3. DEFINITION
• Acute viral hepatitis (AVH) is a systemic infection predominantly affecting the liver. It is
most often caused by viruses that are hepatotropic (hepatitis A, B, C, D, and E).
• Other viral infections may also occasionally affect the liver, such as cytomegalovirus
(CMV), herpes simplex, coxsackievirus, and adenovirus.
• Whereas hepatitis A and E are self-limiting, infection with hepatitis C and to a lesser
extent hepatitis B usually become chronic.
4. KEY POINTS
• A case of acute “hepatitis” maybe caused by a virus, a toxin, or may be the first manifestation of a chronic liver
disease.
• Acute viral hepatitis is almost always self-limiting.
• In almost every case, it is best to do nothing (except to stop medications such as the oral contraceptive pill).
• There is no role for vitamins; particularly in developing countries, intravenous vitamins are often given
unnecessarily.
• There is no role for restriction of proteins in uncomplicated acute hepatitis. In developing countries, patients
may already be deprived of
• proteins; this leads to protein deficiency, with the associated complications.
• Exercise should be started as soon as the patient feels fit to do so; there is no need to keep patients in bed.
• A raised serum alanine transaminase (ALT) level is the best indicator of acute hepatic injury, but does not reflect
the severity of the disease; values for bilirubin and international normalized ratios (INR) are required for this.
• All forms of AHV show the same symptoms.
5. KEY POINT
• The endemicity of the conditions should be taken into account — e.g., hepatitis A
predominantly affects children in endemic areas.
• It should be ascertained whether the condition is an acute infection or a flare-up of a
silent chronic infection.
• Other chronic liver diseases may present acutely — for example, autoimmune hepatitis.
• Consideration should be given to the transmission, and thus prevention and
vaccination where appropriate.
• In a pregnant woman with HBV, the infant should be protected with hepatitis B vaccine
and hepatitis B immunoglobulin (HBIg) at birth.
6. D E C I S I O N
A LG O R I T H M I N T H E
D I A G N O S I S O F
A C U T E H E PAT I T I S
HAV- hepatitis A virus;
HBc, - hepatitis B core
(antigen); HBsAg,- hepatitis B
surface antigen
HBV, - hepatitis B virus;
HCV, - hepatitis C virus;
HDV- , hepatitis D virus;
HEV, - hepatitis E virus;
7. DIAGNOSTIC
• In acute HCV, it is important to test for HCV RNA and anti-HCV immediately.
• If both are present, the condition is probably a flare-up of chronic HCV.
• If only HCV RNA is present, then the condition is probably acute HCV; the patient
should be followed up for the development of anti-HCV.
• The onset of drowsiness and/or coagulopathy in a patient with acute viral hepatitis is
always sinister.
9. DEFINITION AND PATHOGENESIS
• Hepatitis A virus (HAV) is an RNA-containing virus of the Picornaviridae family. The key
feature is that it is a self-limiting disease. Management of HAV should therefore be
supportive. The average HAV incubation time is 28 days, but it can vary from 15 to 45
days.
• HAV infection is self-limiting and does not require treatment; contacts should be
vaccinated (particularly in low incidence areas). There is no chronic infection; HAV
infection induces lifelong immunity. Some people with HAV will have relapses after 6–9
months. The risk of fulminant hepatic failure is very low (0.01–0.1%), but increases with
age and in those with preexisting liver disease. In patients over the age of 40, there is a
1% mortality rate.
10. EPIDEMIOLOGY: PREVALENCE AND
INCIDENCE
• There are an estimated 1.5 million cases of acute hepatitis A annually worldwide, or —
depending on local endemicity — around 150 per 100,000. Most of these occur in
areas with poor hygiene and a poor sanitation infrastructure.
11. TRANSMISSION
• HAV is found in the feces of individuals with acute HAV in the presymptomatic and
early phases of the disease. HAV is usually spread between individuals by oral contact
with something that has been contaminated by fecal matter from an HAV-infected
person — HAV transmission is fecal–oral. Most transmission is through contact with a
household member, tourist travel to an endemic area, contact with a sex partner who
has HAV, from an infection in an individual preparing food, or contact with babies in
nurseries. Poor hygiene and poor sanitation pose the greatest risks
12. RISK GROUPS/CIRCUMSTANCES FOR
HAV:
• Children living in poor sanitation and in areas with low hygiene
• Children living in areas with a high incidence of HAV
• Those participating in anal sex
• Users of injected illegal drugs (homeless)
• Poor sanitation
• Consumers of high-risk foods (e.g., raw shellfish)
• Day-care employees and family of children in day care
• People traveling to endemic areas
13. DIAGNOSIS AND DIFFERENTIAL
DIAGNOSIS
• All forms of acute viral hepatitis have the same initial presentation. HAV virus is reliably
diagnosed by anti-HAV immunoglobulin M (IgM); the presence of anti-HAV
immunoglobulin G indicates a previous infection). Persistent anti-HAV IgM can
sometimes be detected in patients with autoimmune hepatitis. In children, the illness is
usually asymptomatic. In adults, HAV infection is usually symptomatic.
14. THE PRINCIPAL SYMPTOMS ARE:
• Jaundice (yellowing of the skin and eyes)
• Fatigue
• Abdominal pain
• Loss of appetite
• Nausea
• Diarrhea
• Fever
• Dark urine
• Relapse with cholestasis or serum sickness
15. PRINCIPLES OF TREATMENT
• The subjective impression of the patient should guide the doctor’s approach. Neither hospital
admission, quarantine or bed rest, or medication (e.g., vitamin administration, dietary restrictions,
blood transfusions) are necessary.
• The treatment should be conservative and supportive. There is no specific medication for HAV
infection. Hygiene is very important — hands should always be washed after bathroom use. The
management should focus on treating the symptoms and identifying the small proportion of
patients with a particular risk of developing fulminant hepatic failure. Patients over the age of 40
and those with underlying chronic liver disease are most at risk.
• Contacts should be vaccinated.
• Oral contraceptive treatment and hormone replacement therapy should be stopped to avoid
cholestasis. Alcohol consumption is not advised.
16. PREVENTION
• There are a number of inactivated vaccines on the market. Vaccination for preexposure
prophylaxis (for example, with VAQTA or Havrix) provides long-term protection for up
to 20 years. Vaccination for postexposure prophylaxis should be given as early as
possible.
17. IMPROVE THE EPIDEMIOLOGY
SITUATION
• Improving sanitation and water supplies are the most important goals in the prevention of HAV
infection (as well as many other infections).
• Key items are:
• Building a better public health infrastructure
• Improving sanitation and water supplies
• Establishing health visitor action programs (education and training, hygiene, and handwashing)
• Development of easy and low-cost diagnostic kits.
• Preexposure vaccination for those at risk (travelers, military personnel, male homosexuals, day-care
employees).
• Postexposure vaccination for contacts of those with acute HAV.
• Always check for hepatitis B immunity and vaccinate when needed (the World Health Organization
advocates universal vaccination for hepatitis B).
19. DEFINITION AND PATHOGENESIS
• HDV only co-occurs with HBV. Hepatitis D virus (HDV) is a defective single-stranded RNA virus
of the Deltaviridae family. It is an incomplete RNA virus that needs the hepatitis B surface
antigen to transmit its genome from cell to cell. It therefore only occurs in people who are
positive for the hepatitis B surface antigen. The mean incubation period varies from 60 to 90
days, but it can vary as widely as 30–180 days.
• Because HDV relies absolutely on HBV, the duration of the HDV infection is entirely
determined by the duration of the HBV infection. HBV replication is suppressed in most HDV-
infected individuals. HDV infection can occur either as a co-infection with HBV or as a
superinfection in those with chronic HBV.
• Co-infection:
• Severe acute disease
• Low risk of chronic infection
• Indistinguishable from acute HBV
• Superinfection
• Usually develops acute exacerbation of chronic hepatitis
• High risk of chronic liver disease
20. EPIDEMIOLOGY
• There is a decreasing prevalence of both acute and chronic hepatitis D in the
Mediterranean area and in many other parts of the world, which has been attributed to
a decline in the prevalence of chronic HBsAg carriers in the general population.
• New foci of high HDV prevalence are continuing to be identified, as in the case of the
island of Okinawa in Japan and areas of China, northern India, and Albania. Global
incidence figures for the prevalence are not available.
21. RISK FACTORS AND TRANSMISSION
• Modes of transmission:
• Percutaneous exposure (injecting drug users)
• Permucosal
• Sexual contact
• The mode of transmission of HDV is similar to that of HBV.
• The risk of fulminant hepatitis in co-infection is 5%. Otherwise, the prognosis of co-
infection is generally good. The prognosis for superinfection is variable. There is some
suggestion that the chronic liver disease is more severe, but this is not universally the
case.
22. DIAGNOSIS AND DIFFERENTIAL
DIAGNOSIS
• During acute HDV infection, HDV Ag and HDV-RNA (PCR) appear early, and anti-HDV
of the IgM class appears later. It may take 30–40 days after the first symptoms appear
before anti-HDV can be detected.
23. SEROLOGY IN THE CASE OF CO-INFECTION
• In most individuals with HBV–HDV co-infection, both IgM antibody to HDV (anti-HDV)
and anti-HDV IgG are detectable during the course of infection.
• However, in about 15% of patients, the only evidence of HDV infection may be the
detection of either anti-HDV IgM alone during the early acute period of illness or anti-
HDV IgG alone during convalescence.
• Anti-HDV generally declines to subdetectable levels after the infection resolves, and
there is no serologic marker that persists to indicate that the patient was ever infected
with HDV.
• Hepatitis delta antigen (HDAg) can be detected in serum in only about 25% of patients
with HBV–HDV co-infection. When HDAg is detectable, it generally disappears as
HBsAg disappears, and most patients do not develop chronic infection.
24. SEROLOGY IN THE CASE OF
SUPERINFECTION
• In patients with chronic HBV infection who are superinfected with HDV, several
characteristic serologic features generally occur, including:
• The titer of HBsAg declines at the time HDAg appears in the serum.
• HDAg and HDV RNA remain detectable in the serum, because chronic HDV infection
generally occurs in most patients with HDV superinfection, in contrast to the case with
co-infection.
• High titers of both IgM and IgG anti-HDV are detectable, which persist indefinitely.
HBV replication is usually suppressed.
25. ACUTE HEPATITIS D MANAGEMENT
• No specific treatment is available. Some success has been
reported with the viral DNA polymerase inhibitor foscarnet.
26. PREVENTION
• HBV–HDV co-infection is prevented by vaccination against HBV.
• Preventing HBV infection prevents HBV–HDV superinfection.
• Education to reduce risk behaviors in individuals with chronic HBV
infection.
• HDV co-infection can be prevented with HBV preexposure or
postexposure prophylaxis.
28. DEFINITION AND PATHOGENESIS
• The hepatitis B virus (HBV) causes acute and chronic liver disease and is endemic in many
areas of the world. The virus is transmitted through contact with blood or other body
fluids from an infected person.
• When transmission occurs vertically (from mother to child) or horizontally to small
children (during play, from household contacts etc), the infection usually becomes
chronic.
• By contrast, when transmission occurs in adolescents/adults—usually via sexual contact,
contaminated needles (“sharps”), and less often from transfusion of blood products—the
infection usually resolves unless the individual is immunocompromised (e.g., infected
with human immunodeficiency virus).
• Education about how to avoid risky behavior plays an important role in HBV prevention.
• HBV is an important occupational hazard for health-care workers.
• A safe and effective vaccine for HBV has been available since 1982 and is 95% effective at
preventing new infections.
29. KEY POINTS
• Every individual with chronic HBV infection (CHB) represents an opportunity for further
cases to be prevented. It is important to take the time needed to educate patients and to
explain the risks that the infection poses to the patients themselves and to others.
• HBV vaccination is highly effective, and universal vaccination at a young age—preferably at
birth in high-endemicity countries—is desirable.
• At the very least, vaccination should be offered to all individuals who are at risk.
• Pregnant women must be screened for HBV before delivery, as this offers an opportunity to
prevent another generation of chronically infected persons.
• Although most patients with CHB do not develop hepatic complications, all infected
individuals are at increased risk of progressive liver fibrosis, leading to cirrhosis and
ultimately to hepatic decompensation and/or hepatocellular carcinoma (HCC). Fortunately,
effective treatment can reduce the risk of HBV-related complications.
30. EPIDEMIOLOGY
• More than 2 billion people alive today have serologic evidence of past or present HBV
infection.
• 250 million are chronically infected and are at risk of developing HBV-related liver
disease [6].
• Some 15–40% of chronically infected patients will develop cirrhosis, progressing to
liver failure and/or HCC during their lifetime.
• Every year, there are over 4 million acute clinical cases of HBV.
• An estimated 1 million people die each year from chronic HBV infection and its
complications: cirrhosis or primary liver cancer [7].
• HBV-related liver deaths (2010) are estimated at 786,000 annually
31. EPIDEMIOLOGY
• The prevalence of HBV varies markedly between different regions of the world. In the
literature, a distinction is usually made between areas of high, medium, low, and very low
endemicity.
• In high-endemicity areas , approximately 70–90% of the population become infected with
HBV before the age of 40, and 8–20% of people develop chronic infection with persistent
carriage of the virus.
• The prevalence of CHB ranges from over 10% of the population in South-East Asia, China,
the Amazon area, and sub-Saharan Africa to less than 1% in Western Europe and North
America.
• Overall, approximately 45% of the global population live in areas of high endemicity. With
globalization, many individuals with HBV are immigrating to areas in which the CHB rate
has traditionally been low and the condition may easily go unnoticed.
32. PATHOGENESIS
• The chance that acute infection will become chronic is 70–90% for perinatally acquired
(vertical) infection and 20–50% for (horizontal) infections acquired during early
childhood (under the age of 5 years).
• The chance of developing CHB is in the range of 1–3% in immunocompetent adult-
acquired HBV infections, with higher rates in immunosuppressed individuals.
• Eight (and possibly up to 10) genotypes of hepatitis B virus have been identified (A–H),
which differ in their geographic distribution and in their potential to affect the clinical
course of disease (Table 1). The current prevalence of HBV genotypes in different
regions is highly dependent on immigration patterns.
33.
34. CLINICAL PICTURE OF HEPATITIS B
• The outcome of HBV infection largely depends on the host–virus
interaction, mediated by the adaptive immune response. The virus-
specific T cell response is one of the key factors in the pathogenesis of
HBV infection. Viral variants may influence the course and outcome of
the disease. The effect of host factors on the progression of disease is
poorly understood. Only very rarely (when there is profound immune
suppression) does the hepatitis B virus probably become directly
cytopathic.
• The clinical course of HBV infection is variable and includes acute (self-
limiting) infection, fulminant hepatic failure, inactive carrier state, and
chronic hepatitis with chances of progression to cirrhosis and
hepatocellular carcinoma
35. RISK OF CHRONIC HBV INFECTION
• The risk of chronicity in acute HBV infection is related to age
at primary infection. Adults who become chronically infected
during childhood have a 15–25% lifetime risk of dying from
HBV-related cirrhosis or liver cancer, with a significantly
increased risk in men in comparison with women
36. PHASES OF HCB
• The following five—not necessarily sequential—phases can be identified
in chronic HBV infection(CHB).
• Immune-tolerant phase:
• — Characterized by high levels of serum HBV DNA, HBeAg positivity,
normal alanine aminotransferase (ALT) levels, and absent liver
necroinflammation.
• — Disease progression is minimal in patients who remain in this phase
[28].
• — Patients are highly contagious in this phase.
37. IMMUNE-REACTIVE PHASE
(HBEAG-POSITIVE CHB):
• — Patients enter this phase after a variable time, linked to the age when HBV infection
occurred.
• — The immune system becomes more active and the infected hepatocytes are
attacked.
• — Characterized by highly fluctuating, but progressively decreasing, HBV-DNA levels,
elevated ALT, and hepatic necroinflammation (HBeAg-positive CHB).
• — A prolonged immune-active phase with multiple ALT flares may result in
progressive liver fibrosis, leading to cirrhosis.
38. IMMUNE-CONTROL PHASE
(AND INACTIVE CARRIER STATE):
• — Transition into this phase as an outcome of the immune-active phase is marked by
seroconversion from HBeAg to anti-HBe positivity.
• — Characterized by low (< 2000 IU/mL) or undetectable serum HBV DNA, normal ALT
levels, and disappearance of liver necroinflammation (inactive carrier state).
39. REACTIVATION PHASE
(HBEAG-NEGATIVE CHB):
• — Despite HBe seroconversion, reactivation of HBV replication may occur due to the
selection of HBeAg-defective HBV mutants.
• — Characterized by positive anti-HBe antibody levels, fluctuating HBV DNA and ALT
levels, and a high risk of progression to severe hepatic fibrosis (HBeAg-negative CHB).
• — Periodic ALT flares with intervening normalization may make it difficult to
distinguish between HBeAg-negative CHB and inactive disease, and thus continued
follow-up is required before patients with normal ALT and low HBV DNA levels are
designated as inactive carriers.
• — Emerging evidence suggests that a low HBV DNA titer (< 2000 IU/mL) combined
with a low hepatitis B surface antigen (HBsAg) titer (< 1000 IU/mL) may help identify
inactive carriers, particularly those with genotype D infection
40. HBSAG-NEGATIVE PHASE:
• HBsAg-negative phase:
• — After HBsAg loss, low-level HBV replication may persist, with detectable HBV DNA in
the liver and rarely in the serum.
• — In patients with “occult” HBV infection, persistence of effective HBV immunological
control has been demonstrated.
• — Significant immunosuppression may lead to HBV reactivation, with reappearance of
HBsAg, known as “reverse seroconversion.”
42. PROGRESSIVE OF HCB
• CHB has a very variable course, ranging from silent subclinical infection to persistent
hepatitis with progressive fibrosis leading to cirrhosis, liver failure and/or liver cancer.
The determinants of disease outcome are incompletely understood, but include viral,
host, and environmental factors (Table 3), all of which interact. Viral determinants of
the prognosis have different significance depending on the stage of the disease.
43. THE DIAGNOSIS
• The diagnosis of acute hepatitis B is based on the detection of HBsAg and anti-HBc
(immunoglobulin M).
• During the initial phase of infection, markers of HBV replication—HBeAg and HBV
DNA—are also present.
• Recovery is accompanied by the disappearance of detectable HBV DNA, HBeAg
seroconversion to anti-HBe, and subsequent clearance of HBsAg with seroconversion
to anti-HBs and appearance of anti-HBc (IgG).
• The course of acute HBV should take place within 3 months of the diagnosis—chronic
HBV infection is characterized by persistence of plasma HBsAg for more than 6
months.
44. RESOLVED HBV INFECTION
• Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-HBc.
Anti-HBs sometimes becomes undetectable after many years. (Anti-HBs is frequently
undetectable if HBV infection occurred during childhood, as is seen in sub-Saharan
Africa). Notably, although these individuals are referred to as having “resolved HBV”
infection, trace amounts of HBV DNA remain in their livers for years and possibly even
lifelong. Immune control prevents viral expansion, but means that with severe
immunosuppression (e.g., with advanced human immunodeficiency virus (HIV)
coinfection, bone marrow transplantation, rituximab use, etc.), HBsAg may reappear
(reverse seroconversion) or viral replication may be detectable in the liver even without
the reappearance of serum HBV DNA. Immunity to HBV infection after vaccination is
characterized by the presence of only anti-HBs.
45. CHRONIC HBV INFECTION
• Diagnosis of chronic HBV infection is defined as the persistence of HBsAg for more than 6
months.
• It must first be established whether the individual is in the HBeAg-positive or HBeAg-
negative phase of the infection.
• Additional tests for markers of HBV replication—namely, HBeAg and serial measurements
of serum HBV DNA, in addition to ALT—should be carried out.
• This will in part determine whether the patient should be considered for HBV therapy.
• Both HBeAg-positive and HBeAg-negative patients, even if they have normal serum ALT
(women < 20 IU/L and men < 30 IU/L) and/or undetectable HBV DNA, still need to be
monitored lifelong, as the condition may change over time even if they remain
asymptomatic.
• Among individuals with chronic persistence of HBsAg, those with elevated serum ALT
concentrations should be followed more closely, preferably with serial HBV DNA
measurements.
46. CHRONIC HBV INFECTION
• It is important to know the lower limit of detection of the method used to measure HBV
DNA, as values that are persistently ≥ 2000 IU/mL will prompt consideration of antiviral
therapy.
• The decision on whether to initiate therapy depends on multiple factors (i.e., not just the
level of HBV DNA and/or ALT). If the liver disease appears to be progressing (as judged by
liver biopsy and noninvasive markers of inflammation and fibrosis such as transient
elastography), treatment should be considered.
• Additional tests for hepatitis C and hepatitis D should also be conducted in order to rule
out superinfection with other hepatitis virus(es), particularly in patients with elevated ALT
but low or undetectable HBV DNA.
• Other things to consider include drug-induced liver injury (due to supplements),
nonalcoholic steatohepatitis (NASH), and iron overload
47. OCCULT HBV
• Occult HBV infection refers to the persistence of HBV DNA in liver tissue (and in some
cases in serum) in individuals in whom hepatitis B surface antigen (HBsAg) is not
detectable in the blood, usually with positive anti-HBc.
• Occult HBV infection is prevalent worldwide, but its frequency is related to the prevalence
of overt HBV infection in a specific geographic area. Occult HBV is transmissible through
blood transfusions and organ transplantation.
• Blood products should be screened for HBsAg, anti-HBc, and ideally HBV DNA.
• Organs from donors with anti-HBc and/or anti-HBs should preferably be used only for
recipients who test positive for anti-HBs or HBsAg.
• Although the true relevance of occult HBV infection is unknown, it may be an additional
risk factor for HCC in anti-HCV–positive patients and in HIV-infected individuals. It may
also be associated with progression of chronic liver disease due to causes other than
HBV.
48. HBV REACTIVATION
• HBV replication is controlled by the host immune system. Immune suppression of any
kind can lead to a loss of immune control and subsequent HBV reactivation, which can
result in a range of consequences, from a subclinical increase in HBV DNA to icteric and
even fulminant and/or fatal liver failure. Reactivation occurs most frequently with cancer
chemotherapy, but may occur with other immunosuppressive or immunomodulator
therapy (e.g., targeted immunotherapy). The addition of systemic corticosteroids (SCS)
to inhaled corticosteroids increases the risk of HBV reactivation, especially when SCS are
administered chronically or at high doses
49. HBV REACTIVATION
• Preemptive treatment with a nucleoside/nucleotide analogue is recommended in HBsAg-
positive patients who are going to receive anticancer or immunosuppressive drugs. Treatment
should continue throughout the course of immunosuppression and for 6–12 months
afterwards, with follow-up monitoring to ensure that flares do not occur upon withdrawal of
antiviral therapy.
• Reactivation may also occur in patients who are HBsAg-negative but anti-HBc-positive (with or
without occult HBV DNA), but more significant immune suppression is required. Reappearance
of HBsAg is referred to as reverse seroconversion. The risk appears to be increased with
rituximab or other anti-CD20–based chemotherapy, probably due to the long-lasting
depletion of B cells. HBV DNA may increase even before HBsAg reappears in the serum.
Preemptive treatment with a nucleoside/nucleotide analogue reduces the risk of HBV
reactivation, but may not be required in all patients. Those who are not preemptively treated
should be monitored with serial HBsAg, ALT, and possibly HBV DNA with antiviral therapy
being started if HBsAg reappears or HBV DNA increases.
50. HCC SCREENING
• The aim is to detect tumors smaller than 3 cm in diameter, and preferably less than 2 cm, in order to
offer a potential for curative treatment. Screening for HCC is advocated in all cirrhotic patients, as they
are at the highest risk of developing HCC. However, in Africa and South-East Asia, where HBV infection is
acquired early in life, HCC may develop in a noncirrhotic liver.
• The AASLD recommends HCC surveillance in the following types of patients with CHB:
• Asian men over the age of 40 and Asian women over the age of 50
• All patients with cirrhosis, regardless of age
• Patients with a family history of HCC; any age
• Africans over the age of 20
• Any individuals with HBV/HIV coinfection
• Singal et al. showed that in a “real-world” clinical setting, a combination of ultrasound and alpha
fetoprotein (AFP) is the most effective strategy for detecting HCC at an early stage. The sensitivity
significantly improved to 90%, with a minimal loss of specificity (83%). AFP alone may be better than
ultrasound alone, as the reliability of ultrasound is very dependent on the skill and experience of the
ultrasonographe
51. BEFORE ANY FORM OF HBV THERAPY IS STARTED, AND
OPTIMALLY AT THE TIME OF FIRST PRESENTATION, THE PATIENT
NEEDS TO BE PROVIDED WITH INFORMATION ABOUT CHB AND
ITS TREATMENT. IMPORTANT INFORMATION INCLUDES:
• The dynamic clinical course of CHB.
• Most infections remain initially entirely asymptomatic, even in the case of severe disease.
• The need for regular lifelong monitoring.
• Possible transmission to contacts—family and contacts need HBV screening and vaccination of
those who are not immune to HBV, and referral for clinical evaluation of those who are HBsAg-
positive.
• Timing of the start of treatment.
• The need for absolute compliance with potentially long-term therapy.
• The need for absolute compliance with follow-up examinations both when the patient is on
treatment and when he/she is off treatment.
• The importance of alcohol abstinence and attention to the use of medications that may be
hepatotoxic or dangerous in patients with advanced liver disease (e.g., NSAIDs) should be
emphasized.
• Those who are not immune to hepatitis A should receive two doses of hepatitis A vaccine 6–18
months apart.
52. • information should be explained and discussed with the patient. In women of
childbearing potential, drugs that are considered safe in pregnancy are preferred,
because once a nucleoside or nucleotide has been prescribed it cannot be stopped in
those who remain HBeAg-positive. The patient needs to understand that cessation of
treatment may precipitate severe hepatitis, which can, rarely, lead to fulminant acute
liver failure, even in the absence of cirrhosis.
53. TREATMENT DEPENDS OF THE PHASE
OF CHB
• The phase of CHB can be determined on the basis of the
serological and virological profile—each type is characterized
by a distinct natural course, prognosis, and treatment
indications
54. 1 IMMUNE-TOLERANT CARRIER:
• Treatment not indicated.
• Appropriate longitudinal follow-up is crucial.
• Measure ALT every 3–6 months.
55. INACTIVE CARRIER:
• Treatment not indicated.
• Appropriate longitudinal follow-up is crucial.
• Assess ALT and HBV DNA levels every 3 months during the first year, then every 6
months.
• If the serum HBV DNA is < 2000 IU/mL and the HBsAg level is < 1000 IU/mL, the
probability of disease reactivation is low and patients may require less frequent
monitoring.
56. ACTIVE CHB TREATMENT:
• Treatment depend of HBeAg-positive CHB or HBeAg-negative CHB..
• The prognosis and management of CHB greatly depend on the phase of the disease and
the stage of liver fibrosis, and thus the risk of cirrhosis developing. Follow-up in CHB
HBsAg carriers includes:
• Continuation of diagnostic work-up.
• Assessment of the severity of the liver disease.
• — Laboratory tests for inflammation (ALT), hepatic function (bilirubin, albumin,
coagulation factors) and viral load (HBV DNA), if available.
• — Hepatic ultrasound examination.
• — Noninvasive measures to assess fibrosis (serum panels, transient elastography).
• — Liver biopsy, useful for determining the grade of necroinflammation and the stage of
fibrosis.
• — Liver biopsy. This can help exclude other coexistent causes of liver disease and clarify
the diagnosis when ALT and HBV DNA levels are discordant.
60. RESEARCH RESULTS ON THE TREATMENT OF HBEAG-
NEGATIVE AND HBEAG-POSITIVE CHRONIC
HEPATITIS B
61. HBV VACCINATION
• A program for universal vaccination of all newborns is a key step toward effective
control of HBV infection throughout the world. HBV vaccination has been shown to be
highly cost-effective. Vaccination prevents infection with HBV and thus reduces the
incidence of chronic hepatitis, cirrhosis, and HCC in the vaccinated population, as well
as reducing transmission by limiting the number of susceptible individuals.
• Active vaccination with hepatitis B vaccine
• HBsAg is the antigen used in the formulation of the hepatitis B vaccine. It is produced
from yeast through recombinant DNA technology. It is available as a single-agent
preparation or as a fixed combination with other vaccines.
62. PASSIVE VACCINATION WITH HEPATITIS
B IMMUNOGLOBULIN
• Hepatitis B immunoglobulin (HBIg) is prepared from the plasma of individuals who
have a high concentration of anti-HBs. The standard dose of HBIg is 0.06 mL/kg for all
applications in adults or 200 IU in infants. In standard doses, it provides temporary
protection (i.e., for approximately 3–6 months) against HBV infection. HBIg is
administered by intramuscular injection, preferably into the deltoid or gluteal muscle. If
it is given with hepatitis B vaccine, the HBIg vaccine should be administered at a
different injection site.
63. PREEXPOSURE PROPHYLAXIS
• A comprehensive strategy for eliminating HBV transmission should start with a
preexposure vaccination program. This should include:
• Universal vaccination of all infants at birth; mandatory for infants born to pregnant
women who test positive when screened for hepatitis B surface antigen.
• Postexposure immunoprophylaxis for children born to mothers whose HBsAg status is
unknown.
• Catch-up vaccination of all children and adolescents who have not previously been
vaccinated.
• Vaccination of unvaccinated adults exposed to risks of HBV infection (however,
typically “high-risk” individuals frequently do not access health care or inform health-
care facilities; hence the need for universal infant vaccination).
• Vaccination of those at risk of more severe infection—e.g., patients with chronic liver
disease.
64. PREGNANCY AND HEPATITIS B
VACCINATION
• There are no teratogenic or other risks to the fetus if hepatitis B vaccine is
administered to pregnant women. There are no contraindications for hepatitis B
vaccination or HBIg administration in pregnant or lactating mothers.
66. • Hepatitis C is a contagious liver disease caused by the hepatitis C virus (HCV).
• The virus is endemic throughout the world, and a recent analysis including 1217
studies representing 117 countries and 90% of the global population concluded that
approximately 180 million people worldwide are HCV-seropositive.
• It was calculated that HCV genotype 1 is the most prevalent worldwide, comprising
83.4 million cases (46.2% of all HCV cases), approximately one-third of which are in
East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%);
genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 makes
up the remaining < 1%.
67. EPIDEMIOLOGY OF HCV
• When the epidemiology of HCV infection globally is being discussed, it is imperative to
discuss “north–west” and “east–south” differences as well. These include a low
prevalence of HCV infection in the “north” and “west” and a moderate to high
prevalence in the “south” and “east”
68. THE MAIN RISK FACTOR FOR HCV
• The main risk factor for HCV in the “east” is unsafe therapeutic injections, due to poor
practical application of universal infection control guidelines, including reutilization of
syringes, needles, or any equipment from patient to patient without adequate sterilization
techniques. This affects the treatment strategies in developing countries and emphasizes the
need for prevention strategies, public awareness, health education, and sensitizing health-care
staff and concerned authorities in governments. On the other hand, in Western developed
countries, HCV is mainly transmitted by injecting drug users sharing injection equipment. The
prevalence of anti-HCV among intravenous drug users may range from 35% to 61% and
intravenous drug use accounts for 60–80% of new HCV infections in the United States.
• Another factor is the availability, cost, and quality of diagnostic tests for HCV infection, which
make screening extremely difficult even in high-risk populations, leading to inaccurate data
collection and reporting. Similarly, the standardization and methodology of polymerase chain
reaction (PCR) testing makes deciding “whom to treat” even more difficult.
• The natural history of HCV is also different in the “east” and “west,” due to specific risk factors
such as alcohol use, addiction, intravenous drug use, co-infections, and superinfections. Other
comorbidities (such as the prevalence of obesity and the metabolic syndrome) and nutritional
deficiencies also affect liver histology and progression of the disease.
69. • Intravenous drug use, tattooing, and medical procedures such as dialysis and blood
transfusion before the era of HCV screening have all contributed to the wide spread of
HCV. It has become a major recognized health problem worldwide. The distribution of
HCV infection shows considerable geographic variation, with a higher prevalence in
countries in east Asia, Latin America, the Mediterranean, and certain areas in Africa and
eastern Europe.
• Chronic hepatitis C is the most common cause of cirrhosis and the most common
indication for liver transplantation in Europe, North and South America, Australia,
Japan, and Egypt. Patients’ risk of developing cirrhosis ranges from 5% to 25% over
periods of 25–30 years
70. CLINICAL PICTURE
• Infections can range in severity from a mild illness lasting only a few weeks to serious illness
(acute infection) or lifelong illness (chronic infection). Approximately 80% of patients infected
with HCV will become chronically infected, and most of these patients will show evidence of
chronic hepatitis. The incubation period is 14–180 days (average 45 days), and no vaccine
against hepatitis C is currently available.
• Predictors of chronicity in HCV infection:
• Male sex
• Age > 25 years at moment of infection
• Acute infection is asymptomatic
• African-American ethnicity
• HIV infection
• Immunosuppression
71. STATISTIC DATA ABOUT THE
PROGNOSIS OF THE DISEASE
• Hepatitis C infection is usually slowly progressive over a period of many years, and
between 5% and 15% of patients with chronic hepatitis may progress to developing
liver cirrhosis over a period of 20 years
• But several studies have suggested a more benign course of the disease and indicate
that fibrosis is a highly unpredictable process . Approximately 80% of patients infected
with HCV will become chronically infected, although some studies suggest higher rates
of spontaneous clearance, particularly in young people
72. STATISTIC DATA ABOUT THE
PROGNOSIS OF THE DISEASE
• Approximately 4–9% of patients with cirrhosis annually will develop progressive liver
failure (decompensation), with a 1–4% annual risk of developing primary hepatocellular
carcinoma (HCC).
• The mortality rate due to progressive liver failure or HCC will continue to increase
during the next few decades. In some countries, HCV infection is the main cause of
death from liver disease and is the leading indication for liver transplantation
• Approximately 70–80% of patients with hepatitis C are asymptomatic; in acute or
acute-on-chronic hepatitis, the symptoms of all types viral hepatitis are similar and can
include one or more of the following: fatigue, abdominal pain, poor appetite, jaundice.
73. PREVENTION
• Counseling of infected persons on avoiding transmission of HCV
• The infected person should cover any bleeding wound or cuts and apply disinfectants
immediately in order to keep the blood away from others..
• An infected person should not donate blood or organs, although organs from HCV-positive
patients may be used in those who are already HCV-positive.
• Those who inject drugs should be counseled regarding the risk of transmission of HCV and
advised to inject safely if they intend to continue.
• Vomit and other bodily secretions from an HCV-infected patient should be disposed of with
disinfectant—e.g., bleaching powder and glutaraldehyde solution.
• The risk of sexual transmission of HCV is low. Spouses are not recommended to take barrier
precautions as a risk reduction strategy.
• Transmission of HCV is low through breast milk, so breast-feeding should not be stopped.
• Household contacts and physical contact are not recognized risk factors for HCV
transmission, so an HCV-infected person should not be barred from any activities of normal
life.
74. PREVENTION IN THE COMMUNITY AND
HEALTH-CARE SETTINGS
• All blood donors must be screened for hepatitis C antibodies and/or HCV RNA.
• In health-care settings, adherence to universal precautions for infection control is essential. This
should include the use of disposable or adequately sterilized materials for invasive procedures,
and adequate cleansing and sterilization of instruments.
• It is important to educate tattooists, barbers, foot/hand care workers, and practitioners of
traditional or alternative therapies about ways of minimizing blood contamination. This involves
sterilization techniques for procedures that involve skin penetration or breaks to mucosal
surfaces.
• As transmission of HCV via injecting drug use is an increasing trend, it is important to implement
an education campaign about the harm of drug use, especially among school-age children. Harm
reduction programs such as needle/syringe programs should also be implemented.
• Those who have received surgical or dental treatment can be at risk of acquiring HCV infection
and should be offered testing, especially in health-care systems in which transmission associated
with surgical and dental treatment has been a major risk.
75. PREVENTION IN THE COMMUNITY AND
HEALTH-CARE SETTINGS
• Individuals with a history of blood transfusion have a higher risk of HCV infection and should
be offered testing.
• Chronic hepatitis C patients should be vaccinated against hepatitis B after screening.
• Use of injections is only preferable in approved health-care settings, and injections should be
discouraged as much as possible, especially in settings in which medical supervision is not
available. When mandatory, injections must be carried out in accordance with WHO
recommendations on safe injecting practice.
• An appropriate protocol for needlestick injury should be drawn up and followed in all
hospitals (public and private), as recommended by the Centers for Disease Control and
Prevention (CDC).
• All skin lesions on the hands of health-care workers should be covered with waterproof
dressing, and if possible double gloving with a blood indicator in the glove should be used.
• Health-care workers should be vaccinated for HBV.
76. DIAGNOSTIC OF HCV
• Infection with HCV is diagnosed by testing for specific antibodies using enzyme-linked
immunoassay (ELISA). The presence of HCV antibody shows that a person has been
infected with HCV virus, but it does not indicate whether the infection is acute or chronic,
or has resolved. Antibodies may not be detectable during the first few weeks after initial
infection, due to the “window period,” or if the patient is immunocompromised.
• In contrast to hepatitis A and hepatitis B virus, in which the diagnosis of acute infection is
based on immunoglobulin M (IgM) antibodies, there is no serologic marker for acute HCV
infection. Screening tests for chronic HCV infection are enzyme immunoassay (EIA) or
chemiluminescence immunoassay (CIA) for anti-HCV and verification by an additional,
more specific assay—e.g., nucleic acid testing for HCV RNA.
77. DIAGNOSIS OF ACUTE HEPATITIS C IS
BASED ON:
• With or without marked elevation of alanine aminotransferase (ALT is sometimes
raised by more than 10 ×)
• With or without jaundice
• Detectable serum HCV RNA
• Followed by anti-HCV seroconversion weeks later
• If both anti-HCV and HCV RNA are detectable from the start, differential diagnosis
between acute and chronic HCV infection with a flare of ALT may be difficult.
79. TREATMENT GOALS
• The goal in treating HCV infection is to reduce virus-related
complications. This goal is achieved by eradicating the virus to
achieve a sustained viral response (SVR). Patients who achieve
SVR have clearance of the virus, and the chances of virus
reactivation are negligible. Improvements in liver
necroinflammation, fibrosis, and in the risk of hepatocellular
carcinoma have been demonstrated in patients who have
achieved an SVR.
• Patients in whom an acute HCV infection has resolved without
therapy do not require antiviral treatment. Depending on the
sources, between 15% and 50% of patients are reported to
80. WHO SHOULD BE TREATED?
• HCV infection can be cured by antiviral treatment; however, due to the asymptomatic
nature of the disease, many infected individuals are unaware of the infection, and for
those who are diagnosed, access to treatment remains poor in many settings
• Patients who are at high risk for liver-related complications should be prioritized for
immediate treatment.
• Patients who are at high risk for liver related complications include the following:
• Patients with advanced fibrosis with metavir stages ≥ F2
• Patients with decompensated cirrhosis who are waiting for liver transplantation
• Patients with liver transplants
• Patients with severe extrahepatic complications such as vasculitis, cryoglobulinemia
causing end organ damage, or glomerulonephritis/nephrotic syndrome causing
significant proteinuria
81. TREATMENT RESPONSE PREDICTORS
• Recommendations for preferred HCV treatment regimens are continuing to evolve, but they still
depend on several factors that compromise a SVR in some cases:
• HCV genotype
• Prior HCV treatment history
• Compensated versus decompensated liver disease
• Drug–drug interactions
• Chronic kidney disease
• Solid organ transplant recipients
• The following are predictive factors for a less favorable response to treatment with DAA
combinations:
• Previous treatment with DAAs
• Liver cirrhosis (Child–Pugh B and C)
• Poor treatment adherence
82. PRETREATMENT ASSESSMENT
• The following should be assessed before direct-acting antiviral agents (DAA)treatment is
started:
• Taking a detailed history and physical examination is essential, including the patient’s
history of any other liver diseases and medical conditions that can adversely affect liver
status, such as hepatitis B infection, alcoholism, autoimmunity, metabolic liver diseases, or
hepatotoxic drugs. These should be inquired into and appropriate measures should be
taken to reduce the risks.
• Other evaluations should be considered (cardiopulmonary and psychiatric evaluation) and
the risk of nonadherence should be assessed. Appropriate measures should be taken to
reduce these risks.
• Assessment for current/prior medications and adherence to previous treatments. Significant
potential drug–drug interactions should also be assessed.
• The extent of hepatic fibrosis should be checked using noninvasive measures:
• — Studies have demonstrated that FibroScan is a sensitive alternative to liver biopsy. The
amount of fibrosis can be quantified very easily and reliably in more than 95% of the
patients .
• A correct interpretation of transient elastography must have an interquartile range/median
values of < 30% and serum ALT < 5 × upper limit of normal. There should be no ongoing
83. PRETREATMENT ASSESSMENT
• In resource-limited regions and in places where FibroScan is not readily available, scores
such as the fibrosis 4 index (FIB4), AST to platelet ratio index (APRI), and acoustic
radiation force impulse (ARFI) can be used. An APRI score ≥ 2 can be used to predict the
presence of cirrhosis. At its cut-off point, the ARFI score has a sensitivity of 48% but a
specificity of 94% for predicting cirrhosis. It can also be used to predict the presence of
significant fibrosis (stages 2–4). Using a cut-off value of 1.5, the sensitivity is 37% and
the specificity is 95% for significant fibrosis.
• — Liver biopsy can only be considered when there is possibility of additional etiology.
• Serum quantitation of HCV-RNA using a sensitive real-time PCR-based assay with a
lower limit of detection of ≤ 15 IU/mL.
• HCV genotyping.
• In patients with suspected or known cirrhosis, the Child–Turcotte–Pugh score and
Model for End-Stage Liver Disease (MELD) score should be calculated.
84. RECOMMENDATIONS FOR PRETREATMENT
MONITORING
• A complete blood count(CBC), liver function tests (LFTs), serum albumin, INR, glomerular
filtration rate (GFR), and a thyroid-stimulating hormone (TSH) test (if an IFN regimen is
planned) should be performed within 12 weeks of the start of therapy.
• Quantitative PCR and genotyping anytime should be done before the start of therapy.
• Women of childbearing age must undergo urinary pregnancy testing before the start of
therapy. Currently, all new oral therapy regimens, with or without ribavirin, are
contraindicated for use during pregnancy or during breastfeeding due to a lack of
sufficient safety information in humans, and adequate measures of contraception are still
routinely recommended for female patients of childbearing age.
• With ribavirin-containing regimens, the patient’s age and cardiovascular comorbidity due
to secondary anemia should be taken into account.
85. ON-TREATMENT ASSESSMENT
• Recommendations for patients receiving HCV treatment during their therapy:
• Compliance should be encouraged either at clinical visits or by phone. Any adverse
events should be inquired about, and advice regarding drug–drug interactions should be
given.
• CBC, serum creatinine, GFR, and LFT assessments should be performed after 4 weeks of
treatment. CBCs can be done more often in patients receiving ribavirin, if clinically
indicated.
• TSH tests should be done at 12 weeks for those patients receiving interferon.
• Quantitative PCR assessment should be performed at the end of treatment and then 12
weeks afterward.
86. WHEN TO STOP THE TREATMENT
BECAUSE OF SIDE EFFECTS
• If there is a 10-fold or greater increase in ALT after 4 weeks of therapy.
• If there is a less than 10-fold increase in ALT with one of the following:
• — Symptoms developing (nausea, vomiting, weakness)
• — Jaundice
• —Increases in bilirubin, alkaline phosphatase (ALP), or INR
• If there is a less than 10-fold increase in ALT and the patient is asymptomatic, ALT
assessment should be repeated at 6 weeks; if it is persistently high, one can consider
stopping therapy.
87. TREATMENT
• In this section, patients with chronic hepatitis C who are eligible for treatment in accordance with
the diagnostic criteria are stratified following internationally accepted criteria into six categories
based on genotype, whether treatment-naïve, failure of treatment, treatment response, and liver
cirrhosis. These parameters are evidence-based and are an integral part of the AASLD, EASL,
APASL, and other regional society treatment guidelines.
• Several options are available to health-care providers, prioritizing on the basis of efficacy of
therapy. Clinicians can select options on the basis of the patient’s liver status and drug
availability/affordability.
• Although the guidelines no longer recommend the use of interferon-based regimens, access to
DAAs is still very difficult in several parts of the world, including developed and developing
countries. There are even still a few countries in which the only treatment option for hepatitis C
consists of interferons. Although interferon-based regimens are not mentioned as options in the
cascades below, we would still recommend their use in regions in which oral drugs are not
available. PEG-IFN alfa-2a should be used at a dosage of 180 µg once per week, whereas PEG-IFN
alfa-2b should be used at a weight-based dosage of 1.5 µg/kg per week, as in the previous
guidelines/cascades
