Managing Treatment Naive Pa/ents in the DAA Era. An Interac/ve Case study

Transcription

1 Managing Treatment Naive Pa/ents in the DAA Era. An Interac/ve Case study Case Prepared by Sinēad Sheils CNC Royal Prince Alfred Hospital, Sydney Friday 17 th May 2013

2 Nigel 63 yrs old caucasian male HCV diagnosed 2003 pre surgery Likely long dura/on of infec/on GT1a viral load 6.77log10 IL28B CC (Duke SNP) Lives alone. Self employed Well. Nil medica/ons.

3 BMI 24.8 ALT 341, AST 194, GGT 141 Bili 15 Alb 48 Plat 115 INR 1.1 Hb 157 Fibroscan 27kPa. Abdo US likely cirrho/c but no splenomegaly, ascites or lesion Seeking treatment now (wasn t interested previously due to work/family commitments) Cannabis one joint most days Alcohol 1 full strength beer + 1/3 bo`le wine most days. 4 mths abs/nence last year.

4 Ques/on 1 Will high LFTs have any impact on fibroscan readings in HCV pa/ents? a) Readings may be higher b) Readings may be lower c) No effect on readings d) I have no idea

5 Ques/on 2 Would you treat this pa/ent and what with? a) Yes Telaprevir triple therapy b) Yes Boceprevir triple therapy with lead in c) Clinical trial d) Not yet

6 HCV Team Challenge clinicalop/ons.com/hepa//s Transient Elastography :All that s/ff is not Fibrosis HBV flare Slide Heading AVH

7 HCV Team Challenge clinicalop/ons.com/hepa//s Transient Elastography :All that s/ff is not Fibrosis ALT -Acute hepatitis Slide Heading Toxic

8 BMI 24.8 ALT 341, AST 194, GGT 141 Bili 15 Alb 48 Plat 115 INR 1.1 Hb 157 Fibroscan 27kPa. Abdo US likely cirrho/c but no splenomegaly, ascites or lesion Seeking treatment now (wasn t interested previously due to work/family commitments) Cannabis one joint most days Alcohol 1 full strength beer + 1/3 bo`le wine most days. 4 mths abs/nence last year.

9 Ceased alcohol + monitored for 8 wks Worked up and commenced on Boceprevir triple therapy with lead in

10 Completed wks 0-4 Peg/riba wk 4 HCVRNA undetectable Tolera/ng well Bit /red No alcohol LFTs improving

11 Ques/on 3 What is liklihood of SVR in a cirrho/c GT1 pt who has RVR on Peg/riba? a) 45-50% b) 60-65% c) 70-75% d) I have no idea

12 Hepatitis C treatment optimisation CHARIOT: SVR rates by first undetectable HCV RNA % %

13 Ques/on 4 What is the SVR with Boceprevir of cirrho/c pt with HCVRNA not det at wks 8 and 24? a) 60-70% b) 75-85% c) >85% d) I have no idea

14 SPRINT-2 SVR in Early (Week 8 HCV-RNA negative) and Late (Week 8 HCV-RNA positive) Responders by Fibrosis Score 144/ / /70 47/60 9/12 12/13 4/8 7/12 F0/1/2 F3/4 BOC RGT BOC/PR48 14

15 SVR According to TW8 Virologic Response SVR rates were high in all patients with undetectable HCV RNA at TW8, intermediate in those with >3 log 10 decline at TW8, and low in those with <3 log 10 decline at TW8, regardless of METAVIR fibrosis score Few F0-2 and no F3-4 patients with detectable HCV RNA and <3 log 10 decline in HCV RNA at TW8 achieved SVR 100% Undetectable 3 log HCV RNA decline and detectable <3 log HCV RNA decline and detectable SVR (%, 95% CI) 75% 50% 25% 0% 86% 85% 89% 766/ % 6% 34% 35% 293/ /47 16/47 0% 65/73 28/79 0% 5/78 0/5 0/17 F0-2 F3 F4 METAVIR Fibrosis Score *Treatment-naive patients and those with previous treatment failure combined. 15 BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.

16 Boceprevir added at wk 5 Remained HCVRNA Not Det at wks 8 & 24 At wk 24 bili 7, alb 33, plat 40, INR 1.2 Wt down 8kg (80-72kg) Reduced appe/te, dysgeusia

17 Ques/on 4 Do you change treatment plans? a) con/nue, with close monitoring b) as above and call in die/cian c) dose reduce d) cease all treatment

18 Pre Hb 149g/L Wk Wk Wk Now wk 36 - Hb 101 Iron stores good Tired. Too hard to work much.

19 Ques/on 5 Which treatment causes more significant anaemia? a) Telaprevir triple therapy b) Boceprevir triple therapy c) Same d) I have no idea

20 Seizing the Opportunity clinicaloptions.com/hepatitis BOC Plus PegIFN alfa-2b/rbv: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, % PR48 (n = 467) BOC + PR RGT/48* (n = 1225) Anemia* Neutropenia Dysgeusia *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR). Boceprevir [US package insert]. July 2012.

21 Seizing the Opportunity clinicaloptions.com/hepatitis TVR Plus PegIFN alfa-2a/rbv: Adverse Events Higher rates of rash, anemia, and anorectal signs and symptoms in TVR arms vs control Adverse Event, % PR48 (n = 493) TVR + PR RGT/48* (n = 1797) Rash Anemia Anorectal events 7 29 *Pooled results from TVR arms. Anemia was managed with RBV dose modification; epoetin alfa was not permitted. In most subjects, rash was mild to moderate Severe rash in 4%; discontinuation due to rash in 6% of subjects Telaprevir [US package insert]. October 2012.

22 To finish Pa/ent currently at wk 40 Remains on full doses Fortnightly bloods. Reports no alcohol. Diet improved. Small freq snax. High protein. Bili 7, Alb 39, plat 39, INR 1.1 HCC surveillance con/nues Op/mis/c of SVR

23 Royal Prince Alfred Hospital, Sydney

24 HCV Team Challenge clinicalop/ons.com/hepa//s Impact of Early Response to Boceprevir- based Therapy SPRINT- 2: BOC + PegIFN/RBV in GT1 Treatment- Naive Pa=ents 57% of pa/ents eligible for shorter therapy HCV RNA undetectable at Weeks 8 and 24 HCV RNA detectable at Week 8, undetectable at Week 24 Nonblacks Blacks SVR (%) / 78/ PR48 143/ 52/ BOC/PR RGT 137/ 48/ BOC/PR 48 Wks 20 0 n/ N = 3/ 3 PR48 8/ 13 13/ 15 7/ 12 BOC/PR RGT 18/ 19 7/ 8 BOC/PR 48 Wks Poordad F, et al. N Engl J Med. 2011;364:

25 HCV Team Challenge clinicalop/ons.com/hepa//s SVR by Advanced Fibrosis/Cirrhosis in Pa/ents Receiving BOC + PegIFN/RBV SVR (%) Recommenda=on: All cirrho/c pa/ents receiving BOC + PR should receive 48 weeks of therapy [1,2] n/ N= Subgroup Analysis of SPRINT- 2 [3] / / 319 F0/1/ / / 24 PR48 BOC RGT BOC/PR / 34 F3/4 1. Boceprevir [package insert]. May Ghany MG, et al. Hepatology. 2011;54: Poordad F, et al. NEJM. 2011;364: Bacon BR, et al. NEJM. 2011;364: / 42 SVR (%) n/ N= Subgroup Analysis of RESPOND- 2 [4] 23 14/ / 117 F0/1/ / / / 32 F3/ / 31

26 Seizing the Opportunity clinicaloptions.com/hepatitis Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts SVR (%) A > 1 log 10 decrease in HCV RNA at Wk 4 of therapy is the strongest predictor of SVR n/n= 0 0/ / / / 75 SPRINT-2 and RESPOND-2 Combined / / / 27 19/ 51 20/ 45 37/ / / / 20 6/ 25 < 1 log 1 log < 1 log 1 log < 1 log 1 log CC CT TT *BOC was administered with pegifn-α2b in these trials. Poordad F, et al. Gastroenterology. 2012;143: / 25 PegIFN-α2b/RBV* BOC + pegifn-α2b/rbv RGT* BOC + pegifn-α2b/rbv 48 wks* 50 13/ / / 34

27 Seizing the Opportunity clinicaloptions.com/hepatitis Lead-in Strategy Can Help Determine Whom to Treat 4 wks of pegifn/rbv lead-in before BOC (or TVR) Lowers HCV RNA burden May identify rapid responders who may not need DAA Allows assessment of IFN responsiveness Provides useful information regarding likelihood of SVR with addition of DAA Provides insight into tolerability of pegifn/rbv backbone Elucidates hematologic response to pegifn/rbv, especially in marginal patients; make needed dose adjustments before addition of DAA

28 HCV Team Challenge clinicaloptions.com/hepatitis AASLD 2012: Analysis of the Impact of Timing and Magnitude of RBV DR on SVR SVR similar for all time points of RBV dose reduction, including within 4 wks of treatment initiation SVR rates similar regardless of the lowest RBV dose received for 14 days HCV RNA at Start of Primary Anemia Management RBV Dose Reduction SVR Rate, n/n (%) ESA Use Undetectable 111/129 (86) 107/124 (86) Detectable 67/120 (56) 71/127 (56) Poordad F, et al. AASLD Abstract 154.

29 Seizing the Opportunity clinicaloptions.com/hepatitis BOC Plus PegIFN alfa-2b/rbv: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, % PR48 (n = 467) BOC + PR RGT/48* (n = 1225) Anemia* Neutropenia Dysgeusia *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR). Boceprevir [US package insert]. July 2012.

30 HCV Team Challenge clinicaloptions.com/hepatitis Outcomes in Clinical Practice: CUPIC Study of the French Early Access Program Outcome, % Telaprevir (N = 292) Boceprevir (N = 205) Serious adverse event Premature discontinuation Hepatic decompensation 2 3 Death* 3 1 Infection (grade 3 or 4) 7 2 *Causes of death: septicemia, septic shock, pneumopathy (2), endocarditis, esophageal varices bleeding. Why are the results different from phase III trials? Higher risk in cirrhotic patients? Study population healthier in phase III trials? Is the population truly compensated cirrhosis? Hezode C, et al. AASLD Abstract 51.

31 HCV Team Challenge clinicaloptions.com/hepatitis Thrombocytopenia Management Approach During Treatment of Chronic HCV Pretreatment evaluation Dose reduction Upper endoscopy to evaluate for portal hypertension if cirrhosis or low platelet count Primary prevention if varices present Imaging to evaluate portal vein thrombosis Consider transplant evaluation Case for experienced HCV treaters PegIFN alfa-2a: 90 µg/wk PegIFN alfa-2b: to 1.0 µg/kg/wk Consider thrombopoietin agonist if unable to tolerate pegifn Risks: hepatotoxicity, thrombotic/ thromboembolic events Anticipate thrombocytopenia and discuss need for close monitoring Be ready to tolerate thrombocytopenia