hepatitis c new

7/28/2019 Hepatitis C New

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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


5/37Host signal peptidase NS2-NS3 protease NS3-4A protease

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



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4. NUCLEIC ACID-BASED

Anti-sense

AVI-4065 Avi BioPharma; phase-I

RNAi

No leads

Ribozymes

No leads


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