Transcript Hepatitis C Virus Infection

HEPATITIS C
DR OKEKE F.I
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INTRODUCTION
EPIDEMIOLOGY
PATHOGENESIS
CLINICAL FEATURES
DIAGNOSIS
TREATMENT
CONCLUSION
INTRODUCTION
• Hepatitis C virus (HCV) is an RNA virus known
to infect humans and chimpanzees, causing
similar disease in these 2 species.
• Is an infectious disease affecting primarily the
liver. It is 4 times more infectious than HIV
• 80% of cases of acute HCV infection will
progress to chronic HCV, 20 to 25 % will
progress to cirrhosis and 1 to 4% to
hepatocellular carcinoma.
• Hepatitis C accounts for 40% of CLD and is the
most frequent indication for liver
transplantation.
• Harvey Alter discovered the virus in the mid
1970s and initially called it ”non-A, non-B
hepatitis (NANBH)”,
• In 1987, Drs Michael Houghton & D.W. Bradley
identified it by molecular cloning and in 1988, Dr
Alter confirmed it was the NANBH. April 1989,
HCV discovery was published.
• In 2000, Drs. Alter and Houghton were honored
with the Lasker Award for Clinical Medical
Research
Discovery of Hepatitis C
4/22/2011
ICVH Baltimore 2011
• The hepatitis C virus (HCV) is a small,
measures (40-60nm) enveloped, singlestranded, positive-sense 9600-nucleotide RNA
virus. It is the only member of the Hepacivirus
genus in the family Flaviviridae.
• The HCV genome contains a single, large open
reading frame (gene) that codes for approx
3000 amino acid polypeptide which is cleaved
after translation into 10 viral proteins.
Pic of genome
EPIDEMIOLOGY
• HCV Infection occurs throughout the world,
and up until the introduction of anti-HCV
screening tests for blood donors, introduced
in 1990/1991 in Europe and the United States,
it has represented the major cause of
transfusion-associated hepatitis.
• The WHO estimates that 3% (170 million) of
the world's population are chronically infected
with HCV.
HCV: A Global Health Problem
170 Million Carriers Worldwide, 3 - 4 MM new cases/year
3% of World Population
CANADA 300,000
U.S.A.
4M
WEST
EUROPE
9M
EAST
MEDITERRANEAN
20M
FAR EAST ASIA
60 M
SOUTH EAST ASIA
30 M
AFRICA
32 M
SOUTH
AMERICA
10 M
SOURCE, WHO 1999
AUSTRALIA
0.2 M
HEPATITIS C AROUND THE WORLD
WHO Region
Total Population
(Millions)
Hepatitis C
prevalence
Rate %
Infected
Population
(Millions)
Africa
602
5.3
31.9
Americas
785
1.7
13.1
Eastern
Mediterranean
466
4.6
21.3
Europe
858
1.03
8.9
South-East Asia
1 500
2.15
32.3
Western Pacific
1 600
3.9
62.2
Total
5 811
3.1
169.7
Worldwide Prevalence
Hepatitis C Virus Infection
Reprinted from Cohen J. Science. 1999;285:26.
• In the United States, about 2% of people have
hepatitis C, with the number of new cases per
year stabilized at 17,000 since 2007. The
number of deaths from hepatitis C has
increased to 15,800 in 2008 and by 2007 had
overtaken HIV/AIDS as a cause of death in the
USA. This mortality rate is expected to
increase, as those infected by transfusion
before HCV testing become apparent
• The prevalence is reported to be highest
(>10 -20%) in Egypt
• The prevalence is higher (>2%) in several
countries in Latin America, Eastern Europe,
and the former Soviet Union, and certain
countries in Africa, the Middle East, and South
Asia;
• Sub-Saharan Africa is of great interest because
it is reported to have the highest HCV
prevalence rate (5.3%), and a concurrent HIV
epidemic
• The Central African Region has an estimated
prevalence of 6%, West Africa has an
estimated prevalence of 2.4%, and South and
East Africa with the lowest estimated
prevalence of 1.6%.
• In Nigeria, a study done by OS Ejiofor et al
over a period of 12 months from January to
December 2009 showed that the prevalence
of hepatitis C virus infection is increasing in
Nigeria, ranging from 4.7-5% in Ilorin, to 5.36.6% in Enugu, to 11% in Ibadan and 20% in
Benin.
• Has 6 distinct major genotypes and over 50
subtypes within genotypes (quasispecies).
• Worldwide, 1 is more common and accounts for
70% in the USA
• Genotypes 1-3 are widely distributed globally,
with genotypes 1a and 1 b accounting for 60% of
infections worldwide. Genotype 4 is characteristic
for the Middle East, Egypt and Central Africa.
Genotype 5 is almost exclusively found in South
Africa. Genotype 6 in Hong kong.
HCV Genotypes and Subtypes
2
Developed countries
Americas + Western Europe
South Africa
5
Middle East
North Africa
1
4
IVDU
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Simmonds P, Journal of Hepatology, 1999
Asia
6
• AGE: occurs in all ages. Mostly 25- 40yrs
– 1988-1994 =30-40yrs
– 1999- 2000 = 40 – 49 yrs
– 1995 >
=55 -64 yrs
• Despite an 80% reduction in new infections,
prevalence in the various populations was
sustained by an aging cohort that acquired
their infections 2 to 3 decades earlier .
• In a retrospective study done in Nnewi by
Odenigbo et al in 2011 to determine Prevalence
Of Antibodies To Hepatitis C Virus In Blood
Donors In Nnewi (2005- 2009)
• The prevalence of HCV antibodies was found to
be 2.0%. The age group 21-30 years was found to
be the lowest risk group (1.4% seroprevalence).
Seroprevalence increased after the age of 30
years, though not linearly, with the highest rate
(3.2%) recorded in the 31-40 years and 51-70
years age groups -
• Chukwurah et al studied the prevalence of the
antibodies to Hepatitis C Virus (anti-HCV) in
1280 blood donors at UNTH Enugu in 2004
showed that 97 (7.6%) of the blood donors
were positive for the anti-HCV.
• A similar study done by Udeze et al in Ibadan
in 2007 showed that 16 (8%) of the donors
had antibodies to HCV and highest prevalence
was amongst blood donors of the age range
30-39 years. (16.5%).
• In 2009, another study was done over a 6mth
period in 507 prospective blood donors in
UCH by Afolabi et al
• 1.4% were positive for anti-HCV. HCV
prevalence was highest among age group of
26 – 35.
• The rates were lower than the previous
studies in Nigeria
• perhaps this is due to the public
enlightenment on transmissible transfusion
infections.
• Obienu et al in 2011 tried to determine the
prevalence of anti-HCV and risk factors
associated with HCV infection in Nigerians.
• The seroprevalence of anti-HCV was 4.7%.
Among the risk factors evaluated, none was
found to be significantly associated with antiHCV seropositivity.
Risk Factors Associated With
Acquiring HCV Infection
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Transfusion (blood, pooled clotting factors)
Transplant from infectious donor
Injecting drug use
Occupational blood exposure (needle sticks)
Birth to an infected mother
Infected sex partner
Multiple heterosexual partners
Unknown (20%)
HIGH RISK INDIVIDUALS
 Intravenous drug users
(even one-time use
 Transfusions of blood or blood
products before 1992
 Current recipients of multiple
blood transfusions
 Hemophiliacs given clotting factors
 Sexual partners of intravenous
drug users
 Intranasal cocaine users
 Tattooing or body piercings
 Long-term hemodialysis
 History of imprisonment
 High risk sexual contact, patients with
multiple sexual partners
 Occupational exposure to blood
or blood products
 Receiving an organ, graft,
or tissue transplant from an
HCV-positive donor
 Health-care workers exposed to
needle-stick and sharp injuries
 Patients with sexually
transmitted diseases, HIV, HBV
PATHOGENESIS
• Study of Infection, Replication and Release
Difficult:
– Lack of reliable culture system
– Does not integrate into host genome
– Low number of circulating virions
Binding and Entry
• Unknown at this time
– Guesses:
• E2 binds to CD81 on liver
– Envelope protein binds to CD81 large extracellular loop
• E2 binds to LDLR
– Envelope coated with LDL during secretion?
Evasion of Immune Response
• HCV is RNA virus: mutates quickly
– E1, E2 in hypervariable region – changes often
• NS5A inhibits PKR(phosphorylase kinase
receptor)
– PKR is effector of host antiviral defense pathway:
represses translation by phosphorylating eIF2
– NS5A has other activities as well: less understood
• cytokines in the Th2 phenotypes are profibrotic and
lead to the development of chronic infection.
• A dominant CD4 Th2 response with a weak CD8
gamma-interferon response may lead to rapid fibrosis.
• Thl cytokines are anti-fibrotic and thus a dominant
CD4 Thl and CD8 cytolytic response may cause less
fibrosis.
• Variability may be related to the genetic phenotype;
persistence of HCV infection has been shown to be
associated with HLA-DRBl*0701 and DRB4*0101..
CLINICAL FEATURES
• Acute Hepatitis C occurs after an incubation
period of 15 -160 days (mean of 50)
• Most – asymptomatic
• 10% - symptomatic – prodromal symptoms
preceding onset of jaundice by 1-2 weeks,
RUQ pain, proceeding to recovery phase (2-12
wks) with complete clinical and biochemical
recovery in those who clear the virus
• Asymptomatic – 10 -15% will clear the virus
while 85 – 90% will progress to the chronic
state
• Symptomatic – 25 – 52% will clear /48 -75%
will progress
• 10- 20% of those who progress will end up in
cirrhosis in 10 -30 years
• 7-15% of cirrhotics will develop hepatocellular
carcinoma.
• Chronic –usually asymptomatic, anorexia, nausea,
fatigue, weight loss, features of CLD, evidence of
decompensation.
• Factors which worsens progression includes
alcohol, male sex, concomitant HBV or HIV or
both, fatty liver, DM, Iron, older age, longer
duration , genotype 1, advanced histologic stage
and grade.
• Persistence of HCV infection has been associated
with HLA DRB1*0701 and DRB4*0101.
Hepatitis C Progression
Fibrosis & Disease Progression in Hepatitis C. Marcellin, et al. Hepatology, 2002
Alcohol
Are you sure he said we
can only have one?
RELATIONSHIP BETWEEN CIRRHOSIS AND YEARS AFTER
EXPOSURE
% CIRRHOSIS
100
85
80
64
58
60
40
40
20
31
18
6
HCV
HCV+ALC
12
0
10
20
30
40
YEARS AFTER EXPOSURE
Wiley et al.
Hepatology, 1998
HCV Infection:
Extrahepatic Manifestations
Hematologic
Ocular
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• Corneal ulcer
• Uveitis
Mixed cryoglobulinemia
Aplastic anemia
Thrombocytopenia
Non-Hodgkin’s b-cell lymphoma
Dermatologic
• Porphyria cutanea tarda
• Lichen planus
• Cutaneous necrotizing
vasculitis
Renal
• Glomerulonephritis
• Nephrotic syndrome
Endocrine
• Anti-thyroid antibodies
• Diabetes mellitus
Vascular
• Necrotizing vasculitis
• Polyarteritis nodosa
Neuromuscular
• Weakness/myalgia
• Peripheral neuropathy
• Arthritis/arthralgia
Autoimmune
Phenomena
•CREST syndrome
•Sjoren’s/Sicca
syndrome
Salivary
• Sialadenitis
Hadziyannis SJ. J Eur Acad Dermatol Venereol. 1998;10:12-21.
• A study done by Dr Ukonu and Uhunmwangho to
determine the prevalence of hep C among lichen
planus patients between Jan 2010 and Dec 2011,
720 new patients in MOPD.
• The control group included patients’ relations and
some dermatology patients known to have low
risk of hepatitis C virus infection
Result: Anti- HCV antibodies were detected in nine
cases (21.4%) and one case (3.3%) in the control
group. Hypertrophic variant was more prevalent.
Investigations
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ACUTE; HCV RNA (1-8 wks),
AntiHCV antibodies after 8weeks.
LFT:Elevated ALT, elevated bilirubin,
FBC: neutropenia, lymphopenia or relative
lymphocytosis,
• prolonged PT
• antiLKM(anti liver/kidney microsomal) antibodies
type 1.
Hepatitis C Antibody (Anti-HCV) Test
• EIA test for detection of hepatitis C antibodies
• Sensitivity over 99%
• Detection of anti-HCV following infection averages 12
weeks
• Positive test usually diagnostic in patients with elevated
levels of liver enzymes and presence of risk factors
• False negatives in Immunosuppressed and Chronic Dialysis
Patients
• False positive in autoimmune hepatitis and
hyperglobulinaemia.
Management of Hepatitis C. NIH Consensus Statement, 2002.
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CHRONIC;
HCV RNA,
AntiHCV,
Elevated or normal ALT,
Liver biopsy ,
HCV genotyping
Serologic testing :antinuclear antibody(41%) ,anti
thyroid antibody(13%) .rheumatoid factor (38%)
,anticardiolipin antibody(27%) and anti smooth mzle
antibody(9%)
HCV RNA
• Genotype
• Viral load
• These two parameters do not affect the rate
of fibrosis.
Liver Biopsy
• May be guided by CT or ultrasound
• Helps determine
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Degree of disease progression
Cause of liver disease
Need for treatment / Patient Motivation
Estimate chance of response
Findings: lymphocytic infiltration ,moderate degrees of
inflammation and necrosis ,portal or bridging fibrosis .
Regenerative nodules in pxs with cirrhosis
Complications
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Pancreatitis
Myocarditis
Atypical pneumonia
Aplastic anaemia
Transverse myelitis
Peripheral neuropathy
DD
ACUTE
– CMV, HSV, leptospirosis,
brucellosis,
mycobacteria,
– Autoimmune hepatitis
– Drug induced hepatitis
– Right ventricular failure
– Severe left ventricular
failure
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Hepatic vein occlusion
Veno-occlusive disease
Constrictive pericarditis
NAFLD
Metabolic liver disorders
• CHRONIC
– METABOLIC
– Genetic
– PBC
– Sclerosing cholangitis
– Metastatic liver disease
TREATMENT
• ACUTE Hepatitis C
– Progression to chronic hepatitis is the rule.
– Aim is to prevent chronic disease
– Evidence of HCV viraemia
– Antiviral- alfa interferon monotherapy 3million
units SC three times a week. Reduces the rate of
chronicity by inducing sustained responses in 3070% of patients.
– Optimum regimen ,duration of treatment and
time to initiate therapy remains undetermined.
• A German study of 44 patients with acute
symptomatic hep C showed a SVR rate of 98%
after administering 5million units SC daily for
4weeks, then three times a week for another
20weeks.
• Drawback –expensive
• Needle stick injuries must be followed up and
treated early if there is evidence of infection,
usually re-tested for at 4weeks.
• Goal of treatment for chronic HCV :
• 1.to achieve sustained eradication of
HCV(sustained virologic response)
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2.prevent progression to cirrhosis, HCC and
decompensated liver disease requiring liver
transplant
• CHRONIC Hepatitis C
– the hepatitis C virus persisting for more than six
months based on the presence of its RNA
• Pegylated interferon alfa (2a or 2b)
• Ribavarin
• NS3 Protease inhibitors – Telaprevir and
Boceprevir, Asunaprevir
• NS5 protease inhibitors - Daclatasvir
• Duration of treatment depends on the
genotype
• RVR- HCV RNA undetectable within 4weeks ..
• EVR- reduced by > 2log10 IU/ml within
12weeks
• Complete EVR- undetectable by 12weeks.
• Absence of EVR predicts failure to experience
subsequent SVR.
• ETR- undetectable at week 48
• SVR – undetectable for 24weeks after ETR
(72weeks)= RESPONDER
• RELAPSE= HCV RNA becomes detectable again by
72weeks in a patient with ETR at week 48
• Non responder- HCV RNA reduction of <2log10
IU/ml at 24weeks
• Partial responder – reduction of >2log10, but not
suppressed to undetectable levels by week 24.
• Standard therapy is subcut PEG IFN alfa once
weekly and oral ribavarin daily
• Genotype 1&4 = 48weeks of therapy(SVR >40%)
• Genotypes 2&3 = 24 weeks of therapy. (>80%)
• PEG IFN alfa 2a =180ug weekly
• PEG IFN alfa 2b =1.5ug/kg weekly
• Ribavarin 800mg/day.
• Monitor HCV RNA at 4wks, 12wks, 48wks,72wks
• HCV/HIV co infection- 48weeks regardless of
genotype.
• Ribavarin can potentiate lactic acidosis of
didanosine,
• lipoatrophy of stavudine and
• haemolytic anemia of ziduvodine
• Factors promoting SVR include
– Low HCV RNA <2million copies/ml /800,000 i.u
– Genotypes 2&3
– Age < 40
– Females
– Absence of obesity/hepatic steatosis
– Absence of insulin resistance and type 2 DM
– Low HCV quasispecies diversity
– Low liver iron levels
– CC homozygosity for the IL-28 polymorphism in
genotype 1.
• Alternate regimen for genotype 1– PEG 2a/R with oral boceprevir 12weeks
– PEG 2b/R with oral telaprevir 24weeks
• Side effects of IFN– Flu-like illness, malaise, headache, aches, myalgia,
depression, reversible hair loss, BM depression,
infection
• Ribavarin
– Haemolysis, pruritus, nasal congestion,
thrombocytopenia, gout precipitation
• Telaprevir- rash, anemia
• Boceprevir – dysguesia, anaemia
NOVEL THERAPIES
• Daclatasvir It is being developed by BristolMyers Squibb.
Daclatasvir's inhibits of the HCV nonstructural protein
NS5A. Recent research suggests that it targets two
steps of the viral replication process, enabling rapid
decline of HCV RNA
• Sofosbuvir is a nucleotide analogue inhibitor of
the hepatitis C virus (HCV) polymerase. The HCV
polymerase or NS5B protein is a RNA-dependent
RNA polymerase critical for the viral cycle.
• It has shown excellent clinical efficacy when used
either with pegylated interferon/ribavirin or in
interferon-free combinations. Combinations of
sofosbuvir with NS5A inhibitors, such as daclatasvir
have shown sustained virological response rates of up
to 100% in people infected with HCV.
• Data from the ELECTRON trial showed that a dual
interferon-free regimen of sofosbuvir plus ribavirin
produced a 24-week post-treatment sustained
virological response (SVR24) rate of 100% for
previously untreated patients with HCV genotypes 2 or
3.
• Data presented at the 20th Conference on
Retroviruses and Opportunistic Infections in
March 2013 showed that a triple regimen of
sofosbuvir, ledipasvir and ribavirin produced a
12-week post-treatment sustained virological
response (SVR12) rate of 100% for both
treatment-naive patients and prior nonresponders with HCV genotype 1. Gilead has
developed a sofosbuvir + ledipasvir coformulation
that is being tested with and without ribavirin
• Asunaprevir is an inhibitor of the hepatitis C
virus enzyme serine protease NS3.[Phase III
clinical trials.
• Ledipasvir is an inhibitor of the hepatitis C
virus HCV NS5A protein. Phase III clinical trials.
• Contraindication to antivirals
– Pregnancy
– Decompensated cirrhosis
– Anaemia
– haemoglobinopathies,
– CAD, CVD
HCV IMMUNIZATION
• French researchers August 2011 announced a
new HCV vaccine in development that is
effective against many variants of HCV.
• So far on mice and monkeys (no human tests
yet).
PROGNOSIS
• Infection with HCV is self-limited in only a small
minority of infected persons.
• Chronic infection develops in 70-80% of patients
infected with HCV.
• Cirrhosis develops within 20 years of disease
onset in 20% of persons with chronic infection.
• The onset of chronic hepatitis C infection early in
life often leads to less serious consequences.
• Hepatitis B virus (HBV) coinfection, iron overload, and
alpha 1-antitrypsin deficiency may promote the
progression of chronic HCV infection to HCV-related
cirrhosis
• The risk of cirrhosis and HCC doubles in patients who
acquired HCV infection via transfusion.
• Progression to HCC is more common in the presence
of cirrhosis, alcoholism, and HBV coinfection
• With the currently recommended therapy for chronic
hepatitis C, which includes pegylated interferon and
ribavirin, cure rates are as high as 60%.
CONCLUSION
• Hepatitis C is an RNA virus
• Has a replication rate of 10^12 and half life of 2.7
hours
• It has 6 distinct genotypes and more than 50
subtypes
• Has an incubation period of 15-60 days
• Infection with HCV is self limited ina small
minority of infected person
• Chronic infection develops in 70 – 80% of patients
infected with HCV
• Transmission through injections is 3%. Transmitted
lesss commonly thru sexual contact than HBV n HIV
• Maternal transmission is very low.3 – 5% of new borns
in HCV RNA positive mothers
• Breast feeding has no risk of transmission
• Immunization not yet available
• Treatment of acute HCV infection is with interferon
• Treatment of chronic HCV infection is mostly with
combined therapy of PEG IFN alpha plua Ribavarin