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 RNA-dependent RNA polymerase Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir Not All Direct-Acting Antivirals are Created Equal Characteristic Resistance profile Pangenotypic efficacy Antiviral potency Protease Inhibitor * Protease Inhibitor ** NS5A Inhibitor Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Adverse events Good profile Average profile Least favorable profile *First generation. **Second generation. Slide Adapted from Clinical Care Options : Hepatitis 9

10 WHERE WE WERE Non-Direct Acting Antivirals and First Generation Protease Inhibitors 29 Ribavirin Dose: Weight-based dosing >75 kg: 1200 mg PO daily in divided doses <75 kg: 1000 mg PO daily in divided doses Mechanism of Action: Virustatic ; alters viral attachment, penetration, and uncoating. Exact mechanism is unknown. Phosphorylated intercellularly to active metabolite. Best absorbed with high fat meal Brands: Copegus, Rebetol, Ribasphere, RibaTab, Virazole Pregnancy Category: X Side Effects: rash, hemolytic anemia, fatigue, altered taste, anorexia Pegylated Interferon 30 Mechanism of Action: Bind to cell surface initiating signaling leading to activation of gene transcription. Stimulated genes inhibit viral replication in infected cells, cell proliferation, and immunomodulation. Interferon covalently bound to polyethylene glycol Slows metabolism, longer half-life Increased serum levels of interferon Improved anti-hcv activity Formulations (dosing differences between the two): Peginterferon Alfa-2a (PEGASYS) Peginterferon Alfa-2b (Peg-Intron) Side Effects: suicide/homicide ideation, increased depression, flu-like symptoms, neutropenia, anemia, thrombocytopenia, fatigue 10

11 Overview of DAAs C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Serine Protease Protease Cofactor RNAdependent HCV Replicase RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex Drugs Boceprevir Telaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 RNA-dependent RNA polymerase Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir Telaprevir (INCIVEK ): HCV NS3/4A Protease Inhibitor Only approved for Genotype 1 Dosed with peginterferon and ribavirin for 48 weeks 3x daily dosing with 20g fat/dose Severe side effects (anemia, rash, anal pain), significant drug interactions Boceprevir (VICTRELIS ): HCV NS3/4A Protease Inhibitor Only approved for Genotype 1 Dosed with peginterferon and ribavirin for 48 weeks 3x daily dosing with 400 calories Severe side effects (anemia, dysgusia), significant drug interactions Triple Therapy for Chronic HCV Infection: A Comparison of Outcomes in Patients with Minimal versus Advanced Fibrosis 110 patients treated at UCH from May 1, 2011 May 31 st, 2013 N=110 Minimal Fibrosis (F0-F2) N = % 46% SVR 57% 36% Early Discontinuation Discontinuation Due to AEs 33% 58% 22% 22% Viral Breakthrough 2% 19% Advanced Fibrosis (F3/F4; Cirrhotic) 11

12 WHERE WE ARE Non-Direct Acting Antivirals and Improved Direct Acting Antivirals First In Its Class C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Serine Protease Protease Cofactor RNAdependent HCV Replicase RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex Drugs Boceprevir Telaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 RNA-dependent RNA polymerase Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir Sofosbuvir (SOVALDI ) HCV nucleotide analog NS5B polymerase inhibitor; interrupts HCV replication Metabolized to GS (>90%), predominant PK activity 400 mg po daily, taken with or without food High barrier to resistance Side effects: nausea, insomnia, headache, fatigue Renally eliminated; do not use in CrCL <30 ml/min 12

13 Sofosbuvir FDA Indication Patients with genotype 1 or 4 CHC Patients with genotype 2 CHC Patients with genotype 3 CHC Treatment Sofosbuvir + peginterferon + ribavirin Sofosbuvir + ribavirin Sofosbuvir + ribavirin Duration 12 weeks 12 weeks 24 weeks Recommended regimens and durations for sofosbuvir combination therapy in HCV Mono-infected and HCV/HIV-1 Co-infected Patients Sofosbuvir and ribavirin for 24 weeks in Geno 1 patients who are ineligible to receive an Interferon-based regimen. Trial Patient Population n Regimen Sofosbuvir Phase III Data Duration, Wks SVR12, % NEUTRINO [1] Tx-naive GT 4 28 SOF + P/R Tx-naive GT SOF + P/R Tx-naive GT 5/6 7 SOF + P/R FISSION [2] Tx-naive GT 2 70 SOF + RBV Tx-naive GT SOF + RBV FUSION [3] Tx-experienced GT 2 36 SOF + RBV Tx-experienced GT 3 64 SOF + RBV Tx-experienced GT 2 32 SOF + RBV Tx-experienced GT 3 63 SOF + RBV POSITRON [4] IFN-UII GT SOF + RBV IFN-UII GT 3 98 SOF + RBV VALENCE [5] Tx-naïve or experienced GT2 Tx-naïve or experienced GT3 73 SOF + RBV SOF + RBV Lawitz E, et al. EASL Abstract Gane E, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract Zeuzem S, et al, AASLD 2013, Abstract 1085 Genotype Prior Treatment Cirrhosis Regimen Duration (Weeks) 1 or 4 Naïve No Peg/RBV/SOF 12 92% 1 or 4 Naïve Yes Peg/RBV/SOF 12 80% Expected SVR 1 or 4 Experienced No Peg/RBV/SOF 12 Estimate 75% 1 or 4 Experienced Yes Peg/RBV/SOF 12 Estimate 75% 1 or 4 Pegintolerant Experienced Yes/No SOF/RBV 24 70% 2 Naïve Yes/No SOF/RBV 12 95% 2 Experienced Yes SOF/RBV 12 60%? 2 Experienced Yes SOF/RBV 16 78% 2 Experienced Yes SOF/RBV 24? 3 Naïve No SOF/RBV 24 94% 3 Naïve Yes SOF/RBV 24 92% 3 Experienced No SOF/RBV 24 87% 3 Experienced Yes SOF/RBV 24 60% Any Listed for HCC Naïve/Experie nced Yes/No SOF/RBV Min 30 days 65-90% ptvr 13

14 PK and Drug Interactions Metabolism: Nucleoside analog Rapidly phosphorylated to active GS Accounts for >90% circulating drug Sofosbuvir is substrate of P-gp transporter and BCRP GS is not Neither drug or metabolite inhibit or induce any hepatic metabolic pathways Drug Interactions: Inducers of P-gp: decrease sofosbuvir and metabolite Package Insert: St. John s Wort, rifampin, rifabutin, tipranavir, carbamazepine, phenytoin, phenobarbital, oxcarbazepine Lexi-comp: Dexamethasone, doxorubicin, nefazodone, Prazosin, vinblastine, tenofovir Inhibitors of P-gp: increase sofosbuvir but NO increase in metabolite PHOTON-1 Open-Label international clinical trial evaluating sofosbuvir and ribavirin for 12 or 24 weeks in Genotype 1, 2, or 3 HIV/HCV Coinfected patients Genotype 1: Treatment Naïve Genotype 2 and 3: Treatment Naïve or Experienced All patients either HIV virologically suppressed, on therapy, with a CD4 count of >200 cell/ml or not on therapy with a CD4 count of >500 cell/ml Total of 210 patients available for SVR12 analysis PHOTON-1: Sofosbuvir + Ribavirin in GT1-3 HCV Pts Coinfected With HIV Open-Label international clinical trial evaluating sofosbuvir and ribavirin for 12 or 24 weeks in Genotype 1, 2, or 3 HIV/HCV Coinfected patients 95% on ART: TDF/FTC, 100%: EFV: 35%; ATV/RTV: 17%; DRV/RTV: 15%; RAL: 16% RPV: 6% 10% of pts with cirrhosis Tx-naive GT1 Tx-naive GT2/3 Tx-expd GT2/3 Naggie S, et al. CROI Abstract 26. Sofosbuvir + Ribavirin (n = 68) Wk 12 Sofosbuvir + Ribavirin (n = 114) Sofosbuvir + Ribavirin (n = 41) Sofosbuvir 400 mg QD; weight-based ribavirin 1000 or 1200 mg/day Wk 24 SVR12, % (n/n) 76% (87/114) GT2: 88% (23/26) GT3: 67% (28/42) GT2: 92% (22/24) GT3: 94% (16/17) 14

15 Photon-2: SOF + Riba in Genotypes 1-4 HCV Pts Coinfected with HIV 97% on ART; regimens included TDF/FTC with ATV/r, DAR/r, EFV, RPV, or raltegravir HIV undetectable for 8 weeks 20% compensated cirrhosis Presented at International AIDS Conference in Melbourne, Australia on 7/21/14 Slide created by Jules Levin for NATAP Cirrhotic versus Non-cirrhotic No Cirrhosis Cirrhosis Geno 1 Geno 2 Geno 3 Geno 4 Presented at International AIDS Conference in Melbourne, Australia on 7/21/

16 Simeprevir C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Serine Protease Protease Cofactor RNAdependent HCV Replicase RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex Drugs Boceprevir Telaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 RNA-dependent RNA polymerase Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir Simeprevir (OLYSIO ) Next-generation HCV NS3/4A protease inhibitor 150 mg po daily, with food (no fat or calorie requirement) Contains a sulfonamide moiety, no patients experienced a reaction No dose adjustment required for patients with mild, moderate, or severe renal dysfunction 2-5x increase in plasma levels in decomensated cirrhotic patients, not recommended per Guidelines Side effects: photosensitivity, rash, pruritis, nausea, increased bilirubin Summary of Efficacy Genotyp e Prior Treatment Cirrhosis Regimen Duration (Weeks) 1 & 4 Naïve No Peg/Riba/SIM 24/48 84% 1 & 4 Naive Yes Peg/Riba/SIM 48 68% 1 & 4 Experienced Relapse 1 & 4 Experienced Partial 1 & 4 Experienced Null No Peg/Riba/SIM 24 85% No Peg/Riba/SIM 48 75% No Peg/Riba/SIM 48 51% 1 & 4 Experienced Yes Peg/Riba/SIM 48?? Expected SVR *ervr, HCV RNA negative at 4 and 12 weeks If positive ervr, 24 weeks treatment, if no ervr 48 weeks of treatment 16

17 Simeprevir FDA Indication Genotype 1a versus 1b Pooled Quest-1 and Quest-2 data: 1a: 75% (191/254) versus 1b: 85% (228/267) 1a without Q80K: 84% (131/165) 1a with Q80K: 58% (49/84) FDA: strong recommendation for baseline HCV polymorphism testing Drug Interactions Simeprevir s affect on other drugs: Mildly inhibits CYP1A2 Mildly inhibits intestinal CYP3A4 Inhibits OAT1B1/3 and P-gp transport Meds to watch: digoxin, antiarrhythmics, erythromycin, HMG CO-A reductase inhibitors, PDE-5 inhibitors, calcium channel blockers, midazolam, triazolam Affect of other drugs on simeprevir: Metabolized through CYP3A <1% cleared through urine Meds to watch: any moderate/strong CYP3A inhibitor/inducer; antiepileptics, antibiotics, rifampin/rifabutin, antifungals, HMG Co-A reductase inhibitors, cyclosporin 17

18 C212: Simeprevir with Peginterferon and Ribavirin for HCV/HIV-1 Co-infected Patients Treatment Naïve Prior Relapser Partial Responder Regimen Simerprevir 12 weeks + peg/riba weeks RGT Simerprevir 12 weeks + peg/riba weeks RGT Efficacy 79% (42/53) 87% (15/17) Simerprevir 12 weeks + peg/riba 48 weeks 70% (7/10) Null Responder Simerprevir 12 weeks + peg/riba 48 weeks 57% (16/28) Genotype Efficacy 1a 71% (62/88) 1a with Q80K 67% (20/30) 1a without Q80K 72% (42/58) 1b 89% (16/18) HCV Therapy Coinfection Boceprevir Telaprevir Simeprevir Sofosbuvir Atazanavir/r X X Darunavir/r X X X Fosamprenavir/r No Data X No Data No Data Lopinavir/r X X No Data No Data Nelfinavir No Data No Data No Data No Data Efavirenz X * X Rilpiverine? Etravirine? No Data No Data Raltegravir Elvitegravir/cobist at No Data X X No Data Maraviroc * * No Data No Data X = Interaction = absence of clinically important interaction * = combination requires a dose adjustment COMBINATION DAAS FOR HCV TREATMENT Its like déjà vu all over again! 18

19 COSMOS: Simeprevir + Sofosbuvir ± RBV in Genotype 1 HCV Patients Randomized phase IIa study Wk 12 Wk 24 Patients With GT1 HCV Cohort 1: Previous null responders, F0-F2 [1] (N = 80) Cohort 2: Naives and previous null responders, F3-F4 [2] (N = 87) Simeprevir + Sofosbuvir + RBV Simeprevir + Sofosbuvir Simeprevir + Sofosbuvir + RBV Simeprevir + Sofosbuvir Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV mg/day. 1. Sulkowski M, et al. EASL Abstract O7. 2. Lawitz E, et al. EASL Abstract O165. COSMOS: Simeprevir + Sofosbuvir ± RBV in Genotype 1 HCV Patients 167 total patients Response Rates: % No statistically significant difference between: 12 versus 24 weeks Geno 1a versus Geno 1b With or without ribavirin 1. Sulkowski M, et al. EASL Abstract O7. 2. Lawitz E, et al. EASL Abstract O165. Hepatitis C Treatment Guidelines Joint guidelines published by AASLD and IDSA Recommends per: Genotype Past treatment experience Degree of liver dysfunction Special populations: HIV/HCV Coinfection Post-liver transplant Updated regularly Last update: March 21 st,

20 Preferred Treatment Recommendations: Coinfected Patients Genotype 1 INF Eligible SOF + PR 12 weeks Class 1 Level B INF Ineligible Naïve or prior relapser SOF + RIBA 24 weeks Class 1 Level B SIM + SOF ± RIBA 12 weeks Class 2a Level C Either PR nonresponse SIM + SOF ± RIBA 12 weeks Class 2a Level C *For genotype 1a, baseline resistance testing for the Q80K polymorphism should be performed and alternative treatments considered if this mutation is present. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014 Preferred Treatment Recommendations: Coinfected Patients Genotype 2 INF Eligible or Ineligible SOF + RIBA 12 weeks Class 1 Level B INF Eligible or Ineligible Null-responder and cirrhotic SOF + RIBA 16 weeks Class 1 Level B Genotype 3 INF Eligible or Ineligible SOF + RIBA 24 weeks Class 1 Level B AASLD and IDSA. Available at: Version March 21, 2014 Where We Are Going: What is in the Pipeline? 20

21 HCV RNA< LLQ, % patients 8/11/2014 Simeprevir C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Serine Protease Protease Cofactor RNAdependent HCV Replicase RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex Drugs Boceprevir Telaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 RNA-dependent RNA polymerase Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir HIV-ERADICATE: Sofosbuvir + Ledipasvir SOF + LDV ARV Untreated CD4 count stable and HIV RNA <500 copies OR CD4 count >500 cells/mm3 SVR12 ARV Treated CD4 count >100 cells/mm3 HIV RNA <40 copies Current ARVs 8 weeks Currently SVR Fixed Dose Combination: SOF 400 mg + LDV 90 mg 50 Subjects - HIV/HCV Co-infected ~80% Genotype 1a HCV Treatment-Naive Minimal Liver Disease: F0-3 HIV ARVs: tenofovir, emtricitabine, efavirenze, rilviverine, and raltegravir Osinusi A, et al. EASL International Liver Congress, Abstract O14. HIV-ERADICATE: Sofosbuvir + Ledipasvir Interim Results ARV Untreated ARV Treated Week End of Treatment SVR4 SVR8 SVR12 Osinusi A, et al. EASL International Liver Congress, Abstract O14. 21

22 AbbVie 3D Combination ABT-450/ritonavir (150/100 mg) + ombitasvir (25 mg) Once Daily dasabuvir (250 mg) ± ribavirin Twice Daily Study Patients Weeks Riba? SVR12 Pearl-II Geno1b experienced 12 Yes n=88 97% No n=91 99% Pearl-III Geno1b naive 12 Yes n=201 99% No n=209 99% Pearl-IV Geno1a naive 12 Yes n=100 97% Turquoise-II Geno1 compensated cirrhosis No n=205 90% 12 Yes n=208 92% 24 Yes n=172 96% Sapphire-I Geno1 naive 12 Yes n=473 96% Sapphire-II Geno1 experienced 12 Yes n=297 96% Turquoise-1: HCV treatment naïve and experienced with HIV coinfection Presented at 20 th Annual International AIDS Conference by Mark Sulkowski 7/21/14 2 part, multicenter, Phase2/3 study assessing safety and efficacy of the Abbvie 3D regimen + ribavirin in HIV/HCV Coinfection Only Genotype 1 Part 1: 63 patient on either 12 or 24 weeks Part 2: Ongoing Include darunavir/ritonavir Only 12 weeks Main reported side effects: Fatigue, insomnia, nausea, headache, 12-15% upper respiratory tract infection, 19% cirrhotic; Hep B infection excluded Stable on either Atazanavir or raltegravir regimen 22

23 HCV RNA< LLQ, % patients 8/11/2014 C-WORTHY: MK-5172/ MK-8742 RBV MK-5172 MK RBV MK-5172 MK-8742 No RBV SVR12 SVR HIV/HCV Co-infected HCV Genotype 1 Non-cirrhotic Stable on raltegravir + two NRTIs for 8 weeks prior to enrollment ART dose modification not permitted during 8 weeks preceding enrollment unless dose modification due to tolerability failure CD4 >300 cells/mm 3 Undetectable HIV RNA for 24 weeks Sulkowski M, et al. EASL International Liver Congress, Abstract O63. C-WORTHY: MK-5172/ MK-8742 RBV Interim Results MK MK RBV No RBV Week 4 Week 8 Week 12 SVR4 Sulkowski M, et al. EASL International Liver Congress, Abstract O63. Atazanavir/r HCV Therapy Daclatasvir Ledipasvir MK-8742 ABT-450 (Dose adjust to 30 mg) No Data Increase in MK levels Darunavir/r No Data No Data Increase in MK8742 levels No Data Fosamprenavir/r No Data No Data No Data No Data Lopinavir/r No Data No Data No Data No Data Nelfinavir No Data No Data No Data No Data Efavirenz (Dose adjust to mg) No Data No Data Rilpiverine No Data No Data No Data Etravirine No Data No Data No Data No Data Raltegravir No Data Elvitegravir/cobistat No Data No Data No Data No Data Maraviroc No Data No Data No Data No Data 23

24 IN CONCLUSION Challenging Patient Groups Patients with cirrhosis HCV genotype 3 infection Patients nonresponsive to DAA regimens HIV Co-infection Still A Challenge? Higher rates of substance abuse, comorbidities Coinfected patients progress towards liver disease quicker Earlier and greater risk of HCC Less likely to qualify for a liver transplant Coinfected patients respond to HCV DAAs in same way as HCV monoinfected patients Move towards combined trials Coinfection as a subset of each trial 24

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