Viral Hepatitis A-E, including currently approved triple therapy for hepatitis C. For undergraduates and young trainees in GI and Infectious Diseases.

1. 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

2. HAV

3. Geographical Distribution of HAV Infection
Prevalence of anti-HAV
High
Intermediate
Low
Very low

4. n. of cases
Cases of Hepatitis A in Italy, 1987-2005
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
Year

5. HAV: Mode of Transmission
• Person-to-Person contacts (intrafamiliar,
sexual, kinder garden)
• Contaminated food or water (raw seafood,
clams, mussels)
• Blood exposure (very rare: blood transfusion)

6. HAV in Biological Fluids
Stool
Serum
Saliva
Urine
100
102
104
106
Infectious doses/ml
Source: Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
108
1010

7. HAV Infection: Typical Serological Profile
Symptoms
Anti-HAV IgG
Titre
ALT
HAV
Faeces
0
1
anti-HAV IgM
2
3
4
5
Months after exposure
6
12
24

8. 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

9. 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

10. 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

11. HEV

12. Geographical Distribution of Cases of Hepatitis E
Cornwall
Sporadic cases in Spain, Italy, France, US…

13. Epidemiology of HEV Infection
• 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)

14. 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
correlated with human HEV strains.
and
epidemiologically
• 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

15. HEV Infection: Typical Serological Profile
Symptoms
ALT
Titre
IgG anti-HEV
IgM anti-HEV
Virus in stools
0
1
2
3
4
5
6
7
8
Weeks after Exposure
9
10
11
12
13

16. HEV: Clinical Evolution
Acute Illness
Immune
suppression?
Chronic Infection
(prevalence unkown)
Recovery
20% pregnant
women
Fulminant
Hepatitis
Death

17. Hepatitis E: Clinical Presentation
• Incubation:
Mean 40 d (range 15-60 d)
• Mortality:
1%-3%, pregnant 15%-25%
• Severity of symptoms:
Increase with age
• Cronic evolution:
Rare (immunosuppressed +++)

18. 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.

19. General Prophylactic Measures for Travellers
to Countries Where HEV Is Endemic
• 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

20. Hepatitis B:
Essential Epidemiology
 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
Source: WHO

21. 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

22. Excess Mortality Associated with
Chronic HBV Infection
Survival curves of total mortality stratified by HBsAg status
1.0
Survival
HBsAg(-) n=19,655
HBsAg(+) n=4,155
0.9
P<0.01
0.8
0
1
2
3
4
5
6
7
Year of Follow-Up
Iloeje U, et al. Gastroenterology 2006; 130:678–686
8
9
10
11
12

23. Crude Mortality Rate by Sex and HBsAg Status
in Haimen City, China
Mortality Rate per 100,000 PYs
1500
1000
Liver deaths
HCC
CLD
500
0
HBsAg+
Males
Chen G, et al., Int J Epidemiol 2005;34:132-7
HBsAg+
Females
HBsAgMales
HBsAgFemales

24. HBV

25. HBV Ultrastructure
DNA polymerase
HBV DNA
Envelope (HBsAg)
Nucleoproteine
core (HBcAg)
HBsAg
HBeAg

26. HBV Life Cycle
Covalently closed
circular DNA
cccDNA
Nuclear transport
Binding and
penetration
cccDNA
Uncoating
NUCLEUS
Re-entry
MINICHROMOSOME
Pregenomic RNA
HBV RNA
HBV
polymerase
Envelope protein
L, M, S
Pre-core
protein
Core protein
Virion
Secretory
pathway
HBsAg
HBeAg

27. Worldwide Distribution of HBV Genotypes
F
A B
C
A
G
D
D
H
D
G
D
E
F
D
D
C
Ba
F
C
Bj
A
(Fung & Lok, Hepatology 2004;40:790-2)

28. HBV: Mode of Transmission
• Sexual
• Parenteral
• Perinatal

29. Concentration of HBV In Biological Fluids
High
Blood
Exudates
Moderate
Low/Absent
Seminal fluid
Vaginal secretions
Saliva
Urine
Stools
Sweat
Tears
Maternal milk

30. N. of Cases of Hepatitis B in Italy, 1987-2005.
Source: ISS
N. of cases
4000
3000
2000
1000
0
Year
2005: dati provvisori

31. Clinical Evolution of HBV Infection
Acute Infection
90% neonates
~0.1%
25–30% infants
<1% adults
%?
Chronic Infection
15–40%
Fulminant Hepatitis
Chronic Hepatitis
Inactive Carrier
Cirrhosis
2 - 4%/year
Decompensation
EASL Consensus Guidelines. J Hepatol 2003;
Lok, McMahon. Hepatology 2004 (AASLD Guidelines)
Death
Transplant
HCC

32. Risk of Chronic Infection Decreases with Age
100
Risk %
75
50
25
0
Neonates
Toddlers
Children
Adults

33. Hepatitis B – Clinical Presentation
• 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%

34. Virological and Serological Markers of Acute HBV Infection
Jaundice
Symptoms
HBeAg
ALT
Anti-HBe
Titre
HBV-DNA
Anti-HBc
HBsAg
Anti-HBs
IgM anti-HBc
4
8 12 16 20 24 28 32 36 40
Weeks after Exposure
52

35. Chronically-Evolving Hepatitis B
HBV DNA
Acute
(6 mos.)
Chronic
(yrs)
HBeAg
anti-HBe
HBsAg
Titre
Total anti-HBc
IgM anti-HBc
0
4
8
12 16 20 24 28 32 36
Weeks after Exposure
52
years

36. Natural Course of Chronic HBV Infection
Perinatal
Transmission
Immune tolerance
HBsAg+
HBeAg+
HBV DNA↑↑↑
ALT normal
Adulthood
Transmission
HBeAg positive CHB
HBsAg+
HBe Ag+
HBV DNA↑↑↑
ALT↑↑
(Patient age; gender; BMI,
duration of hepatitis, baseline ALT,
histology, HBV DNA load, genotype)
Progressive Liver Damage
Cirrhosis
HCC
Liver failure
Death from liver disease
Resolved Hepatitis
HBsAg negative
Seroconversion
Reactivation
Inactive Carrier
HBeAgHBsAg+
Anti-HBe+
HBV DNA ↓
Normal ALT
HBeAg neg CHB
HBeAgHBsAg+
Anti-HBe+
HBV DNA ↑↑
ALT↑↑

37. Natural History of Inactive HBsAg Carriers
Incidence per 100 person years of major events
De Franchis
1993
Bellentani
2002
Manno
2004
Hsu
2002
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
1.0
0.9
1.0
0.6
• area
• HBsAg loss

38. ALT Profiles in Chronic HBV Infection
400
ALT IU/l
300
200
100
0
400
ALT IU/l
300
200
100
0
Years

39. Factors Influencing Progression of HBV
Infection
• Demographics:
– Age
– Gender
– Family history (HCC)
• Environmental/Metabolic:
–
–
–
–
Alcohol
Aflatoxin
NAFLD (?)
Tobacco (?)
• Host immune response
• Viral factors

40. Natural History of HBV Cirrhosis
5-year rate of HCC:
9%
5-year rate of decompensation:
16%.
5-year survival:
86%
5-year survival after decompensation: 28%.
G. Fattovich, Seminars Liver Disease 2003

41. 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.

43. REVEAL: High HBV Viral Load is Associated with
Increased Incidence of Cirrhosis
Cumulative incidence liver cirrhosis
All participants (n=3,582)
Baseline HBV DNA Level
≥106
≥104–<105
103–<104
300–103
<300
.4
.3
.2
.1
0
0
1
2
3
4
5
6
7
8
Year of follow-up
Iloeje UH, et al. Gastroenterology 2006;130:678–686
9
10
11
12
13

44. REVEAL: High HBV Viral Load is Associated with
Increased Incidence of HCC
All participants (n=3,653)
Cumulative incidence of HCC
.16
Baseline HBV DNA Level
≥106
≥104–<105
103–<104
300–103
<300
.14
.12
.1
.08
.06
.04
.02
0
0
1
2
3
4
5
6
7
8
Year of follow-up
Chen CJ, et al. JAMA 2006; 295:65–73
9
10
11
12
13

45. Treatment Options in Chronic Hepatitis B
Decision to treat
IFN
(PegIFN alfa-2a)
Nucleos(t)ide
analogues

46. Potency and Genetic Barrier for Resistance of
Current Anti-HBV Drugs
Potency
LDT
LAM
ETV
TDF
FTC
ADF
IFN
Genetic Barrier
Ruiz-Sancho A, et al. Expert Opinion Biol Ther 2007

47. Cumulative Rates of Resistance With Oral Agents
in Nucleos(t)ide-Naϊve Patients
Not head-to-head trials; different patient populations and trial designs
Yr 1
Yr 2
Yr 3
Yr 4
Yr 5
Yr 6
Drug
Generation
1st
2nd
3rd
LAM
24%
38%
49%
67%
70%
ADV
0%
3%
11%
18%
29%
LdT
ETV
TDF
4%
0.2%
0%
17%
0.5%
0%
1.2%
0%
1.2%
1.2%
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.
1.2%

48. Natural Life Cycle of a Chronic HBsAg Carrier
HBsAg+
Mother
X
Infected
Neonate
Female
Chronic HBsAg
Male
Carrier

49. Prevalence of HBsAg Carriers among 6 Year-Old
Children in Taiwan
Prevalence (%)
12
10.5
10
8
6.3
6
4
1.7
2
0
1989
1991
Year studied
Hsu et al. J Infect Dis 1999;179:367-70
1993

50. Average Annual Incidence of Hepatocellular Carcinoma in Children
Aged 6-14 years before and after Introduction of the
HBV Immunisation Programme
Average annual
incidence/100,000
10.8 -
0.70
0.57
0.6 0.36
0.4 0.2 01981-1986
1986-1990
Years
Chang et al. N Engl J Med 1997;336:1855-9
1990-1994

51. Italian Strategy for Hepatitis B Vaccination
Age
24
24
12
12
0
0
1991
Years
2003 STOP
Vaccination of teens

52. Incidence of Acute Hepatitis B by Age Class
SEIEVA, 1985-2003
45
40
35
30
25
20
15
10
5
0
Vaccinazione
Anti-HBV
0-14
15-24
> 24

53. Impact of Hepatitis B Vaccination
Prevalence of anti-HBc in military recruits
16.8%
5.8%
<1%
1981
Journal of Hepatology 1997
1990
2001

54. Hepatitis D (Delta) Virus
antigen
HBsAg
RNA

55. Geographical Distribution of HDV Infection
Taiwan
Pacific Islands
Prevalence of HDV
High
Intermediate
Low (ITALY ~6%, 2000)
Very low
No Data

56. HDV: Replication and Mode of Transmission
• Satellite virus: requires HBV for replication
• Percutaneous exposure
– IVDU
• Mucosal exposure
– Sexual contacts

57. Hepatitis D – Clinical Presentation
• 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

58. Virological and Serological Profile of HBV–HDV Coinfection
Symptoms
Titre
ALT ↑
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure

59. Virological and Serological Profile of HBV–HDV Superinfection
Symptoms
Total anti-HDV
Titre
ALT
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure

60. HDV: Prophylaxis
• Primary prophylaxis
• Hepatitis B vaccine prevents HDV infection

61. About 170 Millions of Hepatitis C Carriers
Woldwide
3-4 millions new infections/year
Prevalence
> 10%
2.5%-10%
1%-2.50%
NA
World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html.

62. Distribution of Chronic HCV Carriers in
Geographical Areas
 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)
62

63. 2.5
HCV Infection: Incidence/100,000
persons year
2
1.5
1
0.5
0.4
0
‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘08
Year
Courtesy from A. Mele, ISS; SEIEVA 1991-2008

64. Age-Specific Prevalence of anti-HCV by Age Class
and Geographical Area in Italy
% 35
Sud
30
25
20
Centro
15
10
Nord
5
0
< 30
> 60
30-39
40-49
Age class
50-59

65. Residual Risk/Year to Acquire HCV Infection
Following NAT Screening
(Cases/106 blood units, 95% C.I. )
2004
HCV
HBV
2005
2006
2007
2008
2009
0.3
0.2
0.2
0.2
0.1
0.1
(0.1-0.6)
(0.1-0,4)
(0.1-0.3)
(0.1-0.3)
(0.1-0.2)
(0.1-0.2)
-
-
1.6
1.9
1.6
1.6
(0.3-1.8)
(0.9-2.7)
(0.6- 2.1)
(0.6-2.1)
Società Italiana di Medicina Trasfusionale e di Immunoematologia – Settore Ricerca & Sviluppo
Gruppo Italiano per lo Studio delle Malattie Trasmissibili con la Trasfusione

66. Populations at Risk of HCV Infection
• 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.
66

67. Risk of HCV Infection Following Invasive Procedures
Type of surgery
OR (95% CI)
Minor
O&G
Orthopaedic
Abdominal
Cardiovascular
Oral
Ophtalmologic
Urologic
Other
Endoscopy
3.0 (1.5-6.1)
12.1 (1.2-5.5)
3.5 (1.6-7.5)
7.0 (3.2-14.9)
4.1 (1.4-11.9)
2.8 (1.4-5.7)
5.2 (1.1-23.2)
0.8 (0.1-4.8)
3.3 (1.9-5.7)
2.1 (1.2-3.6)

68. Hepatitis C Virus Genome
5’ UTR
C
E1
E2
Nucleocapsid
Envelope
p7
NS2
NS3
?
NS2-NS3
autoprotease
NS4a
NS4b NS5a NS5b
NS3
protease
cofactor
Serine
protease,
helicase,
NTPase
?
3’ UTR
RNA-dependent
RNA-polymerase
?
(binds to PKR)

69. Phylogenetic Tree of HCV and its Major Genotypes
Nakano et al. Liver Int 2012;32:339-45

70. A Traditional HCV Vaccine Is Difficult to Produce
6 major genotypes, several subtypes, infinite possible variants!

71. 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)

72. Markers of HCV Infection
Self-limited acute hepatitis
Chronically Evolving Acute Hepatitis
Anti-HCV
anti-HCV
Symptoms+/-
HCV RNA
HCV RNA
Titre
Titre
Symptoms +/-
ALT
ALT
0
1
2
3 4
Mos.
5
6
1
2 3
Years
Time after Exposure
4
0
1
2
3 4
Mos.
5
6
1
2
3 4
Years
Time after Exposure

73. (Slow)
Female sex, young age at infection
Progression
30 years
Normal
Liver
Acute
Infection
Chronic
Infection
(60-80%)
Chronic
Hepatitis
Cirrhosis
(20 %)
(Fast)
20 years
Alcohol, steatosis, IR, coinfections,
age>45 yrs, male sex
Modified from Lauer et al., N Engl J Med 2001;345:41-52.
HCC
(1-4%/yr)

74. IL28B Polymorphism Is a Powerful Host Prognostic Marker in
Chronic Hepatitis C
rs12979860
IL28B locus SNPs associated with spontaneous and treatment-induced
HCV clearance in genotype 1 chronic hepatitis
Ge et al., Nature 2009;461:399-401

75. Genetic Variation in IL28B and Spontaneous HCV Clearance
% of HCV clearance by rs12979860 snp
Thomas DL et al., Nature 2009;461:798–801

76. 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 (?)

77. Broad Differences in HBV and HCV Replication
HBV1,2
Host cell
Host cell
cccDNA
Host DNA
HCV1,3
H
Host DNA
HCV RNA
H
Integrated DNA
Nucleus
Long-term suppression
of viral replication
Nucleus
Definitive viral clearance
and SVR
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.

78. What Does Recovery Mean for HCV Infection?
• Prevent liver decompensation
• Prevent liver cancer
• Prevent death fom end-stage liver disease

79. Treatment of Chronic Hepatitis C
PI + PegIFN/RBV
(6-12 mos)[8-10]
100
70-75
SVR (%)
80
PegIFN/ribavirin
(6-12 mos)[6,7]
Interferon/
ribavirin
(6-12 mos)[3,4]
60
40
20
Standard
interferon
(6 mos)[1]
Standard
interferon
(12-18 mos)[2,3]
38-43
50-60
PegIFN
monotherapy
(6-12 mos)[5,6]
25-30
15-20
8-12
0
1991
1995
1998
2001
2011
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;358:958965. 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.

80. Standard Dual Treatment of HCV Infection
Sustained Virological
Response (%)
Peginterferon + Ribavirin
100
80
60
PegIFN- 2a/RBV
PegIFN- 2b/RBV
40
20
0
1
2-3
Genotype
Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

81. IL28B SNPs in 670 Patients with Chronic Hepatitis C:
the HCV-AIFA Italian Study
p N.S.
90
80
SVR %
70
p 0.00001
79%
81%
70%
67%
p 0.03.
p N.S.
83%
71%
60
50
rs12979860 C/C
40
33%
29%
30
rs12979860 C/T
or T/T
20
10
103
234
0
Genotype 1
(337 pts)
63
102
Genotype 2
(165 pts)
40
55
Genotype 3
(95 pts)
6
24
Genotype 4
(30 pts)

82. HCV Replication and Directly-Acting Anti-Virals
NS5B
Polymerase
Inhibitors
NS3/4
Protease
Inhibitors

83. HCV Protease and Co-Factor NS4A
Active site
“catalytic triad“
NS4A
Zn finger

84. 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 PEGIFN/RBV backbone

85. Percent SVR in Patients With Genotype 1 Naïve and
Non-Responders to SOC
100
100
SOC
80
80
SOC + Telaprevir or Boceprevir
63-75[1-2]
SVR (%)
SVR (%)
59-66[3-4]
60
38-44[1-2]
40
60
40
17-21[3-4]
20
20
0
Naïve
Experienced
0
Naïve
Experienced
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.

86. The HCV Polymerase Has the Shape of a Closed Right Hand
Thumb
Fingers
Active Site
Palm

87. Combination Therapies
Ribavirina
PEG-IFN
Inibitori
Proteasi
Inibitori
Polimerasi