Introduction

Why Hepatology for a Clinical Pharmacist?

x Pharmacotherapist
x Can interfere in drug induced liver diseases management.
x Pharmacist consultations for DDI before initiation of any medication in liver disease
patients.
x Pharmacist consultations before initiation of anti-viral therapy can minimize DDI.
x Sharing in prevention campaigns.
x Conducts research in the area of hepatology ( drug design……..Clinical trials).

LIVER
Largest organ in body, integral to most metabolic functions of body, performing over 500
tasks, including:
- Synthesis and storage of amino acids, proteins, vitamins and fats.
- Detoxification of drugs, hormones, peptides and toxins.
- Blood glucose regulation.
- Bile synthesis and drainage.
- Blood coagulation.
„ Only 10-20% of functioning liver is required to sustain life.
„ Removal of liver will result in death within 24 hours.

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Liver Biochemical Profile

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 Liver biochemical profile
Liver Function Tests (LFT’s)

It is performed to test for a variety of tasks, ‫ ׵‬no single test is diagnostic. They are not very
sensitive (cirrhosis) or specific (non-hepatic factors) the word “function” = misnomer.
May measure synthetic function, excretory function, or indicate damage to cells. The
determination of specific enzymes may be used to show the location of liver damage

Tests that assess:

1. Synthetic Function: ↓ Albumin ↑ INR
2. Liver Damage
a. Hepatocellular disease
b. Cholestastic disease
Aminotransferases: these are enzymes that leak when liver cells are damaged, AST =
aspartate aminotransferase, cytosol & mitochondria. ALT = alanine aminotransferase. ALT is
more specific for liver disease. AST:ALT ratio: >2:1 alcoholic liver disease.
Bilirubin : increases in cases of
Excessive load of bilirubin to liver (prehepatic-unconjugated): Hemolytic diseases.
Defective transport through hepatocyte (Hepatic)
Impairment of Esterification (Hepatic)
Hepatocellular damage (hepatic)
Obstruction of flow of bile ( cholestasis-posthepatic-conjugated) .

Alkaline Phosphatase (ALP): It is an enzyme found in many body tissues, >80% in liver
and bone ,a component of cells lining bile ducts. ↑ ALP synthesis by liver in cholestasis:

a – Obstruction in bile ducts Intrahepatic.

b- Impairment in bile formation in liver or obstruction of bile ducts within liver

γ-Glutamyl Transpeptidase(GGT): enzyme produced in bile ducts.

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 Acute Hepatitis
Definition

„ Inflammation of the liver cells.

„ May be caused by alcohol, drugs, autoimmune diseases, metabolic diseases, and
viruses

Causes of acute hepatitis

„ Infectious Disease
- Viruses: A, B, C, D (on B), and E
- Infrequently: include adenovirus, CMV, EBV, HSV.
- Bacterial: septicemia, T.B., leptospirosis, typhoid.
„ Toxic: Alcohol , Acetaminophen, INH, sulphonamides, antiepileptics .
„ Ischemia: after shock
„ Budd-Chiari syndrome
„ Wilson’s disease (Acute)
„ Microvesicular steatosis (Fat) Syndromes
- Acute fatty liver of pregnancy
- Reye’s syndrome

Typical patterns of viral transmission

HAV HBV HCV HDV HEV HGV

Fecal-oral transmission +++ +++

Parenteral transmission + +++ +++ +++ ++

Sexual transmission +++ + ++

Perinatal transmission +++ + +

Sporadic (unknown) transmission + +

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 Overview of main viruses

HAV HBV HCV HDV HEV

Type of virus RNA (picorna) DNA RNA RNA RNA

(flavivirus) (calicivirus)

Poor countries +++ + ++ + +++

IP 15-45d 45-150d 15-180d 20-45d 14-60d

Complications Cholestasis Chronic hep Chronic hep Worsen Fulminant hep

(5% adults, (85%) HBV in pregnant
Relapse 95% disease
Fulmin. hep (1%) neonates)
Co-
HCC
Super-
Fulmin. hep
(0.1%)

Diagnosis IgM: recent HBsAg/Ab HCV Ab HDVAb HEV Ab

IgG: >2m HBcAb PCR (+HBV)

HBeAg/Ab

PCR

Treatment Symptomatic Chronic: Acute:? IFN Symptomatic

IFN,
Chronic:
Lamivudine IFN+ribavirin

Prevention Vaccine Vaccine Protect against Prevent Health

infected blood HBV appraisal
2 doses, 20 Y 3 doses, 15 product
Y

Ig:
postexposure

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Clinical presentation of acute hepatitis

Different presentations:

x Anicteric hepatitis ( no jaundice)

x self-limited Icteric hepatitis
x Icteric hepatitis with prolonged cholestasis (6 months)
x Fulminant hepatitis.

Anicteric hepatitis

- Asymptomatic, or mild disease (flu-like) with no jaundice

- Passes undiagnosed
- May progress to chronicity.

Icteric hepatitis

I- Pericteric stage: few days with acute onset of fever, malaise, dyspepsia, upper
abdominal pain, nausea, ANOREXIA, dark urine ± pale stools. Tender hepatomegaly

II- Icteric stage: few weeks with appearance of jaundice systemic symptoms disappear
(wane), Hepatosplenomegaly.

III- Convalescent stage

Complete histopathological recovery of the liver may take 6 months

All clinical manifestations disappear. Jaundice may persist for days to weeks (high
affinity of bile pigments to collagen of sclera)

Acute hepatitis Investigations

Urinalysis

- Bilirubin and bile salts: present

- Possible evidence of glomerular affection: Slight albuminuria , Microscopic

hematuria , Granular casts.

Stool analysis: Pale (low stercobilinogen content)

Complete blood count (CBC) & ESR: Moderate rise in ESR, Leucopenia with relative
lymphocytosis.

Viral markers: anti- HAV IgM , HBsAg, anti- HBc Ig M, anti -HDV IgM , anti- HEV IgM,
HCV RNA by PCR, EBV, CMV IgM

HAV:

- IgG: positive= old infection or vaccine

- IgM: recent infection (cause of hepatitis)

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 HBV

- HBsAg: positive 2-6 weeks after onset, lasts for 6 months (more if chronicity occurs)

- Anti HBc Ab: Total (IgG): previous exposure, IgM: active disease.

- Anti HBs Ab: 3 months after infection. Gives immunity

- HBeAg and DNA= replication= active disease

Acute Hepatitis B Virus Infection with Recovery

Typical Serologic Course
Symptoms
HBeAg anti-HBe
Titer

Total anti-HBc

HBsAg IgM anti-HBc anti-HBs

0 4 8 12 16 20 24 28 32 36 52 100
Weeks after Exposure
HBV

HCV

- Anti HCV Ab: Total (IgG): appears few weeks after infection. IgM: recent infection.

- HCV RNA: earliest to detect in acute infection

Sequelae of acute hepatitis

- Complete recovery: is the rule in the great majority of HAV & HEV, most HBV, and
few HCV
- Relapse: as the original disease
- Fulminant hepatitis : Acute liver failure complicated by hepatic encephalopathy. If
the course is very rapid, jaundice may be not have time to appear!! Occur in 1% of
cases of acute hepatitis A or B. Hepatitis E is a common cause in Asia. Fatal in most
case.
- Prolonged cholestasis
- Chronicity: hepatitis, cirrhosis, carrier state, hepatocellular carcinoma (HCC)

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Treatment of acute hepatitis

- Rest: till symptoms and lab are normal

- Normal diet. Heavy diet is nauseating: avoid it! Stop alcohol and hepatotoxic drugs!
- Symptomatic treatment
… If there is nausea: domperidone

… If there is itching: cholestyramine

- Prevent transmission

Hepatitis A Virus

First identified in 1973, classified as Picornavirus, contains single stranded RNA

Spread of infection: Fecal-oral transmission, in poor countries, incubation period 2-6

weeks.

- Person to person contact

o living with someone who has hepatitis A

o in child care centers (especially centers that have children in diapers) where a
child or an employee has hepatitis A

- Eating food contaminated with hepatitis A virus

o fruits, vegetables, or other food contaminated during handling

o Eating raw shellfish harvested from sewage-contaminated water

- Ingesting contaminated water or ice.

Complications: Usually HAV infection runs a benign course, rarely cholestasis, relapse
and fulminant hepatitis might occur specially in adolescents and young adults.

Age Shift in HAV infection

HAV may affect adolescents and adults with more prolonged and severe form of clinically
manifested disease.

Hepatitis A Vaccine

HAV vaccine is usually given as 2 doses over a 6-18 month period (HAV vaccine is
approved for persons ≥ 1 year of age)

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Hepatitis A vaccines are safe and effective; protection will probably last for at least 20
years. It is indicated for:

- All children at age 1 year (i.e., 12–23 months).

- Children and adolescents ages 2–18 who live in states or communities where routine
Hepatitis A vaccination has been implemented because of high disease incidence.
- Persons traveling to or working in countries that have high or intermediate rates of
Hepatitis A.
- Persons who have occupational risk for infection.
- Persons who have chronic liver disease.

Additional methods of prevention

- Boiling or cooking food and beverage items for at least 1 minute to 185°F (85°C)
inactivates the virus (makes the virus NOT infectious)

- When in countries where hepatitis A is common

… Do not drink beverages (with or without ice) of unknown purity

… Do not eat uncooked shellfish

… Do not eat uncooked fruits and vegetables that are not peeled or prepared by
you personally

- Wash your hands after using the toilet or changing a diaper and before preparing or
eating food

- Wear gloves if you have to clean surfaces contaminated with stool (e.g., diaper
changing tables)

- Immune globulin (IG) (preparation that contains hepatitis A antibodies) can be used
before exposure to HAV and within 2 weeks of HAV exposure to prevent infection.
IG can be used for all age groups.

Treatment

- No specific medical treatment

- Once fully recovered, the individual:

o has lifelong protection against HAV

o Is no longer infected and cannot give the infection to others.

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 Chronic Hepatitis
Definition: Inflammation of the liver cells that lasts ≥ 6 months.
Can persist for years, even decades. In most people, it is mild and does not cause
significant liver damage. In some people, continued inflammation slowly damages the
liver, eventually producing cirrhosis, liver failure, and sometimes liver cancer

Etiology:

- HCV (75%) ,HBV (15%) ± HDV : direct cytopathic effect and/or immune-mediated
- Drugs and alcohol: Through altered immune response, cytotoxic intermediate
metabolites or genetically determined metabolic defects:
- Isoniazid
- Methyldopa
- Nitrofurantoin
- Acetaminophen
- Non-alcoholic steatohepatitis (NASH)
- Wilson's disease
- Autoimmune hepatitis
- α1-AT deficiency
Symptoms

- Many patients are asymptomatic, especially in chronic hepatitis C

- Nonspecific malaise, anorexia, and fatigue are common, sometimes with low-grade
fever and upper abdominal discomfort
- Symptoms of cirrhosis if this occured.

Signs

- Palpable liver, splenomegaly, jaundice.

- Signs of cirrhosis or its complications.
- Extrahepatic manifestations in some cases of autoimmune hepatitis, HBV or HCV

Lab diagnosis

- The biochemical hallmark of chronic hepatitis is an increased serum transaminase

(AST and ALT). When inflammation is severe and/or prolonged, hepatic
dysfunction may become apparentÆ n serum bilirubin and INR/prothrombin
time, and p serum albumin
- Search for etiology:
Viral markers
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 NASH: Diabetes, dsylipidemia
Autoimmune markers:
Cu in urine, Ceruloplasmin in serum.

Liver biopsy

- Liver biopsy is essential for definitive diagnosis: to assess severity, detect etiology
and to plan for therapy.
- Histopathology examination of chronic hepatitis to assess degree of inflammation
and stage of fibrosis using different scoring systems(Modified Knodell's -Metavir).
Treatment of chronic hepatitis: According to the etiology.

Hepatitis B Virus
•

- First recognized in 1960s

- Scientifically classified as Hepadnavirus
- Contains deoxyribonucleic acid (DNA)

HBV Genetics

- Eight genotypes of HBV (labeled A though H) have been identified.

- The clinical significance of HBV genotypes is not as clear as that of hepatitis C virus
genotypes.

Although recent data have suggested that different HBV genotypes may be associated
with different rates of progression of liver disease and different rates of response to
interferon therapy, these data were not enough to recommend routine testing for HBV
genotypes in clinical practice.

HBV: epidemiology

- Hepatitis B virus (HBV) is 100 times more infectious than HIV.

- People who get infected with HBV can also get infected with the hepatitis D virus
(HDV)
- Parenteral transmission (Exposure to blood and blood products)
- Receiving untested blood (or product) transfusion
- Healthcare settings.
- Injection drug use: Sharing needles, syringes.
- Tattoos and body piercing
- Sharing personal care items, such as toothbrushes or razors with an infected person

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- Sexual transmission (sexual contact with an infected person without using a condom)
- Perinatal transmission( From an infected mother to her child at or after birth)
- Sporadic (unknown) transmission.

HBV seromarkers

- HBsAg: Rises first in infection. Indicates acute HBV infection

- HBeAg: Rises first in infection .Indicates active virus and infectious state.

- Anti-HBe: Rises after core antibodies. Indicates resolution of infection.

- Anti-HBc: IgG. Indicates exposure. Used to monitor chronic infection.

- Anti-HBc, IgM :First antibody to appear. Indicates acute HBV infection.

- Anti-HBs : Appears months after infection or vaccination. Indicates immunity.

Diagnosis of HBV

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 Fate of Acute HBV

Disease progression occurs in 15–40% of chronic hepatitis B patients

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Chronic phase of hepatitis B

- Inactive HBsAg carrier

- Chronic hepatitis

o ~ 90% of infants infected with HBV at birth

o ~ 30% of children infected at age 1- 5 years

o 2- 6% of people infected after age 5 years: adults have more symptoms than
children

- Cirrhosis (15-40%) ± its complications

- HCC: HBV is mutagenic even with no cirrhosis

Extrahepatic manifestations of hepatitis B

- Polyarteritis nodosa

- Cryoglobulinemia

- Glomerulonephritis

Hepatitis B Vaccine

- Hepatitis B vaccine is usually given as three doses over a 4-6 month period

o Hepatitis vaccines are safe and effective

ƒ protection will last for at least 15 years.

- Hepatitis B vaccine is recommended for:

o all infants

o all children and adolescents

o adults at increased risk

Other Ways to Prevent Hepatitis B

- Protection against blood and blood product transmission

o Blood bank supervision

o Prevent healthcare transmission (Universal precautions)

o Do not share toothbrushes, razors, or other personal care articles that

might have blood on them

o Avoid tatoo & body piercing or do the procedure in sterile fashion

- Prevent sexual transmission:

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 o Legitimate sexual practice. Protection of spouses: use condoms till vaccine
is protective

- Test pregnant ladies for HBV to protect babies

HBV Therapy

Goals of therapy: Primary aim is to eliminate or reduce HBV DNA to the lowest possible
level. Secondary aim: prevent progression to cirrhosis, liver cell failure (LCF), HCC

Who to treat?

Evidence of active HBV infection

1. HBV DNA > 104 copies ( 2000 IU)/ml in patients +ve or -ve for HBeAg.

2. Abnormal liver chemistry. Treatment may be offered to patients with a normal ALT
level, but it may be less efficacious.

3. Better to have liver biopsy before treatment to confirm clinical diagnosis document
severity of liver disease.

Egyptian MOH Regulations

HBeAg (+) OR HBeAg (-)

HBV DNA ALT ACTION

iu/ml

≥2000 >ULN Treat

≥2000 Normal
Do LBx

Treat if ≥ A2 or F2

< 2000 > ULN

Do LBx

Treat if ≥ A2 or F2

< 2000 Normal + Do LBx

Clinical or imaging evidence of Treat if ≥ A2 or F2

CLD

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 Treatment Landscape

- Treatment has advanced dramatically due to the introduction of new agents with
different safety, efficacy, and resistance profiles

- Cytokines: Interferon (1992), Peg Interferon a-2a (2005)

- Nucleoside Analogue: Lamivudine (1999) Entecavir (2005) Telbuvidine (2006) .
- Nucleotide Analogue Adefovir dipivoxil (2003) Tenofovir(2008)
Nucleoside analogues for the treatment of HBV

- All have high response rate, but need to be continued for >1 year.

- AllÆ resistant mutants. Common with prolonged lamivudine, rare with others

- All can affect kidneys: rare with lamivudine, common with others

- All taken orally once/day

- Lamivudine (Epivir, Zeffix) 100mg/d

- Adefovir dipivoxil (HepSera) 10 mg/d

- Entecavir (Baraclude) 0.5 mg/d

- Patients who have HBeAg(+ ve) or patients who have Delta virus infection will be
treated by: Peg IFN

- for 6 month if HBeAg Seroconversion occurs continue to12 months

- If no HBeAg Seroconversion Treatment can then be switched to antiviral till

seroconversion. Then for 6-12 months after HBeAg serconversion

Naive patients who have HBeAg (- ve)

1-Entecavir ( 0.5 mg/dl O.D)

2-Tenofovir (300 mg/day)

Special groups

- Compensated Cirrhosis: Entecavir 0.5 mg or Tenofovir 300mg daily

- Decompensated Cirrhosis: Entecavir 1 mg daily.

- Renal Insufficiency: Entecavir preferred with dose adjustments according to

creatinine clearance.

- Pregnant females Lamivudine or Tenofovir 300 mg are the only drugs which could
be used in pregnant women and should be used during the last trimester in HBV-
DNA positive(≥ 10⁵ IU/ML) ladies even if they do not have liver disease to decrease
chance of new-born infection. - HBIG and first dose of HBV vaccine for the baby
in the first 6-12 hours after delivery.After labour, re-evaluate the condition and
consider treatment according to the previous guidelines.
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 - Co-infected patients with HCV: Peg IFN + Ribavirin

Follow up

I) Monthly visits for receiving medications and follow up for side effects and relapsing
symptoms.

II) Checking liver enzymes every 3 months.

III) Serum creatinine is done every 3 months in those receiving Adefovir.

IV) Liver function tests, complete blood count, A.F.P., Abdominal U/S & HBV/DNA by
PCR quantitative is done every 6 months

Patients with positive viremia after one year of therapy are considered non responders.

Antiviral Resistance

The genetic barrier to resistance refers to the number of mutations that the virus must
accumulate in order to replicate efficiently in the presence of the antiviral agent.

The genetic barrier to resistance is partly dependent upon the structure of the antiviral
compound and the constraints imposed by the ability of the viral polymerase to tolerate
compensatory mutations without significantly impairing its enzymatic activity.

Thus, an agent with a high genetic barrier to accumulation of mutations will naturally have a
lower likelihood of developing resistance.

Nomenclature of Antiviral Resistance

- Primary Non-response.

- Virological Breakthrough.

- Biochemical Breakthrough.

- Genotypic Resistance.

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 Hepatitis C Virus
- First identified in 1989. Scientifically classified as Flavivirus . Contains ribonucleic
acid (RNA)

Epidemiology of HCV:

- Affects more than 200 000 people all over the world, it has at least 6 genotypes with
many subtypes.
- Egypt is among the highest prevalence countries with 90% having genotype 4.

HCV Spread

- Same as HBV but to a lesser extent!

- Exposure to blood and blood products
- Receiving untested blood (or product) transfusion
- Healthcare settings.
- Injection drug use: Sharing needles, syringes or “works” (e.g., water, cookers,
cotton, spoons) when “shooting” drugs
- Tattoos and body piercing
- Sharing personal care items, such as toothbrushes or razors with an infected
person.

- Poor Injection Practices and their Worldwide Consequence

ƒ Breaks in injection safety reported in many countries
ƒ Re-use of equipment in the absence of sterilisation
ƒ Improper cleaning and sterilization practices
ƒ Contamination of sterile equipment/medication
ƒ Overuse of injections frequent
ƒ High prevalence of HCV

HCV PREVENTION

- Blood screening anti-HBV core, HCV PCR

- Avoid unnecessary injections and reused syringes
- Safe medical procedures
- Control of community acquired infections: Barbers , Tattooing, circumcision
- Interfamilial spread control: Razors , toothbrush , shaving tools,…

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 Projection of Lifetime Outcomes in HCV Infection

End-stage disease,
HCC, Liver Treatment Failure Sustained Response
transplant, death

Factors that may affect the natural history of HCV infection

- Consistently normal ALT levels

- Therapy
- Steatohepatitis
- HIV co-infection
- HBV co-infection (HBsAg) accelerate disease progression
- Alcohol intake
- Smoking

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Factor that probably does not affect the natural history of HCV infection: Viral load

HCV and Schistosomiasis Concomitant HCV and Schistosoma mansoni infection is

common in Egypt and has a severe impact on the course of liver disease in this
population. This may result in increased viral replication and more aggressive
progression to fibrosis. Coinfected patients had significantly high HCV-RNA titres .

Dual infections of schistosomiasis and viral has impact on response to anitiviral therapy.

Thus screening for active schistosomiasis and treating the infection prior to initiating
therapy is mandatory

HCV Treatment

The goal of treatment is to prevent sequelae of HCV infection; this is mainly achieved by
elimination of the virus.

The standard of care in genotypes 1 and 4 was PEG-IFNα2a (180 μg) per week plus
daily ribavirin (11-15/mg/kg/day) for 48 weeks in Or PEG-IFN α2b(1.5 μg/kg) per week
plus daily ribavirin (11-15/mg/kg/day) for 48 weeks. Since 2012 a new era of anti HCV
therapy began with the introduction of oral Directly Acting anti-Viral(DDAs)

{ Interferons are a group of proteins with antiviral activity, growth regulatory

properties, and a wide variety of immunomodulatory activities. There is evidence
that, when interferon α is used therapeutically in chronic hepatitis B or C and in
certain malignancies, it can precipitate or exacerbate autoimmune endocrine diseases

{ Ribavirin is a synthetic nucleoside analogue. The mechanism by which the

combination of Ribavirin and an interferon product exerts its effects against the
hepatitis C virus has not been fully established.

Approach to patients with anti-HCV

{ When anti-HCV is present, a single determination of ALT level gives limited

information about the severity of the underlying liver disease.

{ Patients who initially have a normal ALT should undergo three measurements over a
six months period to confirm persistence of normal ALT levels.

{ When anti-HCV is present, HCV RNA determination should be performed.

{ If HCV RNA is negative, the presence of anti-HCV is probably due to past infection
while if HCV RNA is positive, ALT persistently normal ,and liver biopsy shows
minimal changes, annual follow-up is proposed, but no treatment is considered.

PRETREATMENT DIAGNOSTIC EVALUATION OF PATIENTS WITH

CHRONIC HEPATITIS C

{ Persons seropositive for anti-HCV in the presence of HCV RNA and compensated
liver disease are considered as potential candidates for antiviral therapy.

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 HCV Ab +ve

Clinical examination
Laboratory investigation
Ultrasonographic examination

Hepatic Medical problems Candidate for

decompensation Which interfere with Antiviral treatment
antiviral treatment
Double etiology
1.Autoimmune
Liver 2.NASH
cirrhosis 3.HBsAg +ve
Separate guidelines 4.Active Schistoma

Liver biopsy

Despite its complications and interpretation errors, liver biopsy remains the gold standard
for determining histological grade and stage to assess the current status of the liver and to
provide prognostic information for future disease progression.

The degree of liver fibrosis is an important predictor of response to therapy. Patients with
mild degree of fibrosis respond more better to treatment than patients with higher fibrosis
stage.

Directly Acting Anti-Viral Therapy DAAs

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Nucleotide Inhibitors possess pan-genotype activity since the NS5B active site is well
conserved across genotypes.

They are reported to have a high genetic barrier to resistance.

Treatment Protocol for Interferon Free Regimen

Inclusion Criteria

• HCV RNA positivity.

• Age: above 18 years.
Exclusion criteria: Any of the following :

• Total serum bilirubin > 3 mg/dl.

• Serum albumin <2.8 g/dl.
• INR ≥ 1.7.
• Platelet count < 50000/mm3.
• If any of these criteria is not caused by liver disease, the patient can be included in the
treatment protocol.
• HCC, except 4 weeks after intervention aiming at cure with no evidence of activity by
dynamic imaging (CT or MRI).
• Extra-hepatic malignancy except after two years of disease-free interval.
• In cases of lymphomas and chronic lymphocytic leukemia, treatment can be initiated
immediately after remission based on the treating oncologist report.
• Inadequately controlled diabetes mellitus (HbA1c > 9 %).
• Pregnancy or inability to use effective contraception.

Categorization of Patients

1-Easy to treat group

• Treatment naïve .
• Total serum bilirubin ≤1.2 mg/dl.
• INR ≤ 1.2.
• Serum albumin ≥3.5 g/dl.
• Platelet count ≥ 150.000/mm3

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 2-Difficult to treat group

• Peg-IFN treatment experienced.

• Total serum bilirubin > 1.2 mg/dl.
• Serum albumin < 3.5 g/dl.
• Platelet count < 150.000/mm3

Easy to treat groups can be treated by any of these regimens for 12 weeks:

Sofosbuvir +daclatasvir

Sofosbuvir + simeprevir.

Paritaprevir-r/ombitasvir

Sofosbuvir+ ledipasvir

Difficult to treat groups are eligible to be treated by any of the following regimens for 12
weeks:

Sofosbuvir +daclatasvir +ribavirin

Sofosbuvir + simeprevir

Sofosbuvir+ ledipasvir +ribavirin

Paritaprevir-r/Ombitasvir +ribavirin

Ribavirin Dosage: The starting dose of ribavirin is 600 mg/day.

A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability.

Follow-up of treatment

{ Once treatment has been decided for a particular patient, routine follow-up is planned.

{ Patients should return two weeks after initiation of therapy and subsequently every
four weeks.

{ At these encounters, the routine laboratory studies (ALT,AST, Bilirubin , Albumin,

Creatinine and CBC) should be obtained as well to monitor for signs of adverse
effects due to the drugs.

{ During each follow-up, signs and symptoms of possible adverse effects should be
evaluated.

Definitions of Response

x End of Treatment Response (EOT) :Undetectable HCVRNA at end of treatment(12 or

24 weeks).
x Sustained Virological Response SVR: Undetectable HCVRNA during the follow up (4
and 12 weeks) SVR4 and SVR12.

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x Non Response: Detectable HCVRNA at end of treatment (12 or 24 weeks).
x Breakthrough: Undetectable HCVRNA during treatment but subsequently return to
detectable at end of treatment(12 or 24 weeks).
x Relapse: Undetectable HCVRNA at end of treatment (12 or 24 weeks) but
subsequently return to detectable during the follow up (4 and 12 weeks).

Side effects of IFN/Ribavirin common ones are:

{ IFN: flu-like, neutropenia, thrombocytopenia, autoimmune disease (thryoiditis,

arthropathy), nALT!!

{ Ribavirin: hemolytic anemia

{ Both: depression, retinopathy

Others Related to ribavirin: Chest congestion, dry cough, and dyspnea,pneumonitis,

Sarcoidosis , Pruritus , Sinus disorders , Rash, Gout, Nausea, Diarrhea, Teratogenicity

Management of common side effects

FLU-LIKE SYMPTOMS

{ The most common side effects are mainly muscle aches, headaches and low-grade
fever which are seen in over 80 percent of patients.

{ Flu-like symptoms are most severe in the first 48 hours after interferon administration
and persist beyond the third month of therapy in only 10 percent of patients.

{ Patients should be advised to anticipate such symptoms and reassured that they tend
to improve with continued therapy. Patients may take acetaminophen (1 g 30 minutes
before injection) and increase their fluid intake.

Anemia

{ The etiology of anemia is multifactorial

{ IFN is a potent suppressor of all components of the bone marrow and inhibits
erythropoiesis, as evidenced by an inadequate reticulocyte response to anemia. In
these cases erethropeitin might be used cautiously.

{ IFN has also been associated with autoimmune hemolytic anemia.

{ RBV induced hemolytic anemia is dose dependent. Temporary dose reduction by

200mg/day might be needed

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