Highlights from AASLD 2009

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Highlights From AASLD 2009

CCO Independent Conference Coverage
of the 2009 Annual Meeting of the American Association for the Study of Liver Diseases*
October 30 - November 3, 2009 Boston, Massachusetts
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

This program is supported by educational grants from

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Faculty
Robert G. Gish, MD
Medical Director Liver Transplant Program California Pacific Medical Center San Francisco, California

Highlights from AASLD 2009

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Outline
Investigational Agents for the Treatment of HCV
HCV/HIV Coinfection Advances in HBV Therapy

Complications of Advanced Liver Disease

Investigational Agents for the Treatment of HCV

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Worldwide Distribution of HCV Genotypes

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.

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SPRINT-1: Boceprevir + PegIFN/RBV in Treatment-Naive G1 Pts

Wk 4 PegIFN alfa-2b/ RBV PegIFN alfa-2b/ RBV Wk 28 PegIFN alfa-2b/RBV + Boceprevir 800 mg TID (n = 103) PegIFN/RBV + Boceprevir 800 mg TID (n = 103) Wk 48 44-wk follow-up 24-wk follow-up 44-wk follow-up 24-wk follow-up 24-wk follow-up

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.

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SPRINT-1: SVR by Early Response to Boceprevir/PegIFN/RBV

P = NS 100 100 82 94 83

P < .004
79

PegIFN/RBV 48 wks PegIFN/RBV 4 wks PegIFN/RBV/boceprevir 24 wks

PegIFN/RBV 4 wks PegIFN/RBV/boceprevir 44 wks

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.

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SPRINT-1: Boceprevir + PegIFN/RBV in Null Responders to SOC

IDEAL study found 1 log10 decrease in HCV RNA at Wk 4 of pegIFN alfa-2b + RBV associated with ~ 2 log10 decrease at Wk 12[1] Two 4-wk lead-in arms of pegIFN alfa-2b + RBV allowed determination of likely virologic response to SOC[2]
Definition of a null response to pegIFN alfa-2b + RBV: < 1 log10 decrease at Wk 4
< 0.5 log drop at Wk 4 of pegIFN/RBV lead-in 0.5 to < 1.0 log drop at Wk 4 of pegIFN/RBV lead-in

100 80 SVR (%) 62 44 29 24 5/21 4/9 8/13

60
40 20 0

2/7

PegIFN/RBV 4 wks PegIFN/RBV 4 wks PegIFN/RBV/Boceprevir 24 wks PegIFN/RBV/Boceprevir 44 wks

1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. 2. Kwo PY, et al. AASLD 2009. Abstract 62.

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Phase II PROVE Studies: Telaprevir + PegIFN alfa-2a RBV in HCV-Infected Pts

Treatment-Naive G1 PROVE 1
(N = 250) Wk 12 Wk 24 Wk 36 Wk 48 Follow-up Follow-up Wk 72

PR TVR + PR TVR + PR TVR + PR PR TVR + P TVR + PR TVR + PR

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)

PR TVR + P TVR + PR TVR + PR

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.

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PROVE 1 and 2 Pooled Subanalysis: TVR in Difficult-to-Cure Pts

100 Virologic Response (%) 80 60 40 20 P < .001 59 12-wk TVR + 24-wk pegIFN/RBV (n = 160) PegIFN/RBV control (n = 157) P < .001 63 P = .045 61 P < .001 69

39 29 30

44

0
Age > 50 Yrs

HCV RNA 800,000 IU/mL

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)

Everson GT, et al. AASLD 2009. Abstract 1565.

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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.

McHutchison JG, et al. AASLD 2009. Abstract 66.

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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, %

SVR in pts with RVR, % (n/N)

Virologic breakthrough in 14 pts, 7 of which occurred before or at Wk 4

More breakthroughs during TVR dosing phase (n = 9) vs pegIFN/RBV dosing phase (n = 5) More frequent in genotype 1a pts (n = 11) vs genotype 1b pts (n = 3)

Marcellin P, et al. AASLD 2009. Abstract 194.

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NEXT-1: HCV Protease Inhibitor Narlaprevir in Treatment-Naive G1 Pts

Wk -4 Wk 0 Wk 12 PegIFN/RBV (n = 18) Wk 48

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 24-wk PegIFN/RBV follow-up

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.

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NEXT-1: NVR Potent in Treatment-Naive Pts, Wk 4 PegIFN/RBV Null Responders

Rapid decline in HCV RNA upon initiation of NVR-based regimens vs pegIFN/RBV 11 null responders to pegIFN/RBV lead-in achieved HCV RNA below LLQ (< 25 IU/mL) at Wk 4 of NVRbased therapy
9 maintained HCV RNA < 10 IU/mL through Wk 12 (NVR 200 mg and 400 mg QD dosing arms) 2 pts experienced virologic breakthrough by Wk 8 (200 mg QD dosing arm only)
P/R control P/R + NVR* 200 mg QD P/R + NVR* 400 mg QD

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

*Each dose of NVR administered with RTV 100 mg.

Wk 12

Vierling JM, et al. AASLD 2009. Abstract LB4. Figure reproduced with permission.

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SILEN-C1: Rapid Virologic Response With Protease Inhibitor BI 201335 + PegIFN/RBV

Double-blind, placebo-controlled trial
100 Virologic Response (%) 80 60 40 20 0 n= 16 71 143 146 69 71 143 146 69 42 Wk 4 BLQ (< 25 IU/mL) 92 90 84 Wk 12 BLQ (< 10 IU/mL)

91
82 84

*LI, 3-day pegIFN lead-in. Sulkowski MS, et al. AASLD 2009. Abstract LB3. Figure reproduced with permission.

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SILEN-C1: Virologic Rebound and Adverse Events

< 3.5% of pts in all arms rebounded between Wks 0-12
No pts in control arm rebounded
Adverse Events, % Control Arm (n = 71) 40.8 31.0 9.9 1.4 9.9 1.4 240 mg BI 201335 (n = 143) 34.2 25.3 30.1 21.0 16.4 1.4 240 mg BI 201335 + LI* (n = 146) 31.5 23.8 28.0 16.4 23.1 4.2 120 mg BI 201335 + LI* (n = 69) 33.3 21.7 26.1 5.8 17.4 0

Flu-like symptoms Fatigue Pruritus Jaundice* Rash Mild Severe

*LI, 3-day pegIFN lead-in.

Sulkowski MS, et al. AASLD 2009. Abstract LB3.

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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

PegIFN/RBV PegIFN/RBV PegIFN/RBV PegIFN/RBV PegIFN/RBV PegIFN/RBV PegIFN/RBV

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)

Pts infected with G1 HCV (N = 86)*

Previous nonresponders to IFN (excluding null responders)
Previous null responders to IFN

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.

Gane EJ, et al. AASLD 2009. Abstract 193.

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INFORM-1: 14-Day Response Rates in Tx-Naive and Tx-Experienced G1 HCV Pts

HCV RNA R7128/R7227 Doses, mg n Pt Population Median Change From Baseline, Log10 IU/mL < LLOQ, % < 40 IU/mL < 15 IU/mL

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.

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NS5B Polymerase Inhibitor MK-3281 in TxNaive and -Experienced HCV Pts

Double-blind, placebo-controlled, 7-day monotherapy
HCV RNA log10 Change 1 0 -2 -3 -4 -5 0 5 10 Days 15 20
G1a (n = 6)/G1 nontypeable (n = 1) Genotype 1b (n = 4) G3 (n = 6)

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.

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Thymosin alpha-1 Plus PegIFN/RBV for HCV Nonresponders

Stratified by HCV RNA (> vs < 800,000 IU/mL), prior failed regimen (pegIFN alfa-2a vs alfa-2b), cirrhosis (with vs without) Wk 24 efficacy assessment for discontinuation* Wk 48

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.

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SVR and EOT Response Rates in Thymosin alpha-1-Treated Pts vs Placebo

Outcome, % (n/N) Thymosin alpha-1 + PegIFN/RBV 12.7 (35/275) 42.5 (31/73) 41.0 (34/83) Placebo + PegIFN/RBV 10.5 (29/277) 28.2 (24/85) 26.3 (26/99) P Value

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

Incidence of adverse events similar between treatment groups

Ciancio A, et al. AASLD 2009. Abstract 1564.

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Summary and Conclusions: Investigational HCV Agents

Pts with undetectable HCV RNA after 4 wks of pegIFN/RBV lead-in and 4 wks of boceprevir + pegIFN/RBV more likely to achieve SVR vs pts with undetectable HCV RNA later in therapy
Up to 55% of G1 HCV pts with null response after 4 wks of pegIFN lead-in achieved SVR with boceprevir + pegIFN/RBV Among HCV-infected pts with poor prognostic indicators, TVR + pegIFN/RBV significantly improved virologic response vs SOC

TVR + pegIFN/RBV effective, durable in G1 HCV pegIFN/RBV nonresponders to previous pegIFN/RBV

Similar SVR rates for pts receiving TVR q8h vs q12h, both plus pegIFN/RBV

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Summary and Conclusions: Investigational HCV Agents

High rate of virologic response at Wks 4 and 12 with NVR + pegIFN/RBV in treatment-naive HCV pts
High rate of virologic response at Wks 4 and 12 with BI 201335 + pegIFN/RBV for first-line treatment of G1 HCV

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

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PARADIGM: 800 vs 1000/1200 mg RBV Plus PegIFN in HCV/HIV-Coinfected Pts

Double-blind, multicenter phase IV study of G1, treatmentnaive pts
100

Ribavirin 800 mg/day Ribavirin 1000/1200 mg/day

75 64 63 66

80
SVR (%) 60 40 20

P = .6119 19 22/ 4/ 35 11 Pts With a cEVR 22

7/ 16/ 11 20 0 All Pts With an RVR

26/ 60/ 135 275 All Pts

Rodriguez-Torres M, et al. AASLD 2009. Abstract 1561. Figure reproduced with permission.

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Pt and Liver Graft Survival in HCV/HIVCoinfected Pts

HCV/HIV-coinfected liver transplantation recipients with controlled HIV-1 RNA from HIVTR Study Group (n = 81) compared with HCV-monoinfected liver transplantation recipient matched controls (n = 213) Pt and graft survival significantly lower in HCV/HIV-coinfected liver transplantation recipients vs HCV-monoinfected recipients (P = .01)
HR (95% CI) P Value

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

.003 .001 .05 .02

10 12 14

16 18

Terrault N, et al. AASLD 2009. Abstract 195.

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Summary and Conclusions: HCV/HIV Coinfection

1000/1200 mg vs 800 mg RBV + pegIFN alfa-2a not associated with improved SVR rate in HCV/HIV-coinfected pts
Pt and graft survival lower among HCV/HIV-coinfected vs HCV-monoinfected liver transplantation recipients
Dual-organ transplantation (liver and kidney), HCV-positive donor, BMI < 21 at wait listing, and treatment for acute rejection significantly predictive of graft survival

Advances in HBV Therapy

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Entecavir in Pts With HBeAg-Positive and HBeAg-Negative Chronic Hepatitis B

Retrospective analysis of 153 treatment-naive or experienced pts who received > 1 yr entecavir
Naive: entecavir 0.5 mg/day
Undetectable HBV DNA (%) 100 80 60 40 Treatment naive 20 0

Treatment History
100 100 93

Expd: entecavir 1.0 mg/day

Similar, high rates of undetectable HBV DNA through 3 yrs of follow-up

82% of pts with elevated ALT (n = 85) achieved biochemical response by Mo 12

Lamivudine exposed Adefovir exposed 0 6 12 18 24 Months 30 36

Baqai SF, et al. AASLD 2009. Abstract 476. Figure reproduced with permission.

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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)

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Virologic Suppression, Safety in HBV Pts Receiving 2- vs 1-Drug Regimen at Wk 48

HBV DNA < 400 copies/mL (%) 100 88 80 60 40 71 73 50 33 89 TDF (n = 45) TDF/FTC (n = 45) ETV (n = 22)

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.

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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

Baseline intrahepatic cccDNA not predictive of

HBeAg seroconversion in HBeAg-positive pts EOT response, SVR, or relapse in HBeAg-negative pts

EOT intrahepatic cccDNA predicted SVR

Positive predictive value for HBeAg-positive pts: 73% for cccDNA < 0.02 log10 copies/cell Positive predictive value for HBeAg-negative pts: 72% for cccDNA < -1.77 log10 copies/cell
Takkenberg B, et al. AASLD 2009. Abstract 486.

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Summary and Conclusions: Advances in HBV Therapy

ETV associated with high response rates over 36 mos in pts with HBeAg-positive and HBeAg-negative chronic hepatitis B
Fixed-dose TDF/FTC safe and effective option for treatment of pts with chronic hepatitis B and decompensated liver disease Intrahepatic cccDNA levels at EOT with pegIFN alfa-2a + adefovir predictive of SVR in pts with chronic hepatitis B
SVR defined as sustained undetectable HBV DNA after treatment discontinuation

Complications of Advanced Liver Disease

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PegIFN alfa-2b/RBV To Prevent HCV Recurrence PostLiver Transplantation

59 HCV pts treated with pegIFN alfa-2b/RBV LADR regimen pretransplant analyzed for posttransplant virologic response (pTVR*)
28% of pts achieved pTVR
18% with G1/4/6 vs 39% with G2/3 (P = .17)

Significantly higher pTVR rate with longer pretransplantation treatment duration (P = .04)
Outcome, %
HCV RNA negative at liver transplantation pTVR*

< 10 Wks Treatment

46 15

10-15 Wks Treatment

64 18

> 15 Wks Treatment

69 44

*Undetectable HCV RNA 12 wks postliver transplantation. Everson GT, et al. AASLD 2009. Abstract 1.

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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.

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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.

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Prevalence of Hepatorenal Syndrome Types in 21 Italian Hepatology Centers

Hepatorenal syndrome (HRS) common in pts with cirrhosis, ascites
Type 1 most severe, characterized by rapid decline in kidney function

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

Higher MELD score

Higher MELD-sodium score

Salerno F, et al. AASLD 2009. Abstract 342.

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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.

Terlipressin + Albumin (n = 40) 35 52 80

17 50 71

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Treatment of Acute Alcoholic Hepatitis With Prednisolone N-Acetyl Cysteine

Stratified by center Prednisolone 40 mg/day for 28 days + NAC IV on Days 1-5* (n = 85) Prednisolone 40 mg/day for 28 days + 5% Glucose (Carrier) IV on Days 1-5 (n = 89) Follow-up: Mos 1, 2, 3, 6

Pts with acute alcoholic hepatitis (N = 174)

*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, %

Prednisolone + NAC (n = 85)

Prednisolone + Carrier (n = 89)

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

Nguyen-Khac E, et al. AASLD 2009. Abstract 91.

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Rifaximin for Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhotic Pts

Day -3
Day 168 Randomized controlled trial* (RFHE3001) Open-label maintenance trial* (RFHE3002)

Pts with cirrhosis and history of HE (N = 299)

Rifaximin 550 mg twice daily (n = 140)

(n = 70) Rifaximin 550 mg twice daily (N = 267)

Placebo (n = 159)

(n = 82)

Additional pts with history of HE (n = 115)

*Lactulose permitted. Poordad F, et al. AASLD 2009. Abstract 305.

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Rifaximin Provides Durable Reduction in Risk of Breakthrough HE in Cirrhotic Pts

1.00 Proportion of Subjects in Remission From HE 0.75 0.50 0.25 0

RCT rifaximin RCT placebo OLM crossover OLM new rifaximin

14

28

42

56

70 84 98 112 126 140 154 168 Study Day

Poordad F, et al. AASLD 2009. Abstract 305. Figure reproduced with permission.

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Summary and Conclusions: Complications of Advanced Liver Disease

Virologic response 12 wks after liver transplantation feasible with pretransplantation pegIFN/RBV HCC risk remains high following 12 mos of antiviral therapy in cirrhotic pts with chronic hepatitis B Sorafenib plus DEB-TACE for pts with unresectable HCC shows acceptable toxicity profile and potential efficacy HRS common in pts with cirrhosis and ascites Low survival rate in pts with HRS type 1 treated with vasoconstrictors + albumin Survival benefit with corticosteroid + NAC vs corticosteroid alone at 2 mos but not at 6 mos in pts with severe acute alcoholic hepatitis Rifaximin provides durable reduction in risk of breakthrough HE in pts with cirrhosis

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