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to the recommendation to screen for HCC in person at least 40years of age with
chronic hepatitis B [111].
Mutations in the BCP region of the HBV to A1762T and G1764A have been
reported as independent factors that predict the development of HCC in patients
with chronic HBV genotypes A2, B, C, and D [112]; mutations in the pre-core
region have been inconsistently reported in association with risk for HCC, although
they have been reported in association with active inammation in patients who are
in the HBe-antigen + immune active chronic hepatitis B phase (Table7.1).
Chronic HBV infection is associated with cirrhosis and its complications and
with HCC.From a study that comprised 1536 natives of Alaska with chronic HBV,
41.7% of whom were HBeAg-positive and who were enrolled in a surveillance
program for detection of HCC over a follow-up period of 12.3years, the reported
observed probability to clear HBeAg within 10years of diagnosis was 72.5%, with
7% of subjects losing HBsAg, events associated with increased age and presence of
anti-HBe antibodies. The incidence of complications from liver disease was reported
as 2.3 per 1000 carrier-years, and that of HCC, which was related to reversion from
anti-HBe antibodies to e Ag positivity, as 1.9 per 1000 carrier-years, being docu-
mented as more common in men, 2.3, than in women, 1.2 [109].
Seroconversion from e antigen to its loss is an important step in the natural his-
tory of chronic HBV virus infection, as it is associated with histological improve-
ment. Seroconversion from e Ag positive to anti-HBe was reported not to be
inuenced by HBV genotype; however, sustained seroconversion was more com-
mon in patients infected with genotype A than in those infected with genotype D.In
addition, death from complications of liver disease was signicantly higher in
patients infected with genotype F than in those infected with genotype D [113].
Infection with HBV genotype C was reported in association with high viral load and
with a greater risk for development of HCC in a study comprised of 154 patients
from Taiwan who had developed this type of cancer over 14years of follow-up
compared to a control group of subjects [114]. A less aggressive disease was
reported in patients with HBV genotype B infection in a study from Japan; however,
the long-term complications were not documented to be signicantly different
between infections from genotypes B and C [114]. However, from another study
conducted in Taiwan, HBV infection with genotype B or C was signicantly associ-
ated with the development of HCC [115]. In the presence of the G1896A variant,
HCC was signicantly more common than when the infection was associated with
G1896 (wild type); for patients infected with a virus that had the BCP A1762T/
G1764A double mutation, the risk for HCC was also higher than that in patients
infected with a virus that had the BCP A1762/G1764 (wild type). The highest risk
to develop HCC was for patients infected with HBV genotype C, wild type precore
variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio= 2.99,
95% CI= 1.57 to 5.70, p<0.001) [115]. In Alaska, genotype F was found in the
majority of patients with HCC from a cohort of 47 patients with chronic HBV and
HCC, but no association with mutations in the core promoter and precore regions
was demonstrated [116].
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A retrospective study from the hepatology clinic in a community hospital in
Northern Brooklyn attended by the author documented that patients with chronic
hepatitis B came from all continents[117]. The most common genotypes in this
study were A, D, and E, which are the most prevalent in North America, Southern
Europe, the Middle East, and sub-Saharan Africa [54], a reection of the geographi-
cal areas of origin of the population that the hospital serves. The patients with high
levels of serum HBV DNA in association with a pre-core mutation and negative
anti-HBe antibody were infected with genotype D mostly, consistent with other
reports [118].
The impact of HBV treatment on the natural history of the disease was examined
in a prospective study in which 103 patients with chronic hepatitis B, with e antigen
+ disease who had been treated with interferon alpha, were followed for a mean
period of 50.0 (±SD) ±19.8months. Treatment with interferon alpha was associated
with the disappearance of HBeAg and HBV DNA in 53 of 103 (51%) patients. Of
these, ten lost HBsAg, with estimates of a cumulative clearance at 5years of 56%
for HBeAg loss, and 11.6% for HBsAg, by the Kaplan-Meier analysis. These results
were signicantly different from those of the control group, which was comprised
of 53 patients who had not been treated, and from whom seven lost HBeAg sponta-
neously at 5years, and none of whom lost HBsAg. Of the treated patients, six died
of liver failure, and two had a liver transplant, all of whom had remained HBeAg+.
Eight other patients who had also maintained e Ag+ status developed complications
of cirrhosis. Survival and survival without complications were reported to be sig-
nicantly longer in patients who had lost e Ag in association with therapy than those
who had remained e Ag+. HBeAg loss was reported as the strongest predictor of
survival in association with treatment. In the control group, 13 of the 53 patients
who had remained HBeAg+ developed complications of liver disease, including
death and liver transplantation [119].
The probability of survival at 1, 3, and 5years was reported as 92%, 79%, and
71%, respectively, in a group of 98 patients with cirrhosis in association with
chronic HBV infection that was followed for a mean period of 4.3years, with age,
serum bilirubin concentration, and ascites independently related to survival.
Decompensated liver disease was associated with a survival of 14% at 5years, in
contrast to that of patients with compensated cirrhosis of 84%. In this study, the
presence of hepatitis B e antigen was associated with the probability of survival at
5years of 72% compared to 97% for patients who were e antigen negative. The
importance of e antigen seroconversion was also conrmed, as it was associated
with a decrease in the risk of death [120].
Indeed, studies from different geographical areas have documented the morbid-
ity and mortality risk in patients with chronic hepatitis B.From a study conducted
in Italy, it was reported that regardless of a specic serology at the time of diagnosis,
chronic hepatitis B, with cirrhosis and inammatory activity as contributing factors,
wasassociated with increased mortality, 5.2 times that of the general population
[121]. From Taiwan, it was documented from a study that included 1506 patients
with chronic HBV infection that cirrhosis, inferred by clinical and sonographic
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changes, was a risk factor for HCC, which was identied in a group of patients after
7years of follow-up, with a multivariate-adjusted relative risk (RR) of 11.8 (95%
condence interval (CI) 3.9–35.8); the presence of e antigen and consistent increase
in the serum activity of ALT for 6months were identied by multivariate analysis
as risk factors for cirrhosis [82]. In Japan, 3769 women diagnosed as carrying hepa-
titis B surface antigen during blood donation were followed from 1977 to 1985; the
population attributable risk was estimated to be 6.5% for HCC, signicantly higher
than that found in the general population of women of the same age [122].
Most of the complications associated with chronic hepatitis B were reported in
association with cirrhosis [123], with an estimated 5-year survival of 80% reported
from a study that enrolled 76 patients at the time the diagnosis of cirrhosis was made
and that were followed for 34.4months. The annual incidence of acute exacerba-
tions, which tended to occur 2years after enrollment, which were usually in asso-
ciation with the presence of e antigen, was reported to be 11.9%. Reactivation of
HBV infection was the cause of the acute exacerbation in the majority of patients.
In 30% of subjects, it was associated with seroconversion from e antigen + to anti-
HBe, with the loss of surface antigen being uncommon. The incidence of hepatic
decompensation, esophageal variceal bleeding, and HCC was reported as 2.3%,
2.3%, and 2.8%, respectively. Liver failure and variceal bleeding were the cause of
death in 9.2% of the patients [123]. Important information was provided by a mul-
ticenter European study that examined survival and prognostic factors in 366
patients with compensated cirrhosis in association with chronic hepatitis B. The
study followed patients with compensated cirrhosis for a mean period of 72months
(6–202months). At enrollment, 35% of the patients were HBeAg positive, serum
HBV DNA was present in 48% of the patients in whom it was measured, and 20%
had antibodies against the delta hepatitis virus. Eighty-four (23%) of the patients
died, 45 of complications of liver failure, and 23 of HCC.The cumulative probabil-
ity of survival was reported as 84 and 68% at 5 and 10years, respectively. Hepatitis
B virus replication, evidenced by the presence of HBV DNA in serum, increased
age, portal hypertension, as suggested by splenomegaly and hypersplenism, and
synthetic hepatic dysfunction correlated with a decrease in survival. Absence of
serum HBV DNA and normal activity of transaminases highly correlated with sur-
vival [124].
The incidence of cirrhosis was studied in a histological follow-up study of 105
patients with HBsAg in serum, 59 of whom were reported to have chronic active
hepatitis (i.e., presence of interface hepatitis, Fig.7.2) without cirrhosis, and 46
were reported to have no interface hepatitis at enrollment. Liver histology, reex-
amined after a mean follow-up of 3.7years, was reported to show cirrhosis in 21
patients (20%) 1 to 13years after entry into the study, with a calculated annual
incidence of 5.9%. The presence of interface hepatitis (Fig.7.2) and bridging
brosis increased the probability of cirrhosis development signicantly over nd-
ings of limited inammation. Advanced age, the presence of bridging necrosis on
histology, and active replication, as suggested by the detection of HBV DNA in
serum, were reported as independent variables that portended poor progno-
sis [125].
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Impact ofCoinfection withHIV, HCV, andDelta Hepatitis
Viri ontheNatural History ofChronic Hepatitis B
Coinfection with the hepatitis C virus also contributes to the development of HCC
in patients with chronic hepatitis B.In a study comprised of 231 black patients with
HCC from South Africa, the risk for HCC was increased by 23.3 fold in those
patients positive for HBsAg, and 6.6in those positive for HCV, as compared to
those without markers of viral hepatitis infection. The relative risk to develop HCC
in patients with markers of hepatitis B and C viral infections was 82.5 [126]. A
dominating presence of HBV infection and the contribution of coinfection with
HCV was conrmed by a study from Gambia, West Africa, in which 216 incident
cases of HCC and 408 control were enrolled and from which it was reported a 61%
infection state for HBV in patients with HCC versus 16% of the control subjects,
and 19% HCV positive serology in the HCC group versus 3% in the control group.
The increased risk for HCC in patients with chronic hepatitis B was calculated as an
odds ratio (OR) of 16.7, 95% CI, 9.7–28.7, and for patients with HCV infection, an
OR of 16.7; 95% CI, 6.9–40.1, with marked increase by coinfection, with an OR of
35.3; 95% CI, 3.9–323 [127]. Studies from Europe have conrmed the ndings of
those from Africa. Patients with chronic hepatitis B co-infected with HCV, which
tends to be the predominant virus with associated suppression HBV DNA [128],
and be associated with loss of HBsAg on long-term follow-up [129], tend to develop
advanced disease and are at risk for HCC.A synergism between HBV and HCV
infection has been reported towards the risk of development of HCC, with the odds
ratio for this type of cancer being reported as 165 (95% CI: 81.2–374), in a meta-
analysis of epidemiological studies that examined the combined effect of hepatitis
B and C virus infections in causing hepatocellular carcinoma [130]. Also, fulminant
liver failure from acute HCV has been documented in patients who are carriers for
Fig. 7.2 Liver histology
exhibiting interface
hepatitis (arrows) in a
patients with chronic
hepatitis B (40X)
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HBsAg with a reported incidence of 23.1% (95% CI=9.9–36.3%), compared to
that in patients who did not have HCV infection, in whom the incidence of fulmi-
nant liver failure was 2.9% (95% CI=−1.0–6.8%) in a study from Taiwan [131].
Delta Hepatitis
The delta hepatitis virus is 36nm in diameter. It is comprised of a single-stranded,
circular RNA genome of negative polarity; eight genotypes have been identied,
genotype1 being the most prevalent in North America [132] and also the most viru-
lent [133]. HBsAg proteins are embedded in the lipid envelope that surrounds the
HDV genome, which encodes a small delta antigen and the large delta antigen, and
which uses the HBV envelope proteins for its assembly and propagation of infec-
tion; thus, the presence of the HBV is required for HDV replication, which occurs
in the nucleus of the hepatocyte, and perpetuation of the infection.
Infection with HDV occurs simultaneously with that of HBV, or as superinfec-
tion, in a subject already infected with HBV.In contrast to HBV, HDV does have
cytopathic effects on hepatocytes, mostly related tothe small deltal antigen SHDAg,
via innate and adaptive immunity, which tends to be weak and thus facilitates dis-
ease progression. The clinical presentation of coinfection is similar to that of mono
infection with HBV, but the inammatory response is severe, and it can be associ-
ated with acute liver failure [134]. Because replication of HDV requires HBV, char-
acteristically, there are two peaks in serum activity of ALT separated by several
weeks because the establishment of HBV infection is required [134, 135]. Infection
with HDV in patients with chronic hepatitis B, i.e., superinfection, is more severe
than coinfection, associated with an increased risk for acute liver failure. In patients
with chronic HVB infection, superinfection with delta can be misinterpreted as
ares; thus, it is important to rule out HBV superinfection in those cases. HDV
RNA can be detected in serum only in the rst 2weeks of infection and transiently
after that; IgM antibodies tend to appear within 2 to 3weeks of infection, usually
lasting from 2 to 9months, occasionally followed by IgG.It is recommended to test
HDV RNA when HDV IgG is detected to conrm infection.
The denition of chronic delta hepatitis is anti-HDV antibody positivity. In
adults, HDV coinfection becomes chronic in less than 5% of cases. The probability
of chronicity is greater than 90% when the infection is acquired in the neonatal
period [77, 78]. Progression to cirrhosis can occur in 10–15% of patients within
2 years of infection, and in 80% after 5–10 years of infection [136]. There is a
reported two-fold increase in the risk of hepatic decompensation and HCC in HDV
than in chronic HBV infection. A report from the European Concerted Action on
Viral Hepatitis from a retrospective cohort study of 200 patients from Western
Europe with compensated cirrhosis, 20% of whom were infected with the delta
hepatitis virus with 6.6 years of follow-up, documented that, as determined by
Kaplan-Meier analysis, the 5-year probability of developing HCC was 6, 10, and
9% in patients who had anti-HDV antibodies, e antigen negative, negative for both
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anti-HDV antibodies and e Ag, and negative for anti-HDV antibody and e Ag posi-
tive, respectively; the probability of developing decompensated liver disease was
22, 16, and 19%, respectively, and that for survival was 92, 89, and 83%, respec-
tively. The calculated risk for development of HCC was three times higher for
patients with HBV associated cirrhosis co-infected with the delta hepatitis infec-
tion, and the probability of death two times greater than those not coinfected [137].
The liver in chronic delta hepatitis exhibits panacinar involvement where there is
extensive interface hepatitis; progression to cirrhosis is accelerated. Lymphoid fol-
licles and bile duct lesions can be found in cases of chronic delta hepatitis. The
presence of fat was reported in a study that examined autopsy material from
Indigenous Venezuelan Indians who exhibited liver failure or rapid progression to
cirrhosis in association with HDV infection [107, 138].
Chronic hepatitis B in patients infected with the human immunodeciency virus
(HIV) is associated with a decrease in all the events that lead to seroconversion and
resolution of the HBV infection. Patients coinfected with these two viri have
increased mortality from liver related complications. From a study comprised of
5293 men who had sex with men, 326 (6%) of whom were HBsAg positive with 213
(65%) of this group being HIV-1 positive and in whom the documented mortality
rate was 14.2/1000 as compared to that of subjects who were not coinfected with
HBV, in whom it was 1.7/1000, or that of those with chronic HBV, in whom it was
0.8/1000, both signicantly different from the coinfected patients [139].
Treatment ofChronic Hepatitis B
The cure of chronic hepatitis B would be the eradication of cccDNA, the template
used for viral replication, from the nucleus of the hepatocyte; however, at present,
this has not been accomplished with interferon alpha or nucleos(t)ide reverse tran-
scriptase inhibitors (NRTIs), the therapies available. Loss of surface antigen and the
development of anti-HBs are considered a successful response to treatment, but this
outcome is infrequent in association with the available medications.
The indications for treatment of chronic hepatitis B include inammatory activ-
ity, indirectly assessed by serum activity of ALT, or documented on liver histology,
viral replication, i.e., HBV DNA greater than 2000 IU/ml, and in all cirrhotic
patients regardless of serum HBV DNA [140, 141]. In pregnant women, treatment
in the third trimester when serum HBV DNA is greater than 200,000IU//ml with
nucleoside analogues, e.g., tenofovir, telbivudine, is indicated to decrease the
mother to baby transmission [140, 141].
As it can be appreciated from the natural history of HBV reactivation and ares,
inammatory activity is relevant in the timing to treat patients with chronic hepatitis
B.In regard to ares, it is necessary to follow patients with chronic hepatitis B for
some time to determine the optimal time to treat because there is a greater than 50%
probability of e antigen positive to anti e antibody seroconversion post ares at
18months of follow-up, and close to 50% at 1year post ares, a fact that changes
the indication for treatment, as reported in a study [90]. In this context, there are
notable differences between patients with chronic hepatitis B from the USA and
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those from Asia; the proportion of subjects that experience seroconversion in asso-
ciation with ares, and which changes the indication for treatment, is higher in the
former than in the latter, where not only they tend to recur but do not tend to be
associated with seroconversion [89, 90].
Robust ares increasethe probabilities of seroconversion; however, ares are
also associated with hepatocellular necrosis, brosis, and progression to cirrhosis;
thus, treatment at the time of ares can be benecial in terms of HBV DNA suppres-
sion, which eventually may lead to seroconversion to anti e and over time, to loss of
s Ag and development of anti-HBs. Patients who experience ares associated with
serum ALT activity greater than ve times the upper limit of normal and hyperbili-
rubinemia must be closely followed as decompensation may follow [90]. Patients
who undergo modest HBV ares with serum activity less than ve times the upper
limit of normal are unlikely to experience seroconversion, thus, they are the patients
in whom treatment is indicated, as documented in the guidelines [90, 141].
Current guidelines recommend that patients with + serum HBV DNA and those
with + anti core with or without detected HBV DNA in serum who are going to
receive immunosuppressive therapy be treated with antiviral medications, tenofovir
being the preferred medication (there are limited data with the use of tenofovir alaf-
enamide for this indication) [90, 142, 143].
Treatment with interferon, which stimulates T and NK cells activity, in all its
preparations and doses, can be associated with ares that tend to occur around the
eighth week of treatment and after its completion (Table7.2). Flares can be associ-
ated with seroconversion, and thus, it is a good prognostic sign; however, in patients
with cirrhosis, ares can lead to liver failure; accordingly, interferon should not be
used in this group of patients or used with extreme caution in patients with Child’s
A classication only. Interferon is contraindicated in patients with decompensated
liver disease, i.e., Child’s B and C.
Oral antiviral therapy with nucleoside and nucleotide analogues is associated
with a marked decrease in HBV DNA and low probability of seroconversion, and
with halted disease progression. During treatment with lamivudine, there is an
increase in serum ALT activity during the rst 4–6weeks of treatment; however, the
proportion of patients who exhibited a are was not different from those treated
with the placebo. Lamivudine therapy, which is not the drug of choiceat present,
can be associated with ares in association with the development of mutations in the
polymerase gene, which are resistant to the drug, leading to the reappearance of
HBV DNA [144]. Flares have also been reported in patients co-infected with HIV
on treatment with lamivudine for the latter now considered to be from the develop-
ment of HBV mutants [145].
Indications forTreatment ofHepatitis B
The goal of treatment of chronic hepatitis B is the prevention of cirrhosis and its com-
plications, including hepatocellular carcinoma. It is recommended that patients with
chronic hepatitis B and chronic liver injury, as suggested by the high serum activity of
ALT, be treated. Patients with high HBV serum levels and normal ALT activity do not
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tend to lose e antigen or seroconvert in association with antiviral treatment; thus, it is
not recommended that this type of patients be treated; however, follow-up to detect any
immune activity resulting in an inammatory response as indicated by high serum
ALT activity is necessary to identify a point in time where treatment may be indicated.
In patients with e antigen + chronichepatitis B, serum ALT activity twice the
upper limit of normal, serum HBV DNA lower than 2.0×10(8) IU/mL, and no prior
treatment with interferon was associated with sustained virologic response (SVR),
dened as serum HBV DNA less than 2000IU/mL at 6 months after treatment.
Patients with genotype A, high serum activity of ALT, and relatively low HBV DNA
had a predicted probability of SVR greater than 30% [146]; surface antigen loss in
association with IFN treatment has also been associated with this genotype. The
strongest predictor of response in patients with genotype B was high serum activity
of ALT, and in those with genotype C, it was low HBV DNA; the probability of
response to interferon in patients with genotype D was low, regardless of the serum
activity of ALT or HBV DNA concentration [146]. There are no predictors of SVR
in association with treatment with IFN or nucleoside or nucleotide analogues in
patients with e antigen negative chronic HBV infection. A decrease in serum con-
centration of HBsAg has been identied as a predictor of response in patients with
e antigen + chronic hepatitis B, and a predictor of sustained suppression of HBV
DNA in serum in patients with e antigen negative chronic hepatitis B.These factors
have been used as the basis to discontinue therapy with interferonat 12 or 24weeks
because of predicted futility [147].
Treatment is recommended for patients with cirrhosis, or suggestion of cirrhosis
by clinical, laboratory, radiological, and by the technique of Fibroscan to prevent
decompensation of liver disease, which will happen in time, or in association of
hepatitis ares, which can lead to liver failure, and development of HCC regardless
of the degree of viral replication, as measured by serum HBV DNA.Patients who
experience worsening of their hepatitis as evidenced by increased serum ALT activ-
ity and hyperbilirubinemia and patients with acute liver failure in association with
HBV infection should also get treated.
As the risk of developing cirrhosis increases over time in patients who have
remained in the immune tolerant phase, patients should be treated at age 30–40years
[140, 141, 148, 149]; this recommendation also applies to patients with a family
history of HCC [141, 148].
In pregnant women, a serum HBV DNA>200,000 IU/ml is an indication for
treatment with oral antiviral drugs, e.g., tenofovir, in the third trimester, regardless
of the serum activity of ALT for over 8–12weeks after delivery [141, 150, 151]. In
addition, the infant receives hepatitis B immunoglobulin (HBIG) and vaccination
against HBV is initiated at birth to prevent HBV transmission to the infant [141,
150, 151].
Patients who are HBsAg + or HBsAg– and anti-core + are at risk for HBV reac-
tivation in association with treatment with immunosuppressants, including antican-
cer drugs; thus, prophylaxis therapy with oral antiviral medications, e.g., tenofovir,
is indicated [141].
Treatment with oral antivirals is recommended in acute infections associated
with impaired liver function, i.e., coagulopathy (INR > 1.5) [152, 153] and
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persistent hyperbilirubinemia, i.e., bilirubin >3mg/dl for more than 4weeks after
presentation [141]. It is also recommended that patients with extrahepatic manifes-
tations of chronic HBV infections be treated [153].
Drugs fortheTreatment ofChronic Hepatitis B
Interferon alpha is endogenously produced as a host defense against viral infection.
Its effects include the induction of interferon-stimulated genes, which have antiviral
properties, a decrease in the amount of intracellular HBV nucleocapsids, and the
acceleration of the decline of HBV replication-competent nucleocapsids [154].
Interferon is also an immunomodulator. Treatment with interferon alpha was docu-
mented to deplete CD8-T cells and to stimulate the production of IL-15, a proprolif-
eration cytokine, and an expansion in the number of CD56(bright) NK cells that
exhibited increased activation markers and also, the activation receptor NKp46, in
association with an enhanced expression of TRAIL and interferon gamma [155].
This observation coincided with the peak in the decrease in viral replication, sup-
porting the idea that NK cells contribute to interferon’s antiviral effect. Another pro-
posed mechanism of action of interferon alpha against HBV replication is the
decrease in the transcription of pregenomic RNA (pgRNA) and subgenomic RNA
from the HBV covalently closed circular DNA (cccDNA) minichromosome, as doc-
umented in cultured cells and mouse livers populated with human hepatocytes
infected with this virus [156]. In addition, specic degradation of nuclear viral DNA
by the upregulation of APOBEC3A, a DNA cytidine deaminase with antiviral effects,
by interferon alpha was reported as another mechanism of action of the drug [157].
The pegylation of interferon facilitated this medication’s use by allowing its admin-
istration to be once a week for the duration of treatment, determined to be 48weeks.
Peginterferon alfa-2a has a 40 kilodalton branched polyethylene glycol, which signi-
cantly increased itsserum half-life and plasma concentration [158]; this form of inter-
feron was documented to be more efcacious in the treatment of chronic hepatitis C
prior to its approval for use in chronic hepatitis B [159]. The results of one of the
pivotal studies on which the approval of pegylated interferon was based are shown in
Table 7.3 [160, 161]. A systematic review identied four studies for analysis that
documented that pegylated interferon for at least 6months was superior to lamivudine
on viral and biochemical suppression in patients with e antigen + chronic hepatitis B,
supporting the use of the former as the rst line of therapy [163].
The DNA polymerase of the HBV virus synthesizes DNA via its reverse tran-
scriptase activity [164]. HBV polymerase’s priming activity is inhibited by purine
analogues, which exert this effect by direct inhibition, through competitive binding
with endogenous substrates or through incorporation into the viral DNA to act as
chain terminators. The approved oral medications for the treatment of chronic HBV
are lamivudine, entecavir, and telbivudine, which are nucleoside analogues, and
adefovir dipivoxil and tenofovir disoproxil fumarate (TDF) and its prodrug tenofo-
vir alafenamide (TAF), which are nucleotide analogues [20, 165] (Tables 7.4
and 7.5).
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Table 7.3 Effect of pegylated interferon on chronic hepatitis B
Study design/drugs/
duration
Number of
adult patients
per drug
Histologic
response (%)
in
inammation
Pegylated
interferon/
lamivudine
Histologic response
(%) in brosis
Pegylated interferon/
lamivudine
HBV DNA
Response (%)
Pegylated interferon/
lamivudine
ALT normalization
(%)
Pegylated interferon/
lamivudine
Serology
(HeAg seroconversion
(%)
Pegylated interferon/
lamivudine
HBe Antigen positive
Randomized to
pegylated interferon or
lamivudine/48weeks
duration and 24weeks
of follow-up
271, pegylated
interferon/272,
lamivudine
41/40 Improved
25/32
Unchanged
25/20
Worsened
26/16
32/22 41/28 32/19
Study design/drugs/
duration
Number of adult
patients per drug
a,b
Histologic response (%)
in inammation
Pegylated interferon/
lamivudine
c
Histologic response (%)
in brosis
Pegylated interferon/
lamivudine
HBV DNA response (%)
Pegylated interferon/
lamivudine
ALT normalization (%)
Pegylated interferon/
lamivudine
HBe Antigen negative
Randomized to pegylated
interferon or
lamivudine/48weeks
duration and at 24weeks
of follow-up
177, pegylated
interferon/181,
lamivudine
48/41 Improved
32/31
Unchanged
30/23
Worsened
19/15
43/29 59/44
HBV DNA response dened as less than 100,000 copies/mL for HBeAg positive and less than 20,000 copies/mL for HBeAg negative
a
The proportion of unavailable paired liver biopsies in the pegylated interferon group was 31% and in the lamivudine group, 32%
b
Histological response was dened as greater than or equal to 2-point decrease in Ishak necroinammatory activity and no worsening of Ishak brosis score
c
Change by one point or more in the Ishak brosis score [162]
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