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PREVENTION AND
TREATMENT OF
INFECTIONProf: Anwar Ali Akhund
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Hepatitis-C
300 million people have hepatitis C worldwide ( 5% pop) 1
300
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HCV Structure
RNA virus
Single-stranded
Positive-sense
9400 nucleotide
Virion:
Enveloped
Icosahedral capsid
40-60 nm in diameter
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Hepatitis-C Virus
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Hepatitis C Virus Flaviviridae family (Yellow Fever, Dengue, JEV)
+ sense RNA
9.7 kb in length
Encodes a 3000 AA polyprotein
Cleaved by host and viral encoded proteases
5 and 3 untranslated region
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HCV Genotypes
Genotypes Location
1 Americas, Europe, Asia and Australia
2 US, Europe, Japan and China
3 Australia and South Asia
4 Egypt and Central Africa
5 South Africa
6 Southeast Asia (Hong Kong, Macau, Vietnam)
[7-11 Thailand, Vietnam and Indonesia]
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Transmission: 3
Direct blood or fluid exposure
Sexual Activity
Perinatal Transmission
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Transmission:
Other things thought to be
associated with HCV:
Tatoos
Acupuncture
Ear Piercing
These ARE NOT usual causes of HCV!
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TABLE-4Possible risk factors among positive cases
Sr. No. Risk Factors Number Positive %01 Syringes 68 34.7
02 Blood Transfusion 44 22.44
03 Surgery 24 12.24
04 Dental Procedure 20 10.2
05 Barbers 16 08.2
06 Sexual History 09 04.6
07 Occupuncture 02 01.02
08 Unknown 13 06.6
Total 196 100
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Binding and Entry
Unknown at this timeGuesses:
E2 binds to CD81 on liver
Envelope protein binds to CD81 large extracellular loop
E2 binds to LDLR Envelope coated with LDL during secretion?
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2HN COOH
CD81 and LDLR Co-receptor Complex
LDLRLDLR
LDLLDL
HCVHCV
Viral exit and entry are currently idealized Clearly important in viral replication
Aided by retroviral E1/E2 pseudotypes CD81 receptor antagonists in development
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Replication, Assembly and Release
Replication
Poorly understood
NS5b polymerase, NS3
helicase domain, host factors
all involved
Assembly and Release Poorly understood
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Viral Replication in Infected Host Cell
NUCLEUS
YY
Release of viral
nucleocapsid
Fusion
-Uncoating
Endocytosis
Receptor-virus binding
Packaging
Virion transport and glyco
maturation
Vesicle fusion and releainfectious mature viri
RNA replication
- Generation of (-) strand RNA templa
- Disproportionate synthesis of (+) stran
genomic RNA from (-) template
(+)
Translation into
polyprotein precursor
Proteolytic processing of
polyprotein precursor
(-)
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Immune Responses to HCV
I. Role of Neutralizing Antibody
strain specific and cross-reactive
role of HCIg
role of Hyper Variable Region (HVR) of HCV envelope E2
II. Role of Cell Mediated Immunity
appears to play a key role in the virological outcome during acute infection
Acute HCV
wide variety of vigorous CD4+ T-cell response which persist for many years
memory CD8+ T-cells found
Chronic HCV
weak CD4+ and CD8+ T-cell responses
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Immune Responses to HCV 4
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Evasion of Immune Response
HCV is RNA virus: mutates quickly
E1, E2 in hypervariable region changes often
NS5A inhibits PKR
PKR is effector of host antiviral defense pathway:
represses translation by phosphorylating eIF2
NS5A has other activities as well: less understood
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Natural History of HCV Infection 5
AcuteHepatitis
ChronicHepatitis
Cirrhosis
HCC*Decompensation
Death
Factors affecting
natural history
HLA type
Male gender
Age of onset
Alcohol
Interferon
Hepatitis B*
Alcohol
Interferon*
Transplantation
85%
20%
6% 4%
3.6%
* from A. DiBisceglie 2000 Hepatology 31:1014
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Pathology of HCV
Acute Hepatitis C:
Generally benign:
No jaundice (80%)
Usually asymptomatic
Can be severe, but liver failure rare
Only real threat of acute Hepatitis C is its ability
to reach chronic stages undetected and untreated.
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Pathology of HCV
Chronic Hepatitis C:85% of patients become chronic
Possible results:
Cirrhosis
End-stage liver disease
Hepatocellular carcinoma
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Some pictures of liver disease:
Incidence of HCC 17x greater in HCV-infected than in HCV-negative patients
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1. Liver enzymes (ALT, AST)2. Serum Bilirubin, PT, Alkaline phosphatase, Albumin
3. Detection of Hepatitis C antibodies (Anti HCV) by
ELISA (Enzyme Linked Immuno Sorbant Assay)
RIBA. (Recombinant Immunoblot Assay)
4. HCV RNA by qualitative and quantitative PCR. 6
5. Viral Genotyping with the PCR
6. Liver-biopsy
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There is currently no vaccine for HCV. The
difficulty in developing a vaccine is due, in part,
to the mutability of the HCV. In addition, there is
no effective, short-term prevention such H-BIG or
immune globulin. In the absence of the above, all
precautions to prevent HCV infection must be
taken.
PREVENTION/ PROPHYLAXIS
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WHO recommendations on measures to prevent HCV
include:
Worldwide screening of blood and blood products. Destruction of disposable needle and adequate sterilization of
reusable material such as surgical or dental instruments.
Effective use of universal precautions and barrier techniques
(such as use of sterile equipment, the wearing of gloves, and
wearing eye/ face protection)
Education about the risk of using unsterilized material 7
PREVENTION/ PROPHYLAXIS
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Increased ALT activity
Liver biopsy fibrosis Detectible serum HCV RNA
INDICATIONS FOR
TREATMENT
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Treatment options for Hepatitis-C viral infection
are:
Interferon Alfa mono therapy.Combination of Interferon alfa and ribavirin
Combination of Pegylated interferon and Ribavirin.
CURRENT TREATMENT OF
HEPATITIS-C VIRUS INFECTION
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CURRENT TREATMENT OF
HEPATITIS-C VIRUS INFECTION
Treatment of acute Hepatitis-C patients with interferonalfa (5 million units once daily for 3 weeks then 5 millionunits three times weekly) for 6-24 weeks appreciablydecreases the risk of chronic hepatitis. Because 15-20%of patients with acute hepatitis-C clear the virus withoutsuch treatment, reserving it for patients in whom serumHCV RNA levels fail to clear after 1-2 months may beadvisable. Spontaneous viral clearance is much more
likely in symptomatic patients than in asymptomaticpatients.
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Recombinant human interferon alfa-2b or alfa-2a, in a dose of
millions units three times a week or consensus interferon 9 u
three times weekly for 24-48 weeks.
Peginterferon is -interferon that has been modified chemical
by addition of a large inert molecule of polyethylene glycopegylation changes the uptake, distribution, and excretion
interferon in the blood, where as standard interferon must be give
several times weekly and provide intermittent and fluctuatin
level. In addition, peg interferon is more active than standainterferon in inhibiting HCV and yields higher sustained respon
with similar side effects.
INTERFERON TREATMENT OFCHRONIC HEPATITIS
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Typical side effects are constitutional in nature including a
flue like syndrome within 6 hours dosing in more than 30%
of patients.
Other potential effects include:
- Thrombocytopenia- Granulocytopenia
- Increase in serum aminotransferase level
- Induction of autoantibodies
- Nausea, fatigue, headache
- Arthalgia, rashes, alopecia
- Severe neuro-psychiatric problems e.g. depression and irritability.
SIDE EFFECTS OF INTERFERON
RIBAVIAN
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Rabavian is a synthetic nucleoside similar in structure to
guanosine. Ribavirin has activity against a broad spectrum ofviruses. By itself, ribavirin has little effect on HCV, but
adding it to interferon increases the sustained response rate by
two-to three fold. For these reasons, combination therapy is
now recommended for Hepatitis-C, and interferon
monotherapy is applied only where there are specific reasons
not to use ribavirin.
Side Effects:
Haemolytic anaemias, Depression, Fatigue, Irritability,,Rash, Nausea, Pruritis
RIBAVIAN
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For patients treated with peginterferon monotherapy a 48
weeks course is recommended, regardless of genotype.
For patients treated with combination therapy:
The Patients with genotype 2 and 3 have high rate of
response to combination therapy (70-80 %) with 24weeks course.
In contrast, patients with genotype-I have lower rate of
response to combination therapy (40-45% ) and a 48
weeks course yields a significant better-sustainedresponse rates.
DURATION OF TREATMENT
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Sustained response means HCV RNA remain
undetected for 6 months or more after stoppingtherapy.
48 weeks course of combination therapy using
peginterferon and ribiviran yields a sustained
response rate of 55%.
Similar course of peginterferon yield a sustained
rate of only 35 percent.
SUSTAINED RESPONSE
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CONTRA-INDICATIONS TO ALPHA
INTERFERON THERAPY INCLUDE
Severe depression or other neuro-psychiatricsyndromes.
Active substance or alcohol abuse.
Autoimmune disease (such as rheumatoidarthritis, lupus erythamatoses or psoriasis) that isnot well tolerated.
Bone narrow compromise.
Inability to practice birth control.
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marked anemia,
renal dysfunction
coronary artery disease
cerebro-vascular diseases,
inability to practice birth control.
CONTRA-INDICATION TO RIBIVIRIN /
COMBINATION THERAPY
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THERAPY IS INADVISABLE TO
PATIENTS WITH
Clinically decompensated cirrhosis because of
Hepatitis-C.
Normal amino-transferase levels.
Kidney, liver, heart or other solid organ
transplant
Specific contra indication to either
monotherapy or combination therapy
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Promising Therapies in the Pipeline
1. VACCINES
2. SMALL MOLECULE INHIBITORS
NS3-4A (serine protease)
NS5B (RNA polymerase)
3. IMMUNOMODULATORS
TLR-9
TLR-7
Promising Therapies in the Pipeline
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Promising Therapies in the Pipeline
4. NUCLEIC ACID-BASED
Anti-sense
AVI-4065 Avi BioPharma; phase-I
RNAi
No leads
Ribozymes
No leads
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