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[Minerva Gastroenterol Dietol., 61(2), 2015]
ovvero [Caviglia GP, Abate ML, Pellicano R, Smedile A., 61, Minerva Medica, 2015,
pagg.61-70]
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Chronic Hepatitis B Therapy: Available Drugs and Treatment Guidelines
G. P. CAVIGLIA1, M. L. ABATE1, R. PELLICANO2, A. SMEDILE
1Department of Medical Sciences, University of Turin, Turin, Italy
2Department of Gastroenterology, Molinette Hospital, Turin, Italy
Conflict of interest: None of the authors declare any conflict of interest
Acknowledgements: The authors thank Sharmila Fagoonee (Institute for Biostructures and
Bioimages-CNR c/o Molecular Biotechnology Center, University of Turin, Turin, Italy) for English revision.
Corresponding author: G. P. Caviglia, Department of Medical Sciences, University of Turin, Via San
Massimo 24, 10100, Turin, Italy. E-mail: caviglia.giampi@libero.it
Running title: Chronic hepatitis B treatment
Abstract word count: 183
Abstract
Currently, there are several drugs approved for the treatment of chronic hepatitis B including recombinant interferons, such as Interferon-α and its pegylated formulation, and the nucleos(t)ide analogues, such as Lamivudine, Adefovir, Telbivudine, Entecavir and Tenofovir. Pegylated-Interferon is an immune-modulatory agent that works mainly by enhancing the innate immune response while nucleos(t)ide analogues are oral drugs with direct inhibition of viral replication. Each agent has its own advantages and drawbacks. Pegylated-Interferon treatment has a finite duration without induction of drug resistance but only a limited number of patients achieve a sustained virological response to therapy. On the other hand, the care with
nucleos(t)ide analogues requires a long-term treatment with a potential risk of induction of drug resistance, but higher rates of viral replication suppression are achieved. Nevertheless, second generation nucleos(t)ide analogues, such as Entecavir and Tenofovir, have both high genetic barrier to resistance and potent antiviral action. This review describes the mechanisms of
antiviral activity and the efficacy of viral suppression of the different available drugs for chronic hepatitis B treatment, considering the recent clinical guidelines for an optimal management of chronic HBV infection.
Riassunto
Attualmente, ci sono diversi farmaci approvati per il trattamento dell'epatite cronica B inclusi gli interferoni ricombinanti, come l'interferone-α e la sua formulazione pegilata, e gli analoghi nucleos(t)idici, come ad esempio la Lamivudina, l’Adefovir, la Telbivudina, l’Entecavir e il Tenofovir. L’Interferone-pegilato è un agente immuno-modulatore che agisce principalmente potenziando la risposta immunitaria innata, mentre gli analoghi nucleos(t)idici sono farmaci orali che agiscono inibendo direttamente la replicazione virale. Ogni molecola ha i suoi vantaggi e svantaggi. Il trattamento con Interferone-pegilato ha una durata limitata, non induce farmaco-resistenza, tuttavia solo un numero limitato di pazienti ottengono una risposta virologica
sostenuta alla terapia. D'altra parte, la cura con analoghi nucleos(t)idici richiede un trattamento a lungo termine con un potenziale rischio di induzione di farmaco-resistenza, ma consentono di raggiungere i più alti tassi di soppressione della replicazione virale. Tuttavia, gli analoghi nucleos(t)idici di seconda generazione, come l’Entecavir e il Tenofovir, hanno sia un’alta
barriera genetica verso lo sviluppo di resistenze sia una potente azione antivirale. Questa review descrive i meccanismi d’azione e l'efficacia di soppressione virale dei diversi farmaci disponibili per il trattamento dell’epatite cronica B, considerando le recenti linee guida cliniche per una gestione ottimale dell'infezione cronica da HBV.
Hepatitis B virus (HBV) is the second greatest cause of chronic viral hepatitis worldwide. Despite decades of vaccination, the estimated number of HBV infected patients in the world is approximately 450,000,000.1 Chronic hepatitis B (CHB) is a result of an acute, unresolved infection,
that overtime may lead to cirrhosis and its complications such as liver failure and hepatocellular carcinoma (HCC).2, 3
Remarkable advances have been made in the cure of CHB with antiviral therapy. The reason resides on a better understanding of different phases of HBV infection, new diagnostic tools for the monitoring of liver disease and primarily the introduction of nucleos(t)ide analogues (NAs). These are oral drugs that since their approval in 1998 started to replace almost completely the use of the previous therapy based on standard Interferon-α (IFN) and Pegylated Interferon-α (Peg-IFN).4
The natural history of HBV infection is a dynamic process that varies widely among different phases (Figure 1). The immune tolerant phase is characterized by hepatitis B e antigen (HBeAg) positivity, normal levels of aminotransferases, high viral load but mild or no liver necroinflammation.5
The immune reactive HBeAg-positive phase is characterized by decreasing levels of viremia increasing levels of aminotransferases and necroinflammation. Generally, this phase is followed by appearance of antibodies to HBeAg (anti-HBe) and loss of HBeAg (seroconversion), and it may lead either to the establishment of chronic hepatitis B (HBeAg-negative CHB phase) if HBsAg is detectable at high levels for more than 6 months, ongoing serum HBV DNA and with a progression of liver fibrosis towards cirrhosis,5 or to the resolution of the acute hepatitis where transaminases return to normal
values and clearance of HBV is marked by HBsAg loss with or without anti-HBs (HBsAg-negative status). HBV DNA is undetectable in serum but it may remain integrated in nuclei of hepatocytes or as covalently closed circular DNA (cccDNA).6, 7 The inactive HBV carrier status, with loss of HBeAg and
levels (< 2,000 IU/mL) and normal alanine aminotransferases (ALT) in serum.8 The occult HBV state
is characterized by the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing HBsAg negative by currently available assays. When detectable, the amount of HBV DNA in the serum is usually very low (< 200 IU/ml).9, 10
Clinical impact of HBV genotypes
Due to the high genetic variability of HBV, the virus can be categorized into different genotypes which considerably differ according to geographical distribution (Table I), disease progression and response to antiviral therapy. Genotypes A, B, C and D are the most extensively studied: genotypes A and D are mainly found in Europe and America, while genotypes B and C are endemic in the Asian region.11
Several reports showed that genotypes C and D tend to be related to more severe liver disease and to a worse outcome than genotype A and B. Moreover, cirrhosis and HCC are more frequently diagnosed in carriers of genotypes C and D than in those of genotypes A and B.12
HBV variants who express little or no HBeAg are responsible for the so-called HBeAg-negative chronic hepatitis B (e-CHB), whose prevalence varies widely across different geographical regions. In patients carrying these mutants the natural course of hepatitis is severe and the response to interferon is lower.
Regarding therapy response, in HBeAg-positive patients treated with IFN a higher rate of post treatment HBeAg seroconversion, normalization of serum ALT levels and substantial decrease in serum HBsAg titer was observed in patients infected with genotypes A and B but not in patients infected with genotypes C and D.11 In case of therapy with NAs, it has been showed that genotypes A
and B are more frequently associated with antiviral resistant variants than genotypes C and D, respectively.13
Current available drugs
The goal of CHB therapy is to prevent disease progression suppressing viral replication and maintaining a virological remission. Then, inflammation reduction prevents fibrosis progression, decreasing the risk of cirrhosis and theoretically of HCC.14
In recent years, due to the rapid evolving spectrum of new drugs (Figure 2) and available strategies, Hepatology Societies (American Association for the Study of Liver Diseases - AASLD and European Association for the Study of the Liver - EASL) have formulated and updated guidelines in order to help physicians in the management of CHB.15-17 The introduction of NAs in 1998, with
Lamivudine (LAM) as the prototype of this new class of drugs, was a revolution in the field. Several other potent drugs with high barrier to resistance were afterwards produced, giving physicians the possibility to select different treatment strategies.
Standard Interferon-α and Pegylated Interferon-α
Interferon-α is an immune-modulatory agent that enhances the innate immune response
interacting with IFN-receptors at the cell surface, leading to the activation of kinases of the Jak family that phosphorylate signal transducers and activators of transcriptions (STAT) proteins.18 In the nucleus,
STATs up-regulate multiple IFN-stimulated genes that limit viral replication. With the addition of polyethylene glycol, the pegylated formulation has a longer half-life than standard IFN.19 The
advantages of IFN therapy are the finite duration of therapy and the lack of drug resistance. However, there is a low rate of response to treatment and the majority of patients have to be retreated with NAs.20
Nucleos(t)ide Analogues
At present, there are five approved NAs for the treatment of CHB: L-nucleosides such as Lamivudine (LAM) and Telbivudine (TBV), acyclic diphosphonates such as Adefovir Dipivoxil (ADF) and Tenofovir Disoproxil Fumarate (TDF), and Entecavir (ETV).
LAM is the synthetic cytidine analogue that inhibits HBV DNA synthesis. It is phosphorylated by intracellular kinases to LAM-5’-triphosphate that inhibits HBV DNA polymerase by competing with natural substrates leading to the termination of viral DNA chain extension.21 LAM is effective in
ALT normalization, HBeAg seroconversion, viral replication suppression and histological
improvement. The major drawback of LAM treatment is the high rate of viral resistance development. It has been shown that resistance starts to develop within the first year of therapy and increases over time at an annual rate of 15%-25% while it reaches > 80% after 5 years. The single substitution at amino-acid position 204 of YMDD motif (rtM204V/I), in which the methionine (M) is substituted with either valine (V) or isoleucine (I), is sufficient to determine drug-resistance but is often associated with compensatory mutations rtL80V/I, rtI169T, rtV173L, rtL180M, rtT184S/G, rtS202I and rtQ215S.19, 20, 22
TBV is the synthetic thymidine analogue. It is phosphorylated into TVB-5’-triphosphate, the
active form that competitively inhibits HBV DNA polymerase and prevents HBV DNA synthesis.23 In
contrast to LAM, that inhibits both the first and second strand DNA synthesis, TBV exerts its action primarily on the latter process.24 Despite TBV has a low barrier to resistance with similar patterns of
antiviral resistance mutations, it has been shown that TBV-treated patients have a slower rate of emergence of viral resistance than LAM-treated patients.25 The rate of resistance for TBV is 10%-25%
ADF and TDF are the acyclic analogues of the nucleotide adenosine monophosphate and they are converted to the active metabolite form by intracellular adenylate kinase. ADF and TDF inhibit the HBV polymerase by competitive inhibition of the natural substrate causing the DNA chain termination when it is incorporated into the viral DNA.18 In two phase III trials, it has been shown that ADF treated
patients significantly improved histological, virological and biochemical parameters compared to placebo recipients.26, 27 Moreover, ADF alone or in combination with LAM is effective in CHB patients
with LAM-resistant HBV YMDD and the rate of resistance is about 30% after 5 years.22, 28, 29
TDF has been shown to be superior to ADF in the rate of viral suppression and normalization of ALT in both HBeAg-positive and HBeAg-negative patients.30 Besides viral suppression, another study
reported histologic improvement and fibrosis regression in almost all treated patients. Moreover, the regression of fibrosis was observed in 71% of patients with cirrhosis.31 To date, TDF resistance has not
been detected.16
ETV is the synthetic guanosine analogue that undergoes intracellular phosphorylation to the active ETV-5’-triphosphate metabolite. This form competes with the natural substrate deoxyguanosine triphosphate of HBV polymerase and inhibits viral replication.32 In particular, asides from inhibiting
reverse transcription and DNA synthesis as the other NAs, ETV is also capable of inhibit HBV DNA polymerase priming.33 ETV has a high genetic barrier. In fact, at least 3 mutations are required to
develop resistance: rtL180M + rtM204V and either rtT184G/S or rtS202I/G or rtM250V. The reported rate of ETV resistance among NAs-naive patients was about 1% after 5 years of treatment, whereas in LAM-refractory patients the rate of ETV resistance was 51% after 5 years of therapy.22, 34, 35
At the moment, ETV and TDF are the most potent drugs with the highest genetic barrier to resistance approved for treatment of HBV infection.16 However, novel antivirals are under evaluation
for possible future therapeutic intervention. New antiviral approaches target viral DNA polymerase, viral cellular entry, viral encapsidation, HBsAg release and the host immune response.36
Several inhibitor of viral DNA polymerase are under evaluation in phase I and II clinical trials. Only Clevudine has been already approved for CHB treatment in South Korea and Philippines. Clevudine showed a potent antiviral response, and its effect was higher in HBeAg-negative patients, with rapid viral load reduction and ALT normalization. However, clinical trials of long-term therapy for more than 1 year in the United States resulted in the development of considerable resistance and myopathy.37
Lagociclovir valactate is another inhibitor of viral DNA polymerase that exhibited in vitro and
in vivo a potent antiviral activity against wild-type, LAM-resistant, ADF-resistant and
LAM+ADF-resistant HBV mutants.38 At the moment is still under evaluation for clinical efficacy and safety. Other
viral DNA polymerase inhibitors include Besifovir that is an acyclic nucleotide phosphonate found to be effective in HBV DNA suppression for both treatment-naive and LAM-resistant CHB patients in preliminary studies. Moreover, in a recent multicenter phase IIb study, Besifovir was compared to ETV to evaluate safety and antiviral activity and emerged that Besifovir was not inferior to ETV in terms of HBV DNA clearance, HBeAg loss and HBeAg seronversion without development of HBV resistant mutation.39
Another class of drugs under evaluation for HBV infection treatment are inhibitors of virus entry that can either neutralize activity of viral surface proteins or target essential host factors such as (co)receptors. Myrcludex-B is a synthetic N-acylated preS1-derived lipopeptide that inhibits HBV entry with high efficacy preventing HBV amplification and spread from infected hepatocytes.
Currently, Myrcludex-B has been evaluated in healthy volunteers showing safety and good tolerability,40 representing a potential future therapeutic option for controlling acute and chronic
infections.
Recently, heteroaryldihydropyrimidines and phenylpropenamides have been identified as potent inhibitors of HBV nucleocapsid formation. These effectors act preventing viral capsid formation or interfering with viral encapsidation process producing capsids without genetic material, respectively.41, 42 Despite deregulation of virus assembly may be a powerful approach for antiviral therapeutics,
clinical trials are still required to evaluate safety, tolerability and pharmacokinetics. Conversely, inhibitors of HBsAg release are a novel class of compounds with antiviral activity dependent on their amphipathic characteristics that demonstrated safety and efficacy in phase I/II clinical trials.36
Preclinical trials highlighted the potential role of small RNAs such as microRNAs and small interfering RNAs in reducing expression and release of new viral particles exploiting the mechanism of RNA interference to regulate gene expression. These approach suggests that it might be possible to
supplement existing HBV therapies with small RNA-based therapy.43
Emerging antivirals are those with immune-modulatory activities such as Zadaxin that can trigger lymphocyte maturation and increase T-cell function, GS-9620, a potent selective toll-like receptor agonist that can induce the production of IFN-α, up-regulate IFN-stimulated gene expression, activate natural killer cells and lymphocyte subsets, and GI-13020, a chimera of HBV antigens that can elicit HBV-specific T cell responses.36 These immune-based therapies could be used in the next future
in combination with HBV antivirals to improve the inhibition of viral replication, HBsAg clearance and seroconversion.
The major goal of antiviral therapy is to prevent the evolution of CHB to cirrhosis and in cirrhotic patients to prevent complications. The achievable endpoints in short-term (6-12 months) of successful therapy are seroconversion from HBeAg status to anti-HBe-positive antibody, ALT normalization and HBV DNA negativization. Seroconversion to anti-HBe is considered extremely relevant to the final outcome of liver disease. The suppression of the replication activity is usually followed by the stabilization and even, in some cases, the regression of fibrosis in the liver over time, but it requires years of prolonged therapy.44
Patients to be considered for treatment are those HBV infected with an active liver disease characterized by HBV DNA levels above 20,000 IU/mL, abnormal liver enzymes and a significant degree of fibrosis assessed by liver biopsy (Ishak > S3) or a validated indirect method (liver
elastometry, LE > 8 KPa).45, 46 Inactive HBV carriers, defined by persistent normal liver enzymes with
no replication or low HBV DNA (< 2000 IU/mL) and no or mild fibrosis (LE < 5-7 KPa), should not be treated but monitored and followed over time.47
Recently, several studies pointed out that HBsAg levels vary during the natural course of CHB infection: they are highest in the initial immune tolerant phase (5 log10 IU/mL), progressively lower in
immune reactive phase (3-4 log10 IU/mL) and lowest during the inactive phase (< 3 log10 IU/mL).
Moreover, it has been demonstrated that during IFN treatment, a rapid decline in HBsAg levels appears to be predictive of sustained response. Although a rapid HBsAg decline greater than 1 log10 IU/mL
during NAs therapy appears predictive of an off-treatment response, data are still insufficient to define a therapy stopping rule for NAs-treated patients.48
The indications for treatment are almost the same for both positive and
disease severity. HBeAg-negative/anti-HBe-positive CHB usually affects patients with longer disease duration with fluctuating levels of viral replication and flares of transaminases.49
HBeAg-positive chronic hepatitis B
Patients with CHB/HBeAg-positive considered for treatment must have: HBV DNA > 20,000 IU/mL, HBeAg-positive over 6 months and ALT elevations. In the past, results with standard IFN therapy were disappointing with a high rate of relapse.50 With the use of Peg-IFN, Lau et al. obtained a
rate of seroconversion between 30% for genotype D and 52% for the other genotypes. Sustained virologic response and maintenance of anti-HBe seroconversion was stable after 12 months post-therapy.51 However, in these patients the seroconversion can be unstable, hence it is not unusual to have
a reversion to HBeAg positivity during the follow up.52 For this reason it is recommended to stop
therapy after 6-12 months to stabilize the seroconversion. Predictors of response are elevated ALT (> 5
normal values), HBV DNA < 20,000,000 IU/mL prior therapy, genotype HBV-A and HBV-B.53 For
patients that either do not respond to IFN or develop side effects or are intolerant to therapy, NAs are the second choice of therapy.16
Therapy with Peg-IFN has a definite course, usually 12 months, until the loss of HBeAg and seroconversion to anti-HBe-positive antibody. Conversely, therapy with NAs should be considered of indefinite course in order to completely inhibit the virus in patients that show moderate (METAVIR > F2 or Ishak > S3) or severe (METAVIR > F3 or Ishak > S4) fibrosis. The drugs to be used are those with potent antiviral effect such as ETV 0.5 mg/day or TDF 245 mg/day. ADF and LAM are not suitable because the risk of developing viral resistance. After 5 years of ETV and TDF, the rate of seroconversion from HBeAg- to anti HBe-positive was obtained in 50% and 26% of the patients, respectively.54, 55
Objectives and Monitoring
Overall the clearance of HBsAg with or without the appearance of anti-HBs antibody is
considered a surrogate marker of healing. This is more evident with IFN therapy (16% at 5 years) while with NAs is a rare event (1%), increasing with the duration of therapy.
During therapy with Peg-IFN in HBeAg-positive patients, the evaluation of HBV DNA levels and quantification of HBsAg at week 12 and week 24 may predict HBeAg seroconversion 6 months post therapy. In fact, sustained immune control was achieved respectively in 58% and 42% (week 12) and 57% and 35% (week 24) in CHB patients with low (< 1,500 UI/mL) or medium (1,500-20,000 IU/mL) HBsAg levels at the time point. No immune control was obtained in those with high levels of HBsAg (> 20,000 IU/mL). In this case therapy should be stopped.56 The objective of therapy is also to
reduce the levels of viremia at values lower than 2,000 IU/mL (inactive carrier) after 12 months of therapy. HBeAg, anti-HBe antibodies and serum HBV DNA levels should be monitored during therapy at month 6 and 12 and at 6 and 12 months post treatment. During NAs therapy with potent drugs such as ETV and TDF, the monitoring of HBV DNA suppression is recommended every 3-6 months using sensitive polymerase chain reaction assays. Serological monitoring for the HBeAg/anti-HBe status should be evaluated every 6 months, while HBsAg should be checked every 12 months after anti-HBe seroconversion in order to asses stopping therapy.16 However, HBsAg loss rates are extremely low.57
HBeAg-negative chronic hepatitis B
This type of chronic hepatitis is prevalent in the Mediterranean basin.58 The decision to treat
these patients and the therapeutic strategies are similar to HBeAg-positive patients: a definite course of Peg-IFN therapy if patients still naive to the cytokine or a lifetime course with potent NAs. Treatment
could be deferred in patients with low fibrosis but it is mandatory in case of significant fibrosis (Ishak ≥ S4).
Therapy with a definite Peg-IFN course of at least 12 months should enable seroconversion from HBsAg-positive to anti-HBs antibody. In the case of antiviral therapy with NAs the suppression of HBV DNA is mandatory lifelong, since the interruption of therapy is followed by a rapid relapse due to the reactivation of the virus occulted in the liver. NAs to be used are ETV and TDF, the most potent antivirals with low or almost null rate of HBV resistance. HBV DNA suppression to undetectable levels after 1 year of treatment with ETV and TDF resulted in 90% and 93% cases, respectively,55, 59 but
viral suppression is sustained in only 3% of patients after 24 weeks of post-treatment follow-up.60
Objectives and Monitoring
The end points of therapy are ALT normalization, HBV DNA levels < 2,000 IU/mL (inactive carrier) at the end of treatment and HBsAg loss in the long term.
In patients with HBeAg-negative CHB, naive, undergoing treatment with Peg-IFN, it is important to predict responsive from non-responsive patients in order to reduce side effects. For this reason, a major effort has been made to formulate stopping rules during the course of therapy. It has been observed a greater decline in HBsAg levels in patients who achieve a response to treatment than non-responders. Patients with HBsAg levels < 10 IU/mL at the end of Peg-IFN treatment had a 52% probability of clearing HBsAg during 3 years of follow-up, compared with only 2% in those with higher levels.61 Another study showed that prediction of response can be optimized by combining
HBsAg decline with serum HBV DNA decline. Authors showed that patients who did not achieve a decline in HBsAg levels and a decline in HBV DNA of > 2 log10 IU/mL had no chance of achieving a
with CHB, Peg-IFN treatment for 96 weeks significantly improved the post-treatment virological response compared with 48 weeks of treatment.63
HBV cirrhosis
In patients with cirrhosis, the use of Peg-IFN is very limited due to the high risk of liver decompensation. A special category are young patients, HBeAg-positive, non-D genotype, with HBV DNA levels < 2,000,000 IU/mL, elevated ALT, without portal hypertension that could be considered for a finite course of Peg-IFN, but caution is required.64
Among NAs, mono-therapies with ETV or TDF are recommended because of their potency and minimal risk of resistance.31, 65 Nevertheless, there is still a small cohort of CHB/cirrhotic patients
long-term responder to LAM (> 15 years) maintaining an effective HBV DNA suppression.66
Chang et al. reported histological improvement in 96% of the patients after at least 3 years of ETV therapy.67 Another study showed that ETV treatment in patients with CHB significantly reduced
the risk of cirrhosis and in patients with cirrhosis significantly reduced the risk of decompensation.68
Regression of fibrosis and even reversal of cirrhosis have been reported also in patients treated with TDF. Among 348 paired liver biopsies before TDF and at 5 years post-treatment, it was demonstrated either improvement of the fibrosis score or no change at year 5 in 96% of patients. Moreover, cirrhosis regression occurred in 74% of patients with cirrhosis at baseline. Drug resistance rate at 5 years was 0.5%, suggesting good tolerability and safety.31
However it is still to be determined whether the regression of fibrosis or cirrhosis decreases HCC incidence. In fact, HBV contributes to hepatocyte transformation, playing a direct oncogenic role through both its integration into the host genome and a maintained transcriptional activity, allowing the synthesis of proteins with potential pro-oncogenic properties. For these reasons, it is important to
continue HCC surveillance in NAs-treated patients even in patients who achieve and maintain complete
HBV DNA suppression.69
Conclusions
The success of therapy for CHB is remarkable. Today, it is possible to prevent fibrosis progression, cirrhosis development and its complications with a guideline compliant management. However we need to assess the long-term impact of therapy on the prevention of HCC, which still remain a great risk factor for cirrhotic patients. The final goal of therapy is HBsAg clearance and the seroconversion to anti-HBs antibody. This event is rare with NAs while is more noticeable with the immune-stimulation of IFN. Thus, a personalized therapy, based on patients characteristics, liver disease activity and virus phase of infection should be recommended to plan a successful strategy.
Abbreviations
ADF: Adefovir
ALT: alanine aminotransferases
cccDNA: covalently closed circular DNA
CHB: chronic hepatitis B
ETV: Entecavir
HBeAg: hepatitis B e antigen
HBsAg: hepatitis B s antigen
HBV: hepatitis B virus
HCC: hepatocellular carcinoma
IFN: interferon
LAM: Lamivudine
LE: liver elastometry
NAs: nucleos(t)ide analogues
Peg-IFN: Pegylated Interferon
STAT: signal transducers and activators of transcriptions
TBV: Telbivudine
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Title of Tables
Title of Figures
Figure 1. Natural history of chronic hepatitis B infection. The dynamic process of chronic HBV infection can be divided into different phases, which are not necessarily sequential. Clearance of HBsAg and the seroconversion to anti-HBs-positive antibody is considered a surrogate marker of healing. However, HBV DNA can remain detectable in the liver (occult HBV infection) and may lead to HBV reactivation, in particular in immunosuppressed patients.9
