Hepatitis C Current Therapy Christoph Jochum Clinic for - PowerPoint PPT Presentation

Hepatitis C – Current Therapy Christoph Jochum Clinic for Gastroenterology & Hepatology University Hospital Essen Germany

Use of Predictors to Decide to Treat or Wait: Current issues Long treatment duration  At least 24 wks for genotype 1 HCV  Suboptimal results for non-RVR patients after 48 wks of treatment Challenging safety profile  Several IFN-related adverse effects  New PIs: anemia, rash, etc Low efficacy in certain patients  History of null response  IL28B: TT  Liver cirrhosis Adapted from CCO

Severity of Disease Increases Need for HCV Therapy but Also Impairs Response  May not need immediate  Greater need for treatment treatment  BUT  BUT  Easier to treat  Response may be impaired  High likelihood of response  Perhaps more effective options in future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria Mild disease Advanced disease/ cirrhosis Adapted from CCO

Survival in Patients With HCV and Cirrhosis Survival Probability Compensated 100 After first major complication 80 Patients (%) 60 40 20 0 0 12 24 36 48 60 72 84 96 108 120 Mos 384 376 342 288 236 165 126 79 52 39 25 Pts at Risk, n 65 39 21 11 7 4 4 3 3 2 1 Fattovich G, et al. Gastroenterology. 1997;112:463-472. Adapted from CCO

Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis No SVR 100 SVR 80 Patients With Liver Complications (%) 60 40 20 0 0 24 48 72 96 120 144 168 Mos 759 702 634 527 345 207 34 Pts at Risk, n 124 119 116 108 70 41 12 Bruno S, et al. Hepatology. 2007;45:579-587. Source CCO

Prognostic Factors in Current Therapy  Black  Cirrhosis  White  Genotype 1  No fibrosis (1a worse than 1b)  Genotype 2/3  IFN nonresponsive  IFN responsive (eg,  IL28B TT RVR/EVR or response to lead-in)  Previous relapser  IL28B CC Less favorable Favorable prognostic factors prognostic factors Source CCO

For Genotype 2 - 6, PegIFN/RBV is still Standard of Care  Effective therapy with higher cure rates in Genotype 2 and 3 than genotype 1  24-48 wks of therapy is recommended [1,2]  Some patients (with RVR and low baseline HCV RNA) may be treated for 16 wks if therapy poorly tolerated, although relapse rates may be higher [2]  Future regimens may offer further improvements, such as  Shorter durations  All-oral therapy  Fewer adverse events 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264. Source CCO

N-CORE: 24 vs 48 Wks of PegIFN alfa-2a + RBV in GT2/3 Patients Without RVR Multicenter, international, randomized, open-label phase IIIb trial Wk 72 Wk 24 Wk 48 Stop therapy; 48-wk follow-up Tx-naive patients with (n = 95) chronic GT2/3 HCV infection who initiated pegIFN/RBV therapy and did not achieve RVR but did Continue PegIFN/RBV Stop therapy; 24-wk follow-up achieve EVR (N = 235)* (n = 93) *47 patients dropped out and did not reach randomization at Wk 24. Adapted from CCO; Cheinquer H, et al. AASLD 2012. Abstract 156.

N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/RBV 100 24-wk pegIFN/RBV 80 48-wk pegIFN/RBV 73 63 61 SVR24 (%) 60 54 52 52 40 20 49/ 57/ 49/ 51/ 49/ 46/ n/N = 95 93 95 81 90 63 0 ITT Per Protocol Study Completer (n = 188) (n = 176) (n = 153) Odds Ratio 0.68 0.63 0.44 95% CI 0.38-1.21 0.35-1.16 0.22-0.89 P Value .1934 .1461 .0231  Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm Adapted from CCO Cheinquer H, et al. AASLD 2012. Abstract 156. Reproduced with permission.

Milestones in Therapy of Genotype 1 HCV Direct-acting antivirals 100 2011 Peginterferon 2001 80 Ribavirin 70+ Standard interferon 1998 60 55 1991 42 39 40 34 16 20 6 0 IFN IFN/RBV IFN/RBV PegIFN PegIFN/ IFN PegIFN/ RBV 12 RBV/ 12 mos 6 mos 12 mos 12 mos 6 mos mos DAA Adapted from CCO

Two Protease Inhibitors Approved for GT1 HCV Infection Combined With PR Protease Inhibitor Recommendations Administration  Naive to previous therapy  All patients initiate therapy Boceprevir 800 mg TID  Previous treatment failure (every 7-9 hrs) [1,2] with 4-wk pegIFN/RBV lead-  Compensated cirrhosis in phase  Response-guided therapy  After completion of lead-in  Take with food phase, boceprevir should be added to continued pegIFN/RBV for 24-44 wks  Naive to previous therapy  All patients initiate therapy Telaprevir 750 mg TID  Previous treatment failure (every 7-9 hrs) [2,3] with 12-wk period of triple  Compensated cirrhosis therapy with telaprevir plus  Response-guided therapy pegIFN/RBV  Take with food (not low fat)  Followed by 12-36 wks of pegIFN/RBV 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [US package insert]. October 2012. Source CCO

OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx- Naive Pts With GT1 HCV Infection Randomized, multicenter, open-label phase III noninferiority trial Stratified by fibrosis status (F0-F2 vs F3-F4), IL28B GT (CC, CT, TT) Wk 12 Wk 24 Wk 48 RVR Follow-up Telaprevir 750 mg q8h + PegIFN/RBV PegIFN/RBV Treatment- PegIFN/RBV (n = 371) No naive patients RVR with chronic GT1 HCV RVR Follow-up infection Telaprevir 1125 mg BID + (N = 740) PegIFN/RBV PegIFN/RBV No PegIFN/RBV (n = 369) RVR Buti M, et al. AASLD 2012. Abstract LB-8. Source CCO

OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection  SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups  Similar safety and tolerability profile in both treatment arms TVR q8h/PR TVR BID/PR 100 92 87 81 78 80 68 68 65 66 SVR12 (%) 59 58 60 40 20 n/ 92/ 97/ 141/ 139/ 37/ 38/ 209/ 213/ 61/ 61/ N = 106 105 208 206 57 58 268 264 103 105 0 CC CT TT F0-2 F3/4 IL28B GT Liver Disease Status Buti M, et al. AASLD 2012. Abstract LB-8. Source CCO

SVR Rates With BOC or TVR + PR According to Treatment History Null 100 > > Relapsers Naive > Partial Responders Responders 69-83 80 63-75 40-59 60 SVR (%) 29-40 40 20 0 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364: 2417-2428. Bronowicki JP, et al. EASL 2012. Abstract 11. Source CCO

RGT Paradigm With BOC + PegIFN/RBV in Tx- Naive Noncirrhotic Patients HCV RNA Undetectable Undetectable < 100 IU/mL PegIFN + Early response; stop at Wk 28; BOC + PegIFN + RBV RBV f/u 24 wks 4 8 12 24 28 36 0 48 HCV RNA Detectable Undetectable < 100 IU/mL Slow response; extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks PegIFN + BOC + PegIFN + RBV PegIFN + RBV RBV 4 8 12 24 28 36 0 48 Boceprevir [package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source CCO

RGT Paradigm With TVR + PegIFN/RBV in Treatment-Naive Noncirrhotic Patients HCV RNA Undetectable Undetectable TVR + PegIFN + RBV PegIFN + RBV eRVR; stop at Wk 24, f/u 24 wks 4 12 24 0 48 HCV RNA Undetectable or detectable Detectable (≤ 1000 IU/mL) (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV 4 12 24 0 48 Telaprevir [package insert]. October 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source CCO

Boceprevir + PegIFN/RBV in Cirrhotics and Treatment-Experienced Patients  Previous relapsers or partial responders are eligible for shortened therapy if HCV RNA undetectable at Wks 8 and 24 Early response; stop at PegIFN + Wk 36; f/u 24 wks BOC + PegIFN + RBV RBV Slow response; PegIFN F/u + RBV 24 wks 4 8 12 24 28 36 0 48  Previous null responders or current cirrhotics receive fixed-duration therapy PegIFN + F/u BOC + PegIFN + RBV RBV 24 wks 4 8 12 24 28 36 0 48 Boceprevir [package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source CCO

Telaprevir + PegIFN/RBV in Cirrhotics and Treatment-Experienced Patients  Previous relapsers are eligible for shortened therapy if HCV RNA negative at Wks 4 and 12 eRVR; stop at Wk 24, f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV F/u No eRVR; PegIFN + RBV 24 wks 4 12 24 0 48  Previous partial responders, null responders, and current cirrhotics receive fixed-duration therapy F/u TVR + PegIFN + RBV PegIFN + RBV 24 wks 4 12 24 0 48 Telaprevir [package insert]. October 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source CCO

Adverse Events With HCV Therapy  Treatment-naive, GT1 protease inhibitor phase III trials  IFN adverse events are a dominant feature Adverse Event, % Boceprevir Placebo ADVANCE Placebo RGT (N = 363) T12PR (N = 361) (N = 368) (N = 363) Fatigue 53 60 57 57 Headache 46 42 41 39 Nausea 48 42 43 31 Diarrhea 22 22 28 22 Pyrexia 33 33 26 24 Chills 36 28 13 15 Insomnia 32 33 32 31 Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Source CCO