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Faculty
Robert G. Gish, MD
Medical Director Liver Transplant Program California Pacific Medical Center San Francisco, California
Outline
Investigational Agents for the Treatment of HCV
HCV/HIV Coinfection Advances in HBV Therapy
1a 1b 2 3 4 5 6 7-8-9 Others
Zein N. Clin Microbiol Rev. 2000;13:223-235. Reproduced with permission. http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999.
Phase II Trial Treatment-naive pts with G1 HCV; all liver histology grades (N = 520)
PegIFN alfa-2b/RBV* + Boceprevir 800 mg TID (n = 107) PegIFN alfa-2b/RBV* + Boceprevir 800 mg TID (n = 103) PegIFN alfa-2b/RBV* (n = 104)
*This is a 2-part study; part 2 includes 2 additional arms that are not included in this interim analysis.
P < .004
79
80
SVR (%) 60 40 20 0
30 21 0 4 wks > 4 wks - 12 wks > 12 wks Time to First Undetectable HCV RNA* 0
*Time after pegIFN/RBV initiation in control arm and time after boceprevir dosing in experimental arms. Kwo PY, et al. AASLD 2009. Abstract 1582.
60
40 20 0
2/7
1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. 2. Kwo PY, et al. AASLD 2009. Abstract 62.
PR PR
Follow-up Follow-up
PROVE 2
(N = 323)
Follow-up
Follow-up Follow-up
PR
Follow-up
Previous Nonresponders G1
PROVE 3
(N = 453)
Follow-up Follow-up
PR PR
Follow-up Follow-up
Peginterferon alfa-2a 180 g/wk. Ribavirin 1000 or 1200 mg/day by weight. Telaprevir 1250 mg on Day 1 then 750 mg every 8 hrs.
39 29 30
44
0
Age > 50 Yrs
Bridging Fibrosis
Male Sex
Factors independently predictive of SVR included TVR-based therapy (P < .001), low baseline HCV RNA (P < .001), younger age (P < .04), and white race (P < .001)
PROVE 3: 24/48 Wks of TVR in Pts With Who Failed Prior PegIFN/RBV Therapy
Outcome Control Arm (n = 114) 14 9 (6/68) 20 (8/41) 40 (2/5) 12-Wk TVR + 24-Wk PegIFN/RBV (n = 115) 51* 39* (26/66) 69* (29/42) 57 (4/7) 24-Wk TVR + 48-Wk PegIFN/RBV (n = 113) 53* 38* (24/64) 76* (31/41) 63 (5/8) 24-Wk TVR + PegIFN (n = 111) 24 11 (7/62) 42 (16/38) NR
SVR, % Previous nonresponders, % (n/N) Previous relapsers, % (n/N) Previous breakthroughs, % (n/N)
*P < .001 vs control. P = .024 vs control. P = .297 vs control. P = .029 vs control.
Study C208: TVR q8h vs q12h Plus PegIFN alfa-2a or -2b in Treatment-Naive G1 Pts
Outcome in ITT population 12-Wk TVR q8h + 24-Wk PegIFN alfa-2a/RBV (n = 40) 85 80 91 (29/32) 12-Wk TVR q8h + 24-Wk PegIFN alfa-2b/RBV (n = 42) 81 69 93 (27/29) 12-Wk TVR q12h + 24-Wk PegIFN alfa-2a/RBV (n = 40) 83 83 91 (30/33) 12-Wk TVR q12h + 24-Wk PegIFN alfa-2b/RBV (n = 39) 82 67 92 (24/26)
SVR, % RVR, %
Treatment-naive pts infected with genotype 1 HCV (N = 111) PegIFN/RBV Lead-in PegIFN/RBV Lead-in
NVR 200 mg QD + P/R/RTV (n = 11) NVR 400 mg QD + P/R/RTV (n = 11) NVR 200 mg QD + P/R/RTV (n = 16) NVR 400 mg QD + P/R/RTV (n = 18) NVR 100 mg BID + P/R/RTV (n = 17)
PegIFN/RBV
PegIFN/RBV
PegIFN/RBV
P, peginterferon alfa-2b 1.5 g/kg/wk; R, ribavirin 600-1400 mg/day; RTV, ritonavir 100 mg. Vierling JM, et al. AASLD 2009. Abstract LB4.
100 85
Undetectable HCV RNA (%) 80 60 40 20 0 84
Lead-in P/R + NVR* 200 mg QD Lead-in P/R + NVR* 400 mg QD P/R + NVR* 100 mg BID
87
85
65
17
Wk 12
Vierling JM, et al. AASLD 2009. Abstract LB4. Figure reproduced with permission.
91
82 84
*LI, 3-day pegIFN lead-in. Sulkowski MS, et al. AASLD 2009. Abstract LB3. Figure reproduced with permission.
INFORM-1: Dual Polymerase and Protease Inhibitors R7128 and R7227 For HCV G1
Day 4 Day 7 Day 14 Wk 48
RG7128 500 mg BID + RG7227 100 mg TID (n = 8 active, 2 placebo) RG7128 500 mg BID + RG7227 200 mg TID (n = 8 active, 1 placebo)
Treatment naive
RG7128 1000 mg BID + RG7227 100 mg TID (n = 8 active, 1 placebo) RG7128 1000 mg BID + RG7227 200 mg TID (n = 8 active, 4 placebo) RG7128 1000 mg BID + RG7227 900 mg BID (n = 8 active, 2 placebo)
RG7128 1000 mg BID + RG7227 600 mg BID (n = 8 active, 2 placebo) RG7128 1000 mg BID + RG7227 900 mg BID (n = 8 active, 2 placebo)
*2 additional arms not included in current analysis. PegIFN, peginterferon alfa-2a 180 g/wk; RBV, ribavirin 1000-1200 mg/day.
500/100 TID
500/200 TID 1000/100 TID 1000/200 TID 1000/900 BID 1000/600 BID 1000/900 BID
8
8 7 8 8 8 8
Naive
Naive Naive Naive Naive Exp, non-null Exp, null
-3.9
-5.2 -4.8 -4.8 -5.1 -4.0 -4.9
13
63 71 63 88 50 50
13
25 29 25 63 13 25
No serious adverse events, treatment-related discontinuations, or grade 3/4 laboratory abnormalities observed in any treatment arm No evidence of emergent drug resistance during treatment
Gane EJ, et al. AASLD 2009. Abstract 193. Table reproduced with permission.
Brainard DM, et al. AASLD 2009. Abstract 1568. Adapted with permission of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. Copyright 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved.
Thymosin alpha-1 1.6 mg SC twice wkly + PegIFN alfa-2a 180 g/wk + RBV 800-1200 mg/day (n = 275) Previous HCV nonresponders to pegIFN/RBV (N = 552) Placebo + PegIFN alfa-2a 180 g/wk + RBV 800-1200 mg/day (n = 277) 24-wk follow-up
*All pts with detectable HCV RNA at Wk 24 discontinued treatment; pts with undetectable HCV RNA at Wk 24 continued treatment to Wk 48. Ciancio A, et al. AASLD 2009. Abstract 1564.
SVR
ITT Per protocol Pts with undetectable HCV RNA at Wk 24 who continued to Wk 48 EOT ITT Per protocol Pts with undetectable HCV RNA at Wk 24 who continued to Wk 48 31.3 (86/275) 93.2 (68/73) 94.0 (78/83) 33.2 (92/277) 88.2 (75/85) 87.9 (87/99) .604 .391 .217 .407 .079 .048
Similar antiviral activity of R7128 + R7227 through 14 days of treatment vs previous studies of IFN-based therapy in treatment-naive and treatment-experienced HCV pts
Robust antiviral activity of NS5B polymerase inhibitor MK-3281 in G1 HCV pts during 7-day monotherapy study Addition of thymosin alpha-1 to pegIFN/RBV in previous nonresponders with primarily G1 HCV did not increase SVR rate by intent-to-treat analysis
HCV/HIV Coinfection
80
SVR (%) 60 40 20
Rodriguez-Torres M, et al. AASLD 2009. Abstract 1561. Figure reproduced with permission.
Predictors of Poorer Graft Survival Dual organ transplantation (liver and kidney) HCV-positive donor BMI < 21 at wait listing Treatment for acute rejection* *Time-varying covariate. 0 2.7 2.9
5.5
4.5
10 12 14
16 18
Treatment History
100 100 93
Baqai SF, et al. AASLD 2009. Abstract 476. Figure reproduced with permission.
TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease
Randomized 2:2:1 Interim analysis at Wk 48 Wk 168
Tenofovir DF (n = 45) Pts with chronic hepatitis B and decompensated liver disease (N = 112) Entecavir (n = 22) Baseline Characteristic ALT > upper limit of normal, % Median Childs-Pugh-Turcotte score Median MELD score Resistance to lamivudine, n Liaw Y, et al. AASLD 2009. Abstract 222. TDF (n = 45) 60 7 11.0 8 TDF/FTC (n = 45) 60 7 13.0 10 ETV (n = 22) 77 7 10.5 3 Emtricitabine + Tenofovir DF (n = 45)
20
0 All Pts LAM-Resistant Pts
Lower rate of tolerability failures in fixed-dose TDF/FTC arm compared with TDF or ETV Severe adverse events more common with fixed-dose TDF/FTC
Liaw Y, et al. AASLD 2009. Abstract 222.
EOT Intrahepatic cccDNA Levels Predict SVR in Pts With Chronic Hepatitis B
EOT liver biopsies available in 20 HBeAg-positive, 25 HBeAg-negative pts receiving pegIFN alfa-2a + adefovir for 48 wks
Paired baseline and EOT biopsies available in 16 HBeAg-positive, 24 HBeAg-negative pts
Significantly higher pTVR rate with longer pretransplantation treatment duration (P = .04)
Outcome, %
HCV RNA negative at liver transplantation pTVR*
*Undetectable HCV RNA 12 wks postliver transplantation. Everson GT, et al. AASLD 2009. Abstract 1.
HCC Risk Remains High Despite 1 Yr of Antiviral Therapy in Cirrhotic HBV Pts
Multicenter HEPNET.Greece cohort study of 956 pts with or without cirrhosis who received 1 yr of oral anti-HBV treatment during last 10 yrs HCC diagnosed in 4.8% of cohort within 3.9 yrs (interquartile range: 2.1-5.7) of antiviral therapy initiation
Hazard Ratio 2.3 3.7 7.7 16.7 0.3 2.4 95% CI 1.2-4.6 1.3-10.0 1.7-34.5 3.9-72.1 0.1-0.8 0.6-11.3 P Value .016 .012 .007 < .001 .003 .193
Factors Associated With HCC Disease severity Compensated cirrhosis vs no cirrhosis Decompensated cirrhosis vs no cirrhosis Age at initiation of therapy 50-60 yrs vs younger than 50 yrs Older than 60 yrs vs younger than 50 yrs Female vs male No response/breakthrough vs response
Papatheodoridis GV, et al. AASLD 2009. Abstract 137. Table reproduced with permission.
Sorafenib Plus DEB-TACE for Pts With Unresectable HCC: Interim Analysis
Oral small-molecule multikinase inhibitor sorafenib confers survival benefit in pts with HCC[1] Sorafenib 400 mg twice daily for 1 wk followed by sorafenib plus transarterial chemoembolization with doxorubicin 100 mg eluting beads (DEB-TACE) administered to 11 pts in continuous 6-wk cycles Grade 3/4 toxicities reported by 63% of pts (5 out of 8) assessed during interim analysis (after 8th pt completed cycle 1)
Toxicity rate comparable to previous trials assessing single therapy with either sorafenib or DEB-TACE[2,3]
Response, %
EASL criteria Partial response Stable disease
Pts (N = 11)
45 55
1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.2. Reyes DK, et al. AASLD 2009. Abstract LB9. 3. Geschwind JF, et al. Cancer J. 2009. In press.
Electronic chart data on consecutive 253 in-pts with cirrhosis and renal failure (creatinine > 1.5 mg/dL) during 22-mo period Of 116 pts diagnosed with HRS, HRS type 1 (30%) significantly more likely to present with the following vs no HRS (54%) or HRS type 2 (16%)
More advanced age Grade 3 ascites and grade 3 encephalopathy Higher respiratory rate Higher white blood cell count Higher serum creatinine Higher serum bilirubin Higher INR Higher CTP score
Low Survival Rate in Pts With HRS Type 1 Treated With Vasoconstrictors + Albumin
Significant predictors of 3-mo mortality in pts with HRS type 1 (n = 76) on multivariate analysis included older age (P = .013) and higher serum bilirubin (P = .027)
64 pts with HRS type 1 treated with vasoconstrictors + albumin
Outcome, % HRS Type 1 Treated With Vasoconstrictors + Albumin
Octreotide + Midodrine + Albumin (n = 24) Complete response In-hospital mortality 3-mo mortality
Salerno F, et al. AASLD 2009. Abstract 342.
17 50 71
*Day 1 NAC: 150 mg/kg in 250 mL 5% glucose over 15 mins; 50 mg/kg in 500 mL 5% glucose over 4 hrs; 100 mg/kg in 1000 mL 5% glucose over 16 hrs. Days 2-5 NAC: 100 mg/kg in 1000 mL 5% glucose.
Mortality, %
P Value
Mo 6 (primary endpoint)
Mo 1 Mo 2 Mo 3
27.1
8.2 15.3 22.4
38.2
23.6 32.6 33.7
.117
.005 .007 .095
Placebo (n = 159)
(n = 82)
14
28
42
56
Poordad F, et al. AASLD 2009. Abstract 305. Figure reproduced with permission.
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