Viral Hepatitis 2015

Ray Chung, M.D. Director of Hepatology Vice Chief, GI Division

Kevin and Polly Maroni Research Scholar Massachusetts General Hospital

Source of virus

feces blood/ blood-derived

body fluids

blood/ blood-derived

body fluids

blood/ blood-derived

body fluids

feces

Route of transmission

fecal-oral percutaneous permucosal

percutaneous permucosal

percutaneous permucosal

fecal-oral

Chronic infection

no yes yes yes yes, in I/C

Prevention pre/post- exposure

immunization

pre/post- exposure

immunization

blood donor screening;

risk behavior modification

pre/post- exposure

immunization; risk behavior modification

ensure safe drinking

water; immunization

Viral Hepatitis - Overview

Type of Hepatitis

A B C D E

Acute infections /year* 21,000

falling 38,000 falling

35-180 falling

1,000

Fulminant deaths/year 20 50 ? 10

Chronic infections

0 1.25 million

3.5 million

70,000

Chronic liver disease deaths/year 0 3,000 14,000

rising 600

* CDC, estimated annual incidence, 2009

Estimates of Acute and Chronic Disease Burden for Viral Hepatitis, United States

HAV HBV HCV HDV

• Virology: picornavirus • Incubation period: Average 30 days Range 15-50 days • Jaundice by

• Close personal contact

(household contact, sex contact, day care centers)

• Contaminated food, water (infected food handlers, raw shellfish)

• Blood exposure (rare) (injection drug use, transfusion)

Hepatitis A Virus Transmission

Fecal HAV

Symptoms

0 1 2 3 4 5 6 12 24

IgM anti-HAV

Total anti-HAV

ALT

Hepatitis A Virus Infection Typical Serologic Course

Months after Exposure

Titer

Age group

(years) Case-Fatality (per 1000)

49 17.5

Source: Viral Hepatitis Surveillance Program, 1983-1989

Age-specific Mortality Due to Hepatitis A

Total 4.1

Monovalent Hepatitis A Vaccine, Inactivated

Dose Schedule

Havrix®1 1440 EL.U. in 1.0 mL IM

0, 6 to 12 months

Vaqta®2 ~50 U in 1 mL IM 0, 6 to 12 months

1. Havrix Prescribing Information. See Dosage and Administration. SmithKline Beecham Pharmaceuticals. Philadelphia, PA. Nov. 2001. 2. Vaqta Prescribing Information. Merck & Co, Inc. West Point, PA; 2001. See complete prescribing information.

• recommended: travel to endemic areas (long notice), risk groups, CLD

• Preexposure – travelers to intermediate and high

HAV-endemic regions (short notice

Hepatitis B Virus

• Small partially double-stranded DNA virus

• Prototype of the hepadnavirus family

• 4 major gene products

Precore mutant

CCC DNA

HBV mRNA

ER

Golgi

HBsAg

HBeAg “Dane Particle”

* Includes sexual contact with acute cases, carriers, and multiple partners. Source: CDC Sentinel Counties Study of Viral Hepatitis

Heterosexual* (41%)

Homosexual Activity (9%) Household Contact (2%)

Health Care Employment (1%)

Other (1%) Unknown (31%)

Injecting Drug Use

(15%)

Risk Factors for Acute Hepatitis B United States, 1992-1993

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBs HBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Acute HBV Infection with Recovery Typical Serologic Course

Weeks after Exposure

Titer

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBs HBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Acute HBV Infection with Recovery Typical Serologic Course

Weeks after Exposure

Titer

IgM anti-HBc

Total anti-HBc

HBsAg

Acute (6 months)

HBeAg

Chronic (Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Progression to Chronic HBV Infection Typical Serologic Course

Weeks after Exposure

Titer

Symptomatic Infection

Chronic Infection

Age at Infection

Chr

onic

Infe

ctio

n (%

)

Sym

ptom

atic

Infe

ctio

n (%

)

Birth 1-6 months 7-12 months 1-4 years Older Children and Adults

0

20

40

60

80

100 100

80

60

40

20

0

Outcome of HBV Infection by Age at Infection

CD8+ CD4+

Cytokines (IL-2, IFN-γ, TNF-α, TGF-β, PDGF) Cell killing

Kupffer cell

Hepatocytes

Hepatic stellate cells

TGF-β Activation

FIBROSIS

Death

Hepatitis B disease pathogenesis

Natural History of Chronic HBV Infection

Adapted from Feitelson, Lab Invest, 1994.

Acute Infection

Chronic Carrier

Resolution

30-50 Years

Chronic Hepatitis

Stabilization

Progression (Replicators)

Cirrhosis

Compensated Cirrhosis

Liver Cancer Death

Decompensated Cirrhosis (Death)

< < > > HBeAg+ (wild) HBeAg-/Anti-HBe+ (PC/CP variants)

ALT

HBV DNA

Normal/ mild CH

Moderate/severe CH Moderate/severe CH Normal/mild CH

Cirrhosis

Inactive-carrier state HBeAg- chronic hepatitis

HBeAg+ chronic hepatitis

Immune Tolerance

Immune Clearance

Low Replicative Phase

Reactivation Phase

Cirrhosis

>20M IU/mL < 2000 IU/mL

>2000 IU/mL

Inactive cirrhosis

PC, precore; CP, core promoter; CH, chronic hepatitis

Stages of Chronic HBV Infection

Adapted from G Fattovich, MD

Normal Elevated Elevated Normal Normal Elevated ALT

- or low +

>2,000 IU/mL

>20,000 IU/mL - - +

HBV DNA (PCR)

- - - - - + IgM anti-HBc

+ + + - + + anti-HBc

+ + - - +/- - anti-HBe

- - + - - + HBeAg

- - - + + - Anti-HBs

+ + + - - + HBsAg

Inactive Carrier

Chronic* eAg(-)

(replicative)

Chronic* eAg(+)

(replicative) Vaccinated

Past Exposures (Immunity)

Acute Hepatitis B

Test

Interpretation of HBV Diagnostic Tests

*indicated for antiviral therapy

Yang HI, et al. N Engl J Med. 2002;347:168-174.

HBV replicators are at highest risk of disease progression

• Study of HBV progression and HCC in 11,893 men in Taiwan

• Likelihood of HCC 3.9x higher in patients with detectable HBV DNA vs undetectable – Risk associated with increasing HBV DNA levels

• Relative risk of HCC vs uninfected individuals – HBsAg(+) and HBeAg(+) 60.2x – HBsAg(+) but HBeAg(-) 9.6x

• Antiviral therapy to decrease risk of outcomes

HBV DNA level predicts clinical outcome

Iloeje U, Gastro 2006;130:678-86.

Approved agents for chronic HBV

• Interferon-alfa-2b • Lamivudine • Adefovir • Entecavir • Tenofovir • Telbivudine • PEG-interferon-alfa-2a Other approved agents with anti-HBV activity • Emtricitabine

HBeAg Responses in Phase-III Trials of Lamivudine (100 mg/d x 52 weeks)

0%

20%

40%

60%

HBeAgSeroconversion

HBeAg Loss

LaiDienstagSchalmSchiff

16% 17% 18% 18% 17%

32% 33%

Entecavir vs Lamivudine in HBeAg(+) patients

Entecavir (n = 354)

Lamivudine (n = 355) P Value

Histologic improvement, % 72 62 .0085

Median change in HBV DNA from baseline, log10 copies/mL

-6.98 -5.46 < .0001

HBV DNA < 0.7 mEq/mL, % 91 65 < .0001

HBV DNA < 400 copies/mL, % 69 38 < .0001

HBeAg seroconversion, % 21 18 NS

Chang T, et al. NEJM 2006

Tenofovir vs Adefovir in HBeAg-positive CHB: Patients With HBV DNA Levels of

Rates of Genotypic Resistance FDA approved nucs

24

4 0 0 0

38

22

3 0 0

49

111

71

18

1

65

29

10

1020304050607080

Lamivudine Telbivudine Adefovir Tenofovir Entecavir

Year 1 Year 2 Year 3 Year 4 Year 5

Perc

ent

0%

10%

20%

30%

40%

50%

Any Endpoint CTP increase HCC

% w

ith S

tudy

End

poin

t

Placebo (n = 215) Lamivudine (n = 436)

9%

18%

8% 3%

Antiviral therapy postpones clinical outcomes in cirrhotic HBV

≥2 point CTP elevation, HCC, SBP, renal insufficiency, bleeding varices

Study terminated early after 72 endpoints

Median time to event 32 months

Liaw Y-F et al. N Engl J Med 2004; 351:1521

P=0.001

P=0.023

4% 7% P=0.047

HBV Management

• HBV DNA levels have prognostic value • Treat replicative, active HBV • Goal is eAg seroconversion or HBV DNA suppression

– sAg seroconversion elusive • Entecavir, Tenofovir 1st line monotherapy agents • PEGIFN can be considered in young persons with low HBV

DNA, inc ALT • In any HBsAg+ pt undergoing chemo, steroids, rituximab,

biologics, prophylax! • We need curative strategies directed against other viral

lifecycle steps

HCV Genomic Organization

Core E1 E2 NS2 NS3 NS4a/NS4b NS5a/NS5b

Metalloproteinase

Serine protease (trans)

Serine protease (cis)

3' UTR 5' UTR

RNA polymerase Helicase

Structural proteins Nonstructural proteins

p7

RNA virus does not integrate into genome – curable RNA polymerase error-prone – high genetic diversity

Genetic Diversity of HCV

H1480 5a

JK049

Tr 3b NZL1 3a HK2 6a Th580 6b

JK046

VN235

VN405

VN004

ED43 4a

J8 2b J6 2a

HCV A 1b HCV J 1b

G9 1c HCV 1 1a H77 H90

BEBE1 2c • 6 major genotypes • many subtypes • in US,

gt 1 75% gt 2,3 25%

Sources of Infection for Persons With Acute Hepatitis C in 6 Months Prior to

Illness Onset, 1994-2006

Sexual 20%

Occupational 3%

None reported 8%

Injecting drug use 65%

Household 1%

Williams IT, et al. Arch Intern Med. 2011;171:242-248

CDC data. Armstrong GL et al. Ann Intern Med 2006;144:705-14 Denniston MM et al, Ann Intern Med 2014; 160:293-300

In general, the HCV cohort has aged…

NHANES 2003-10: 2.7M chronically infected

…but there has been a youthful spike

Onofrey et al. MMWR May 6, 2011 / 60(17);537-541

C p7 NS2 NS3 NS4B NS5B NS4A E1 E2 Core Envelope Glycoproteins

Protease Serine Helicase Protease

Serine Protease Cofactor

RNA-dependent RNA polymerase

NS3-4A protease inhibitors

NS5B polymerase inhibitors

nucleoside inhibitors

non-nucleoside inhibitors

NS5A

Targets for Direct Acting Antivirals (DAA)

McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

Needed for Replication Assembly

NS5A

inhibitors

HCV life cycle

Moradpour, Nat Rev Microbiol 2007;5:453

HCV Genotypes and Subtypes

1

6 3

4

5

2

Simmonds P, Journal of Hepatology, 1999

Americas + Western Europe Developed countries

South Africa

Middle East North Africa

Asia IDU

U.S. 1 75% (45%SVR) 2,3 25% (80%SVR)

CD8+ CD4+

Cytokines (IL-2, IFN-γ, TNF-α, TGF-β, PDGF) Cell killing

Kupffer cell

Hepatocytes

Hepatic stellate cells

TGF- Activation

FIBROSIS

Death

Hepatitis C disease pathogenesis

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

Normal

HCV RNA

Symptoms +/-

1 2 3 4 5 6 1 2 3 4 0 Months Years

Tite

r

Time after Exposure

ALT

anti-HCV

Adapted from MMWR 1998; 47(No. RR19)

Natural History of HCV Infection Exposure

(Acute phase)

Resolved Chronic

Cirrhosis Stable or variably progressive

Slowly Progressive

HCC Transplant

Death

20% (16)

20% (20) 80% (80)

25% (4)

80% (64)

75% (12)

EtOH HIV

25 yrs 20 yrs

39% 42%

34%

16%

6%

0

20

40

60

80

100

IFN 6 m

IFN/RBV 6 m

Peg-IFN/ RBV 12 m

IFN 12 m

IFN/RBV 12 m

Peg-IFN 12 m

Adapted from Strader DB, et al. Hepatology. 2004;39:1147-71

1991

1999

2001 2002

PEG-IFN-α and RBV Produce SVR in About Half of Patients with HCV

54 – 56%

99.0% 100% 99.1%

166

99.1%

0

20

40

60

80

100

All

PEG RBV

Abnormal ALT

PEG Mono

therapy

PEG RBV

NormalALT

PEG +/-RBV

HCV HIV

Swain M, et al. Gastroenterology 2010;139:1593

The good news: a sustained response is truly sustained

98.8%

1343 998 79

100

mean F/U 0.8-7.1 yrs

Histologic Progression of HCV

Normal Mild Chronic Hepatitis (F1)

Moderate Chronic Hepatitis (F3) Cirrhosis (F4)

Rate of Progression to Cirrhosis from Chronic Hepatitis C

Degree of Fibrosis on Initial Liver Biopsy

100

75

50

25

0 5 10 15 20 Years

% of

Pro

gres

sion t

o Cirr

hosis

Grade C (3.0-3.45) Grade B (2.0-2.9)

Grade A (-1.9)

Yano M et al. Hepatology. 1996;23:1336

≈ 50% of Biopsies Avoidable with FibroTest

Imbert-Bismut. Lancet 2001;357:1069-75

Indeterminate 54%

FT > 0.80 Spec 97% PPV 92%

FT ≤ 0.20 Sens 92% NPV 87%

n=134 F2-F4 fibrosis: 45%

TBili, α-2-MG, hapto, GGT, ApoA1

New Tools: Liver Stiffness by Transient Elastography

Ultrasound-based technique Determines liver “stiffness” Correlates well with fibrosis No ceiling, ie, increases with worsening cirrhosis → predicts complications (eg, varices) Simple to use – minimal training

Liver Stiffness by Transient Elastography (Fibroscan)

Vergera. CID. 2007.

Very good for minimal fibrosis (F0-2) vs cirrhosis (F4)

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

100

63

40

25

16

10

6.3

4.0

2.5

P < 0.001

Loga

rithm

of T

rans

ient

Ela

stom

etry

M

easu

rem

ent (

log

kPa)

Tran

sien

t Ela

stom

etry

Mea

sure

men

t (kP

a)

0 1 2 3 4

n = 15 n = 49 n = 26 n = 14 n = 65

Fibrosis Stage

HHS Action Plan for the Prevention, Care and Treatment of Viral Hepatitis

By 2020, goal will be to achieve • an increase in the proportion of persons who are aware of

their hepatitis B virus infection, from 33% to 66% • elimination of mother-to-child transmission of HBV • an increase in the proportion of persons who are aware of

their hepatitis C virus infection, from 45% to 66% • Birth cohort initiative: screen all persons born between 1945-

65 (75% of epidemic in this group) • 25% reduction in the number of new cases of HCV infection

HHS Action Plan. May 12, 2011. www.hhs.gov

ION-1: Sofosbuvir + Ledipasvir (NS5A Inhibitor) Genotype 1: Treatment Naïve, n=865

Cirrhosis in 16% n=468

12 weeks 24 weeks

SVR12 (%)

209/214 211/217 212/217 215/217

99 97

Afdhal N et al, N Engl J Med 2014;370:1889

98 99

Chart1

SOF/LDV

SOF/LDV+RBV

SOF/LDV

SOF/LDV+RBV

Series 1

99

97

98

99

Sheet1

Series 1Series 2Series 3

SOF/LDV992.42

SOF/LDV+RBV974.42

SOF/LDV981.83

SOF/LDV+RBV992.85

To resize chart data range, drag lower right corner of range.

ION-2: Sofosbuvir + Ledipasvir ± RBV Genotype 1 Treatment Experienced

Cirrhosis in 20% n=440

12 weeks 24 weeks

SVR12 (%)

102/109 107/111 108/109 110.111

94 96

Afdhal N et al, N Engl J Med 2014;370:1483

99 99

Chart1

SOF/LDV

SOF/LDV+RBV

SOF/LDV

SOF/LDV+RBV

Series 1

94

96

99

99

Sheet1

Series 1Series 2Series 3

SOF/LDV942.42

SOF/LDV+RBV964.42

SOF/LDV991.83

SOF/LDV+RBV992.85

To resize chart data range, drag lower right corner of range.

ION-2: Sofosbuvir + Ledipasvir ± RBV Genotype 1 Treatment Experienced

Patients With Cirrhosis

12 weeks 24 weeks

SVR12 (%) 86 82

100 100

19/22 18/22 22/22 22/22

Afdhal N et al, N Engl J Med 2014;370:1483

Chart1

SOF/LDV

SOF/LDV+RBV

SOF/LDV

SOF/LDV+RBV

Series 1

86

82

99

99

Sheet1

Series 1Series 2Series 3

SOF/LDV862.42

SOF/LDV+RBV824.42

SOF/LDV991.83

SOF/LDV+RBV992.85

To resize chart data range, drag lower right corner of range.

Genotype 1, treatment naïve, noncirrhotic,12 weeks, n=473

Paritaprevir (PI)/ritonavir/Ombitasvir (NS5A) + Dasabuvir

(NNI) + RBV SAPPHIRE-1

96 95 98

455/473 307/322 148/151

SVR12 %

Feld JJ et al, N Engl J Med 2014;370:1594-1603

PEARL III Trial, gt1b treatment naïve (n=419): 3DAA + RBV 99%, 3DAA no RBV 99%

Chart1

Overall

G1a

G1b

Series 1

96

95

98

Sheet1

Series 1Series 2Series 3

Overall962

G1a9592

G1b983

Category 44.52.85

To resize chart data range, drag lower right corner of range.

Genotype 1, treatment experienced, noncirrhotic, 12 weeks, n=394

Paritaprevir (PI)/ritonavir/Ombitasvir (NS5A) + Dasabuvir

(NNI) + RBV SAPPHIRE-2

SVR12 (%)

96 96 97

Zeuzem S et al, N Engl J Med 2014; 370:1604

PEARL II Trial, gt1b treatment experienced (n=179): 3DAA + RBV 97%, 3DAA no RBV 100%

Chart1

Overall

G1a

G1b

Series 1

96

96

97

Sheet1

Series 1Series 2Series 3

Overall962.42

G1a964.42

G1b971.83

Category 44.52.85

To resize chart data range, drag lower right corner of range.

Paritaprevir (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV TURQUOISE-II

Gt1 compensated cirrhosis (naïve and experienced) n=380

Poordad F et al, EASL 2014; NEJM 2014 370:1973

Response by group: •Prior partial: 94 v 100

87 87 86 89 89 90

0

20

40

60

80

100

Overall CPT B CPT C

12 Weeks 24 Weeks

45/52 42/47 26/30 24/27 19/22 18/20

Sofosbuvir/Ledipasvir + RBV in Decompensated Cirrhosis: Preliminary Results of a Prospective, Multicenter Study

• n=99 • Randomized to SOF + LDV + RBV (600 mg w/escalation) for 12 or 24 wks • Patients with GT 1 or 4 and decompensated cirrhosis • Median albumin = 2.6-3.0 g/L; Median platelets = 71-88K

Flamm, Abst# 239, AASLD 2014

Sofosbuvir/Ledipasvir + RBV in Patients with Decompensated Cirrhosis: improved clinical status

5

4

3

2

1

0 BL PT Wk4

5

4

3

2

1

0 Baseline PT Wk4

5

4

3

2

1

0 BL PT Wk4

5

4

3

2

1

0 Baseline PT Wk4

12 Weeks 24 Weeks

• SAE = 10%-42% (only 4 considered treatment-related) • 5 deaths: Septic shock (4), renal failure/cardiac arrest

-6

-4

-2

0

2

4

-6

-4

-2

0

2

4

12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=24)

CPT B CPT C

n=3 n=3 n=5 n=5

Flamm, Abst# 239, AASLD 2014

Changes in MELD Albumin

CPT C

CPT B CPT B

100% 100% 97% 97%

0%

20%

40%

60%

80%

100%

Wk4 EOT SVR4 SVR12

AVR-Naїve AVR Treated

High Efficacy of Sofosbuvir/Ledipasvir for HCV GT1 in Patients Coinfected With HIV: NIAID ERADICATE

Trial

• HCV, GT1, tx naïve noncirrhotic subjects (n=50) treated with SOF/LDV x12 wks

• GT1a =74% • African American = 84% • F0-2 78%

•Arm A (n=13): ARV naїve •Arm B (n=37): ARV treated

•ARV: Tenofovir/FTC with Efavirenz, Rilpivirine or Raltegrevir

•No change in CD4 or HIV RNA •No SAE or early DC due to AE

Osinusi, Abst# 84, AASLD 2014

Sofosbuvir in Treatment Naïve GT 2,3 Patients

67

SVR

%

67

FISSION

78

97

0

20

40

60

80

100

Sofosbuvir 400mg + Ribavirin daily x12w

PEG-2a weekly + Ribavirin 800mg daily x24w

n= 243 70 253 Overall

67 GT2 GT3

56 63

183 176

Lawitz E et al., NEJM 2013; 368:1878-87

Sofosbuvir/Ribavirin for Treatment-Naïve and Experienced Patients with Genotype 2 or 3:

VALENCE

• Phase 3 trial in Europe – Amended to treat GT3 for 24 weeks

• SOF/RBV x12W (GT2, n=73) or 24W (GT3, n=250) – Cirrhosis 14–23% – Treatment experienced 58%

• Discontinuation due to AE, n=2

Zeuzem et al, N Engl J Med 2014; 370:1993

94 92 9391

68

85

0

25

50

75

100

No cirrhosis Cirrhosis Overall

SVR12 G2 (blue), G3 (red)

Chart1

No cirrhosisNo cirrhosis

CirrhosisCirrhosis

OverallOverall

Naïve

Experienced

SVR12 G2 (blue), G3 (red)

94

91

92

68

93

85

Sheet1

NaïveExperienced

No cirrhosis9491

Cirrhosis9268

Overall9385

All-Oral Combination of Daclatasvir (NS5A) and Sofosbuvir in Patients with GT 3: ALLY-3

Treatment Naїve 19% w/ cirrhosis

Prior Treatment 25% w/cirrhosis

Daclatasvir + Sofosbuvir

Daclatasvir + Sofosbuvir

ALLY-3

N=101

N=51

0 Weeks 12 24 EOT SVR

99% 90%

99%

SVR F0-F3 = 96% (105/109) SVR F4 = 63% (20/32)

• No SAEs related to treatment, no premature D/C due to AEs • Most AE mild: fatigue, headache, nausea, diarrhea

Nelson, LB-3, AASLD 2014

86%

Summary All oral, tolerable, high efficacy regimens (>90% cure) now available Several roads to the same IFN-free destination

– High barrier compounds desirable for simplified regimens but can be matched by combinations of DAA classes

– High SVR rates now possible in historically difficult populations (nulls, cirrhotics, decompensated, post-LT, HIV)

Timelines for FDA approval – Dec 2013

– Sofosbuvir + P/R, Simeprevir + P/R for gt 1 – Sofosbuvir + RBV for gt 2/3

– Oct 2014 – Sofosbuvir + simeprevir for gt1 – Sofosbuvir/ledipasvir for gt1

– Dec 2014 – Paritaprevir/r/ombitasvir + dasabuvir +/- RBV for gt 1

– July 2015 – Daclatasvir + sofosbuvir for gt 3

Beyond: grazoprevir/elbasvir +/- RBV, ASV/DCV/BCV

Who should be treated and how? Genotype 1

– Sofosbuvir + ledipasvir x 8-24W (TE cirrhosis) – 1a: Paritaprevir/r/ombitasvir + dasabuvir + RBV x 12-24W (cirrhosis) – 1b: Paritaprevir/r/ombitasvir + dasabuvir x 12W – Sofosbuvir + simeprevir x 12-24W (cirrhosis)

Genotype 2 – SOF/RBV x 12W (naïve and experienced) – Extend to 16W in cirrhotics

Genotype 3 – SOF/RBV x 24W – PEG/RBV/SOF x 12W – Daclatasvir and Sofosbuvir x 12 wks (noncirrhotic)

Ideally: all treated Priority: F3-4, extrahepatic disease, symptomatic

www.hcvguidelines.org

http://www.hcvguidelines.org/

Summary • HAV

– vaccine-preventable • HBV

– vaccine-preventable – chronicity dictated by age at exposure – replication is associated with more severe outcomes – therapeutic strategies therefore aimed at replicative HBV

• HCV – not likely to be vaccine-preventable – much more likely to be clinically silent – highest rates of chronicity – curable! – strongly consider evaluating with liver biopsy (gt 1)

Viral Hepatitis 2015 Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Natural History of Chronic HBV InfectionSlide Number 19Interpretation of HBV Diagnostic TestsHBV replicators are at highest risk of disease progressionHBV DNA level predicts clinical outcomeApproved agents for chronic HBVHBeAg Responses in Phase-III Trials of Lamivudine (100 mg/d x 52 weeks)Entecavir vs Lamivudine in HBeAg(+) patientsTenofovir vs Adefovir in HBeAg-positive CHB: Patients With HBV DNA Levels of