Workshop I Planning Committee

Transcription

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2 Workshop I Planning Committee Nancy Reau, MD Associate Professor of Medicine University of Chicago School of Medicine Chicago, IL Stuart C. Gordon, MD Professor of Medicine Wayne State University School of Medicine Director of Hepatology Henry Ford Medical Center Detroit, MI Ira M. Jacobson, MD Vincent Astor Professor of Medicine Chief, Division of Gastroenterology and Hepatology Weill Cornell Medical College New York, NY Paul I. Pockros, MD Director, Liver Disease Center Scripps Clinic Clinical Director of Research Translational Science Institute Director, SC Liver Research Consortium La Jolla, CA K. Rajender Reddy, MD Professor of Medicine Professor of Medicine in Surgery Director of Hepatology Director, Viral Hepatitis Center University of Pennsylvania Philadelphia, PA

3 Workshop II Planning Committee David R. Nelson, MD Professor and Assistant Vice President for Research University of Florida Gainesville, FL Robert Brown, Jr., MD Frank Cardile Professor of Medicine Director, Transplantation Initiative Center for Liver Disease and Transplantation Columbia University New York, NY Gregory T. Everson, MD Professor of Medicine Director, Section of Hepatology University of Colorado Division of Gastroenterology Aurora, CO Joseph K. Lim, MD Associate Professor of Medicine Director, Yale Viral Hepatitis Program Section of Digestive Diseases Yale University School of Medicine New Haven, CT Kenneth E. Sherman, MD, PhD Gould Professor of Medicine University of Cincinnati College of Medicine Cincinnati, OH

4 HCV Council 2014 Overview 10 clinical practice statements were evaluated by the Council A review of the available literature was conducted The level of support and level of evidence for the statements were discussed A summary of the Council findings will be provided in this Medscape activity

5 Workshop I Clinical Management and Treatment Strategies: Utilizing the New SOC in HCV Summary of findings presented by Nancy Reau, MD Topics: Patients with cirrhosis Patient characteristics and duration of therapy Genotype 1a vs. 1b Preferred approach to treatment for genotypes 2 and 3

6 Field Survey Conducted through peer audience prior to the Council Sent to gastroenterologists/hepatologists (N=185) Used as a comparison against the Council vote

7 Please Vote on the Upcoming Statements

8 Clinical Management and Treatment Strategies: Statement 1 Patients with cirrhosis have lower rates of SVR compared to patients who are non-cirrhotic and, thus, treatment efficacy remains suboptimal for this population. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

9 Clinical Management and Treatment Strategies: Statement 2 Patients with easier to treat characteristics can be defined and treated for shorter duration. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

10 Clinical Management and Treatment Strategies: Statement 3 Genotype 1a and 1b will be treated with different regimens. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

11 Clinical Management and Treatment Strategies: Statement 4 The preferred approach to treatment for all subgroups of patients with genotype 2 is sofosbuvir and ribavirin for 12 weeks. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

12 Clinical Management and Treatment Strategies: Statement 5 The preferred approach to treatment for all subgroups of patients with genotype 3 is sofosbuvir and ribavirin for 24 weeks. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

13 Workshop I Clinical Management and Treatment Strategies: Utilizing the New SOC in HCV Nancy Reau, MD Workshop Leader

14 Statement 1 Patients with cirrhosis have lower rates of SVR compared to patients who are non-cirrhotic and, thus, treatment efficacy remains suboptimal for this population. Why make this statement? Historical data suggest cirrhosis is strongest baseline factor to predict treatment failure Cirrhotics felt to have higher SAE, dose modifications, and treatment discontinuation Compounded by prior treatment failure Trend blunted but not eliminated with SOF-PR and SMV-PR

15 SVR12 (%) SVR12 (%) COSMOS: SMV + SOF ± RBV SVR12 Cohort 1 (F0-F2 nulls): SVR12 (n=80, all arms) SMV + SOF + RBV SMV + SOF Cohort 2 (F3-F4 naïves/nulls): SVR12 (n=87, all arms) /24 14/15 26/27 13/14 28/30 16/16 25/27 13/14 24-wk Arms 12-wk Arms 24-wk Arms 12-wk Arms 20 0 Relapse in 3 pts in Cohort 1 and 3 pts in Cohort 2, all with GT 1a and 2 with Q80K polymorphism at baseline AEs (anemia and indirect bilirubin increases) largely confined to RBV arms SVR in patients with GT 1a and Q80K+: 88%-100% Jacobson I, et al. AASLD Abstract LB-3. Lawitz E, et al. EASL Abstract 165. Lawitz E, et al. Lancet Jul 26. [Epub ahead of print]

16 SVR Effect of Cirrhosis Nearly Eliminated with Combination All-oral Therapy SVR 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ION-1: Cirrhotic vs Non-Cirrhotic SVR ION-2: Cirrhotic vs Non-Cirrhotic SVR Cirrhotic Non-Cirrhotic Cirrhotic Non-Cirrhotic 100% 100% 100% 100% 100% 100% 97% 96% 100% 90% 80% 70% 60% 50% 100% 100% 99% 100% 99% 95% 86% 82% 40% 30% 20% 10% % wk-rbv 12 wk+rbv 24 wk-rbv 24 wk+rbv 12 wk-rbv 12 wk+rbv 24 wk-rbv 24 wk+rbv Ledipasvir/ sofosbuvir (LDV/SOF) ± RBV Afdhal N, et al. N Engl J Med; 2014;370: Afdhal N, et al. N Engl J Med; 2014;370:

17 SVR12, % Patients TURQUOISE-II (3D + RBV): ITT SVR12 by Prior Treatment Response 3D (ABT-450/r-ombitasvir and dasabuvir) + RBV 12-week arm 24-week arm 100.0% 92.2% 92.9% 93.3% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 85.7% 100.0% 100.0% 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% 59/64 52/56 Naive 14/15 13/13 11/11 10/10 Prior Relapse Response Prior Relapse Response 22/22 18/18 Naive 25/25 20/20 Prior Relapse Response 6/7 3/3 14/14 10/10 Prior Relapse Response Prior Null Response G1a G1b Poordad F, et al. N Engl J Med; 2014; 370:

18 Summary of Key Issues Cirrhosis is still a baseline factor that effects efficacy The impact can be blunted by other factors, such as favorable baseline characteristics (G1b) and the treatment regimen Patients continue to have lower rates of SVR, but the difference in SVR rate between non-cirrhotic and cirrhotic is now much smaller

19 Statement 1: Patients with cirrhosis have lower rates of SVR compared to patients who are non-cirrhotic and, thus, treatment efficacy remains suboptimal for this population. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 91% 52% 27% 9% 13% 7% 0% 0% 1% 0% Field Survey Council Members

20 Statement 2 Patients with easier-to-treat characteristics can be defined and treated for shorter duration. Why make this statement? PR data suggested that some populations may be able to shorten therapy Low viral load IL28B CC Shorter therapy is desirable as treatment duration drives cost and compliance

21 SVR12 (%) SVR12 by Number of Negative Predictors Derived From Multivariate Analysis (combined dataset) > /9 70/70 181/ / /239 60/88 12/ *Prior treatment, sex, weight, IL28B, cirrhosis, and HCV RNA level. Phase 3 studies of sofosbuvir regimens Foster GR, et al. Abstract O66, EASL, 2014 Number of Negative Predictors*

22 SVR12 (%) ION-3: Ledipasvir/Sofosbuvir (LDV/SOF) ± RBV in HCV G1 Treatment-naïve, Non-cirrhotic Patients P = 0.52 P = 0.70 P = / / /216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 Weeks 12 Weeks Kowdley, KV et al. N Engl J Med. 2014;370(20):

23 Summary of Key Issues Next-wave DAA trials confirm that shortening therapy for easier-to-treat patients is plausible Especially treatment-naïve without cirrhosis Even within difficult populations, cohorts of patients can be identified for shorter duration therapy Treatment experienced genotype 1b with cirrhosis and treatment experienced genotype 1a (without prior null response) can shorten to 12 weeks with 3D regimen (ABT-450/r-ombitasvir and dasabuvir)

24 Statement 2: Patients with easier-to-treat characteristics can be defined and treated for shorter duration. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 64% 47% 36% 18% 10% 18% 7% 0% 0% 0% Field Survey Council Members

25 Statement 3 Genotype 1a and 1b will be treated with different regimens. Why make this statement? Traditionally SVR is higher for genotype 1b compared to 1a Lost impact with first wave DAA triple therapy Recognized very important with simeprevir QUEST-1 trial 1 SVR12: G1a 75.2%; G1b: 85.4% (G1a w/o Q80K 83.6% w/ 58.3%) (PBO 52.3%) SOF+PR may have better efficacy in G1a NEUTRINO and PHOTON-1 Some therapy may only be appropriate for G1b 1 Jacobson IM, et al. Lancet. 2014:pii;S (14)

26 ABT-450/r-Ombitasvir and Dasabuvir (3D) +/- RBV in Previously Untreated Chronic HCV Genotype 1 Infection HCV Genotype 1a / /205 Antiviral Regimen with Ribavirin Antiviral Regimen without Ribavirin HCV Genotype 1b / /209 Antiviral Regimen with Ribavirin Antiviral Regimen without Ribavirin 3D+RBV HCV G1 subtype did not impact SVR12 in non-cirrhotic and cirrhotic treatmentnaïve or experienced population Cirrhosis, G1a prior null responders had better efficacy with 24 weeks PEARL-III and PEARL-IV Reprinted with permission from Ferenci P, et al. N Engl J Med. 2014;370:

27 Ledipasvir/Sofosbuvir +/- RBV for 12 to 24 weeks HCV Genotype 1 subtype had no impact on efficacy Treatment naïve or treatment experienced With or without RBV 8,12, or 24 weeks Afdhal N, et al. N Engl J Med. 2014;370: Afdhal N, et al. N Engl J Med. 2014;370: Kowdley KV, et al. N Engl J Med. 2014;370:

28 Summary of Key Issues Impact of genotype 1 subtype will vary by regimen used and baseline characteristics Highly impactful for simeprevir 3D (ABT-450/r-ombitasvir and dasabuvir): G1b may not require RBV No impact on ledipasvir/sofosbuvir

29 Statement 3: Genotype 1a and 1b will be treated with different regimens. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 73% 44% 15% 27% 15% 19% 7% 0% 0% 0% Field Survey Council Members

30 Statements 4 and 5 What Does the Viability of the Statements Depend Upon? Preferred Approach to Treatment for Patients with Genotype 2/3 The efficacy and safety of regimen The consequences of failure The existence of current alternatives The prospect of future alternatives (and the acceptability of waiting)

31 Statement 4 The preferred approach to treatment for all subgroups of patients with genotype 2 is sofosbuvir and ribavirin for 12 weeks. Why make this statement? Genotype 2 is traditionally seen as the easiest type of HCV to cure Efficacy is not 100% for all populations Alternative regimens are possible including deferral of therapy for next generation of agents

32 SVR12 (%) SVR12 (%) Impact of Cirrhosis on SVR12 in G / / 54 No Cirrhosis SOF + RBV 12 wks PEG + RBV 24 wks 83 10/ / 13 Cirrhosis / / 26 No Cirrhosis SOF + RBV 12 wks SOF + RBV 16 wks 60 6/ / 9 Cirrhosis Treatment-naïve Relapsers/Non-responders Sofosbuvir (SOVALDI ) Prescribing Information. Gilead Sciences, Inc. December, 2013.

33 Patients with SVR12 (%) LONESTAR-2: Sofosbuvir + PR in Treatment-experienced HCV SVR12 in G2 Patients by Cirrhosis Status No cirrhosis Cirrhosis HCV G Lawitz E, et al. AAASLD Abstract LB-4.

34 Patients with < LLOQ (%) Sofosbuvir (SOF) + PEG/RBV for Prior SOF/RBV Treatment Failures: SVR12 for HCV G2 12 weeks SOF+PEG/RBV 24 weeks SOF/RBV /2 20/22 Genotype 2 Esteban R, et al. EASL 2014, Abstract O8.

35 Summary of Key Issues G2 has high SVR rates with SOF/RBV for 12 weeks Cirrhosis and prior response still impact efficacy Alternative regimens include increasing the duration of SOF/RBV or SOF+PEG/RBV for 12 weeks Future therapy may offer additional options

36 Statement 4: The preferred approach for treatment for all subgroups of patients with genotype 2 is sofosbuvir and ribavirin for 12 weeks. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 49% 45% 31% 36% 18% 0% 10% 7% 3% 0% Field Survey Council Members

37 Statement 5 The preferred approach to treatment for all subgroups of patients with genotype 3 is sofosbuvir and ribavirin for 24 weeks. Why make this statement? G3 continues to have lower efficacy despite longer duration of therapy The impact of the next wave of therapy remains controversial

38 SVR 12 (%) Sofosbuvir + Ribavirin for Genotype VALENCE: 24 weeks, n= /92 2/13 87/100 28/45 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Naïve Treatment-experienced Zeuzem S, et al. N Engl J Med. 2014;370:

39 SVR12 (%) Retreatment of Genotype 3: Sofosbuvir + RBV Failures PR + SOF 12 Wks SOF + RBV 24 Wks /14 17/23 7/8 7/15 No cirrhosis Cirrhosis Esteban R, et al. EASL 2014, Abstract O8.

40 Variable EC50 s for NS5A Inhibitors Against HCV Genotype 3 EC50 (nm) in replicons Drug 1a 1b 3a 4a Daclatasvir Ledipasvir GS MK ACH <0.2 <0.2 IDX Gao M, et al. Curr Op Vir. 2013;3:

41 Summary of Key Issues 24 weeks of SOF + RBV highly effective in G3 AEs are those of RBV No virologic price to pay for failure PEG + RBV + SOF may be more effective in certain populations (eg, treatment-experienced cirrhotics) Drugs in development may increase the number of options

42 Statement 5: The preferred approach to treatment for all subgroups of patients with genotype 3 is sofosbuvir and ribavirin for 24 weeks. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 73% 40% 39% 27% 0% 0% 12% 8% 1% 0% Field Survey Council Members

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44 Workshop II A Patient-Oriented Approach: Addressing Treatment Challenges in 2014 Summary of findings presented by David Nelson, MD Topics: Prioritizing access to care On-treatment viral load monitoring Patients with decompensated cirrhosis HIV/HCV co-infected patients Expansion of HCV treatment to non-specialty providers

45 Please Vote on the Upcoming Statements

46 Treatment Challenges: Statement 6 Due to the high costs of medications, only patients with advanced fibrosis should be offered treatment with all oral regimens for HCV. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

47 Treatment Challenges: Statement 7 Given the high-efficacy and low-viral breakthrough rates, on-treatment viral load monitoring is no longer required. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

48 Treatment Challenges: Statement 8 Patients with decompensated cirrhosis should be treated with an all-oral regimen for HCV in order to improve survival. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

49 Treatment Challenges: Statement 9 Patients co-infected with HIV/HCV should no longer be considered a special population. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

50 Treatment Challenges: Statement 10 Treatment of hepatitis C should remain within the domain of hepatologists, gastroenterologists, and ID physicians. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely

51 Workshop II A Patient Oriented Approach: Addressing Treatment Challenges in 2014 David Nelson, MD Workshop Leader

52 Statement 6 Due to the high costs of medications, only patients with advanced fibrosis should be offered treatment with all-oral regimens for HCV. Why make this statement? To treat the entire U.S. HCV population would cost > $250 billion, thus need to prioritize access Based on the premise that patients with advanced fibrosis have the most at risk and thus most to gain with therapy, while those with mild disease can wait Historical context: challenging regimens with high AEs, long duration, and relative low SVR, risk benefit favored patients with cirrhosis

53 Cumulative Mortality (%) Cumulative Mortality (%) Chronic HCV Increases Mortality for Hepatic and Non-hepatic Diseases 23,820 adults in Taiwan prospectively followed since were anti-hcv positive; 69.4% had detectable HCV RNA 25 Hepatic Diseases 25 Extrahepatic Diseases P <.001 for comparison among three groups P <.001 for HCV RNA detectable vs undetectable 12.8% % P <.001 for comparison among three groups P=.002 for HCV RNA detectable vs undetectable 12.3% 11.0% 5 0 Anti-HCV seropositives, HCV RNA detectable 1.6% Anti-HCV seropositives, HCV RNA undetectable 0.7% Anti-HCV seropositives 5 0 Anti-HCV seropositives, HCV RNA detectable Anti-HCV seropositives, HCV RNA undetectable Anti-HCV seropositives Lee MH, et al. J Infect Dis. 2012;206:

54 10-year Cumulative Incidence Rate SVR (Cure) Associated with Decreased All-cause Mortality 530 patients with advanced fibrosis, treated with IFN-based therapy, and followed for 8.4 (IQR ) years SVR (n=192) No-SVR (n=338) IQR, interquartile range All-Cause Mortality Van der Meer AJ, et al. JAMA. 2012;308(24): HCC 2.1 Liver Failure

55 Adjusted Hazard Ratio for Mortality Adjusted Hazard Ratio for Mortality Adjusted Hazard Ratio for Mortality SVR Reduces All-cause Mortality Even in the Absence of Cirrhosis 1.2 Genotype 1 (n=12,166) SVR rate: 35% 1.2 Genotype 2 (n=2904) SVR rate: 72% 1.2 Genotype 3 (n=1794) SVR rate: 62% ( ) (P=0.0003) 0.72 ( ) (P=0.001) ( ) (P=0.005) 0.69 ( ) (P=0.049) ( ) (P=0.0002) 0.40 ( ) (P=0.0001) Overall SVR Group SVR With No Baseline Cirrhosis 0 Overall SVR Group SVR With No Baseline Cirrhosis 0 Overall SVR Group SVR With No Baseline Cirrhosis Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:

56 ION-2 Study: Sofosbuvir/Ledipasvir + RBV in Previously Treated Genotype 1 HCV Infection SVR12 by Prespecified Subgroups *When 12 week arms are combined, statistically significant difference SVR12 (%) Afdhal N, et al. EASL Abstract O109.

57 Impact of IFN-free Regimens on Clinical and Cost Outcomes Triple Therapy Staging Treat all Oral Therapy Staging Treat all Life expectancy (yr) Progression to: Cirrhosis (%) Decompensation (%) HCC (%) Decomp or HCC Transplant (%) Strategy Oral staging Oral-treat all Cost ($) 77,133 90,681 Effectiveness (QALYs) ICER ($/QALY) 15,709 HCC: hepatocellular carcinoma; QALY: quality adjusted life years; ICER: incremental cost effectiveness analysis Younossi ZM, et al. J Hepatol. 2014;60:

58 Summary of Key Issues HCV has significant effect on morbidity and mortality Highest in those with cirrhosis, but also impacts non-cirrhotics HCV cure reduces morbidity and mortality Effect seen in both cirrhotics and non-cirrhotics Cirrhosis has a negative impact on SVR, especially in treatment experienced population Requires longer duration and more expensive therapy Treating all patients who are HCV-infected, without using fibrosis screening based intervention has the greatest impact on morbidity/mortality and is the most cost-effective strategy

59 Statement 6: Due to the high cost of medications, only patients with advanced fibrosis should be offered treatment with all-oral regimens for HCV. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 73% 8% 15% 17% 0% 0% 0% 28% 27% 32% Field Survey Council Members

60 Statement 7 Given the high-efficacy and low-viral breakthrough rates, on-treatment viral load monitoring is no longer required. Why make this statement? New treatment regimens have high rates of rapid viral response Response-guided therapy is no longer used to determine duration of therapy No stopping rules based on anything other than viral breakthrough (rare event)

61 The Case to Not Monitor HCV RNA? 95% to 100% become HCV RNA (-) by week 4 There are no effective stopping rules NPV for + HCV RNA at week 4: low Relapse accounts for virtually all failures Little or no antiviral resistance Breakthrough rates < 1% to 2% in all phase 3 trials of new all-oral regimens $ associated with useless HCV RNA testing

62 The Case to Monitor HCV RNA We need to measure safety labs anyway Will this still be true when RBV-free? Negative HCV RNA is a powerful motivator, increases patient compliance Identifying breakthrough early will help limit multi-drug resistance Positive HCV RNA is marker for potential non-compliance Some insurers requiring week 4 HCV RNA prior to filling rest of prescription Cost of HCV RNA << Cost of Rx

63 Summary of Key Issues In well-motivated compliant patients on IFN-free, RBV-free Rx no labs are really needed with the use of high-potency DAA combos Similar to H. pylori: take these pills and return in 6 months to see if you responded However, data in real world are lacking on safety, breakthrough rates, and adherence Thus, some reluctance to give up on treatment safety and efficacy assessment

64 Statement 7: Given the high-efficacy and low-viral breakthrough rates, on-treatment viral load monitoring is no longer required. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 91% 31% 16% 0% 21% 18% 9% 14% 0% 0% Field Survey Council Members

65 Statement 8 Patients with decompensated cirrhosis should be treated with an all-oral regimen for HCV in order to improve survival. Why make this statement? Curing HCV may allow liver regeneration and/or prevent post-liver transplant HCV recurrence Safe, oral regimens have allowed many patients with chronic HBV with decompensated cirrhosis to be treated Use of all oral Rx much better tolerated than IFN-based options in decompensated cirrhosis Interferon: Relatively contra-indicated (infection, decompensation; platelet <100K, albumin <3.5 g/dl) SVR (G1): IFN/RBV 22%; IFN/RBV/TVR 38 to 49% IFN-free regimen with high cure rates is likely coming soon to this population (Sofosbuvir is not hepatic cleared)

66 10-year Cumulative Incidence Rate SVR (Cure) Associated with Decreased Allcause Mortality and Liver-related Events patients with advanced fibrosis, treated with IFN-based therapy, and followed for 8.4 (IQR ) years 8.9 SVR (n=192) No-SVR (n=338) All-Cause Mortality HCC Liver Failure IQR, interquartile range Van der Meer AJ et al. JAMA. 2012;308(24):

67 SOF/RBV in Cirrhosis with Portal Hypertension Outcomes Safety: first 24 weeks, Arm 1 (treatment) vs. Arm 2 (control) Discontinuations from study Arm 1: 1 AE, 1 non-responder, 1 withdrew Arm 2: 2 Disease progression (HCC, decomp), 1 withdrew, 1 LTFU Ascites and Encephalopathy Ascites Hepatic Encephalopathy Patients, n SOF + RBV n=25 Observation n=25 SOF + RBV n=25 Observation n=25 Baseline Week Week Afdhal N, et al. J Hepatology. 2014;60:S28.

68 SOF/RBV in Cirrhosis with Portal Hypertension Outcomes Virologic Response RVR 4: CTP A 100% CTP B 75% Week 24: CTP A 100% CTP B 93% SVR 12: CTP A N/A CTP B N/A Laboratory Normalization of ALT (decrease in necroinflammation) Improvement in albumin and platelet count in some HVPG: data not presented CTP score: no consistent change MELD score: no consistent change Afdhal N, et al. J Hepatology. 2014;60:S28.

69 Summary of Key Issues Pre-cirrhotic Fibrosis Compensated Cirrhosis Decompensated Cirrhosis * Likelihood of Achieving SVR With All Oral is High? Prevents Progression to Cirrhosis Prevents Decompensation and HCC? Prevents HCC, Death, and Need for LTx? * Suspect data will show that SVR can be obtained

70 Statement 8: Patients with decompensated cirrhosis should be treated with an all-oral regimen for HCV in order to improve survival. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 55% 37% 36% 22% 24% 0% 9% 9% 8% 0% Field Survey Council Members

71 Statement 9 Patients co-infected with HIV/HCV should no longer be considered a special population. Why make this statement? Patients co-infected with HIV/HCV now have SVR rates similar to patients infected with mono and their special designation delays therapy to this group Pharma can perform DDI studies early and include some patients infected with HIV in usual phase 2 and 3 studies EASL guidelines has already proclaimed patients coinfected with HIV/HCV non-special

72 FDA Special Populations Special populations listed in regulatory guidance on HCV drug development Decompensated liver disease and/or pre-transplant Post-transplant Hepatic impairment HIV/HCV co-infected patients PEG-IFN and RBV intolerant patients Patients with prior DAA experience Pediatric patients EMA: Guideline on Clinical Evaluation of Medicinal Products for Treatment of Hepatitis C. Draft for Consultation. January 2011; FDA: Guidance for Industry. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment. September 2010.

73 What Features Make HIV/HCV Special or Unique Faster rates of fibrotic progression Increased risk of hepatic decompensation Higher viral loads Drug-drug interactions Potential for altered absorption

74 Drug Interactions of DAAs with ARVs HIV Therapy Atazanavir/ritonavir Darunavir/ritonavir Fosamprenavir/ ritonavir Lopinavir/ritonavir HCV Therapy Boceprevir Telaprevir Simeprevir Faldaprevir Daclatasvir Sofosbuvir No data No data No data Reprinted with permission from Kiser J, et al. Nature Rev Gastro Hep; 2013:10(10) * No data sa No data No data No data No data No data No data No data No data No data Nelfinavir No data No data No data No data No data No data Efavirenz Rilpivirine Etravirine Raltegravir * * *?? No data No data No data No data No data No data No data No data Elvitegravir/cobicistat No data No data No data No data No data No data Maraviroc * * No data No data No data No data Indicates presence of an interaction Indicates absence of a clinically important interaction * Indicates that the combination is acceptable, but requires dose adjustment? Indicates the presence of an interaction with uncertain clinical importance

75 SVR (%) Sofosbuvir in HIV/HCV Co-infection: PHOTON-1 Trial Phase 3, open label Treatment-naïve (TN) with G1 or G2/3 Treatment-experienced (TE) with G2/ n= Treatment arms SOF/RBV, 24 wks (TN G1) 60 SOF/RBV, 12 wks (TN G2/3) 50 SOF/RBV, 24 wks (TE G2/3) EFV, ATA/R, DAR/R, RAL, RIL with TNF/EMT Most on cart No resistance in virologic failures Naggie et al. CROI 2014, Abstract TN G1 TN G2 TN G3 TE G2 TE G3

76 Sofosbuvir/Ledipasvir (SOF/LDV) in HIV/HCV Co-infection: ERADICATE Trial 100 NIH phase 2, open label n=50 (13 w/o cart) SOF/LDV daily x 12 weeks G1 Treatment-naïve with or w/o cart Difficult cohort G1a: 78% African-American: 84% F3: 26% BMI: 26 % SVR4 SVR12 Osinusi, et al. EASL Abstract O14. 0 No ARV cart

77 Summary of Key Issues Efficacy with newer agents now comparable to HCV mono-infection, raising possibility that HIV/HCV co-infection no longer is a special population Need expansion to larger and more diverse populations High viral loads may remain an important factor Results tend to be with limited array of cart regimens Drug-drug interactions require ongoing evaluation but are reduced for selected agents and combinations Many interactions not yet evaluated Healthy volunteer trials may not be sufficient to determine extent and importance of interactions

78 Statement 9: Patients co-infected with HIV/HCV should no longer be considered a special population. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 37% 27% 45% 45% 12% 9% 17% 7% 0% 0% Field Survey Council Members

79 Statement 10 Treatment of hepatitis C should remain within the domain of hepatologists, gastroenterologists, and ID physicians. Why make this statement? Given the cost and complicated decisions/management around HCV therapy, subspecialists have previously treated most patients with HCV HCV treatment will soon be characterized by short courses of safe and well-tolerated all-oral regimens with viral cure rates exceeding 90% Impact of HCV treatment is limited due to ongoing under-diagnosis and under-treatment Expansion of HCV treatment to non-specialty providers, such as primary care physicians, may help address the substantial HCV burden in the U.S.

80 Impact of Provider on Treatment Completion ERCHIVES database (n=134,934 HCV-infected veterans) 16,043 (11.9%) prescribed antiviral therapy Among 10,641 veterans with >1 year follow-up, 2396 (22.5%) completed a 48-week course Sites treating 200 individuals: OR 1.87 (95% CI, ) Site volume (number of HCV-infected subjects initiated on treatment) Adapted from Butt AA, et al. Liver Int. 2010;30(2): % completing a 48-week course < >

81 Treatment of HCV in Primary Care Can Be Done Successfully PROJECT ECHO (Extension for Community Healthcare Outcomes) at University of New Mexico Disease management model involving telemedicine clinics involving collaboration between university-based specialists and rural/prison primary care FP/NP Prospective cohort study comparing HCV treatment outcomes between UNM HCV Clinic (n=261) and primary care clinicians at 21 ECHO sites (n=146) Outcome Project ECHO (n=261), % University of New Mexico Hospital (n=146), % P Value Nonwhite <.01 SVR, HCV genotype 1 infection NS SVR, HCV genotype 2/3 infection NS NS, not significant Arora S, et al. N Engl J Med. 2011;364:

82 Summary of Key Issues Volume and experience of provider appears to be more important than specialty, thus primary care should be able to deliver good HCV care Concern about the time and feasibility to appropriately train primary care community, especially when they do not see large volumes Concern about the management of liver disease, HCC, endoscopy, etc. in primary care community Concern about the capacity to scale up of traditional GI/ID practices and challenges around the under-insured

83 Statement 10: Treatment of hepatitis C should remain within the domain of hepatologists, gastroenterologists, and ID physicians. 1. Accept statement completely 2. Accept statement with some reservations 3. Accept statement with major reservations 4. Reject statement with reservations 5. Reject statement completely 48% 45% 55% 29% 0% 13% 0% 8% 2% 0% Field Survey Council Members

84