viral hepatitis 2014
Post on 14-Dec-2014
812 Views
Preview:
DESCRIPTION
TRANSCRIPT
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
$
top related