• The structure of the hepatitis C virus is like that of most complex viruses - a core of genetic material (RNA), surrounded by a protective shell of protein, and further encased in a lipid (fatty) envelope of cellular material and on the surface Glycoproteins

Acute infection

Resolve

15%

(mainly children and young women)

(usually within 6 month)

Chronic infection

85%

Stable

80%

Cirrhosis

20%

Stable

75%

Mortality

25%

(due to liver cancer or liver failure)

• Come and Go at start

• After Cirrhosis More prominent

• But for most cases no symptoms

1) HCV antibody testing (See anibodies in blood) Enzyme Immunoassay (EIA): detects antibodies that

bind to recombinant antigens derived from four viral regions.

Has an Accuracy of 99% ; Rare circumstances associated with a false-negative EIA include patients with major immunosuppression (advanced HIV infection or organ transplantation recipients), with chronic renal failure on long-term hemodialysis, and with acute or early HCV infection. Chemiluminescence Immunoassay (CIA): The CIA test

is an antibody test similar to the EIA

2) Nucleic Acid Test (NAT) or Nucleic Acid Amplification Test (NAT): specifically detect HCV RNA ; positive approximately 1 to 2 weeks after initial HCV infection.

Determine whether a patient with a positive HCV antibody test (EIA- CIA) has current (active) or resolved HCV infection. In addition, the NAT can be used to diagnose individuals with acute HCV infection.

Qualitative HCV RNA( PCR test): Yes or No

Quantitative HCV RNA: Not FDA approved

3) Liver Function Tests: Alanine aminotransferase (ALT or SGPT):

About 2/3 of pt. with chronic hepatitis C have continuously elevated ALT levels, reflecting ongoing damage to liver cells.

In 1/3 of pt. with chronic hepatitis C, the ALT levels remain normal, even though they have +ve NAT test.

ALT, in particular, is often one of the criteria in deciding when to start HCV treatment.

Aspartate aminotransferase (AST; sometimes listed as "SGOT"):

AST levels are often elevated in people with chronic hepatitis C. However, AST levels are usually lower than ALT levels. If cirrhosis occurs, AST levels can increase higher than ALT levels—a sign that damage to the liver is worsening Alkaline phosphatase and gamma glutamyl

transpeptidase (GGT or GGTP): These levels are usually normal. However, they may become elevated if hepatitis C progresses to cirrhosis.

4) Liver biopsy: Determine amount of damage actually been done to the liver.

5) HCV Genotypic Testing: 6 different genotypes each has many subtypes

VIP to know genotype: To determine type and length of treatment ; also like-hood of curing

1) Interferon and Peginterferon

Interferon is a protein made by the immune system, named because it interferes with viral reproduction.

In addition, interferon signals the immune system to recognize and respond to microorganisms, including viral and bacterial infections.

Infected cells release interferon to trigger the immune response. Interferon alfa is used to treat viral hepatitis and some types of cancer.

By 1996, FDA approves alfa interferon to treat hepatitis C.

Peginterferon = Interferon covalently linked to a 12-kd linear polyethylene glycol (PEG).

Compared with the native interferon alfa, the peginterferon alfa has sustained absorption, delayed clearance, and a prolonged half life..

By 2001 Peginterferon alfa-2b (PegIntron) FDA approved : o Here interferon alfa-2b o Dosed according to weight

2002 Peginterferon alfa-2a (Pegasys) FDA approved: o Here interferon alfa-2a o Given at a fixed dose (in other words, the same dose for

everybody).

The Dark Side of Interferon

Continous Dosing Adjustment : In Case of Leukopenia, Thrombocytopenia, Renal Insufficiency, and depression in all those cases the dose of the interferon must be reduced

N.B: Mild depression ( no problem), Moderate(reduce), Severe(discontinue).

numerous problematic side effects:. significant hematologic toxicity (neutropenia and thrombocytopenia) , ophthalmologic disorders , Neuropsychiatric (insomnia, depression, and irritability) or aggravate life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders.

2)Ribavirin(Copegus, Rebetol, Ribasphere)

Ribavirin is a purine nucleoside analog that has an incompletely understood mechanism of action against hepatitis C virus.

Four main potential sites of ribavirin action against hepatitis C virus: clearance of HCV, inhibition synthesis of guanosine triphosphate, an essential substrate for viral RNA synthesis , direct inhibition of HCV replication, and induction of RNA virus mutagenesis .

Not Effective alone but it has a synergistic action with another anti-HCV drug (In Combination)

The major side effect of ribavirin is Hemolytic Anemia (worsen Cardiac Diseases) and Birth Defects

Nucleoside and nucleotide HS5B polymerase inhibitors:

• These drugs mimic a nucleotide, which the virus would ordinarily use to help copy itself. When the nucleotide analog is substituted for the normal nucleotide, the virus cannot replicate.

• Therefore this Group Inhibit RNA Replication

By Dec 2013 Sofosbuvir(sovaldi) FDA approved o Taken once a day with ribavirin and often pegylated

interferon o In hepatocytes it convert to its Active Form (triphosphate

compound) mimics the natural cellular uridine nucleotide and is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination.

o The active compound doesn’t Affect host cell o Advantage : No dose adjustment with pt. suffering from

renal impairment o It was very well-tolerated in clinical trial with an adverse

effects (fatigue and headache)

Main Problem

The co-administration of sofosbuvir with the following medications lowers its levels:

Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin

Antimycobacterials: rifabutin, rifampin, rifapentine

Herbal Supplements: St. John's wort (Hypericum perforatum)

HIV Protease Inhibitiors: tipranavir-ritonavir

NS3/4A protease inhibitors:

• These drugs also block an important step in the HCV replication process. The hepatitis C virus uses its protease enzyme to cut, or cleave, long strands of virus into shorter pieces, so that they can be rearranged and reassembled to form new viruses. Protease inhibitors stop viral cleavage by binding to the protease enzyme so it cannot cut, similar to covering scissor blades with glue.

By May 2011 Boceprevir (Victrelis)and Telpriver (Incivek ) FDA approved o Taken in combination with pegylated

interferon and ribavirin, these oral antiviral drugs are used three times per day, for 12 to 44 weeks.

oRegimens with Victrelis and Incivek are associated with increased side effects (rash, anorectal complaints, and anemia)and longer duration of treatment and are therefore not preferred.

By Nov 2013 Simieprevir (Olysio) o For TTT of HCV genotype 1 in combination with

pegylated interferon and ribavirin.

oMost VIP Side effect is photosensitivity reactions which may lead to hospitalization.

o Those taking Olysio are advised to limit sun exposure and to protect themselves against the sun during treatment.

o Advantage: No need for dose adjustment in case of renal problems or mild hepatic impairment but since drug is metabolized in liver and increased dose would be needed with moderate to sever hepatic impairment

o Ledipasvir is a potent inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion.

o Sofosbuvir is a Inhibit HCV RNA replication

• The drug combination known as “3D” is an all-oral regimen comprised of four medications:

1) paritaprevir (ABT-450): an inhibitor of the NS3/4A serine protease, which is a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion. 2) Ritonavir: HIV protease inhibitor used as a pharmacologic booster for paritaprevir. 3) ombitasvir (ABT-267):Ombitasvir is a NS5A inhibitor, and has potent pangenotypic picomolar antiviral activity. 4) dasabuvir (ABT-333): nonnucleoside NS5B polymerase inhibitor.

Active against All Genotypes of HCV from 1 to 6 Excellent tolerance and no serious adverse effects

With or without Ribavirin

1957 : Interferon first discovered in body and its antiviral activity

1980-1990’s : investigators identified the virus.

1991 : FDA approves first alfa interferon (Intron A) to treat hepatitis C.

1996 : FDA approves alfa interferon (Roferon A ) to treat hepatitis C.

1997 : FDA approves consensus interferon (Infergen) to treat hepatitis C.

1998: FDA approves Rebetron (Intron A plus ribavirin) for the treatment of hepatitis C.

2001 :Peg-Intron (pegylated interferon alpha-2b) was approved to treat hepatitis C

2002: Pegasys (Roche’s pegylated interferon alpha-2a) was approved to treat hepatitis C

2003: Intron A (interferon) plus Rebetol (ribavirin- available in oral solution) approved for treating pediatric chronic hepatitis C.

• 2005: For the first time scientists were able to replicate the hepatitis C virus (genotype 1) in a test tube.

• May 2011: Boceprevir (Victrelis) and Telpriver (Incivek ) were FDA approved

• 22 Nov 2013: Simieprevir (Olysio)

• 6 December 2013: Sofosbuvir(Sovaldi )

• october 2014 : Combined pill Ledipasvir-sofosbuvir (Harvoni)