The Large Family of Hepatitis Viruses

Virus Family Genus Genome

HAV Picornaviridae Heparnavirus RNA

HBV Hepadnaviridae Orthohepadnavirus DNA

HCV Flaviviridae Hepacivirus RNA

HDV Deltaviridae Deltavirus RNA

HEV Hepeviridae Hepevirus RNA

HAV

Prevalence of anti-HAV

High

Intermediate

Low

Very low

Geographical Distribution of HAV Infection

Cases of Hepatitis A in Italy, 1987-2005n

. of

cases

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

87 88 89 90 91 92 93 94 95 96 97 98 9920

0020

0120

0220

0320

0420

05

Year

• Person-to-Person contacts (intrafamiliar, sexual, kinder garden)

• Contaminated food or water (raw seafood, clams, mussels)

• Blood exposure (very rare: blood transfusion)

HAV: Mode of Transmission

HAV in Biological Fluids

Source: Viral Hepatitis and Liver Disease 1984;9-22J Infect Dis 1989;160:887-890

Stool

Serum

Saliva

Urine

Infectious doses/ ml

100 102 104 106 108 1010

HAV Faeces

Symptoms

ALTALT

anti-HAV IgManti-HAV IgM

Anti-HAV IgGAnti-HAV IgG

Months after exposureMonths after exposure

Tit

reTit

re

0 1 2 3 4 5 6 12 24

HAV Infection: Typical Serological ProfileHAV Infection: Typical Serological Profile

Hepatitis A – Clinical Presentation

• Incubation:– Mean 30 d (15-50 d)

• Jaundice by age class:– <6 a., <10%– 6-14 a., 40%-50%– >14 a., 70%-80%

• Complications:– Fulminant hepatitis (rare)– Cholestasis– Long-term ALT fluctuations with virus shedding

• Evolution to chronic infection: No

Prophylaxis

• Improve hygiene, sewage, safe water supply

• At least 4 different types of inactivated vaccine plus one recombinant in combination with HBV

• Post-exposure prophylaxis with normal immunoglobulin which must contain antibodies to HAV

Who Should be Vaccinated

Recommended to:

all children leaving in endemic areas

persons at risk of acquiring HAV: travellers to endemic areas, militaries, food workers, contacts with patients

HEV

Geographical Distribution of Cases of Hepatitis E

Cornwall

Sporadic cases in Spain, Italy, France, US…

• Large epidemics described in the past (New Delhi 1955; Burma 1976; Algeria 1980; Messico 1986…) associated with faecal contamination of drinking water.

• Human transmission extremely rare• History of travel in endemic areas• Game meat eating (UK)

Epidemiology of HEV Infection

Hepatitis E: a Zoonosis ?• Anti-HEV detected in pigs, poultry, dogs, rats, and cattle

presente in both industrialized and developing countries: strongly suggestive of an animal reservoir.

• Animal HEV strains genetically and epidemiologically correlated with human HEV strains.

• Genetically homologous HEV strains detected in human faeces and pigsty sewages.

• Cross-species infection possible: pig primate pig.

• Prevalence of anti-HEV higher in rural than in urban areas.

• HEV infection associated with eating game meat

Weeks after ExposureWeeks after Exposure

Tit

reTit

re

Symptoms

ALT

IgG anti-HEV

IgM anti-HEV

Virus in stools

0 1 2 3 4 5 6 7 8 9 10 11 12 13

HEV Infection: Typical Serological Profile

HEV: Clinical Evolution

Acute Illness

Recovery Fulminant Hepatitis

Death

20% pregnant women

Chronic Infection(prevalence unkown)

Immunesuppression?

• Incubation: Mean 40 d (range 15-60 d)

• Mortality: 1%-3%, pregnant 15%-25%

• Severity of symptoms: Increase with age

• Cronic evolution: Rare (immunosuppressed +++)

Hepatitis E: Clinical Presentation

Prophylaxis of Hepatitis E

• Improve hygiene as for HAV

• A safe and effective vaccine is available but

not commercially available yet because

financially not profitable.

• Avoid unsafe water and seafood. Avoid eating game meat from endemic regions.

• Commercially available Ig preparations do not usually contain antibodies to HEV.

• The efficacy of Ig preparations from convalescent or immune patients is unknown

• Vaccination when available

General Prophylactic Measures for Travellers to Countries Where HEV Is Endemic

Hepatitis B: Essential Epidemiology

Source: WHO

World population 7 billions

About 2 billions have markers of exposure to HBV

Every year about 4 millions new HBV infections

400 millions are chronic HBV carriers

Mortality: about 1 million/yr

HBV Infection: Clinical Significance

• Most frequent cause of cirrhosis and HCC

• East:• Prevalence 5-20% of the general population• Perinatal or early childhood infecton

• West: • Prevalence 0.2-1% of the general adult population• 5-10% of all chronic liver diseases

Year of Follow-Up

Su

rviv

al

HBsAg(-) n=19,655

HBsAg(+) n=4,155

P<0.01

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12

Excess Mortality Associated withChronic HBV Infection

Iloeje U, et al. Gastroenterology 2006; 130:678–686

Survival curves of total mortality stratified by HBsAg status

Crude Mortality Rate by Sex and HBsAg Status

in Haimen City, China

Chen G, et al., Int J Epidemiol 2005;34:132-7

Mo

rta

lity

Ra

te p

er

10

0,0

00

PY

s

0

500

1000

1500

HBsAg+

Males

HBsAg+

Females

HBsAg-

Males

HBsAg-

Females

Liver deaths

HCC

CLD

HBV

DNA polymerase HBV DNA

Envelope (HBsAg)

Nucleoproteinecore (HBcAg)

HBeAg

HBsAg

HBV Ultrastructure

cccDNA

HBV RNA

MINICHROMOSOME

Binding and penetration

Uncoating

Envelope proteinL, M, S

HBV polymerase

Pregenomic RNARe-entry

Pre-core proteinCore protein

HBeAg

NUCLEUS

Nuclear transport

HBV Life Cycle

HBsAg

VirionSecretory pathway

Covalently closedcircular DNA

cccDNA

Worldwide Distribution of HBV Genotypes

(Fung & Lok, Hepatology 2004;40:790-2)

A

DD

DD Ba

CC

Bj

F

D

E

A

AD

BC

F

FG

H

G

• Sexual

• Parenteral

• Perinatal

HBV: Mode of Transmission HBV: Mode of Transmission

Concentration of HBV In Biological FluidsConcentration of HBV In Biological Fluids

High Moderate Low/Absent

Blood Seminal fluid UrineVaginal secretions StoolsExudates

Saliva Sweat

TearsMaternal milk

N. of Cases of Hepatitis B in Italy, 1987-2005.Source: ISS

2005: dati provvisori

N.

of

cases

0

1000

2000

3000

4000

87 88 89 90 91 92 93 94 95 96 97 98 9920

0020

0120

0220

0320

0420

05

Year

Clinical Evolution of HBV Infection

Acute Infection

90% neonates 25–30% infants

<1% adults

Chronic Hepatitis

Cirrhosis

HCCDeathDecompensation

Inactive Carrier

EASL Consensus Guidelines. J Hepatol 2003;Lok, McMahon. Hepatology 2004 (AASLD Guidelines)

Chronic Infection

15–40%

Fulminant Hepatitis

~0.1%

Transplant

2 - 4%/year

% ?

Risk of Chronic Infection Decreases with Age

Ris

k %

0

25

50

75

100

Neonates Toddlers Children Adults

• Incubation: Mean 60-90 d (range 45-180 d)

• Jaundice:o <5 a., <10%; o 5 a., 30%-50%

• Infezione cronica: <1%-90%: age major factor

• Mortality from chronic liver disease:15%-25%

Hepatitis B – Clinical Presentation

4 8 12 16 20 24 28 32 36 40 52

Virological and Serological Markers of Acute HBV Infection

Jaundice Symptoms

ALT HBeAg Anti-HBe

Anti-HBc

Anti-HBs

IgM anti-HBc

HBsAg

Weeks after Exposure

Tit

re

HBV-DNA

Weeks after ExposureWeeks after Exposure

Tit

reTit

re

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 mos.)

HBeAg

Chronic(yrs)

anti-HBe

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

Chronically-Evolving Hepatitis B

HBV DNA

AdulthoodTransmission

Resolved HepatitisHBsAg negative

HBeAg neg CHBHBeAg-HBsAg+Anti-HBe+HBV DNA ↑↑ ALT↑↑

Inactive CarrierHBeAg-HBsAg+Anti-HBe+HBV DNA ↓Normal ALT

HBeAg positive CHBHBsAg+HBe Ag+HBV DNA↑↑↑ALT↑↑

(Patient age; gender; BMI,duration of hepatitis, baseline ALT, histology, HBV DNA load, genotype)

Immune toleranceHBsAg+HBeAg+HBV DNA↑↑↑ALT normal

Progressive Liver DamageCirrhosisHCCLiver failure Death from liver disease

PerinatalTransmission

SeroconversionReactivation

Natural Course of Chronic HBV Infection

Natural History of Inactive HBsAg CarriersIncidence per 100 person years of major events

De Franchis1993

Bellentani2002

Manno2004

Hsu2002

• area Europe Europe Europe Asia

• Number of patients 68 46 296 189

• Median follow-up (yrs) 10 9 29 8

• HCC 0 0 0.02 0.19

• Liver-related death 0 0 0.01 0

• HBsAg loss 1.0 0.9 1.0 0.6

ALT Profiles in Chronic HBV Infection

Series1

0

100

200

300

400

Series1

0

100

200

300

400

ALT

IU/l

ALT

IU/l

Years

Factors Influencing Progression of HBV Infection

• Demographics:– Age– Gender– Family history (HCC)

• Environmental/Metabolic:– Alcohol– Aflatoxin– NAFLD (?)– Tobacco (?)

• Host immune response• Viral factors

5-year rate of HCC: 9%5-year rate of decompensation: 16%.5-year survival: 86%5-year survival after decompensation: 28%.

Natural History of HBV Cirrhosis

G. Fattovich, Seminars Liver Disease 2003

HCC Is Common and Increasing

• 5th most common cancer in men and 7th in women• Most of the burden (85%) borne in developing countries.

Incidence:– >10/100,000: Sub-Saharan Africa, South-East Asia– 5-10/100,000: Eastern, Southern & Western Europe, South Africa,

Caribbean– <5/100,000: Northern Europe, the Americas, North Africa, Australia, New

Zealand

• Peak at 70 yrs of age, rare <40• HCV-related HCC fastest rising cause of cancer-related deaths

in the Western world

World Health Organization. Available at: http://www.who.int/whosis/en/. Accessed October 6, 2008.

REVEAL: High HBV Viral Load is Associated with Increased Incidence of Cirrhosis

Iloeje UH, et al. Gastroenterology 2006;130:678–686

All participants (n=3,582)

.4

.3

.2

.1

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Cu

mu

lati

ve i

nci

den

ce l

iver

cir

rho

sis

Year of follow-up

Baseline HBV DNA Level≥106

≥104–<105

103–<104

300–103

<300

REVEAL: High HBV Viral Load is Associated with Increased Incidence of HCC

Chen CJ, et al. JAMA 2006; 295:65–73

All participants (n=3,653)

.14

.1

.06

.04

.02

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Cu

mu

lati

ve i

nci

den

ce o

f H

CC

Year of follow-up

≥106

≥104–<105

103–<104

300–103

<300

Baseline HBV DNA Level.16

.12

.08

Decision to treat

IFN(PegIFN alfa-2a)

Nucleos(t)ideanalogues

Treatment Options in Chronic Hepatitis B

Potency and Genetic Barrier for Resistance of Current Anti-HBV Drugs

LAM FTC

LDTETV TDF

ADF

IFN

Pot

ency

Genetic Barrier

Ruiz-Sancho A, et al. Expert Opinion Biol Ther 2007

0%0% 0%

24% 49% 67%38%

0% 3% 11% 18%

70%

4% 17%

29%

0.2% 1.2% 1.2% 0.5% 1.2% 1.2%

Yr 3 Yr 4Yr 2Yr 1 Yr 5 Yr 6

LAM

ETVLdT

ADV

TDF

EASL. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. AASLD 2009. Abstract 483.

Not head-to-head trials; different patient populations and trial designs

Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naϊve Patients

Drug Generation

1st

2nd

3rd

Natural Life Cycle of a Chronic HBsAg Carrier

HBsAg+ Mother

Infected

Neonate

Chronic HBsAg

Carrier

Female

Male

X

1989 1991 19930

2

4

6

8

10

12

Year studied

Pre

vale

nce (

%)

10.5

6.3

1.7

Prevalence of HBsAg Carriers among 6 Year-OldChildren in Taiwan

Hsu et al. J Infect Dis 1999;179:367-70

Avera

ge a

nn

ual

incid

en

ce/1

00,0

00

0 -

0.2 -

0.4 -

0.6 -

0.8 -

1 -

0.70

0.57

0.36

Chang et al. N Engl J Med 1997;336:1855-9

Average Annual Incidence of Hepatocellular Carcinoma in Children Aged 6-14 years before and after Introduction of the

HBV Immunisation Programme

1981-1986 1986-1990 1990-1994

Years

24

12

0

Years

Age

0

12

24

Italian Strategy for Hepatitis B Vaccination

20031991 STOP

Vaccination of teens

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

05

1015202530354045

0-14

15-24

> 24

Incidence of Acute Hepatitis B by Age ClassSEIEVA, 1985-2003

VaccinazioneAnti-HBV

Impact of Hepatitis B Vaccination

1981 1990 2001

Prevalence of anti-HBc in military recruits

Journal of Hepatology 1997

16.8%

5.8%

<1%

HBsAg

RNA

antigen

Hepatitis D (Delta) Virus

Prevalence of HDVHigh

Intermediate

Low (ITALY ~6%, 2000)

Very low

No Data

Taiwan

Pacific Islands

Geographical Distribution of HDV Infection

• Satellite virus: requires HBV for replication

• Percutaneous exposure– IVDU

• Mucosal exposure– Sexual contacts

HDV: Replication and Mode of Transmission

• HBV-HDV Coinfection – Severe acute hepatitis– Relatively low risk of chronic evolution

• HDV Superinfection of a Chronic HBV Carrier– High probability of chronic HBV-HDV co-

infection– High probability of developing severe chronic

liver disease

Hepatitis D – Clinical Presentation

Time after ExposureTime after Exposure

Tit

reTit

re anti-HBs

Symptoms

ALT ↑

Total anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

Virological and Serological Profile of HBV–HDV Coinfection

Time after ExposureTime after Exposure

Tit

reTit

re

Symptoms

ALTTotal anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

Virological and Serological Profile of HBV–HDV Superinfection

HDV: Prophylaxis

• Primary prophylaxis

• Hepatitis B vaccine prevents HDV infection

About 170 Millions of Hepatitis C Carriers Woldwide

3-4 millions new infections/year

World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html.

> 10%2.5%-10%

1%-2.50%Prevalence

NA

Distribution of Chronic HCV Carriers in Geographical Areas

62

The prevalence of chronic HCV carriers differs in various countries (0.4-22%).• Italy shows an intermediate value: 1-2%

• Areas of very high endemicity (>35%, South) • North-South gradient

• Cohort effect caused by epidemics due to injecting therapies in the 40’s and 50’s.

• I.V. treatment of Schistosomiasis in Japan (1920-40)

‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘080

0.5

1

1.5

2

2.5HCV Infection: Incidence/100,000

persons year

0.4

Courtesy from A. Mele, ISS; SEIEVA 1991-2008

Year

Age-Specific Prevalence of anti-HCV by Age Class and Geographical Area in Italy

< 30 30-39 40-49 50-590

5

10

15

20

25

30

35

NordNorth

Centro

Sud

> 60

Age class

%

Residual Risk/Year to Acquire HCV Infection Following NAT Screening

(Cases/106 blood units, 95% C.I. )

Società Italiana di Medicina Trasfusionale e di Immunoematologia – Settore Ricerca & SviluppoGruppo Italiano per lo Studio delle Malattie Trasmissibili con la Trasfusione

2004 2005 2006 2007 2008 2009

HCV0.3

(0.1-0.6)0.2

(0.1-0,4)0.2

(0.1-0.3)0.2

(0.1-0.3)0.1

(0.1-0.2)0.1

(0.1-0.2)

HBV - -1.6

(0.3-1.8)1.9

(0.9-2.7)1.6

(0.6- 2.1)1.6

(0.6-2.1)

Populations at Risk of HCV Infection

66

• 27.000-29.000 new cases diagnosed every year in the EU.• M/F= 2/1.• Populations at risk: IVDU, HIV-infected persons, prison

inmates, haemodialysis patients, migrants from high endemicity countries, surgery.

• Sexual transmission is rare although promiscuity is considered a risk factor.

Risk of HCV Infection Following Invasive Procedures

Type of surgery OR (95% CI)

Minor 3.0 (1.5-6.1)O & G 12.1 (1.2-5.5)Orthopaedic 3.5 (1.6-7.5)Abdominal 7.0 (3.2-14.9)Cardiovascular 4.1 (1.4-11.9)Oral 2.8 (1.4-5.7)Ophtalmologic 5.2 (1.1-23.2)Urologic 0.8 (0.1-4.8)Other 3.3 (1.9-5.7)Endoscopy 2.1 (1.2-3.6)

Hepatitis C Virus Genome

C E1 E2 NS4bNS2 NS3 NS5a NS5b5’ UTR

p7 NS4a

? ?Nucleocapsid

Envelope

NS3proteasecofactor

NS2-NS3auto-

proteaseSerine

protease,helicase,NTPase

?(binds to PKR)

RNA-dependentRNA-polymerase

3’ UTR

Phylogenetic Tree of HCV and its Major Genotypes

Nakano et al. Liver Int 2012;32:339-45

A Traditional HCV Vaccine Is Difficult to Produce

6 major genotypes, several subtypes, infinite possible variants!

Hepatitis C: Clinical Presentation

• Incubation Mean 30-50 d (15-150 d)

• Jaundice Rare (<10%)

• Chronic evolution 60%-80% (asymptomatic)

• Cirrhosis 10%-20%

• Liver-related mortality 1%-5% (after >20 yrs)

Markers of HCV Infection

Self-limited acute hepatitis

Symptoms +/-

Time after Exposure

Titr

e

anti-HCV

ALT

0 1 2 3 4 5 6 1 2 3 4YearsMos.

HCV RNA

Chronically Evolving Acute Hepatitis

Symptoms+/-

Time after ExposureTi

tre

Anti-HCV

ALT

0 1 2 3 4 5 6 1 2 3 4YearsMos.

HCV RNA

Female sex, young age at infection

(Fast)

(Slo

w)

Pro

gre

ssio

n

Normal Liver

AcuteInfectio

n

Chronic Infection(60-80%)

Chronic Hepatiti

s

Cirrhosis

(20 %)

HCC(1-4%/

yr)

20 years

30 years

Alcohol, steatosis, IR, coinfections, age>45 yrs, male sex

Modified from Lauer et al., N Engl J Med 2001;345:41-52.

IL28B Polymorphism Is a Powerful Host Prognostic Marker in Chronic Hepatitis C

rs12979860

Ge et al., Nature 2009;461:399-401

IL28B locus SNPs associated with spontaneous and treatment-induced HCV clearance in genotype 1 chronic hepatitis

Genetic Variation in IL28B and Spontaneous HCV Clearance

% of HCV clearance by rs12979860 snp

Thomas DL et al., Nature 2009;461:798–801

Factors Influencing the Development of Fibrosis

• Age > 40 years

• Male sex

• Alcohol (oxydative stress)

• Metabolism (steatosis, IR, metabolic syndrome)

• Coinfections (HIV or HBV)

• Iron overload (?)

Broad Differences in HBV and HCV Replication

H

HBV1,2

Host cell

cccDNAHost DNA

Integrated DNA

Nucleus

H

HCV1,3

Host cell

Host DNA

Nucleus

HCV RNA

Definitive viral clearance and SVR

Long-term suppression of viral replication

Adapted from 1. Soriano V, et al. J Antimicrob Chemother 2008;62:1-4. 2. Locarnini S and Zoulim F. Antiviral Therapy 2010;15 (suppl 3):3-14. 3. Sarrazin C and Zeuzem S. Gastroenterology 2010;138:447-462.

• Prevent liver decompensation

• Prevent liver cancer

• Prevent death fom end-stage liver disease

What Does Recovery Mean for HCV Infection?

Treatment of Chronic Hepatitis C

1991 20010

20

40

60

80

100

8-12

SV

R (

%)

15-20

38-43

25-30

50-60

1995 1998

Standard interferon (6 mos)[1]

Standardinterferon

(12-18 mos)[2,3]

Interferon/ribavirin

(6-12 mos)[3,4] PegIFNmonotherapy(6-12 mos)[5,6]

PegIFN/ribavirin(6-12 mos)[6,7]

2011

70-75

PI + PegIFN/RBV(6-12 mos)[8-10]

1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

Standard Dual Treatment of HCV InfectionPeginterferon + Ribavirin

0

20

40

60

80

100

1 2-3Genotype

Sust

aine

d Vi

rolo

gica

l Re

spon

se (%

)

PegIFN-2a/RBVPegIFN-2b/RBV

Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

0

10

20

30

40

50

60

70

80

90

Genotype 1(337 pts)

Genotype 2(165 pts)

Genotype 3(95 pts)

Genotype 4(30 pts)

rs12979860 C/C

rs12979860 C/Tor T/T

SVR

%

103 234 63 102 40 55 6 24

67%

33%

79%81%

70% 71%

83%

29%

p 0.00001

p N.S.

p N.S. p 0.03.

IL28B SNPs in 670 Patients with Chronic Hepatitis C: the HCV-AIFA Italian Study

HCV Replication and Directly-Acting Anti-Virals

NS3/4 Protease

Inhibitors

NS5B Polymerase Inhibitors

Active site“catalytic triad“ NS4A

Zn finger

HCV Protease and Co-Factor NS4A

PI Registered for Triple Therapy of HCV G1 Infection in Combination with PEG-IFN + RBV

• Telaprevir: NS3/4A• Boceprevir: NS3

– High risk of resistance if used without PEG-IFN/RBV backbone

Percent SVR in Patients With Genotype 1 Naïve and Non-Responders to SOC

0

20

40

60

80

100

SV

R (

%)

Naïve Experienced

38-44[1-2]

17-21[3-4]

SOC

0

20

40

60

80

100

SV

R (

%)

63-75[1-2]

59-66[3-4]

SOC + Telaprevir or Boceprevir

1. Poordad F, et al. N Engl J Med 2011;364:1195-206. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-17. 4. Foster GR, et al. APASL 2011. Abstract 1529.

Naïve Experienced

Active Site

The HCV Polymerase Has the Shape of a Closed Right Hand

Thumb

Palm

Fingers

Combination Therapies

PEG-IFN

Ribavirina

InibitoriProteasi

Inibitori Polimerasi