system-mediated hyperventilation or a lactic acid-induced metabolic acidosis.
Hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, hypoglycemia,
seizures, infections (bacterial or fungal), and pancreatitis are additional findings
associated with ALF. Thus, sodium, potassium, calcium, magnesium, blood glucose,
and amylase should be monitored closely in W.H.
66,69 Prophylactic antimicrobial
therapy reduces the incidence of infections in selected groups of ALF patients, but no
survival benefit has been demonstrated.
66,69 Therefore, if antibiotics are not initiated,
surveillance for infection (via chest radiography and blood, urine, and sputum
cultures) should be undertaken while having a low threshold for initiating
appropriate antibacterial or antifungal therapy. Finally, pulmonary complications
(hypoxemia, aspiration, adult respiratory distress syndrome, and pulmonary edema)
may also occur in patients with ALF.
CASE 80-4, QUESTION 2: What is W.H.’s prognosis?
Although the incidence of ALF is less than 1%, the prognosis for these patients is
poor once encephalopathy has developed.
70,71 Survival depends on the etiology and
degree of hepatic destruction, the ability of the remaining liver cells to regenerate,
and the management of complications that may develop during the course of illness.
Survival rates often depend on the etiology of ALF. Non-A, non-B (NANB) hepatitis
and halothane or drug hepatotoxicity have been associated with worse survivals
compared with those with hepatitis A, hepatitis B, or acetaminophen overdose.
younger than 14 years, worsening grade of encephalopathy, reduced liver size, and
significantly abnormal LFT values (e.g., serum bilirubin, aminotransferases, alkaline
phosphatase, PT, and serum albumin) are also poor prognostic indicators in patients
70,71 Because W.H. has evidence of encephalopathy, cerebral edema, and
abnormal LFT values, he has a poor prognosis.
CASE 80-4, QUESTION 3: Outline an appropriate treatment plan for W.H.’s ALF.
The primary therapy for ALF is supportive care for the comatose patient. Systemic
therapies with heparin, prostaglandin, or insulin and glucagon have shown limited
66 Blood or plasma exchange, hemodialysis, or other methods implemented
to detoxify the blood or improve the coma grade do not result in long-term benefits if
liver mass is not reconstituted as well. Thiopental may be useful in lowering ICP, but
corticosteroids and prolonged hyperventilation are of no value.
benefit from prophylactic histamine H2
-blockers because they have been shown to
reduce the incidence of upper GI hemorrhage.
66 The role of proton-pump inhibitors
has not been clearly defined, although limited data have also supported their role in
this setting. Blood products (packed red blood cells, fresh-frozen plasma, or
platelets) should be given as needed if W.H. develops active bleeding, and
pulmonary artery monitoring should be implemented to guide management of
intravascular volume and gas exchange. W.H. should be closely monitored for
additional complications, especially cardiac abnormalities (arrhythmias),
hemodynamic changes, renal failure, acidosis, pulmonary complications, and sepsis.
In cases in which prognostic information indicates less than 20% chance of
survival without transplantation, liver transplantation is indicated. In patients with
acetaminophen poisoning resulting in ALF, a pH less than 7.3, a PT longer than 100
seconds, and a serum creatinine greater than 3.4 mg/dL, with grade III or IV
encephalopathy, usually require transplantation.
71 Other causes of ALF, a PT longer
than 50 seconds, or any three of the following variables (irrespective of grade of
encephalopathy)—age younger than 10 years or older than 40 years; liver failure
caused by NANB hepatitis, halothane-induced hepatitis, or idiosyncratic drug
reactions; duration of jaundice before encephalopathy more than 7 days; or serum
bilirubin greater than 17.5 mg/dL—indicate a need for transplantation.
these criteria continue to be used worldwide, they are less reliable in patients with
moderate illness; sensitivity is acceptable although specificity is poor. Therefore,
other models and surrogate markers have emerged to predict survival, such as the
model for end-stage liver disease, Acute Physiology and Chronic Health Evaluation
II scoring system, and biomarkers such as Gc protein (also known as vitamin D3
binding protein), α-fetoprotein, or troponin.
71 To date, none of these methods have
been flawless in their ability to accurately predict outcome in ALF.
Coinfection with Human Immunodeficiency Virus (HIV)
CASE 80-4, QUESTION 4: What is the likelihood for HIV and HBV coinfection for W.H.?
Coinfection with other viruses has been reported in patients with HBV infection.
For example, markers of prior or active HBV infection are present in more than 80%
of patients with acquired immunodeficiency syndrome, with approximately 10% of
these cases seropositive for HBsAg.
42,43 HIV has also been reported to coexist in up
to 13% of patients with chronic HBV infection.
42,43 Compared with patients with
HBV infection alone, patients coinfected with HBV and HIV have significantly higher
levels of viral replication, lower ALT levels, and less severe histologic disease.
HBV infection does not reduce survival in HIV-positive patients; however, because
these patients live longer, hepatic decompensation and manifestations of HBV may
Alterations in sexual behavior, screening of high-risk patients or settings (e.g., STD
and HIV testing at treatment facilities, drug abuse treatment and prevention settings,
healthcare settings targeting services to IV drug users, healthcare settings targeting
services to MSM, and correctional facilities) and blood products, developing needle
exchange programs, and cultural outreach and education may have an impact on HBV
transmission. The goals of preventive therapy should be to identify all persons who
require immunoprophylaxis for the prevention of infection and provide long-term
protection through vaccination to decrease the risk of chronic HBV infection and its
subsequent complications, as well as minimizing adverse effects and cost of therapy.
should P.G. receive to prevent hepatitis secondary to HBV?
Manufactured using recombinant DNA technology, Recombivax HB (10 mg
HBsAg/mL) and Engerix-B (20 mg HBsAg/mL) are yeast-derived HBV vaccines that
induce an immunologic response.
Because P.G. will come in contact with potentially infectious bodily secretions
during her rotations, she should be immunized against hepatitis B with either
Relative potency comparisons are not clinically important because comparative trials
using Recombivax HB and Engerix-B in the recommended dosages have
demonstrated equivalent immunogenicity and tolerability. P.G. can be immunized
with either product, provided she receives the manufacturer’s recommended dosage
with each injection. Hepatitis B vaccine is administered as an IM injection in the
deltoid muscle of adults and children or in the anterolateral thigh muscle of neonates
and infants. The immunogenicity of hepatitis B vaccine is significantly lower when
injections are given in the buttocks, probably because the greater amount of fat tissue
in the buttocks inhibits interfacing of vaccine and antigen-recognition leukocytes. The
results of a small vaccination series suggest that healthy adults who do not respond to
hepatitis B vaccine injection to the buttocks have a significantly higher response
when vaccinated in the arm. P.G. should be immunized with either Recombivax HB
(10 mcg) or Engerix-B (20 mcg) administered as a 1-mL IM injection in the deltoid
Recombinant yeast-derived vaccines (e.g., Recombivax HB, Engerix-B) produce
71–73 A protective antibody response has been defined as anti-HBs
63,77 This threshold was derived from early HBV vaccine
trials in homosexual men, in which vaccine recipients with serum antibody levels of
at least 10 sample ratio units (SRUs) were protected from HBV infection.
serum antibody level of 10 SRU is roughly equivalent to 10 milli-international
units/mL when the international standard is used. For this reason, an anti-HBs level
of at least 10 IU/mLis considered a protective antibody titer and is the standard used
by the ACIP. Although HBV infections have occurred in vaccine recipients with a
detectable immune response, almost all infections have been asymptomatic,
identified only through the presence of anti-HBc. These infections have been limited
largely to patients with no response or a poor response to vaccination.
CASE 80-5, QUESTION 2: P.G. has completed her three-dose vaccination series with Engerix-B. Routine
negative. Why did P.G. not respond to the hepatitis B vaccine, and how should she be managed?
Two important determinants of vaccine efficacy appear to be the age at
vaccination and underlying immune function. In healthy recipients, the immune
response to vaccination decreases with advancing age. In one study, 99% of patients
aged 0 to 19 years, 93% of those aged 20 to 49 years, and 73% of those older than 50
years of age achieved protective anti-HBs levels (>10 SRU) after three doses of the
Immunocompromised patients, including those receiving
hemodialysis, those infected with HIV, or children receiving cytotoxic chemotherapy,
respond poorly to the hepatitis B vaccine. Patients who smoke, or are obese, also
74,75 P.G. has two risk factors for a poor response to the
hepatitis B vaccine: She is older than 50 years of age, and she is moderately obese
(ideal body weight for her height is 50 kg).
Vaccine recipients who respond poorly to hepatitis B vaccine have been classified
either as hyporesponders who can probably be protected by additional doses of
vaccine or as true nonresponders. Patients with inadequate initial response to the
HBV vaccine series should be revaccinated. Of the hyporesponders (anti-HBs levels
<10 IU/mL), 50% to 90% achieve a protective level after a single booster injection
or after repeating the entire three-dose series.
76,77 Of patients not responding to a
primary vaccination series with Engerix-B, 60% produced an immune response after
a three-dose series with HBVax II (Recombivax), suggesting a repeat course with the
alternative HBV vaccine may be a reasonable approach in some patients.
Revaccination of nonresponders (no detectable anti-HBs) is less successful, and
protective levels, if achieved, are not sustained.
vaccination are rare in the immunocompetent population, and these persons may have
a genetic predisposition toward nonresponsiveness.
76,78 P.G. should be revaccinated
with a booster dose of hepatitis B vaccine. Her anti-HBs levels can be rechecked 1
month after the injection. If she still has not responded, it is reasonable to administer
an additional two injections to complete a second vaccination series.
Interchangeability of Hepatitis B Virus Vaccines
different manufacturers be used interchangeably?
Although it is recommended that patients receive the complete vaccination series
with the same product, it is not absolutely necessary. To determine whether a
hepatitis B vaccination series initiated with Recombivax HB could be completed
with Engerix-B, healthy adults received 10 mcg of Recombivax HB at baseline and 1
month. At 6 months, the subjects were randomly assigned to receive either Engerix-B
20 mcg or Recombivax HB 10 mcg. One month after the third dose, 100% of those
who had received Engerix-B and 92% of those who had received Recombivax HB
had protective anti-HBs levels.
78 studied the booster response to either recombinant hepatitis B vaccine
or plasma-derived vaccine in children who had been vaccinated originally with the
plasma-derived product (Heptavax-B). Children were randomly assigned to receive
either 5 mcg of the plasma-derived vaccine or 20 mcg of Engerix-B. One month after
response in persons who originally received the plasma-derived vaccine. According
to the ACIP, the immune response from one or two doses of a vaccine produced by
one manufacturer, when followed by subsequent doses from a different manufacturer,
is comparable with that resulting from a full course of vaccination with a single
T.M. may complete the hepatitis B vaccine series with Engerix-B provided he
receives the recommended dosage of 20 mcg administered as a 1-mL IM injection to
CASE 80-6, QUESTION 2: Does T.M. require a booster injection for sustained protection from HBV
The duration of vaccine-induced immunity has been evaluated in many long-term
79–82 The duration of detectable anti-HBs appears proportional to the peak
antibody response achieved after
vaccination, and protective anti-HBs levels were sustained in 68% to 85% of
patients receiving the plasma-derived HBV vaccine from 6 to 12 years.
Importantly, the protective efficacy of the HBV vaccine in these trials was high, even
in patients with anti-HBs levels <10 IU/mL. HBsAg was only rarely detected, and
most HBV events consisted of asymptomatic seroconversion to anti-HBc. These
studies suggest that successful HBV vaccination is associated with long-lasting
protection without the need for additional booster doses for up to 12 years.
The mechanism of sustained protection from HBV, despite low or undetectable
anti-HBs levels, is thought to be related to the phenomenon of immunologic memory
in previously sensitized B lymphocytes. This amnestic response, in combination with
the long incubation period of HBV, may allow the synthesis of protective antibodies
sufficiently quickly to block infection in patients rechallenged with HBV.
In summary, no need exists for routine administration of HBV vaccine booster
doses to immunocompetent persons after successful vaccination.
Immunocompromised patients may require a persistent minimal level of protective
antibody, and the ACIP does recommend annual antibody testing for patients
receiving chronic hemodialysis with administration of a booster dose when antibody
levels are less than 10 IU/mL.
53 Based on available evidence, T.M. does not require
a scheduled booster dose of hepatitis B vaccine.
CASE 80-6, QUESTION 3: Why is it appropriate for T.M. to be vaccinated with hepatitis B vaccine, and
who else should be vaccinated with this vaccine?
The ACIP has recommended pre-exposure hepatitis B vaccination for the
following high-risk groups: Healthcare workers with exposure to blood, staff of
institutions for the developmentally disabled, hemodialysis patients, recipients of
blood products, household and sexual contacts of HBV carriers, international
travelers to HBV-endemic areas, injecting drug users, sexually active homosexual
men, bisexual men, and inmates of long-term correctional facilities.
T.M. is a hospital laboratory technician, he is at high risk for exposure to HBV and
Universal Hepatitis B Vaccination
In addition to the previously listed high-risk groups, all infants should receive
hepatitis B vaccination. The practice of vaccinating only high-risk persons has
resulted in little impact on the incidence of HBV disease. Populations at risk for
HBV disease (injecting drug users, persons with multiple sexual partners) generally
are not vaccinated before they begin engaging in high-risk behaviors. In addition,
many persons who become infected have no identifiable risk factors for infection and
thus would not be recognized as candidates for vaccination. A program designed to
immunize children before they initiate high-risk behaviors is likely to have a greater
impact in reducing the incidence of HBV infection. As a means to achieve this goal,
the hepatitis B vaccine now is incorporated into the existing pediatric vaccination
schedule. The first dose is administered during the newborn period (preferably
before the infant is discharged from the hospital) but no later than 2 months of age.
The recommended vaccination schedule is shown in Table 80-5.
QUESTION 1: R.M. is a mother of two children aged 11 years and 2 months. Her infant daughter just
Recommended Schedules of Hepatitis B Vaccination for Infants Born to HBsAg
Hepatitis B Vaccine Age of Infant
Dose 1 Birth (before hospital discharge)
influenzae type b conjugate, measles–mumps–rubella, and oral polio vaccines.
The Centers for Disease Control and Prevention (CDC) has addressed the issue of
immunizing children and adolescents born before 1991 who are potentially at risk for
hepatitis B infection. The current recommendations suggest that adolescents who
have not received three doses of hepatitis B vaccine should initiate or complete the
series at ages 11 to 15 years. A schedule of 0, 1 to 2, and 4 to 6 months is
It is anticipated that universal vaccination of all infants and
previously unvaccinated adolescents aged 11 to 12 years, in addition to ongoing
immunization of high-risk persons, will reduce the incidence of acute hepatitis B
infection, hepatitis B-associated chronic liver disease, and HCC. R.M.’s son should
receive either Recombivax HB 5 mcg or Engerix-B 10 mcg IM in the deltoid with
repeat doses 1 to 2 months and 4 to 6 months from the initial injection.
HBV vaccination generally has been well tolerated. The most common side effect is
pain at the injection site, observed in 3% to 29% of patients. Transient febrile
reactions (defined as temperature >99.9°F) occur in less than 6% of recipients, and
other reactions, including nausea, rash, headache, myalgias, and arthralgias, are
observed in less than 1% of recipients. Ongoing monitoring of vaccine safety by the
FDA and CDC is assessed through the Vaccine Safety Datalink project and Vaccine
Adverse Events Reporting System.
52,53 On the basis of these reporting systems,
additional “causal” adverse effects associated with vaccination include anaphylaxis
(1 case/1.1 million vaccine doses), Guillain–Barré syndrome, and multiple sclerosis.
Additional rare adverse events that have been reported but remain to be validated are
chronic fatigue syndrome, neurologic disorders (leukoencephalitis, optic neuritis, and
transverse myelitis), rheumatoid arthritis, type 1 diabetes, and autoimmune disease.
a contaminated needle while drawing blood from an HBsAg-positive patient. K.N. was not vaccinated
weighs 56 kg. How should K.N. be treated for percutaneous exposure to hepatitis B?
After exposure to HBV, prophylactic treatment with hepatitis B vaccination and
possibly passive immunization with hepatitis B immunoglobulin (HBIG) should be
53 The ACIP recommends postexposure immunoprophylaxis after hepatitis
B exposure. K.N.’s percutaneous exposure warrants active immunization with HBV
and passive immunization with HBIG. The source of K.N.’s exposure is HBsAg
positive, and K.N. had not been vaccinated previously with the hepatitis B vaccine.
She should receive a single dose of HBIG 0.06 mL/kg (3.4 mL) as an IM injection in
either the gluteal or deltoid region as soon as possible after exposure, preferably
within 24 hours. HBIG is prepared from plasma of persons preselected for high-titer
anti-HBs. The ratio of anti-HBs of HBIG in the United States is 1:100,000 as
determined by radioimmunoassay. HBIG is superior to immunoglobulin in the
prevention of hepatitis B infection after percutaneous exposure. K.N. also should
receive active immunization with IM hepatitis B vaccine (at a separate site)
simultaneously with HBIG. The second and third doses should be given 1 month and
6 months later. Passively acquired antibodies against HBV from HBIG or
immunoglobulin will not interfere with active immunization via hepatitis B vaccine.
If the HBsAg status of the donor source of a percutaneous exposure is unknown,
recommendations for prophylaxis of HBV infection depend on whether the donor
source is at high risk or at low risk for being HBsAg positive. High-risk donor
sources include homosexual men, IV drug abusers, patients undergoing hemodialysis,
residents of mental institutions, immigrants from endemic areas, and household
contact with an HBsAg-positive person?
Sexual transmission of HBV is an important cause of HBV infection, accounting
for approximately 30% to 60% of all new cases annually.
with a single 5-mL dose of HBIG was found highly effective in preventing HBV
infection after sexual exposure when compared with a control globulin (with no anti-
63,83 The CDC recommends that susceptible persons exposed to HBV
through sexual contact with a person who has acute or chronic HBV infection should
receive postexposure prophylaxis with 0.06 mL/kg of HBIG as a single IM dose
within 14 days of the last exposure.
19,83 Patients also should receive the standard
three-dose immunization series with hepatitis B vaccine beginning at the time of
HBV infection, and how should he be treated?
In many Asian and developing countries, perinatal (vertical) transmission accounts
for most HBV infections. Infants born to HBV-infected mothers have a greater than
85% risk of acquiring HBV during the perinatal period. Of those who become
infected, 80% to 90% become chronic HBsAg carriers.
62,84 Although fulminant cases
have been reported, most hepatitis infections in neonates are asymptomatic. Despite
the usually innocuous initial disease, significant adverse consequences are associated
with chronic HBsAg carriage in neonates. Chronic hepatitis B infection is associated
with chronic liver disease and has been clearly implicated as a major risk factor in
the development of primary HCC.
Mothers who are chronic carriers of HBV can transmit HBV to their infants. The
risk is related to the presence of HBsAg and HBeAg (suggesting a high degree of
viral replication and infectivity). The likelihood that S.L. will develop HBV
infection is high. S.L. requires immediate therapy with HBIG to provide immediate
high titers of circulating anti-HBs, and simultaneous vaccination with hepatitis B
vaccine to induce long-lasting protective immunity. Screening pregnant women for
the presence of HBeAg and administration of HBIG and hepatitis B vaccine is 85%
to 98% effective in preventing HBV infection and the chronic carrier state.
compares with a 71% efficacy rate for administration of HBIG alone. Simultaneous
administration of HBIG and hepatitis B vaccine does not adversely affect the
production of anti-HBs in neonates.
Infants born to mothers who are HBsAg-positive should receive simultaneous IM
injections of the appropriate doses of hepatitis B vaccine (Table 80-5) and HBIG
(0.5 mL) within 12 hours of birth. The injections should be administered at separate
sites. S.L. should receive HBIG (0.5 mL) as soon as possible after birth,
administered as an IM injection. He also should receive 0.5 mL of either
Recombivax HB (5 mcg) or Engerix-B (10 mcg) as an IM injection at a separate site.
CASE 80-10, QUESTION 2: What would the management plan be if the HBsAg status of S.L.’s mother
The ACIP has developed recommendations for the prevention of perinatal HBV
infection. This includes the routine testing of all pregnant women for HBsAg during
an early prenatal visit. HBsAg testing should be repeated late in the pregnancy for
women who are HBsAg negative, but who are at high risk of HBV infection or who
have had clinically apparent hepatitis. Women admitted for delivery who have not
had prenatal HBsAg testing should have blood drawn for testing. Although test
results are pending, the infant should receive hepatitis B vaccine within 12 hours of
birth. If the mother is found later to be HBsAg positive, her infant should receive
HBIG as soon as possible within 7 days of birth. The second and third doses of
vaccine should be administered at 1 and 6 months, respectively. If the mother is
found to be HBsAg negative, her infant should continue to receive hepatitis B vaccine
as part of the routine vaccination series.
Evaluation and Management of Patients with Chronic
Initially, a thorough history and physical examination should be performed with
greater emphasis placed on risk factors for coinfection, alcohol use, and family
history of HBV and liver cancer. Laboratory tests should include assessment of liver
disease, markers of HBV replication, and screening tests for HCV, HDV, or HIV.
Vaccinations for hepatitis A should also be administered as described above. The
decision to perform a liver biopsy should be made based on knowledge of a patient’s
age, the ALT level, HBeAg status, HBV DNA levels, and additional clinical features
suggestive of chronic liver disease or portal hypertension. In patients who are not
initially considered for treatment (inactive HBV carriers), a guideline for follow-up
based on HBeAg status is described in Figure 80-5. Periodic screening for HCC
should also be performed in high-risk populations such as Asian men older than 40
and Asian women older than 50 years of age, persons with cirrhosis, persons with a
family history of HCC, blacks older than 20 years of age, and any carrier older than
40 years of age with persistent or intermittent ALT or HBV DNA elevations.
Figure 80-5 Overview of algorithm used to determine treatment of hepatitis B virus.
QUESTION 1: C.R., a 48-year-old man, presents to the ED with jaundice, complaints of incapacitating
C.R. has a history of severe depression, managed with escitalopram.
C.R.’s laboratory evaluation is significant for the following:
Alkaline phosphatase: 142 units/mL
anti-HAV, and anti-HCV. HBV DNA is reported as greater than 20,000 IU/mL. A liver biopsy reveals
support the diagnosis of chronic HBV infection?
The chronic occurrence of jaundice and hepatosplenomegaly with significantly
elevated AST and ALT in a young patient such as C.R. is suggestive of chronic
hepatitis. Although alcoholic hepatitis secondary to long-term alcohol use is
consistent with these clinical features, his serologic tests are positive for HBV.
Hepatitis serology with positive HBsAg and HBeAg suggests ongoing viral
replication and a high degree of infectivity.
Serum concentrations of aminotransferases can range from slightly abnormal to
greatly elevated, with ALT concentrations generally greater than AST. Serum
bilirubin concentrations greater than 3.0 mg/dL are common, serum concentration of
alkaline phosphatase usually is increased, and the PT may be prolonged. Patients
such as C.R. with a prolonged PT, thrombocytopenia, and low serum albumin
concentration generally have a more severe form of chronic hepatitis and can be
considered to have decompensated liver disease.
Liver biopsy is important for the diagnosis, treatment, and prognosis of patients
with chronic hepatitis. C.R.’s liver biopsy reveals the classic triad of periportal
inflammation as well as piecemeal and bridging necrosis. The liver biopsy and
hepatitis serologic test results are consistent with a diagnosis of chronic HBV
infection. Treatment of chronic HBV infection requires knowledge of the natural
history of the untreated disease and the potential benefits of intervention. Currently,
six agents are approved by the FDA for treating chronic HBV infection.
CASE 80-12, QUESTION 2: Does C.R. require treatment for chronic hepatitis secondary to hepatitis B?
The decision to treat C.R. depends on the severity of symptoms, the serum
biochemistries, and the liver biopsy results. C.R. has evidence of severe chronic
HBV infection. He is symptomatic with jaundice, severe fatigue, and abdominal pain,
and the results of his LFTs and HBV DNA levels suggest his disease is advanced
(decreased albumin, elevated PT, low platelets). Therefore, he should be treated to
CASE 80-12, QUESTION 3: What are the goals of therapy for chronic hepatitis secondary to HBV?
Progression of chronic hepatitis to cirrhosis is likely because of continued
replication of the HBV. Loss of active viral replication usually is associated with a
decrease in infectivity, a reduction
in inflammatory cells within the liver, and a fall of serum aminotransferase
activities into the normal range. The disappearance of detectable HBeAg and HBV
DNA is considered an indicator of loss of active viral replication.
The goals of therapy in chronic HBV infection are to achieve sustained
suppression of HBV replication and remission of liver disease.
achieving these goals should lead to resolving ongoing hepatocellular damage and
reducing the development of cirrhosis and HCC. Clinical trials for chronic HBV
infection have used the following markers as end points for successful therapy:
DNA, and improvement in liver histology. The elimination of HBsAg (termination of
HBV carrier state) has been difficult to achieve in clinical trials. Additionally, the
responses to antiviral therapy of chronic HBV can be categorized as biochemical,
virologic, or histologic, and as on therapy or sustained off therapy.
CASE 80-12, QUESTION 4: Would initiating therapy during the acute phase of the HBV infection have
Pharmacologic interventions in the management of acute hepatitis B have been
disappointing. Early studies demonstrated a transient decrease in serum
aminotransferase activity and bilirubin concentration associated with corticosteroids.
More recent studies, however, have resulted in a higher incidence of relapse and
mortality in patients receiving corticosteroids.
85–88 Other therapies, including HBIG
and interferon alpha, have been ineffective in managing acute viral hepatitis
63,84 Nucleoside and nucleotide RT inhibitors reduce HBV DNA
levels in patients with chronic disease,
88–92 but their use in acute HBV infection
requires further investigation. Thus, administration of antivirals during the acute
phase of HBV infection is not recommended in C.R.
CASE 80-12, QUESTION 5: What drug therapy should C.R. receive to treat chronic HBV-associated
Previously, the most effective agents for treating chronic hepatitis B have been
89,90 which appear to activate their target cells by binding to
specific cell surface receptors to induce synthesis of effector proteins.
intracellular proteins induce the antiviral, antiproliferative, and immunomodulatory
actions of the IFNs. Their antiviral activity possibly arises from their ability to abate
viral entry into the host cells and modulate several steps of the viral replication cycle
(e.g., viral uncoating, inhibition of messenger RNA, and protein synthesis). The only
FDA-approved and commercially available IFN is pegylated IFN (PegIFN-α2a,
Pegasys) for the treatment of chronic HBV infection. The formulation involves adding
polyethylene glycol to IFN that leads to an increased serum half-life, resulting in a
prolonged antiviral effect. As a result, the frequency in administration is extended
from three times weekly to once a week.
Pegylated interferons (PegIFN-α2a) have the advantage of more convenient dosing
and additional viral suppression for patients with HBV. Clinical data suggest that this
agent has slightly enhanced efficacy than standard IFN formulations. PegIFN-α2a 180
mcg SQ weekly monotherapy was compared with PegIFN-α2a SQ weekly plus
lamivudine 100 mg PO daily or lamivudine 100 mg PO daily alone.
the 24-week follow-up, significantly more patients who received PegIFN
monotherapy or combination therapy than those who received lamivudine
monotherapy had HBeAg conversion. PegIFN-α2a (alone or in combination) resulted
in HBsAg conversion in 16 patients compared with none in the lamivudine
monotherapy group (p = 0.001). Additionally, at the end of treatment, viral
suppression was most pronounced in the group that received combination therapy.
Similar results were reported in HBeAg-positive patients receiving PegIFN-α2b.
the only published trial performed in HBeAg-negative patients, PegIFN-α2a 180 mcg
weekly (n = 177) was compared with either PegIFN-α2a 180 mcg weekly plus 100
mg of lamivudine (n = 179) or 100 mg of lamivudine alone (n = 181). Viral
suppression was greater in the combination group, but sustained response (HBV
DNA and ALT levels at week 72) was comparable in the group that received
PegIFN-α2a alone (or in combination), and superior to the lamivudine monotherapy
group. Loss of HBsAg occurred in 12 patients in the PegIFN groups, as compared
with none in the lamivudine group. Ultimately, the addition of lamivudine to PegIFN
did not improve post-therapy response rates.
The recommended dose of PegIFN-α2a, the only pegylated IFN approved for the
treatment of HBV infection in the United States, is 180 mcg SQ weekly for 48
It is possible that more severe flu-like symptoms and headache occur with
thrice-weekly dosing when compared with weekly administration. In contrast, severe
bone marrow suppression tends to occur less often with thrice-weekly
CASE 80-12, QUESTION 6: Would C.R. be likely to respond to PegIFN-α2a therapy?
Certain patient variables can predict the response to therapy with PegIFN-α2a.
The most reliable predictor of a positive response to PegIFN-α2a in HBeAg-positive
patients is pretreatment ALT and HBV DNA levels.
pretreatment ALT levels >2 times the upper limit of normal, and HBV DNA levels
less than 20 IU/mL are more likely to respond to therapy.
with PegIFN treatment is associated with improved survival and reduced
complications. Other predictors of a positive response include a short duration of
disease, negative HIV status, and a high histologic activity index as demonstrated by
liver biopsy or other diagnostic tools. No consistent predictor of sustained response
in patients who are HBeAg negative exists. Thus, C.R. is not a reasonable candidate
for PegIFN-α therapy. His liver biopsy is consistent with chronic disease, he has high
pretreatment aminotransferase levels, his HBV DNA is greater than 20,000 IU/mL,
and his duration of chronic hepatitis is long.
CASE 80-12, QUESTION 7: What are some additional reasons for avoiding PegIFN-α therapy in C.R.?
Adverse effects associated with PegIFN therapy can be categorized as early side
effects that rarely limit the use of PegIFN, and late side effects that may necessitate
dose reduction or discontinuation of therapy altogether.
90–92 The early side effects of
PegIFN therapy generally appear hours after administration and resemble an
influenza-like syndrome with fever, chills, anorexia, nausea, myalgias, fatigue, and
headache. Virtually all patients receiving PegIFN experience these toxicities, and
they tend to resolve after repeated exposure to the drug over time. Administration of
at bedtime may decrease the severity of early onset of the side effects.
Acetaminophen can be used to treat early side effects of PegIFN therapy, but should
be limited to 2 g/day to minimize the risk of hepatotoxicity. The late-onset side
effects usually are observed after 2 to 4 weeks of therapy and are more serious.
These toxicities, which limit the use of PegIFN, include worsening of the flu-like
syndrome, alopecia, bone marrow suppression, bacterial infections, thyroid
dysfunction (both hypothyroidism and hyperthyroidism), and psychiatric disturbances
(emotional lability, irritability, depression, anxiety, delirium, and suicidal ideation).
The use of PegIFN can also cause a flare (increase) in ALT levels in 30% to 40% of
patients. These flares are considered to be a favorable prognostic indicator, but they
have been reported to cause hepatic decompensation, especially in cirrhotic patients.
C.R.’s history of severe depression should be considered a relative contraindication
to treating him with PegIFN. Furthermore, the use of PegIFN in patients with
decompensated liver disease may lead to FHF. Therefore, this agent, although
approved for HBV, is not optimal for him.
CASE 80-12, QUESTION 8: What other antiviral therapies are available to treat C.R.’s chronic HBV
Although PegIFN-α2a have been important in the treatment of chronic HBV
infection, patients included in most clinical trials represented a highly select group of
chronic HBV carriers. Specifically, patients with decompensated liver disease were
excluded because they often have leukopenia and thrombocytopenia as a result of
hypersplenism, which limits the dose of PegIFN that can be administered. In addition
to PegIFN-α2a, the FDA has approved several oral antiviral agents for treatment of
chronic HBV infection (lamivudine, adefovir dipivoxil, entecavir, tenofovir
disoproxil fumarate, and tenofovir alafenamide).
Lamivudine (Epivir-HB) was the first oral nucleoside analog approved by the FDA
for use in patients with compensated liver disease who had evidence of active viral
replication and liver inflammation caused by chronic HBV infection. Nucleoside
analogs represent an alternative approach to treatment in patients with
85–87 Lamivudine, the (−) enantiomer of 3′-thiacytidine,
is an oral 2′-,3′-dideoxynucleoside that inhibits DNA synthesis by terminating the
nascent proviral DNA chain and interferes with the RT activity of HBV.
chronic HBV treatment, Epivir-HB is administered as 100 mg orally daily.
Lamivudine is well tolerated and reduces serum levels of HBV DNA.
Lamivudine is also used as an alternative nucleoside analog for HIV treatment and is
administered at a higher dose of 600 mg orally once daily in combination with
CASE 80-12, QUESTION 9: What is the risk of development of lamivudine resistance in C.R.?
Considering the high rate of viral turnover and the error-susceptible nature of the
polymerase (particularly the RT), acquisition of resistance mutations is common. The
most common mutation leading to lamivudine resistance is a specific point mutation
in the highly conserved methionine motif of the HBV DNA polymerase.
mutation, the methionine residue is changed to a valine or isoleucine. These
genotypic mutations in the YMDD locus associated with a reduced sensitivity to
lamivudine occur after long-term therapy (e.g., 52 weeks). This motif is thought to be
representative of the active site of the enzyme, similar to that associated with HIV
RT, leading to lamivudine resistance.
96,97 Lamivudine-resistant HBV mutants
generally are detectable after 6 months or more of continuous therapy. Integrated data
from four studies show a 16% to 32% incidence at 1 year, increasing to 47% to 56%
at 2 years of therapy and 69% to 75% at 3 years of therapy.
YMDD mutants results in a loss of the clinical response, a rise in ALT levels, and
worsening of hepatic histology. Reports of continued improvement despite
lamivudine resistance exist, but the long-term consequences of viral resistance
(including hepatic decompensation and exacerbation of liver disease) are substantial.
Thus, lamivudine has limited clinical utility in patients with chronic HBV and is
currently considered a second-line agent.
CASE 80-12, QUESTION 10: What other nucleoside or nucleotide therapies are available for managing
Adefovir dipivoxil (Hepsera) was approved for the oral treatment of chronic
hepatitis B in adults with evidence of either active viral replication or persistent
elevations in serum aminotransferases (ALT or AST) or histologically active
98–100 Adefovir dipivoxil is the oral prodrug of an acyclic nucleotide
monophosphate analog, 9-(2-phosphonylmethoxyethyl)-adenine. The active drug is a
selective inhibitor of numerous species of viral nucleic acid polymerases and RTs.
Previously, two trials reported the efficacy of adefovir 10 mg orally once daily for
the treatment of patients who were HBeAg negative
Adverse effects from adefovir included abdominal pain, diarrhea, dyspepsia,
headaches, nausea, and nephrotoxicity.
Resistance to adefovir occurs at a much slower rate compared with lamivudine.
The cumulative probability of resistance in the HBeAg-negative patient trial was
estimated to be 0%, 3%, 1%, 18%, and 29% at years 1, 2, 3, 4, and 5 years,
In the trial with HBeAg-positive patients, resistance was estimated to
100 Other reports have described adefovir resistance rates as high
as 20% after 2 years of treatment.
98 Risk factors for adefovir resistance appear to be
suboptimal viral suppression and sequential monotherapy. Thus, adefovir should also
be considered a second-line therapy for C.R.
Entecavir (Baraclude) is an oral acyclic guanosine nucleoside derivative with potent
101–103 The drug inhibits HBV replication at three different steps:
(a) the priming of HBV DNA polymerase; (b) the RT of the negative-strand HBV
DNA from the pregenomic RNA; and (c) the synthesis of positive-strand HBV DNA.
In vitro studies have shown that the drug is more potent than lamivudine and adefovir
and is highly effective against lamivudine-resistant HBV mutants.
In two published Phase III clinical trials, the efficacy of entecavir was reported in
Patients with compensated liver disease who had not previously received a
nucleoside analog were assigned to receive entecavir 0.5 mg, or lamivudine 100 mg
orally once daily for a minimum of 52 weeks. By week 48, HBeAg-positive patients
receiving entecavir had higher rates of histologic (72% vs. 62%), virologic (HBV
DNA undetectable by PCR; 67% vs. 36%), and biochemical (ALT normalization;
68% vs. 60%) responses when compared with lamivudine.
seroconversion rates were similar among the two treatment groups (21% vs. 18%;
entecavir vs. lamivudine, respectively). No viral resistance to entecavir was
detected during the study period, but follow-up data suggest a low rate of resistance
102 The authors concluded that entecavir was as safe and
higher histologic, virologic, and biochemical response rates than HBeAg-positive
patients treated with lamivudine. In patients who remained HBeAg positive with low
levels of HBV DNA replication, a second year of entecavir and lamivudine therapy
resulted in seroconversion in 11% and 13% of patients, respectively.
In another trial of HBeAg-negative hepatitis B infection, patients received either
entecavir 0.5 mg or 100 mg of lamivudine daily for a minimum of 52 weeks. At week
48, patients receiving entecavir had significantly higher rates of histologic (70% vs.
61%; p < 0.01), virologic (90% vs. 72%), and biochemical (78% vs. 71%) response
103 No resistance was seen among patients receiving entecavir. Safety and
adverse events were similar in the two groups. Thus, C.R. could receive entecavir
0.5 mg daily. As with all of the nucleoside agents, dosage adjustments should be
implemented with changes in renal function. Furthermore, entecavir may be used for
lamivudine-refractory or lamivudine-resistant patients. In these patients, lamivudine
should be discontinued to reduce the risk of entecavir cross-resistance. The dose of
entecavir used for lamivudine-resistant patients is 1 mg orally once daily. In these
patients, entecavir resistance has been reported to be 51% after 5 years of therapy.
Thus, alternatives may be warranted for these patients.
liver improvement, entecavir was ranked superior over tenofovir disoproxil
Tenofovir disoproxil fumarate (Viread) is approved for the oral treatment of chronic
110–112 This agent is a potent nucleotide analog that is structurally similar, yet
equipotent, but less nephrotoxic than adefovir. Clinical trials in HBeAg-positive and
HBeAg-negative patients with chronic HBV infection have demonstrated the efficacy
of tenofovir DF. In the first Phase III trial of HBeAg-positive patients with
compensated liver disease, a significantly higher proportion of tenofovir-treated
patients had undetectable HBV DNA (76% vs. 13%), ALT normalization (68% vs.
54%), and HBsAg loss (3% vs. 0%) at the end of therapy. Histologic response rates
and HBeAg conversion were similar between the two groups. Of note, at the end of
therapy, patients in the adefovir group were switched to tenofovir DF, and any
patient who had detectable HBV DNA by week 72 had emtricitabine added to their
regimen with subsequent additional serologic benefit.
In the second trial, HBeAg-negative patients with compensated liver disease were
given a similar regimen (300 mg of tenofovir DF or 10 mg of adefovir daily for 48
111 By week 48, a higher percentage of tenofovir-treated patients had
undetectable serum HBV DNA than those treated with adefovir (93% vs. 63%). The
proportions of patients having ALT normalization (76% vs. 77%) or histologic
response (72% vs. 69%) were similar. No patients in the study became HBsAg
negative. Again, at week 48, patients receiving adefovir were switched to tenofovir.
Patients in both groups who still had detectable HBV DNA by 72 weeks were given
emtricitabine. Similar to the HBeAg-positive group, the change to tenofovir DF led
to additional viral suppression in the patients initially treated with adefovir. In the
previous two trials, only 7 patients were observed to have virologic breakthrough
during 96 weeks of therapy, but no tenofovir-resistant HBV mutations were detected.
Current guidelines suggest and clinical data support tenofovir (300 mg PO every day)
as a viable first-line agent for C.R.
112 Generally, tenofovir is well tolerated, but it has
been reported to cause Fanconi syndrome, renal insufficiency, osteomalacia, and a
110 Similar to other agents in this class, the dose of tenofovir
DF should be adjusted based on renal function.
110–112 Recommendations for treatment
of chronic HBV can be found in Table 80-6.
Treatment Preferred as First Choice Comments
Entecavir Yes (unless previous history of lamivudine
High potency, high genetic barrier to
Tenofovir DF Yes High potency, high genetic barrier to
TAF Yes High potency, high genetic barrier to
PegIFN Yes Less safe in pts with cirrhosis
Adefovir No Low genetic barrier to resistance;
Lamivudine No Low genetic barrier to resistance
Tenofovir alafenamide, or TAF (Vemlidy), is the latest oral antiviral approved for
the treatment of chronic HBV infection. It is a nucleotide prodrug that is converted to
tenofovir diphosphate in a two-step process, which inhibits replication of the
113 TAF has a similar antiviral profile as its sibling drug, tenofovir DF, but at a
dose one-tenth less than 300 mg. Approved at 25 mg orally once daily, TAF exhibits
greater plasma stability and more efficiently delivers tenofovir to hepatocytes and
results in less tenofovir in the bloodstream, leading to improved renal (eGFR and
renal tubular function) and bone safety parameters (smaller declines in spine and hip
bone mineral density) compared to tenofovir DF.
113–115 Two pivotal international
Phase III clinical studies (Studies 108 and 110) demonstrated TAF’s efficacy among
1,298 treatment-naïve and treatment-experienced adults with chronic HBV infection
over 48 weeks. Study 108 was a randomized, double-blind, active-controlled trial
randomized and treated 873 HBeAg-positive patients with either TAF or tenofovir
DF. The study results were similar showing noninferiority to tenofovir DF based on
the percentage of participants with a decline of HBV DNA below 29 IU/mL at 48
115 Upon further data analysis through 96 weeks, higher rates of
ALT normalization occurred with participants in the TAF study arm compared to
those in the tenofovir DF arm. No viral resistance developed with either TAF or
TAF was generally well tolerated by the study participants, and discontinuations
from adverse events were 1% compared to 1.2% of participants in the tenofovir DF
arm. The most common adverse events (incidence ≥5%) reported for TAF included
headache, fatigue, abdominal pain, cough, nausea, and back pain. Similar to tenofovir
DF, TAF has a safety warning of risk of lactic acidosis/severe hepatomegaly with
steatosis and post-treatment severe acute exacerbations of hepatitis B, especially
114,115 There have been no reported cases of Fanconi syndrome
or proximal renal tubulopathy associated with TAF. Nevertheless, renal monitoring
of the serum creatinine, phosphorus,
creatinine clearance, urine glucose, and urine protein prior to initiating and during
TAF treatment is clinically recommended. The antiviral has also been approved for
HIV-1 treatment as part of a combination antiretroviral regimen with integrase strand
transfer inhibitors. However, the safety and efficacy of TAF have not been
established in patients with HBV and HIV coinfections. TAF is less nephrotoxic than
tenofovir DF and, however, is not recommended for patients with CrCl <15
mL/minute. It is also not recommended for patients with decompensated (Child-Pugh
Regarding the drug interaction profile of TAF, it is not recommended to be
coadministered with anticonvulsants (i.e., oxcarbazepine, phenobarbital, and
phenytoin), anti-tuberculosis medications (i.e., rifabutin, rifampin, and rifapentine),
or Saint-John’s-wort. Such coadministration will result in decreased serum levels of
TAF, thus reducing its therapeutic effect. TAF is also a substrate of P-glycoprotein
(P-gp) and breast cancer resistance protein (BCRP). Drugs that strongly affect P-gp
and BCRP activity may lead to changes in TAF absorption.
PegIFN with the oral antivirals can be found in Table 80-7.
Combination therapy for HIV and HBV is more effective than monotherapy. The
potential for additive or synergistic antiviral effects and reduced or delayed rates of
viral resistance may also be possible in patients with HBV infection. Several
combination therapies have been evaluated (PegIFN and lamivudine, lamivudine and
adefovir, lamivudine and telbivudine), but none are superior to monotherapy.
Comments
Post a Comment
اكتب تعليق حول الموضوع