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Guo-Yi Wu,
Hong-Song Chen, Hepatology Institute, People’s Hospital, Peking
University, Beijing 100044, China
Supported by the National Basic Research Program, No. 2005CB522902; the
Municipal Science and Technique Program, H030230150130
Correspondence to: Dr. Hong-Song Chen, Hepatology Institute,
People’s Hospital, Peking University, Beijing 100044,
China. chen2999@sohu.com
Telephone: +86-13501196710 Fax: +86-10-68318386
Received: 2006-12-11
Accepted: 2007-01-09
Abstract
Currently approved treatments for hepatitis B virus (HBV) infection
include the immunomodulatory agent, IFN-α, and nucleos(t)ide analogues.
Their efficacy is limited by their side effects, as well as the
induction of viral mutations that render them less potent. It is thus
necessary to develop drugs that target additional viral antigens.
Chemicals and biomaterials by unique methods of preventing HBV
replication are currently being developed, including novel nucleosides
and newly synthesized compounds such as capsid assembling and mRNA
transcription inhibitors. Molecular therapies that target different
stages of the HBV life cycle will aid current methods to manage chronic
hepatitis B (CHB) infection. The use of immunomodulators and gene
therapy are also under consideration. This report summarizes the most
recent treatment possibilities for CHB infection. Emerging therapies and
their potential mechanisms, efficacy, and pitfalls are discussed.
© 2007 The WJG Press. All rights reserved.
Key words: Hepatitis B virus; Antiviral drugs; Drug evaluation;
Immunomodulatory agents; Gene therapy
Wu GY, Chen HS. Novel approaches towards conquering hepatitis B virus
infection. World J Gastroenterol 2007; 13(6): 830-836
http://www.wjgnet.com/1007-9327/13/830.asp
INTRODUCTION
The hepatitis B virus (HBV) is a major world health problem, Leading to
1.2 million deaths per year according to the World Health Organization
(WHO)[1]. HBV infection can result in acute, fulminant, or chronic
disease, liver cirrhosis, and the development of hepatocellular
carcinomas (HCC). There is a vaccine, but no 100% effective antiviral
treatment available for patients with chronic hepatitis B (CHB). The
response rate to IFN therapy, as measured by the loss of hepatitis B e
antigen (HBeAg), is less than 40%[2]. This treatment is even less
effective in Asian patients (primarily Chinese), particularly for those
with below normal alanine transaminase (ALT) levels[3]. IFN therapy is
also associated with many disabling side effects and is therefore only
suitable for some patients.
Since HBV DNA replication occurs via reverse transcription[4], the
use of reverse transcriptase inhibitors is an attractive target for
anti-HBV therapy. Nucleoside analogues are chemically synthesized drugs
that mimic natural nucleosides. In China, three nucleoside/nucleotide
drugs are used to manage chronic HBV infection: lamivudine (3TC),
adefovir dipivoxil (ADV), and entecavir (ETV). Although all three are
potent viral suppressors, none is able to permanently eradicate HBV[5].
As a result, the durability of the antiviral response is suboptimal once
treatment is halted. In some patients, HBV DNA levels and ALT
concentrations increase and result in a potentially life-threatening
recurrence of disease[6,7]. Patients can only be safely withdrawn from
nucleos(t)ide therapy if HBeAg seroconverts to anti-HBe or HBV DNA
diminishes to undetectable levels[8,9]. To prevent disease recurrence,
long-term polymerase inhibitor maintenance therapy is often
required[10]. In addition, prolonged use of nucleoside/nucleotide is
associated with the emergence of drug-resistant mutants[11,12], and
clinically characterized by increasing serum HBV DNA and ALT
levels[10,13]. Each drug has a different profile of resistant
mutations[14], so it is essential that each is appropriately managed.
These findings underscore a requirement for new and better-tolerated
therapies for hepatitis B virus infection.
In this report, we review different strategies for drug design, and
evaluate their effectiveness in vitro, in models of HBV replication in
vivo, and in clinical trials.
NUCLEOSIDE ANALOGUES
Orally applied nucleoside and nucleotide analogs have been important
therapies against HBV infection throughout the last decade. The
nucleoside analogs, lamivudine and entecavir, and the nucleotide analog,
adefovir dipivoxil, are approved for use in humans. Many similar
compounds are being tested in preclinical or clinical settings (Table
1).
EMTRICITABINE (FTC)
Emtricitabine is a nucleoside analogue used for treatment against human
immunodeficiency virus (HIV) and also has clinical activity against HBV.
It has a similar structure to lamivudine, differing only in a fluorine
at its 5 prime end. In a randomized double-blind study, patients
received 200 mg of emtricitabine (n = 167) or a placebo (n = 81) once
daily for 48 wk and underwent a pretreatment and end-of-treatment liver
biopsy. Following treatment, 62% of patients who had received
emtricitabine had improved liver histology, while only 25% of the
placebo patients showed improvement (P < 0.001). Significant
improvement was also demonstrated between subgroups that were positive
(P < 0.001) and negative (P = 0.002) for hepatitis B e (HBe) antigen.
Serum HBV DNA levels were below 400 copies/mL in 54% (n = 167) of the
emtricitabine group and only 2% (n = 81) of the placebo group (P <
0.001), while alanine aminotransferase levels were normal in 65%
(109/167) of the emtricitabine group and 25% (20/81) of the control
group (P < 0.001). At wk 48, 20 of 159 patients (13%) from the
emtricitabine group in whom HBV DNA was detected at the end of
treatment, had virus with resistance mutations (95% confidence interval,
8%-18%). The rate of seroconversion to anti-HBe (12%) and loss of HBe
antigen were not different between arms, and the safety profiles of
emtricitabine and placebo were similar during treatment. Forty-eight
weeks of emtricitabine treatment resulted in significant histologic,
virologic, and biochemical improvement in chronic HBV infected patients,
regardless of whether HBe antigen was detectable[15].
Phase Ⅲ clinical trials are underway to determine the
long-term safety and efficacy of emtricitabine, however its role as a
monotherapy may be limited by its structural similarity to lamivudine
and the corresponding risk of drug resistance.
TENOFOVIR
(VIREAD, PMPA)
Tenofovir was FDA approved in 2001 for use in HIV infected adults in
combination with other antiretroviral agents. Lamivudine-associated and
ADEFOVIR-resistant mutations were not detected when tenofovir was used
in a clinical trial. Thus, tenofovir may be a highly effective rescue
drug in HBV-infected patients who show altered responsiveness to
lamivudine and ADEFOVIR[16]. An additional double-blind,
placebo-controlled trial showed that tenofovir may be a useful component
of antiretroviral therapy for HIV/HBV co-infected patients. Importantly,
tenofovir is equivalent to adefovir in its ability to reduce HBV DNA
levels, and may, in fact, be superior[17]. If HBV treatment can be
deferred until combination antiretroviral therapy for HIV infection is
needed, the combination of tenofovir plus lamivudine or emtricitabine
will be the potent HBV therapy and a solid backbone for HIV combination
antiretroviral therapy, and a potent treatment for HBV and it likely
decreases the emergence of HBV resistance. It will decrease the chance
that HBV resistance will emerge as well[18].
CLEVUDINE (L-FMAU)
Clevudine is a nucleoside analog with an unnatural beta-L configuration,
and in vitro studies suggest that it is effective against
lamivudine-resistant HBV mutants. In the Woodchuck model, a daily
clevudine dose of 10 mg/kg resulted in a 100 million copies' decrease in
viral load. Interestingly, a delayed rebound in viral load was observed
after drug cessation in a dose-dependent manner. No evidence of
clevudine toxicity was observed in treated animals, however, further
studies are being conducted to assess its long-term efficacy and
safety[19]. Clinical trials show that clevudine is one of the most
potent analogs available for treating HBV, and that its antiviral
effects can last up to 6 mo after treatment, as illustrated by sustained
normalization of ALT levels[18]. The mechanism by which clevudine
elicits its anti-hepadna virus activity is distinct from other
nucleoside analogs. It acts as a competitive inhibitor by binding to the
catalytic site of HBV polymerase and inhibiting the priming of HBV DNA
chain elongation. Nucleoside inhibitors, in general, interfere with
viral polymerase activity through competitive inhibition and
incorporation into the viral DNA strands[20].
TELBIVUDINE
(LdT)
Telbivudine is a novel nucleoside analog that is being developed for the
oral treatment of chronic HBV. It is a highly specific and selective
inhibitor of replication in vitro, and specifically targets the HBV DNA
polymerase. Unlike other nucleoside antivirals, telbivudine does not act
against other viruses or induce mitochondrial toxicity by targeting
mammalian DNA polymerases. Telbivudine preferentially inhibits HBV
second-strand (DNA-dependent) DNA synthesis, in contrast to LdC and
lamivudine, which are first-strand (RNA-dependent) DNA synthesis
inhibitors[21].
Telbivudine has a significantly higher rate of response than
the standard HBV treatment, lamivudine, as well as superior viral
suppression capability. It is generally well tolerated, with a low
adverse effect profile, and no toxicity at its effective treatment dose.
Preclinical and clinical studies show that telbivudine has
good pharmacokinetic properties that support once-daily dosing, and are
not affected by gender, food intake, or liver health. Patients with
moderate to severe renal impairment do require dose adjustment, however,
which is also necessary for other drugs of this class.
Phase Ⅱb clinical trial results illustrate that patients with
chronic HBV who are treated with telbivudine have significantly greater
virologic and biochemical responses than those treated with lamivudine.
Combination therapies revealed similar results to those obtained using
telbivudine alone. These data support the ongoing phase Ⅲ evaluation of
telbivudine as a treatment for patients with chronic HBV[22].
OTHER NUCLEOSIDE ANALOGS
Additional nucleoside analogs that have favorable toxicity profiles and
a promise of increased effectiveness against HBV are in various stages
of clinical development. The phase Ⅲ trials of emtricitabine, clevudine,
tenofovir, and telbivudine will help define the efficacy and safety
profiles of these drugs, while the profiles of newer and more potent
drugs like LB80380 remain to be confirmed. It is important to recognize,
however, that many of these compounds share cross-resistance profiles
with existing nucleoside analogues such as lamivudine, adefovir, and
entecavir[23,24]. As a result, these drugs may not offer much advantage
over current treatment regimens. Current research efforts are focusing
on the development of drugs that offer low rates of resistance or little
cross-resistance with other nucleoside analogues.
NOVEL MOLECULAR TARGETS OF HBV THERAPY
Because HBV pol carries out the enzymatic functions of reverse
transcription and DNA synthesis, it is the primary target of HBV
antiviral development[25]. Nucleoside and nucleotide analogues are the
primary class of antiviral agents used for this purpose. In recent
years, several compounds that specifically attack molecular targets
other than HBV pol have been identified, including inhibitors of HBV
encapsidation and HBcAg translation. Encapsidation occurs when the viral
RNA, pol, and core are assembled into the nucleocapsid prior to viral
replication[26].
HETEROARYLDIHYDROPYRIMIDINE (HAP)
The heteroaryldihydropyrimidines (HAPs), including BAY41-4109,
BAY38-7690, and BAY39-5493, are a new class of antivirals that inhibit
production of HBV virions. HAPs show more favorable (50% and 90%)
inhibitory concentrations (IC50 and IC90) than lamivudine in a
cell-based HBV replication assay. They act as allosteric effectors,
binding the HBV core protein and resulting in its degradation, which
subsequently inhibits nucleocapsid formation[27]. HAPs inhibit HBV
replication in a transgenic mouse model with an efficacy similar to that
of lamivudine[28]. Since these drugs destabilize preformed capsids, they
may be used to treat blood products in order to lower the HBV
transmission rates. Thus, HAPs may become a valuable addition to
anti-HBV therapy. None of them has yet been tested in humans, but the
clinical trial results of Bay 41-4109 are expected.
PHENYLPROPENAMIDES
The phenylpropenamides represent another group of compounds that inhibit
encapsidation[29]. The phenylpropenamide derivatives, AT-61 and AT-130,
are synthesized and shown to inhibit HBV replication. These agents
inhibit encapsidation by directly preventing nucleocapsid formation, a
mechanism distinct from that used by HAPs. In a cell-based replication
system, the phenylpropenamides are not as potent as lamivudine in
inhibiting HBV replication (the IC50 is approximately 10 times higher),
but are active against the lamivudine-resistant YMDD mutant[29,30].
These drugs are specific for HBV and have no activity against related
viruses such as woodchuck hepatitis virus (WHV) and DHB. Although this
class of compounds has a favorable toxicity profile, clinical trials are
still required.
HELIOXANTHIN ANALOGUES
Helioxanthin was originally isolated from the shrub, Taiwania
ctyptomerioides, and its derivative, 5-4-2, was synthesized in the
laboratory. Helioxanthin and 5-4-2 belong to a class of small molecules
that inhibit the HBV DNA as well as the HBV RNA and viral protein
expression. Their structures are different from other anti-HBV
compounds, suggesting that they may have a unique mode of action. Cheng
YC et al found that helioxanthin and 5-4-2 inhibited HBV mRNA levels in
HepG2 2.2.15, as well as the HBV transcripts, 3.5 kb and 2.4/2.1 kb. The
HBV core protein also decreased after treatment. Anti-HBV activity was
evaluated in vitro using the HBV stably transfected hepatoma cell lines,
Wl0 (adr, wt) and DM2 (adr, rtL180M/rtM204V, lamivudine-resistant), and
helioxanthin and 5-4-2 inhibited both wild type and mutated HBV. Since
the core protein activates the pregenomic/pre C promoters, it is
possible that the decrease in 3.5 kb transcript results from a lack of
transactivation by the core protein. Helioxanthin and 5-4-2 profoundly
inhibited pregenomic/preC and preS/S promoter activity using a gene
reporter system, suggesting that they target multiple steps of the viral
life cycle. The detailed mechanism of action by this class of compounds
is being explored[31], and clinical trials are still required.
GLUCOSIDASE AND PEPTIDE INHIBITORS OF CAPSID ASSEMBLY
The heavy glycosylation of HBV envelope proteins is important for viral
assembly. As a result, specific glucosidase inhibitors have been
developed to inhibit the assembly process. N-nonyl-deoxynojirimycin
(N-nonyl-DNJ) is an inhibitor of N-linked glycan processing and the
endoplasmic reticulum (ER) glucosidase. Researchers show the N-nonyl-DNJ
has antiviral activity in the woodchuck model of HBV infection[32].
Another glucosidase inhibitor, N-nonyl-deoxygalactojirimycin
(N-nonyl-DGJ), exerts its antiviral activity prior to viral envelopment,
thus may prevent proper encapsidation of the HBV pregenomic RNA. These
agents show promise in inhibiting viral replication using the WHV model,
but toxicity may limit their clinical efficacy. Using a molecular
approach to screen a phage display library, Dyson et al identified
peptide aptamers that specifically interfere with the interaction
between core particles and envelop proteins during assembly[33]. These
peptides bind specifically to the tip of the core protein shell that
comprises conserved amino acid residues within the nucleocapsid[34].
This is important because of the risk of drug resistance. One candidate
peptide inhibited HBV replication in a cell-based assay and exhibited no
toxicity.
These promising approaches underscore the importance of
identifying other molecular targets that may be used in combination
therapies.
IMMUNOMODULATORY AGENTS
A variety of immunomodulatory therapies have been developed over the
last few decades to manage CHB. These therapies are designed to
eliminate the virus by activating either nonspecific host immune
responses or HBV-specific CD4+ T helper and CD8+ cytotoxic
lymphocytes[35]. The nonspecific modalities include the use of TLRs,
thymosin, IFN-α, and IFN-γ, and the specific modalities include
dendritic cell and cytotoxic T-lymphocyte (CTL)-based therapies. In
recent years, the APOBEC family has shown promise as an anti-HBV drug.
APOBEC3G
To replicate efficiently, viruses must overcome innate defense
mechanisms. Human APOBEC3G is a cytidine deaminase that represents one
such barrier by conferring broad intracellular antiretroviral
protection. This enzyme is packaged in virions and acts during reverse
transcription to deaminate deoxycytidine residues to deoxyuridine (dU)
within the growing minus-strand of viral DNA. These dU-rich reverse
transcripts are either degraded or result in proviruses that are largely
nonfunctional due to a G-to-A hypermutation. Most lentiviruses escape
APOBEC3G inhibition by expressing a protein, Vif, which prevents
deaminase incorporation into the virion and triggers its proteasomal
degradation. However, APOBEC3G is capable of blocking a wide spectrum of
distantly related retroviruses. Turelli et al show APOBEC3G-mediated
inhibition of HBV and DHBV DNA production in human HuH-7 hepatoma cells
and avian hepatoma cells[36]. Thus, the viral and cellular interaction
partners required for anti-hepadnaviral APOBEC3G action are conserved
among these species. Rosler C et al found that core-associated HBV RNA
is not reduced in the presence of A3G, and that wild-type levels of
pgRNA associate with HBV core protein in the presence or absence of
A3G[37]. Yang DL et al showed a dose dependent decrease in the levels of
intracellular core-associated HBV DNA, however, as well as a decrease in
the extracellular production of HBsAg and HBeAg following APOBEC3G
treatment. The levels of intracellular core-associated viral RNA also
decreased, but the expression of HBcAg in transfected cells remained the
same. Consistent with these in vitro results, levels of HBsAg in the
sera of mice decreased dramatically. A larger 1.5-log10 decrease in
serum HBV DNA and liver HBV RNA levels were observed in APOBEC3G-treated
versus control groups[38]. These findings suggest that APOBEC3G
suppresses HBV replication and antigen expression both in vivo and in
vitro, and is a promising advance in HBV therapy.
THERAPEUTIC VACCINATION
HBV persistence is thought to result from poor HBV-specific T cell
responses[39]. This has resulted in efforts to stimulate HBV-specific T
cells using therapeutic vaccines[40]. Mancini-Bourgine et al conducted a
phase Ⅰ study to evaluate the effectiveness of an HBV DNA vaccine that
encodes HBV envelope proteins in ten chronic HBV carriers who did not
respond to current antiviral therapies[41]. Patients received four 1 mg
intramuscular injections of the vaccine and an increased frequency of
HBV specific T cell responses was observed. HBV DNA levels declined in
five patients, and one patient successfully cleared the infection.
Yuan et al constructed a hepatitis B immunogenic complex
therapeutic vaccine from a combination of yeast-derived recombinant
HBsAg and human anti-HBs immunoglobulin (YIC)[42]. Its safety profile
and the immune responses it elicited were examined in a phase Ⅰ clinical
trial. IFN-γ levels were higher in all eight subjects studied (P =
0.015) and IL-2 levels increased in seven of the eight subjects (P =
0.002). These results show that the hepatitis B immunogenic complex
therapeutic vaccine (YIC) can induce a potent anti-HBs response.
Wu et al also developed an innovative minovirus vaccine to
induce hepatitis B virus specific cytotoxic T-lymphocyte responses[43].
They proved that their mimovirus could induce an HBsAg28-39-specific CTL
response in vivo. This type of vaccine is now under the phase Ⅱ clinical
trial in China.
The promise of these approaches requires further examinations
in a large randomized study.
DENDRITIC
CELL VACCINATION
Dendritic cells (DCs) function as antigen-presenting cells. Peripheral
DCs phagocytose microbes and viruses, and migrate to the regional lymph
nodes where they mature and present foreign protein peptides to naive T
cells[44]. These T cells then become activated, and acquire direct
antiviral function as well as the ability to produce a variety of
cytokines, including IFN, IL-2, IL-12, and IL-18. Many viruses,
including HBV, are able to escape immune surveillance and persist in the
host without evoking an immune response. Zheng et al studied the
functional defects of DCs in patients with CHB and showed that human
leukocyte antigen (HLA) class Ⅱ and B7 expression are not upregulated on
these cells, leading to inadequate IL-12 levels to fight against
infection[45]. Although DC vaccination shows promise, it is still in the
preclinical phase. With advances in technology, DC-based therapy may be
an important method of managing CHB[46].
TLR LIGANDS
TLRs play an important role in innate immune recognition and
regulation[47]. They belong to a family of evolutionarily conserved
receptors that recognize structural patterns on different pathogens[48].
After finding a particular virus or microbe, TLRs activate phagocytes
and DCs to mount an immune response[49]. In an HBV transgenic mouse
model, Isogawa et al showed that a single injection of a TLR ligand can
inhibit HBV replication in hepatocytes by inducing the production of
antiviral cytokines[50]. These data support the further development of
this approach.
CTL-BASED THERAPY
CTL-based immunotherapy is based on the concept that HBV-specific CTLs
control infection by suppressing HBV replication in infected humans[51].
Vitiello et al developed a lipopeptide-based vaccine containing one CTL
epitope from the HBV core region. This vaccine induced an HBV-specific
CTL response in healthy volunteers in a phase Ⅰ clinical trial that was
comparable to CTL responses observed during acute HBV infection[52]. In
a phase Ⅱ trial in patients with chronic HBV, however, CTL-based therapy
was much less effective for suppressing HBV DNA[53]. This therapeutic
approach may still be clinically useful if it is designed to recognize
multiple CTL epitopes.
CYTOKINES
Cytokines play a major role in controlling viral infections[54]. In a
transgenic mouse model, type 1 IFNs (α and β) were shown to inhibit HBV
viral replication[55,56]. IFN-γ also prevents HBV replication by
activating natural killer T (NKT) cells and T cells[57], however,
clinical trials with IFN-γ did not show much benefit in patients with
CHB[58]. Robek et al reported that IFN-λ inhibits HBV replication and
induces IFN-stimulated gene expression using a mechanism distinct from
that used by IFN-α, -β, or -γ. Thus, IFN-λ may be useful as a
therapeutic agent in the management of CHB[59].
Because of its ability to induce T cell proliferation,
IL-2 is hypothesized to be an important immunostimulatory molecule,
especially during chronic viral diseases[60]. IL-2 downregulates HBV
gene expression in a transgenic mouse model and in patients with HIV,
intermittent rIL-2 therapy prolongs CD4 T cell survival[61]. As a
result, rIL-2 may be used as an adjunct therapy to prime other forms of
immunomodulation such as therapeutic vaccination[62].
Cavanaugh et al demonstrated the antiviral efficacy of
IL-12 in an HBV transgenic mouse model[63], however the overall
reduction in viral titers was modest compared to other anti-HBV
treatments[64]. Kimura et al showed that IL-18 also inhibits HBV
replication in a transgenic mouse model[65], but its efficacy in humans
remains to be tested.
While many of these cytokines may not be potent as
single agents they may help understand the mechanisms used by various
immunomodulatory strategies to control HBV infection[62].
ADOPTED CELL THERAPY
Sun et al isolated peripheral blood mononuclear cells from patients and
activated them by anti-CD3 monoclonal antibody, interleukin-2 and
interferon-γ in vitro for 10 d to produce multifactors activated immune
cells (MAICs)[66]. When the cells have expanded and activated
effectively 10 d later, these patients were transfused with these cells.
Significant HBV inhibition was observed in 8 out of 14 until 1 year
after transfusion. These findings strongly suggest that MAICs
transfusion can effectively inhibit the replication of hepatitis B
virus.
GENE THERAPY
Researchers are developing novel nucleic acid-based interventions
against HBV. These tools for manipulating gene expression are an
attractive means of targeting HBV at different stages of its life cycle,
with the ultimate goal of completely eradicating the virus[67]. Although
this approach is not realistic for clinical use at this time, tremendous
advances in this field have been made over the past few years. There are
three gene therapy approaches: the use of antisense
oligodeoxyribonucleic acids (ODNs), ribozymes, and short interfering
RNAs (siRNAs). Some researches have shown significant results using
these treatments, but the mode of delivering nucleic acid-based
therapies remains a problem. Since HBV primarily replicates in
hepatocytes, it is important that these compounds target the liver in
order to reduce the required dose and minimize nonspecific effects[68].
Safety is also a potential concern with this therapeutic approach[69],
as is the issue of host enzymes biodegrading these compounds and
rendering them ineffective. Nonspecific activation of the immune system
is further noted as a risk of administering nucleic acid-based
compounds[70]. Advances in delivery strategies and an improved
understanding of the mechanisms of these technologies should lead to
safer and more efficacious nucleic acid-based therapeutic approaches.
CONCLUSIONS
Treatment of chronic HBV requires inhibiting hepatitis B virus
replication or eliminating the virus from cells. The major problem with
current treatments is the emergence of drug resistant variants over
time. Novel therapies that target unique molecules or require shorter
treatment time are still in demand. Several new anti-HBV nucleoside
analogues are in different stages of clinical trials, and in the next
decade we should see an increase in the use of agents designed to target
specific molecules. The greatest challenge in the future of HBV
treatment is the achievement of a safe, cost-effective, and durable
regimen that takes advantage of novel therapeutic modalities.
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