1. HCV EASL CPG 2011: what is (still) new? Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of Palermo, Italy antonio.craxi@unipa.it

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3. Goal of HCV management: To improve quality of life and survival in patients with chronic hepatitis C by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end- stage liver disease, HCC and death HCV Clinical Practice Guidelines

4. This goal can be achieved only if HCV is eradicated. After sustained HCV RNA clearance: Necroinflammatory activity of chronic hepatitis ceases. Progression of fibrosis and development of cirrhosis (in non-cirrhotic patients) are blocked. Non-cirrhotic fibrosis (METAVIR  F3) may regress. The risk of development of HCC: is eliminated in non-cirrhotic patients. Is reduced, but not canceled altogether, in patients with cirrhosis.

5. HCV Clinical Practice Guidelines End-points of therapy The only endpoint of therapy is the sustained virological response (SVR), defined by an undetectable HCV RNA 24 weeks after the end of therapy, as assessed by a sensitive molecular method with a lower limit of detection ≤50 IU/mL, ideally a real-time PCR-based assay. Long-term follow-up studies have shown that SVR corresponds to a definitive cure of HCV infection in more than 99% of cases. ≤25

6. Durability of SVR after TVR-based Therapy SVR was durable in 222/223 patients (>99%) –Median time to follow-up: 21 months after SVR (range 4-45) –One previously described patient experienced late relapse in parent study 48 weeks after prematurely discontinuing treatment after 10 weeks Keet al, AASLD 2011, oral presentation Viral load was determined by Roche Taqman® v2 LLOQ of 25 IU/mL Months after SVR 0 5 10 15 20 25 30 0 to 56 to 1112 to 1718 to 2324 to 2930 to 3536 to 45 Percent of patients 56 19 17 30 27 34 40

7. HCV Clinical Practice Guidelines Evaluation of patients for treatment -The causal relationship between HCV infection and liver disease must be established - Liver disease severity must be assessed prior to therapy. - Baseline virological parameters that will be useful to tailor therapy should be determined. - Identifying patients with cirrhosis is of particular importance, as their prognosis and likelihood to respond to therapy are altered. - As liver disease can progress in patients with repeatedly normal ALT levels, disease severity evaluation should be performed regardless of ALT.

8. Liver biopsy remains the reference method. The risk of severe complications is very low (1/4,000-10,000), but it remains an invasive procedure. As such, biopsy is more and more hardly accepted by patients as part of their pre-treatment evaluation. Alternative, non-invasive methods can now be safely used in patients with chronic hepatitis C to assess liver disease severity prior to therapy. HCV Clinical Practice Guidelines Assessment of liver disease severity: biopsy

9. Both transient elastography and biomarkers have been shown to accurately identify patients with mild fibrosis or cirrhosis. They are less discriminant for moderate to severe fibrosis. The combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty. However, they increase the cost. Assessment of fibrosis may become less relevant as the efficacy of treatments increases. HCV Clinical Practice Guidelines Assessment of liver disease severity: non-invasive vs. invasive

10. HCV Clinical Practice Guidelines Indications for treatment : who should be treated ? All treatment-naïve patients with compensated chronic liver disease related to HCV who are willing to be treated and have no contra- indication to pegylated IFN-  or ribavirin should be considered for therapy, whatever their baseline ALT level. Treatment should be initiated rapidly in patients with significant fibrosis (METAVIR score F2-F4). In the patients with less severe disease, a balance between the benefit and risk related to therapy must be struck. If treatment is decided, there is no reason to wait for the advent of new HCV therapies, as these patients have a good chance of achieving a sustained virological response with current therapy for a reasonable cost.

11. HCV Clinical Practice Guidelines End-points of therapy Intermediate checkpoints are used on treatment to assess the likelihood of an SVR and tailor treatment duration. They include HCV RNA measurements at 4, 12 and eventually 24 weeks of therapy, to be interpreted in comparison with the baseline HCV RNA level.

12. Monitoring of on-therapy response to PEG IFN/RBV

13. DVR, delayed virological response; EVR, early virological response; RVR, rapid virological response. RVREVR DVR Clearance of infected cells Phase 1 (24–48 hours) Phase 2 HCV RNA 4 Limit of Detection (  50 IU/ml) Likelihood of SVR weeks 1224480172 Likelihood of SVR according to viral response in the first weeks of therapy

14. Viral Genotype Determines the Approach to HCV Therapy Genotypes 2, 3, 4,5,6 –Therapy today and in the near future remains pegIFN/RBV Genotype 1 –Additional option of an HCV protease inhibitor combined with pegIFN/RBV –Boceprevir and telaprevir approved in Europe in July- September 2011 Both indicated for untreated and previously treated HCV Different regimen formats Different criteria for shortening therapy

15. HCV-RNA 24 12 4 Week 0 72 weeks of therapy Neg (DVR) pos <2 log drop (NR) 24 weeks of therapy, only if LVL* at baseline Neg (RVR) stop Tx pos (PR) pos 48 weeks of therapy Neg (EVR) pos >2 log drop *LVL: < 400,000-800,000 IU/ml Response-guided therapy in patients with genotype 1 (applies also to genotype 4 at a B2 grade of evidence)

16. Phase III virological efficacy Boceprevir ( Victrelis®) or Telaprevir ( Incivo®) Boceprevir SVR increases from 38% to 63/66% Naive patients Increased SVR compared to Peg-IFN/RBV Telaprevir SVR increases from 44% to 72/75% RBV is needed Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A. Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.

17. INCIVO EMA approval September 2011. Noncirrhotic patients can be considered for response-guided therapy with TVR TVR + PegIFN + RBV 48024124 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV TVR + PegIFN + RBV 48024124 PegIFN + RBV HCV RNA Undetectable Detectable (≤ 1000 IU/mL) Undetectable or detectable (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks HCV RNA Response-guided therapy with TVR + PegIFN/RBV in naive patients: EU/EMA

18. Treatment-naive patients Cirrhotic patients and/or Null-Responders Stopping rules: discontinuation of entire therapy HCV-RNA measurement PegIFN + RBV PegIFN + RBV + Boceprevir 48 1228 48 0 36 24 STOP if HCV-RNA ≥ 100 IE/ml STOP if HCV-RNA detectable Week HCV-RNA 32 wks 24 wks 44 wks 4 wks 12 wks VICTRELIS ® EMA approval July 2011 Treatment-naive patients Response-guided therapy with BOC + PegIFN/RBV in naive patients: EU/EMA

19. 12 4 Week 0 pos, <2 log drop and positive thereafter (NR or PR) stop Tx pos >2 log drop but negative thereafter (DVR) 48 weeks of therapy Neg (EVR) Response-guided therapy in patients with genotypes 2 and 3 (applies also to genotypes 5 and 6, excluding 12-16 weeks, at a C2 grade of evidence) pos *marginally less effective due to higher relapse rates, especially for G3 with high viral load 24 weeks of therapy Neg (RVR) Risk factors (fibrosis, IR) 12-16 weeks of therapy* HCV-RNA

20. The strongest predictors of an SVR are –the HCV genotype –the genetic polymorphisms located in chromosome 19, close to the region coding for IL28B (or IFN 3), which are associated with the ability of IFN to induce an antiviral response in liver cells. Other predictors of response include: baseline HCV RNA levels dose and duration of therapy stage of fibrosis host factors (body mass index, age, insulin resistance, gender) coinfection with another hepatotropic virus or with HIV. HCV Clinical Practice Guidelines Predictors of response to SoC

21. IL28B genotype and response to TPV in naïve patients 1. Jacobson IM, et al. EASL 2011. Abstract 1369. ADVANCE: T12PR* [] Eligibility for RGT (%) 39/ 50 39/ 68 10/ 22 78 100 80 60 40 20 0 57 45 n/ N = *IL28B testing in ADVANCE was in whites only. CC CT TT ADVANCE: T12PR48* [2] SVR (%) 45/ 50 48/ 68 16/ 22 CC CT TT 90 100 80 60 40 20 0 71 73 n/ N = Likelihood of Achieving SVRLikelihood of Shortened Therapy

22. IL28B genotype and response to BOC in naïve patients Likelihood of Achieving SVRLikelihood of Shortened Therapy SPRINT-2: BOC + PR48 [1] SVR (%) 44/ 55 82/ 115 26/ 44 80 100 80 60 40 20 0 71 59 n/ N = SPRINT-2: BOC + PR [1] Eligibility for RGT (%) 118/ 132 158/ 304 CC CT/TT 89 100 80 60 40 20 0 52 n/ N = 1. Jacobson IM, et al. EASL 2011. Abstract 1369.

23. HCV-AIFA Italian study: RVR and SRV to PR in genotype 1 patients according to baseline factors MALES Variables N. of patientsRVRSVR No favorable factors21/179 (11.7%)1/19 (5.2%)3/21 (14.3%) 1 favorable factor82/179 (45.8%)17/80 (21.2%)25/82 (30.5%) 2 favorable factors62/179 (34.6%)25/58 (43.1%)37/62 (59.6%) 3 favorable factors14/179 (7.8%)9/14 (64.3%)12/14 (85.7%) FEMALES Variables N. of patientsRVRSVR No favorable factors58/152 (38.1%)8/57 (14.1%)16/58 (27.6%) 1 favorable factor75/152 (49.4%)20/70 (28.6%)26/75 (48.0%) 2 favorable factors19/152 (12.5%)12/17 (70.1%)16/19 (84.2%) Favorable factors:  HCV-RNA < 400,000 UI/ml  C/C genotype of rs12979860 SNP  No visceral obesity (VOB) Favorable factors:  Age < 50 years  C/C genotype of rs12979860 SNP

24. HCV Clinical Practice Guidelines Indications for treatment : who should be re-treated ? Patients infected with HCV genotype 1 who failed to eradicate HCV on prior therapy with pegylated IFN-  and ribavirin should not be retreated with the same drug regimen, as the SVR rates were reported to be low (of the order of 15%). These patients should wait for the approval of new combination therapies, which have been shown to yield high SVR rates, of the order of 50%-60%, in this particular group. Patients infected with HCV genotypes other than 1 who failed on prior therapy with IFN-  with or without ribavirin can be retreated with pegylated IFN-  and ribavirin.

25. Boceprevir Relapsers SVR increases from 29% to 75% Partial-Responders SVR increases from 7% to 52% Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV Telaprevir Relapsers SVR increases from 24% to 83/88% Partial-responders SVR increases from 15% to 54-59% Null-responders SVR increases from 5% to 29/33% Phase III virological efficacy Boceprevir ( Victrelis®) and Telaprevir (Incivo ®) Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3 RBV is needed

26. Retreatment with TVR + PegIFN/RBV in treatment-experienced patients: EU/EMA F/u 24 wks TVR + PegIFN + RBV 48024124 PegIFN + RBV No eRVR; PegIFN + RBV TVR + PegIFN + RBV 48024 12 4 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u 24 wks Previous relapsers* (same as naives) Previous partial responders † and null responders *Response-guided therapy not studied in relapsers in registration trials. † AASLD guidelines say RGT “may be considered” for prior partial responders [1] but package insert recommends 48 weeks of therapy Undetectable HCV RNA Detectable (≤ 1000 IU/mL) Undetectable/detectable (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Week 48; f/u 24 wks INCIVO EMA approval September 2011.

27. Treatment- experienced patients Cirrhotic patients and/or Null-Responders Stopping rules: discontinuation of entire therapy HCV-RNA measurement PegIFN + RBV PegIFN + RBV + Boceprevir 48 1228 48 0 36 24 STOP if HCV-RNA ≥ 100 IE/ml STOP if HCV-RNA detectable Week HCV-RNA 32 wks 44 wks 4 wks 12 wks VICTRELIS ® EMA approval July 2011 Retreatment with BOC + PegIFN/RBV in treatment-experienced patients: EU/EMA

28. Patients with compensated cirrhosis must be treated in the absence of contra-indications, in order to prevent the complications of chronic HCV infection that occur exclusively in this group on the short- to mid-term. Large cohort studies and meta-analyses have shown that an SVR in patients with advanced fibrosis is associated with a significant decrease of the incidence of clinical decompensation and HCC. However, the SVR rates with pegylated IFN-  and ribavirin are lower in patients with advanced fibrosis of cirrhosis than in patients with mild to moderate fibrosis. HCV Clinical Practice Guidelines Compensated cirrhosis

29. Monitoring and management of side-effects should be particularly careful in this group of patients, who are generally older and have worse tolerance than patients with less advanced liver disease. Due to portal hypertension and hypersplenism, leucocyte and platelet counts at baseline may be low in cirrhotic patients. They may contra-indicate therapy. As a result, haematological side effects are more frequent in cirrhotic than in non-cirrhotic patients. Growth factors are particularly useful in this group and should be used as described above. Irrespective of the achievement of an SVR, patients with cirrhosis should undergo regular surveillance for the occurrence of HCC, as this risk is decreased but not abolished when HCV infection has been eradicated. HCV Clinical Practice Guidelines Compensated cirrhosis

30. SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving BOC + PegIFN/RBV All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy [1,2] Subgroup Analysis of SPRINT-2 [3] PR48 BOC RGT BOC/PR48 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217. F3/4 100 80 60 40 20 0 SVR (%) F0/1/2 38 67 213/ 319 n/ N= 38 9/ 24 52 22/ 42 41 14/ 34 211/ 313 67 F3/4 100 80 60 40 20 0 SVR (%)F0/1/2 23 66 77/ 117 13 2/ 15 68 21/ 31 44 14/ 32 81/ 119 68 Subgroup Analysis of RESPOND-2 [4] 123/ 328 n/ N= 14/ 61

31. PR48 T12PR T8PR SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving TVR + PegIFN/RBV All cirrhotic patients receiving TVR + PR may benefit from 48 weeks of therapy [1,2] 1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416. 78 62 73 53 47 33 0 20 40 60 80 100 No, Minimal, or Portal FibrosisBridging Fibrosis or Cirrhosis SVR (%) [3,4] 134/ 288 n/ N = 226/ 290 205/ 279 24/ 73 45/ 73 45/ 85

32. REALIZE: SVR by Fibrosis and Prior Response Prior relapsers Prior partial responders Prior null responders No, minimal or portal fibrosis Cirrhosis Stage Pooled T12/PR48 Pbo/PR48 Patients with SVR (%) Bridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis 2/ 15 n/N= 53/ 62 145/ 167 12/ 38 0/ 5 10/ 18 36/ 47 3/ 17 0/ 9 16/ 38 11/ 32 1/ 5 1/ 15 48/ 57 24/ 59 1/ 18 7/ 50 1/ 10 1. Pol S, et al. AASLD 2011 - Cirrhotic patients receiving TVR + PR need 48 weeks of therapy [1] - Cirrhotics with previous null response have modest SVR rates

33. Non-cirrhotic patients who achieve an SVR should be retested for ALT and HCV RNA at 48 weeks post- treatment and one year later (2 years post-treatment). If ALT levels are still normal and HCV RNA is still not detected, the patient can be discharged. As hypothyroidism may occur after stopping therapy, TSH levels should also be assessed 1 and 2 years after treatment. Cirrhotic patients who achieve an SVR should undergo surveillance for oesophageal varices and screening for HCC every 3 to 6 months by means of ultrasonography HCV Clinical Practice Guidelines Post-treatment follow-up of patients who achieve an SVR

34. Untreated patients with chronic hepatitis C should be regularly followed. Previous guidelines recommended performing a liver biopsy every 3 to 5 years. With non- invasive methods, more frequent screening can be performed. Thus, untreated patients should be assessed every 1 to 2 years with a non-invasive method. Patients with cirrhosis should undergo screening for HCC every 3 to 6 months. HCV Clinical Practice Guidelines Follow-up of untreated patients

35. Updated AASLD Guidelines on Treatment of HCV Genotype 1 Infection  Optimal treatment is BOC or TVR, each in combination with pegIFN/RBV –All treatment-naive and experienced patients can be considered for treatment with BOC and TVR –Caution is advised when using BOC in null responders given lack of definitive information from phase III studies* –All patients can be considered for shortened duration of therapy except patients with cirrhosis and null responders (who should receive 48 wks of therapy)†  IL28B genotype testing may be considered prior to therapy to inform about probability of response or treatment duration Ghany MG, et al. Hepatology. 2011;54:1433-1444. *Package insert says if BOC tx of previous null responders is considered, it should be 48 wks of therapy. † Package insert recommends 48 wks of therapy with TVR for previous partial responders.

36. What may stay: General aims of treatment Therapeutic approach to non-1 genotypes PR therapy for selected patients with Gt 1 Criteria to evaluate indications for treatment Criteria for post-treatment follow-up Updated EASL HCV CPG 2012: a personal view

37. What must be updated: Indication to triple therapy with first generation PIs as SoC for most naive patients with Gt 1 Clearer definition of role of biomarkers ( IL28B ), of baseline predictors (fibrosis, viral load, IR) and of subgenotypes ( 1a vs 1b ) with triple therapy Indications for practical management of triple therapy (also IFN and RBV dosing) New stopping/futility rules Updated EASL HCV CPG 2012: a personal view

38. Hot topics to be defined: Use of triple therapy with first generation PIs for: – non-sustained responders to PR (excluding relapsers) –Patients with mild, slowly progressive disease –Patients with advanced cirrhosis –OLT subjects –HIV/HCV coinfected Use of the lead-in phase as “IFN sensitivity testing” What to do with non-responders to triple therapy? Who should be treated now? Who can wait? Updated EASL HCV CPG 2012: a personal view