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 Orthohepevirus 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

Hepatitis E: A True Story• In 1983, Dr. Balayan was investigating an outbreak of non-A, non-B

hepatitis among Soviet soldiers in Afghanistan. Though he wanted to bring samples back to his Moscow laboratory, he lacked refrigeration. So he made a shake of yogurt and an infected patient’s stool, drank it, went back to Moscow, and waited until a few weeks later when he developed symptoms of hepatitis.

• He then started collecting and analyzing his own samples. In these he found a new virus, similar to HAV by EM, that produced liver injury in laboratory animals. Dr. Balayan already had antibodies against the HAV which did not protect him from the infection.

Balayan MS, et al. Intervirology 1983;20:23–31.

The Hepatitis E VirusFamily: Hepeviridae, Genus: Hepevirus

• 1/3 of world population exposed to HEV• Mostly transmitted via fecal-oral route, rarely by blood

products. HEV RNA per blood donation: 1:1,430-1:7,040• Usually acute self-limiting disease• Case fatality ratio: 1-3% (pregnant women up to 25%)• Genotype 1: Asia, Africa• Genotype 2: Mexico, Africa• Genotype 3: Western countries• Genotype 4: Asia, Europe

Geographic Distribution of HEV

www.cdc.gov/hepatitis/HEV/HEVfaq.htm

Dendrogram Based on Full-Length Sequences of HEV Strains

Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138

Piscihepevirus

Two Distinct Clinico-Epidemiological Patterns

• In areas of poor sanitation, HEV1 and HEV2 are transmitted between humans by the fecal-oral route, usually via contaminated water. This results in frequent sporadic cases and occasional large outbreaks.– Excess mortality in pregnant women

• In developed countries, HEV3 and HEV4 are sporadically transmitted zoonotically from animal reservoirs through consumption of undercooked pork or game meat and shellfish. – Elderly males are at higher risk for unexplained reasons.– HEV3 may cause chronic infection

HEV Markers

Incubation 2-6 wks

Seroprevalence of anti-HEV IgG among Blood Donors(0.25 WHO U/mL)

• High sensitivity assays show prevalences of:– 52% in SW France1

– 29% in Germany2

– 27% in the Netherlands3

– 16% in SW England4

1. Mansuy JM, et al. Emerg Infect Dis 2013;17:2309–2312. 2. Wenzel JJ, et al. J Infect Dis 2013;207:497–500.3. Slot e, et al. Euro Surveill 2013;18:20550. 4. Dalton HR, et al. Eur J Gastroenterol Hepatol 2008;20:784–790.

Extrahepatic Manifestations of HEV

• Neurological disorders• Kidney injury

• Pancreatitis (HEV1)• Haematological disorders:

– Aplastic anaemia– Thrombocytopaenia

Neurological Disorders

• Retrospectively found in 7/126 (5.5%) of patients with HEV infection: 3 immunocompetent, 4 immunosuppressed (3 SOT, 1 HIV)1

• HEV RNA in CSF from all patients: QS compartmentalization (neurotropic variants?)2

• Described in HEV1 and acute and chronic HEV3– Guillain-Barré syndrome – Bell’s palsy– Neuralgic amyotrophy – Acute transverse myelitis – Meningoencephalitis

Reviewed in Kamar N, et al. Clin Microbiol Rev 2014:27:116-38 1. Kamar N, et al. Emerg Infect Dis 2011;17:173–9. 2. Kamar N, et al. Am J Transplant 2010;10:1321–4.

Chronic Hepatitis E• No standard definition• It may be defined by analogy with other forms of viral

hepatitis, i.e.: Elevated liver enzymes and detectable HEV RNA in serum and/or stools for 3-6 months from diagnosis

• Caused by HEV3 only• Reported in immunocompetent and immunocompromised

patients:• Transplant recipients• HIV-positive persons• Patients with haematological malignancies

Hepatitis E Virus (HEV) Concentration during Ribavirin Therapy.

Kamar N et al. N Engl J Med 2014;370:1111-1120.

Hepatitis E Virus (HEV) Concentration during Ribavirin Therapy

Phase III Vaccination Trial (HEV239, Hecolin, Xiamen Innovax Biotech, Xiamen, China)

(NIH clinicaltrial.gov NCT01014845)

Placebo Vaccinees

n 56,302 56,302

Per-protocol analysis (3 doses) 48,663 (86%) 48,693 (86%)

Developed HE (12-month FU) 15 0

Efficacy 100% (95% CI 72.1 – 100.0)AE: mild, no SAE

ZHU et al, Lancet 2010;376:895-902

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

Acute Infection

Chronic Infection Cirrhosis Death

1. Torresi, J, Locarnini, S. Gastroenterology. 2000.2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995.3. Moyer, LA, Mast, EE. Am J Prev Med. 1994.4. Perrillo, R, et al. Hepatology. 2001.

5%-10% of chronic HBV-infected individuals1

Liver Failure (Decomp.)

30% of chronic HBV-infected individuals1

• >90% of infected children progress to chronic disease

• <5% of infected immunocompetent adults progress to chronic disease1

23% of patients decompensate within 5 years of developing cirrhosis 3

Liver Cancer (HCC)

Chronic HBV is the 6th leading cause of liver transplantation in the US 4

Liver Transplant

Inactive carrier

3%/yr

3%/yr

Natural History of Hepatitis B Virus Infection

• 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

< <> >HBeAg + (wild) HBeAg - / anti-HBe +

ALT

HBV-DNA

mild CH moderate/severe CH moderate/severe CHHAI < 4

cirrhosis

inactive-carrier state

resolved hepatitis B(HBsAg - / anti-HBs +)

HBeAg-negative CHHBeAg-positive CH

immune tolerance

immune clearance

low or non replicative phase

reactivation phase

cirrhosis

109-1010 cp/ml107-108 cp/ml

<105 cp/ml

>105 cp/ml

Adapted from Wong and Lok. Arch Intern Med 2006

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 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

Therapeutic Strategies for Chronic Hepatitis B

Short-term "curative" treatment

Years

HBV DNA < 2000 IU/ml

ALT < UNL

(anti-HBe)

On treatment response

HBsAg Loss

Follow-up (mo/yrs)IFN

Long-term "suppressive" treatment

HBV DNA undetectable by PCR (<10-15 IU)

NUC

HBsAg loss

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

0

20

40

60

80

100

Pat

ien

ts %

3-5 years ETV for real life, naive CHB patients Resistance summary

93%

Europe1

(3 years)

n=243

96%

Hong-Kong2

(4 years)

n=222

99%

Italy3

(5 years)

n=418

96%

Thailand4

(5 years)

n=535

1) Zoutendijk R et al, Hepatology 2011; 2) Seto WK et al, EASL 2011; 3) Lampertico P et al, EASL 2013; 4) Tanwandee T et al, AASLD 2013

no resistance 1 case

no resistance

1 case

Improvement in Ishak Fibrosis Score with Long-Term ETV

Ishak fibrosis score

Missing

1

2

3

4

5

6

0

n=57P

atie

nts

(n

)

Baseline Week 48 Long term†

10

20

30

40

50

60

0

†Up to 7 years (range: 3–7 years) median time: 280 weeks1*

1. Adapted from Chang T-T, et al. Hepatology 2010;52:886–93; 2. Baraclude® (entecavir) SmPC May 2011.

*In the randomised, controlled studies, patients received 0.5 mg ETV. In the 901 rollover study, patients received 1 mg ETV. Please refer to the SmPC for further information on the treatment regimen.2

Months

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120 132 144

Pa

tie

nts

(%

)

83%

7%

EV regression

EV progression*

Changes of esophageal varices (EV) in 107 compensated cirrhotics LAM±TDF treated for 12 yrs

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120 132 144

Pa

tie

nts

(%

) 10% EV development*

Patients without EV at baseline (n=80)

Patients with F1 EV at baseline (n=27)

> 500 endoscopies over 12 years of NUC treatment

* 6 of 7 progressors (86%) had either LMV-R and/or HCCInvernizzi F. et al, EASL 2014 (poster 1059)

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

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

Hajarizadeh, B. et al. (2013) Nat. Rev. Gastroenterol. Hepatol. 10, 553-562.

185M People Worldwide Have HCV Ab

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

Expanded Classification of HCV into 7 Genotypes and 67 Subtypes

Smith DB, et al. Hepatology 2014;59:318-27

Anti-HCV Prevalence in the General Population: Europe

Italy shows a patchy distribution with a N-S gradient

HCV in Different Italian Regions According to Age

(South)

(Centre)

(North)

AGE GROUPS

AISF 2007

Major Drivers of HCV Infection

Resource-rich settings

Resource-poor settings

Old Infections Iatrogenic(Blood transfusions,

unsafe medical procedures)

Iatrogenic(Unsafe injections

during mass parenteral therapies)

New Infections IVDU• Iatrogenic• Immigration from

resource-poor settings

Iatrogenic(IVDU)

Unsafe Blood and Blood Derivatives Are Major Drivers of the HCV Epidemic

• Before1990, ~10% of all blood recipients were infected with HCV, and up to 99% of hemophiliacs were anti-HCV+.

KOZIOL et al,Ann Intern Med 1986; DONAHUE et al, N Engl J Med 1992MAUSER-BUNSCHOTEN et al, J Med Virol 1995

• Screening assays and use of recombinant clotting factors have virtually eliminated bloodborne transmission of HCV.

SCHREIBER et al, N Engl J Med 1996; PIPE. Semin Hematol 2006;43(suppl2):S23-7

• Current risk (NAT screening): 1/107 transfused unitsSource: Gruppo Italiano per lo Studio delle Malattie Trasmissibili con la Trasfusione, 2009

Community-Acquired HCV An Italian Case-Control Study (n = 500)

Adjusted OR (95% CI)

Blood transfusions 2.9 (1.9 – 4.4)

IVDU 112 (14.6 – 860)

Non-disposable needles within the family 1.6 (1.1 – 2.1)

Non-disposable needles outside the family 3.8 (2.7 – 5.3)

Hospitalization before 1970 2.1 (1.4 – 3.1)

Past TB 3.4 (1.8 – 6.2)

CHIARAMONTE et al, J Hepatol 1996;24:129-34

Any IVDU Paraphernalia – If Shared – Can Transmit HCV

• Needles• Syringes• Cookers (e.g. a spoon)• Filters (e.g. cotton)• Water to mix the drug• Alcohol swabs

HAGAN et al, Am J Public Health 2001;91:42-6

Iatrogenic Transmission of HCV

• Inoculum: size does matter

• <1% transmission after needle sticks• HCV concentration in blood critical

Iatrogenic Transmission of HCV: the Case of Egypt

• Estimated national prevalence:

15% among 15-59 years old

(~6,000,000 infections)

• Estimated incidence: 150,000 cases per year

• The estimated peak of HCV-related mortality will occur in 2020-2030 (~20,000 deaths per year)

BREBAN et al, J Viral Hepatitis 2012; GUERRA et al, J Viral Hepatitis 2012; MILLER et al, Proc Natl Acad Sci USA 2010; DEUFFIC et al, J Hepatol 2006

Mother-to-Infant Transmission of HCV

• First cause of HCV infection in children in developed countries

• Average risk ~4%, leading to < 50,000 new infections per year

• About one third of transmissions occur in utero• Factors predisposing transmission:

– High viral load (but no threshold!)– Untreated HIV– Maternal drug use

RESTI et al, J Infect Dis 2002; YEUNG et al, Hepatology 2001; MOHAN et al, J Pediatr 2007; MOK et al, Arch Dis Child Fetal Neonatal 2005; POLIS et al, Clin Infect Dis 2007; PEMBREY et al, J Hepatol 2005

Transmission of HCV: Sex Is Not an Issue?

• Cross-sectional study of 500 monogamous, heterosexual anti-HIV-negative index cases and their spouses (HCV prevalence 4%)

• Median duration of sex activity of 15 years (range 2-52)• 8,377 person-years of observation• 9 couples had concordant genotypes/serotypes• Sequences were compatible with interspousal

transmission in 3 couples (0.6%)• Incidence rate of HCV transmission by sex: 0.07% per

year (95% CI 0.01-0.13) (1 per 190,000 sexual contacts)• No specific sexual practices were related to HCV

positivity among couples

TERRAULT et al, Hepatology 2013;57:881-9

Sexual Transmission of HCV Does Occur

• HCV spread among HIV-positive MSM has increased, with 85% of infection occurring after 19961

• Incidence of HCV has since increased ~20-fold:– 0.23 (95% credible interval [CrI], .08-.54) per 100 py (1998)2

– 4.09 (95% CrI, 2.57-6.18) per 100 py (2011)2

• Risk factors predisposing to HCV seroconversion:– History of inconsistent condom use2

– Past syphilis2

– Unprotected anal intercourse with multiple partners3

• Reinfection after eradication is possible3

1 VAN DE LAAR et al, Gastroenterology 2009;136:1609-17; 2 WANDELER et al, Clin Infect Dis 2012;55:1408-16; 3 COTTE et al, Gastroenterol Clin Biol 2009;33:977-80

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.

HCV and CryoglobulinaemiaPurpura, Vasculitis

• Occurs in dependent areas

• Deposition of cryoglobulins in small capillaries

• Peripheral neuropathy

• Ulcerations and systemic vasculitis may develop

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

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?

Survival Outcomes for All-Cause Mortality, Liver-Related Mortality or OLT, HCC, and Liver Failure in Patients With Chronic Hepatitis C

and Advanced Hepatic Fibrosis With and Without SVR

Van der Meer AJ, et al. JAMA 2012;308:2584-93

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

Treatment of Chronic HCV Infection: 2014

Which Options?

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNATranslation

andpolyprotein processing

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

Block replication complex formation, assembly

NS5A inhibitors

RNA replication

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotide

Nonnucleoside

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

Issues With PI-Based Therapy

Pill burden Food requirement

CYP3A4PI metabolites

Drug-drug interactions

Resistance

BOC = 12/dayRBV = 4-7/day

TVR = 6/dayRBV = 4-7/day

1-Pill Version of Nuc + NS5A

Treatment-naïve patients (non-cirrhotic)

95

19/20

100

21/21

SOF/LDV SOF/LDV + RBV

8 wks

95

18/19

SOF/LDV

18/19

95

21/21

100

SOF/LDV+ RBV

SOF/LDV

12 wks

PI failures (50% cirrhotic)

12 wks

No breakthrough; 2 relapses, both without RBV 1 case of resistance – retreated with SOF/LDV + RBV x 24 weeks → SVR

Lawitz E, et al. AASLD 2013. Abstract 215.

LONESTAR: SOF (Nuc) + ledipasvir (NS5A) FDC ± RBV

100

80

60

40

20

0

SV

R4

or 1

2 (%

)

The Future Is Bright If Money Can Buy…

• Sofosbuvir• Simeprevir• Daclatasvir• Sofosbuvir/Ledipasvir FDC• ABT450/r + ombitasvir + dasabuvir FDC• MK5172 + MK8742

$