Clinical Pharmacy

1. Hepatitis

2. INTRODUCTION
• “Hepatitis is inflammation of the liver caused by a virus or a toxin”
• The major hepatotrophic viruses responsible for viral hepatitis are hepatitis A,
hepatitis B, hepatitis C, delta hepatitis, and hepatitis E.
• All share clinical, biochemical, immunoserologic, and histologic findings.
• Both hepatitis A and E are spread through fecal–oral contamination; whereas hepatitis
B, C, and delta are transmitted parenterally.
• Infection with delta hepatitis requires co-infection with hepatitis B.

3. • Each type of viral hepatitis causes a similar pathology with acute
inflammation of the liver.
• Types A and E are classically associated with an acute and sometimes
severe hepatitis which is invariably self-limited, but occasionally fatal.
• Hepatitis B causes acute hepatitis in adults and 5% of patients
become chronic carriers, while 95% of patients infected in the
neonatal period are chronically infected.
• Hepatitis C rarely causes an acute hepatitis but up to 85% of patients
become chronic carriers.
• Both viruses cause chronic liver inflammation or hepatitis, cirrhosis
and hepatocellular carcinoma.

4. HEPATITIS A
• Self-limiting, acute viral infection, rarely fatal.
• Incubation period 15 – 50 days.
• Spread through fecal-oral route, person to person contact, ingestion
of contaminated food or water.
• Children at higher risk – mostly asymptomatic.
• Mostly linked to poor socioeconomic status.
• Rarely spread through blood transfusion.

5. ETIOLOGY
• RNA virus belonging to the genus Hepatovirus of the Picornaviridae
family.
• Stable in harsh environment.
• For inactivation – heating of food at 85 (185 ) for 1 minute or
℃ ℉
treatment with sodium hypochlorite in 1:100 dilution.
• Multiple genotypes exist – type I and III most common.

6. PATHOPHYSIOLOGY
• Infection is usually acute, self-limiting and confers lifelong immunity
• HAV’s life cycle in the human host classically begins with ingestion of the virus.
• Absorption in the stomach or small intestine allows entry into the circulation and
uptake by the liver.
• Replication of the virus occurs within hepatocytes and gastrointestinal epithelial cells.
• New virus particles are released into the blood and secreted into bile by the liver.
• The virus is then either reabsorbed to continue its cycle or excreted in the stool.
• The enterohepatic cycle will continue until interrupted by antibody neutralization
• On biopsy, acute hepatitis is marked by hepatocellular degeneration, inflammatory
infiltrate, and hepatocyte regeneration.
• Hepatocellular degeneration occurs as a result of immune-mediated
injury

7. CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
• Phase 1 (viral replication phase) – Patients are asymptomatic during this
phase; laboratory studies demonstrate serologic and enzyme markers of
hepatitis.
• Phase 2 (prodromal phase) – Patients experience anorexia, nausea,
vomiting, alterations in taste, arthralgias, malaise, fatigue, urticaria, and
pruritus.
When seen by a health care provider during this phase, patients are often
diagnosed as having gastroenteritis or a viral syndrome.

8. • Phase 3 (icteric phase) – Patients may note dark urine, followed by pale colored stools;
in addition to the predominant gastrointestinal (GI)
symptoms and malaise, patients become icteric and may develop right
upper quadrant pain with hepatomegaly.
Phase 4 (convalescent phase) – Symptoms and icterus resolve, and liver
enzymes return to normal.
PHYSICAL EXAMINATION
• Icteric sclera, skin and secretions.
• Mild weight loss of 2-5 kg.
• Hepatomegaly.

9. DIAGNOSIS
A diagnosis of HAV is based on clinical criteria of an acute onset
of fatigue, abdominal pain, loss of appetite, intermittent nausea and
vomiting, jaundice or elevated serum aminotransferase levels, and
serologic testing for IgM anti-HAV.
Serologic testing is necessary to differentiate the diagnosis from other
types of hepatitis.

10. TREATMENT
• Supportive care.
• Mainly Non-Pharmacologically treated.
• Active immunity can be achieved through vaccination (HAVRIX,
VAQTA, AVAXIM)

11. HEPATITIS B
• Double strand DNA with partial single strand virus.
• 7 genotypes of HBV exist (A to H), Genotype C is the most important type.
TRANSMISSION
• HBV is transmitted sexually, parenterally, and perinatally.
• In areas of high HBV prevalence, perinatal transmission from mother to
infant is most common, whereas in areas of intermediate prevalence,
horizontal transmission contact, both homosexual and heterosexual, and
injection-drug use are the predominant forms of transmission in low endemic countries.
• The virus is detectable in moderate quantities in semen, vaginal fluid, and
saliva, and is present in low concentrations in urine, feces, sweat, tears, and
breast milk.
• Transmission can occur through contact with infected body fluids in the
absence of blood, as the virus may be stable in the environment for a
number of days.

12. PATHOPHYSIOLOGY
• Upon infection, replication of the virus begins by attachment of
the virion to the hepatocyte cell surface receptors.
• The particles are transported to the nucleus where the DNA is
converted into closed circular DNA that serves as a template for
pregenomic RNA.
• Viral RNA is then transcribed and transported back to the cytoplasm
where it can alternatively serve as a reservoir for future viral
templates or bud into the intracellular membrane with the viral
envelope proteins and infect other cells

13. • MAIN ANTIGEN CAUSING HBV
• The HBsAg is the most abundant of the three surface antigens and is
detectable at the onset of clinical symptoms.
• Its persistence past 6 months after initial detection corresponds to chronic
infection and poses an increased risk for cirrhosis, hepatic decompensation,
and Hepatocellular carcinoma (HCC).

14. • CIRRHOSIS
• Cirrhosis results as liver attempts to regenerate while in an environment
of persistent inflammation.
• Continued alcohol consumption exacerbates hepatocellular damage.
• In compensated cirrhosis, patients are either asymptomatic or have mild
symptoms of epigastric pain and dyspepsia.
• During cirrhosis, the liver enters a cycle of ongoing liver damage, fibrosis,
and attempts at regeneration.
• HEPATOCELLULAR CARCINOMA
• HBV is a well-known risk factor of Hepatocellular carcinoma.
• The development of HCC can be insidious, in the absence of cirrhosis or in
the presence of clinically silent, compensated cirrhosis.
• Many patients with HCC have no signs of decompensated cirrhosis.

15. CLINICAL PRESENTATION
• Initial or acute phase: the HBV enters a 4- to 10-week incubation period,
during which antibodies toward the HBV core are produced and the virus
replicates profusely.
• Active viral replication results in high serum HBV DNA levels and HBeAg
secretion.
• Symptoms, if they do occur, include fever, anorexia, nausea, vomiting,
jaundice, dark urine, clay-colored or pale stools, and abdominal pain.
• The initial phase is considered immunotolerant because no hepatic injury is
sustained, as evidenced by generally normal ALT levels. Patients are highly
infectious during this time.
In perinatally acquired infections, and in young children, the phase can last
for decades–until adulthood

16. • Immunoactive phase: marks a decrease in HBV DNA levels with
ongoing secretion of HBeAg. Patients are symptomatic with
intermittent flares of hepatitis and marked increases in ALT levels.
• The phase can last a few weeks in acute disease, and for years in
patients with chronic disease.
• The final phase is seroconversion and is defined by the replacement
of HBeAg with anti-HBeAg.

17. CLINICAL PRESENTATION
Chronic HBV: Patients who continue to have detectable HBsAg and HBeAg
and a high serum titer of HBV DNA for more than 6 months have chronic HBV
SIGNS AND SYMPTOMS
• Easy fatigability, anxiety, anorexia and malaise.
• Ascites, jaundice, variceal bleeding, and hepatic encephalopathy can
manifest with liver decompensation.
• Hepatic encephalopathy is associated with the hyperexcitability, impaired mentation,
confusion, obtundation and eventually coma.
• Vomiting and seizures.
PHYSICAL EXAMINATION
• Asterixis.
• Spider angioma.
• Icteric sclera skin and secretion.
• Decreased bowel sounds increased abdominal girth and detectable fluid
wave

18. TREATMENT
TREATMENT GOALS
• The goals of therapy are to suppress HBV replication and prevent disease
progression to cirrhosis and HCC. The loss of HBsAg is becoming an
increasingly more important goal in therapy.
• Some patients with chronic HBV infection should be treated. Treatment
recommendations consider the patient's age, serum HBV DNA and ALT levels, and
histologic evidence and clinical progression of the disease.
NON-PHARMACOLOGICAL TREATMENT
• Avoid alcohol
• Should be vaccinated
• Avoid Sexual and household contacts
• Consult doctor before any medication

19. PHARMACOLOGICAL TREATMENT
• INTEFERON:
• IFN-α2b therapy was the first approved therapy for treatment of HBV and
improves long-term outcomes and survival.
• Acting as a host cytokine, it has antiviral, antiproliferative, and
immunomodulatory effects in chronic HBV.
• Duration of therapy is finite – optimal duration is unclear – 12 months
duration is associated with sustained viral response. Therapy inconvenience
include three times a week injections.
• Has been replaced by peg-interferon – ease of administration and less side
effects. Not routinely used in decompensated cirrhosis – better results in
compensated.
Side effects of Peginterferon therapy
- Fatigue
- Fever
- Musculoskeletal pain
- Headache
- Nausea
- Depression

20. • LAMIVUDINE
• Lamivudine, a nucleoside analog, has antiviral activity against both HIV
and HBV.
• It is dosed at 100 mg daily; the optimal duration of treatment is unknown.
In both HBe Ag-positive and negative patients, lamivudine demonstrates
profound viral suppression.
• ADEFOVIR
• The drug acts by inhibiting HBV DNA polymerase.
• It is dosed at 10 mg daily for 1 year.
• A 48-week course of treatment is effective in improving histologic findings,
reducing serum HBV DNA and ALT levels, and increasing HBe Ag
seroconversion in both HBe Ag-negative and positive patients.

21. ENTECAVIR
• Entecavir is a guanosine nucleoside analog that acts by inhibiting HBV
polymerase.
• An oral agent, it is more potent than lamivudine in suppressing serum
HBV DNA levels and is effective in lamivudine-resistant HBV.
• The drug is dosed at 0.5 mg daily in non–lamivudine resistant infections
and at 1 mg daily in lamivudine-refractory patients.

22. HEPATITIS C
• HCV is approximately 5 times as common as HIV and is responsible for an
estimated 10,000 chronic liver disease-associated deaths per year.
• Most acute infections are asymptomatic and the course of the infection is
insidious. As a result, many patients are not diagnosed until significant
disease progression.
• HCV is the most common blood-borne pathogen and is most often acquired
through injection drug use, coinfection with sexually transmitted diseases,
multiple sexual partners.

23. ETIOLOGY
• HCV is a single-stranded RNA virus of the family Flaviviridae notable for lacking a
proofreading polymerase and enabling frequent viral mutations
• 6 major genotypes, genotypes are further classified into subtypes (a, b, c,
etc.), genotype 1 and 2 are common with genotype 1 most common
• Infections caused by these genotypes lead to cirrhosis, end-stage liver
disease (ESLD), or Hepatocellular carcinoma (HCC)
• TRANSMISSION
• Sexual
• Vertical (mother-to-infant)
• Percutaneous exposure to blood

24. PATHOPHYSIOLOGY
In the vast majority of cases, an acute HCV infection leads to chronic infection.
The immune response in an acute HCV infection is mostly insufficient to eradicate the virus.
During the early phases of infection, natural killer cells are activated as HCV RNA levels rapidly rise.
A combined effort of HCV specific CD4 and CD8 T lymphocytes and interferon co-expression
decrease viral replication.
The eradication of HCV by cytotoxic T lymphocytes may occur either as a result of induced apoptosis
by infected hepatocytes or by the release of interferon to stifle viral replication.
The extent of hepatocyte apoptosis may correlate with the course of the disease.
Liver damage and HCC are associated with high levels of hepatocyte apoptosis.
Low levels of apoptosis are associated with viral persistence.
Moreover, CD4 T-helper cells are unlikely to mediate liver injury, but rather may promote an
environment conducive for other immune responses damaging to the liver.
Although HCV infects less than 10% of hepatocytes, up to 20% of cells are activated for apoptosis

25. CLINICAL PRESENTATION
• In an acute HCV infection, most patients are asymptomatic and
undiagnosed.
• HCV RNA is detectable within 1 to 2 weeks of exposure and levels rise quickly during the
initial weeks. The HCV RNA levels plateau at 105 to 107 international units/mL and precede a
peak in ALT levels and the onset of symptoms.
• Rising ALT levels indicate hepatic injury and cell necrosis. It is not unusual for levels to exceed
values 10 times the upper limits of normal.
• Approximately one-third of adults will experience some mild and
nonspecific symptoms, including fatigue, anorexia, weakness, jaundice,
abdominal pain, or dark urine
• Up to 85% of acutely infected patients will go on to develop a chronic HCV
infection, defined as persistently detectable HCV RNA for 6 months or
more.
• Additional symptoms include right upper quadrant pain, nausea, or poor
appetite

26. DIAGNOSIS
• Some patients are diagnosed after persistently abnormal
transaminases.
• Unfortunately, those patients who present with symptoms typically
have
advanced disease.
• A diagnosis of chronic HCV is confirmed with a reactive enzyme
immunoassay for anti-HCV.

27. TREATMENT
• Before therapy is initiated, quantitative HCV testing, genotyping, and a liver
biopsy are performed.
• Quantitative amplification assays for HCV RNA are performed in patients
who are candidates for therapy to obtain baseline information on the viral
load.
• A baseline HCV RNA level serves as a prognostic indicator for response and
is used to monitor virologic response once therapy is initiated.
• Genotyping is also necessary for treatment candidates because response to
therapy and duration of therapy vary depending on the infecting genotype.
• Liver biopsy is used to determine histologic grade and stage and to guide
therapy

28. NON-PHARMACOLOGICAL THERAPY
• All chronic HCV patients should be vaccinated against hepatitis A and B.
• Lifestyle changes are an important factor in reducing health consequences in hepatitis C.
• Avoiding alcohol, smoking, illicit drugs.
PHARMACOLOGICAL THERAPY
ASSESSING FOR HCV TREATMENT: All adults and children with chronic HCV
infection, including people who inject drugs, should be assessed for antiviral
treatment.
1. Treatment with pegylated interferon and ribavirin: Pegylated interferon in
combination with ribavirin is recommended for the treatment of chronic
HCV infection rather than standard non-pegylated interferon with ribavirin

30. 2. Treatment with telaprevir or boceprevir: Treatment with the direct-
acting antivirals telaprevir or boceprevir, given in combination with
pegylated interferon and ribavirin, is suggested for genotype 1 chronic
HCV infection rather than pegylated interferon and ribavirin alone.
3. Treatment with sofosbuvir: Sofosbuvir, given in combination with
ribavirin with or without pegylated interferon (depending on the HCV
genotype), is recommended in genotypes 1, 2, 3 and 4 HCV infection
rather than pegylated interferon and ribavirin alone (or no treatment
for persons who cannot tolerate interferon).

31. • 4. Treatment with simeprevir: Simeprevir, given in combination with
pegylated interferon and ribavirin, is recommended for persons with
genotype 1b HCV infection and for persons with genotype 1a HCV infection.
• PREVENTION
No vaccine is available for HCV.
• It is unlikely that a vaccine will be developed in the near future because of
the mutagenesis of the virus.
• Patients infected with HCV should be counseled on not being blood, organ,
donors.
• Although the likelihood of household transmission is small, patients should
minimize risks by avoiding possible blood or mucus exposure, such as not
sharing razors or toothbrushes and covering open wounds.

32. Hepatitis D
Hepatitis D virus (HDV) is an incomplete virus that can establish infection only in
patients simultaneously infected by HBV.
It is estimated that 5% of HBV carriers worldwide are infected with HDV.
It is transmitted permucosally, percutaneously or sexually, intravenous drug
users.

33. Hepatitis E
Hepatitis E virus (HEV) is endemic in India, Asia, the Middle
East and parts of Latin America.
It is an RNA virus which is transmitted enterically and leads to acute
hepatitis.
The symptoms of HEV are no different from other causes of viral
hepatitis, with an average incubation period of 42 days.
It was previously thought that the risk of death was increased in
pregnancy, especially in the final trimester, but more recent
data do not support this belief.

35. Case Study
• Mr JJ has a prescription for interferon alfa in pre-filled injection pens, 15 million
units per mL available as 1.5-mL cartridges. He is 27 years old and was an
intravenous drug user for 9 years. He is well known to you, having been a frequent
visitor to your pharmacy for some years. Mr JJ is of slight build, 180 cm in height,
and weighs 55 kg. He has been ‘clean’ for several months but has been in hospital
recently due to serious health problems. Laboratory tests showed increased levels of
serum alanine aminotransferase (ALT), antibodies to hepatitis Be antigen (HBeAg)
and DNA polymerase activity.

36. Questions:
1 What is hepatitis B infection?
2 What are the risk factors for developing hepatitis B virus (HBV) infection?
3 How is HBV infection diagnosed?
4 How can hepatitis B infection be prevented?
5 What is interferon alfa and how does it work in the management of HBV
infection?
6 What formulations of interferon alfa are available?
7 What additional treatments are used for chronic hepatitis B infection and how do
they act?
8 How should interferon alfa treatment be monitored?
9 What additional advice should be given?

37. What is interferon alfa and how does it work in the
management of HBV infection?
• The cytokine interferon-alpha (IFN-a) belongs to the interferon family (includes IFN-beta and
IFN-g). IFN-a is produced, in vivo, by leucocytes and inhibits viral replication and increases
expression of HLA class I molecules, thus aiding presentation of viral peptides to cytotoxic T
lymphocytes. IFN-α also activates natural killer (NK) cells, which destroy virally infected cells.

38. What formulations of interferon alfa are available?
• Therapeutic formulations contain a recombinant form of IFN-α (either interferon alfa-2a or
interferon alfa-2b). These are available as powders for reconstitution or as prefilled injection
pens. The drug is administered by subcutaneous injection (or intravenous for reconstituted
powder formulations) and intramuscular injection. The dosage is usually stated as units per
millilitre (refer to BNF for various preparations and dosages). Powder formulations of
interferon alfa-2b also contain glycine, sodium phosphate (mono- and dibasic) and human
albumin; prefilled pens contain sodium chloride, edetate disodium, polysorbate 80 and m-
cresol as a preservative. Interferon alfa-2a formulations contain excipients sodium chloride,
polysorbate, ammonium acetate, and benzyl alcohol as a preservative. Interferon alfa is also
approved for use in the treatment of several other disorders. Peginterferon formulations are
also available (polyethyleneglycol-conjugated interferon alfa). These have an extended
serum half-life compared with non-conjugated forms.

39. • What additional treatments are used for chronic hepatitis B infection and how do they act?
• Interferon alfa should typically be used in combination with antiviral agents such as lamivudine or
adefovir dipivoxil (refer to BNF), the first-line treatment for chronic hepatitis B infection.
Lamivudine and adefovir dipivoxil belong to a class of antiviral compounds known as nucleoside
analogues. These substances are incorporated into nascent DNA chains and prevent elongation of
the viral DNA. In this sense, they are also referred to as ‘chain terminators’.
• How should interferon alfa treatment be monitored?
• Mr JJ should be monitored regularly for efficacy. If there is no significant improvement in the
condition, as determined by laboratory measurements of liver function (ALT test) and viral DNA
load, then treatment with interferon alfa should be discontinued. In addition, white blood cell
counts should be monitored, as should cardiovascular function. Fluid replacement may be
required to correct hypotension.

40. • What additional advice should be given?
• The reported side-effects of interferon alfa include: cardiovascular problems such
as arrhythmia, tachycardia and hypotension in the absence of history of such
conditions, severe myelosuppression, depression and suicidal behaviour,
opthalmic disorders, anorexia and ‘flu-like’ symptoms and hypersensitivity
reactions. Mr JJ should be advised of these and of the actions to be taken. The
patient should be informed that under no circumstances should he switch
treatments as different formulations may contain different dosages. Furthermore,
he should be made aware of the proper disposal of used pens/syringes and to take
extra care if blood enters the dispensers, as described in the product literature.
Hepatitis B support groups are available. Dietary advice may be offered as
cytokine-based treatments often cause reduced appetite.