Available online at www.sciencedirect.
com
ScienceDirect
Current treatments for chronic hepatitis B virus
infections
Fabien Zoulim1,2,3,4,5, Fanny Lebossé1,2,3 and
Massimo Levrero1,2,4,6
Over 240 million people worldwide are chronically infected with
hepatitis B virus (HBV) and although a prophylactic vaccine and
effective antiviral therapies are available, no cure exists.
Curative regimens are urgently needed because up to one
million deaths per year are caused by HBV-related liver cancer
and end-stage liver disease. HBV is an hepatotropic virus
which belongs to the Hepadnaviridae family and replicates its
DNA genome via a reverse transcriptase mechanism. Effective
therapies have been developed for chronic hepatitis B (CHB)
infection in the last two decades. They rely on the use of
interferon alpha and its pegylated formulation, and on
nucleos(t)ide analogs that inhibit viral polymerase activity. Their
results are discussed in this review as well as future
perspectives.
Addresses
1 complex mode of action including the activation of natu-
Cancer Research Center of Lyon (CRCL), Lyon 69008, France
2
INSERM, U1052, Lyon 69003, France
3
University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France
4
Hospices Civils de Lyon (HCL), 69002 Lyon, France
5
Institut Universitaire de France (IUF), 75005 Paris, France
6
DMISM and CLNS IIT Sapienza, Sapienza University Rome,
00161 Rome, Italy
Corresponding author: Zoulim, Fabien (fabien.zoulim@inserm.fr)
Current Opinion in Virology 2016, 18:109–116
This review comes from a themed issue on Antiviral strategies
Edited by Raymond Schinazi Erik De Clercq
http://dx.doi.org/10.1016/j.coviro.2016.06.004
1879-6257/# 2016 Elsevier B.V. All rights reserved.
Introduction
Over 240 million people worldwide are chronically
infected with hepatitis B virus (HBV) [1] and although
a prophylactic vaccine and effective antiviral therapies are
available, no cure exists. Curative regimens are urgently
needed because up to one million deaths per year are
caused by HBV-related liver cancer and end-stage liver
disease. HBV is an hepatotropic virus which belongs to
the Hepadnaviridae family and replicates its DNA ge-
nome via a reverse transcriptase mechanism. Effective
therapies have been developed for chronic hepatitis B
www.sciencedirect.com
(CHB) infection in the last two decades; their results are
discussed in this review as well as future perspectives.
Antiviral drugs and their mode of action
Interferon-alpha (IFNa) and its pegylated form (Peg-
IFNa), and 5 other drugs that belong to the class of
nucleos(t)ide analogs (NUCs), have been approved for
this indication in most parts of the world [2–7]. IFNa is an
innate immunity cytokine that induces the expression of
genes (collectively named as interferon stimulated genes;
ISGs) encoding intracellular or secreted proteins with
direct or indirect antiviral properties, and promotes the
differentiation/activation of immune cells [8,9]. In the
HBV setting, the IFNa antiviral activity result from a
ral killer (NK)/NKT cells, inhibition of viral genome
transcription via epigenetic regulation of HBV covalently
closed circular DNA (cccDNA), destabilization of viral
nucleocapsid, but also, as recently suggested, degradation
of cccDNA via the activation of APOBEC3A in infected
cells [10–13]. Overall, its antiviral effect in CHB patients
remains modest and the reason for this remains largely
unknown but could include an insufficient delivery to the
infected liver, a refractoriness of infected hepatocytes to
IFNa signaling, or other mechanisms.
NUCs directly inhibit the reverse transcriptase activity of
the HBV polymerase. The approved NUCs include lami-
vudine (LMV), a deoxy cytidine analog with an unnatural
L-conformation, and the related L-nucleoside, telbivudine
(LdT; b-L-thymidine). A second group, the acyclic phos-
phonates, which include adefovir dipivoxil (ADV), a
prodrug for the acyclic 20 -deoxy adenosine monopho-
sphate analog adefovir, and the structurally similar teno-
fovir disoproxil fumarate (TDF). A third group contains a
D-cyclopentane sugar moiety and has the most potent
anti-HBV drug discovered to date, the deoxy guanosine
analog entecavir (ETV). This structural classification of
NUCs is useful clinically because it helps predict path-
ways of drug resistance [14,15]. In chronically HBV-
infected hepatocytes, NUCs inhibit the viral polymerase
activity resulting in a decreased production of virions, a
reduced recycling of viral nucleocapsids to the nucleus of
infected cells, and theoretically a decline of viral
cccDNA, although the latter can only be observed after
many years of treatment [2,14,15]. NUCs do not inhibit
the de novo formation of cccDNA in newly infected cells,
implying that persistent residual viremia during antiviral
Current Opinion in Virology 2016, 18:109–116
110 Antiviral strategies

Figure 1

Innate responses
Adaptive immune
responses
NK Interferon
Virion
cells alpha
CD8+ hNTCP Hepatocyte
cells
HBV DNA integration
CD4+ Polymerase
Transcription
cells Entry
cccDNA formation
pgRNA

RC DNA cccDNA
B cells mRNA
cccDNA Nucleus
amplification
Translation
DNA (+) DNA (–) pgRNA
(+) strand
synthesis Encapsidation
Reverse
Virion
transcription
secretion
ER
ER
Nucleos(t)ide analogues
Viral
proteins
secretion
HBsAg
HBeAg

Current Opinion in Virology

Mode of action of antivirals for chronic hepatitis B. In clinical studies, Interferon alpha was shown to induce NK cell activity. This, in turn, may
down regulate HBV specific cell activity. In experimental models, its antiviral effect has been ascribed to the repression of transcription of viral
cccDNA and to the partial degradation of the pool of cccDNA. Nucleos(t)ide analogs inhibit the reverse transcriptase activity of the viral
polymerase, thus decreasing the level of circulating viral DNA. Prolonged viral suppression induced by NUC therapy has been associated with
restoration of HBV specific T cells. None of these antivirals are capable to eradicate viral cccDNA from infected hepatocytes.

therapy can lead to infection of new hepatocytes and re-
establishment of viral cccDNA reservoir REF. Further-
more, the lack of complete inhibition of viral DNA
synthesis may also lead to the maintenance of the
cccDNA pool via the recycling of viral nucleocapsids to
the nucleus of infected cells REF. A decrease of the total
amount of intrahepatic cccDNA can be observed during
long-term therapy as a consequence of, firstly, the inhibi-
tion of the intracellular recycling pathway, secondly,
decreased rate of infection of new cells, thirdly, dilution
of cccDNA via hepatocyte turn-over, as cccDNA may be
lost through cell division [16–20].
A simplified view of the mode of actions of the approved
antiviral agents in the HBV life cycle is shown in Figure 1.
Goals of therapy and treatment end-points
The goal of therapy for CHB is to improve the quality of
life and survival by preventing or delaying progression of
the disease toward cirrhosis, decompensated cirrhosis,
and HCC. This goal can be achieved if HBV replication
is suppressed in a sustained manner. It is accompanied by
a reduction in histological inflammatory activity of CHB
and decreased risk of developing cirrhosis and HCC,
particularly in non-cirrhotic patients [3,6,7,21]. Several
recent studies in large cohorts have shown that the risk of
HCC development is significantly decreased by success-
ful antiviral therapy compared to untreated historical
patient cohorts, but is not abated [22–25]. Chronic
HBV infection cannot be completely eradicated due to
the persistence of cccDNA in the nucleus of infected

Current Opinion in Virology 2016, 18:109–116 www.sciencedirect.com


hepatocytes [19,26–28], which explains HBV reactivation,
for instance in patients who receive immunosuppressive
therapy or chemotherapy [29,30]. Thus therapy has at
least to ensure a degree of viral suppression that will lead
to biochemical remission, histological improvement and
prevention of complications. The ideal end-point is
HBsAg loss (i.e. HBsAg seroclearance) associated with
anti-HBs antibody (i.e. HBsAb) seroconversion, as it
would allow treatment cessation. However; it is achieved
only in a minority of treated patients with the available
anti-HBV agents [2,3,5–7].
Treatment indications
The natural history of chronic HBV infection is usually
classified in four phases. These phases are not obligatory
consecutive over time and include: firstly, immune toler-
ance phase or low inflammatory phase associated with
high viral load and normal transaminase levels, secondly,
the immune active phase associated with high viral load,
elevated liver enzymes, and immunohistochemical signs
of necro-inflammation in the liver; patients can be either
HBeAg positive or negative, thirdly, the inactive carrier
state with very low viral load and normal liver enzyme
levels, fourthly, the HBsAg clearance phase where
HBsAg becomes negative, possibly with anti-HBsAb
seroconversion, undetectable HBV DNA in serum and
normal liver function tests. The indications for treatment
are generally the same for both HBeAg-positive and
HBeAg-negative CHB. This is based mainly on the
combination of three criteria: firstly, serum HBV DNA
levels, secondly, serum ALT levels, thirdly, and the
severity of liver disease.
The international clinical practice guidelines from
AASLD, EASL and APASL recommend that patients
with immune — active CHB should be considered for
treatment when they have HBV DNA levels above
2000 IU/mL for HBeAg-negative patients or above
20 000 IU/mL for HBeAg-positive patients, serum
ALT levels above the upper limit of normal (ULN),
and moderate to severe active necro-inflammation and/
or at least moderate liver fibrosis severity [2,3,5–7,21].
Indications for treatment may also take into account age,
health status, family history of cirrhosis or HCC, extrahe-
patic manifestations of the disease, as well as concurrent
medications. For instance, inactive carriers receiving
chemotherapy or other immune suppressant treatments
need to receive pre-emptive antiviral therapy to prevent
viral reactivation; several studies have demonstrated the
efficacy of NUCs in these situations [31,32]. HIV co-
infected patients should be treated with HAART includ-
ing a high barrier to resistance NUC active on both HIV
and HBV, that is, TDF. Currently, ‘Immune-tolerant’
patients are not considered for antiviral therapy by most
guidelines, despite their persisting high viral load. Preg-
nant women with high viral >200 000 UI/mL are now
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Antiviral therapy of hepatitis B Zoulim, Lebossé and Levrero 111
considered for antiviral therapy with TDF to decrease
viral load at the time of delivery and increase the success
rate of prevention of mother to child transmission in
association with hepatitis B immune globulins (HBIG)
and vaccine administration in the new borns; indeed, in
such situation of highly viremic mothers, the classic
immune prophylaxis based on HBIG and vaccine in
newborns fails in approximately 10–20% of cases while
it fails in less than 5% when mothers receive antiviral
treatment [33–35]. Treatment of children presenting
criteria of immune-active disease is now recommended
by international liver societies [36,37].
Results of antiviral therapy
The results of antiviral therapy have been summarized
recently in several international clinical practice guide-
lines and reviews [6,21,38].
The use of peg-IFN in HBeAg positive patients with
CHB allows to obtain viral suppression in 10–40% of
patients, with an HBeAg seroconversion rate of approxi-
mately 30–35% which is accompanied by normalization of
ALT levels in 35–50% patients. HBsAg loss can be
observed in approximately 5% of patients 6 months after
treatment cessation and 10% at 3 years post-treatment.
In HBeAg positive patients, the use of NUCs with a high
barrier to resistance, that is, entecavir or TDF, allows to
achieve viral suppression in substantially higher number
of patients (approximately 60–75% of patients after 3 years
of therapy). HBeAg seroconversion rate remains low
(approximately 20%) despite better viral suppression.
ALT levels normalize in 75–80% of patients. HBsAg loss
is observed in up to 12% after 7 years of continuous of
TDF therapy [39].
In HBeAg negative patients, peg-IFN administration
achieves HBV DNA suppression in approx. 20–40% of
patients, normalization of ALT levels in 60% patients and
HBsAg loss is observed in 6% of patients 3 years after
treatment cessation. The use of NUCs with high barrier
to resistance achieves viral suppression in 90% of patients,
with a similar number of patients normalizing ALT levels.
HBsAg loss is rarely observed (<1%) with both Entecavir
and TDF despite long term administration [39].
Improvement of liver histology has been observed in
patients treated with peg-IFN as well as in patients on
continuous NUC therapy with Entecavir or TDF [40–43].
Control of viral replication has been associated with
decreased rate of progression of liver disease toward
cirrhosis, decompensation of cirrhosis, or HCC [44–48].
The therapeutic efficacy of these treatments can be
affected by factors such as the development of adverse
effects, poor patient compliance, previous treatment with
suboptimal regimens, infection with drug resistant viral
Current Opinion in Virology 2016, 18:109–116
112 Antiviral strategies

Table 1 drug choice and subsequent rescue therapies should be

Efficacy of approved and preferred antiviral therapies in treat- based on the knowledge of cross-resistance, so that the
ment naive CHB patients (adapted from AASLD and EASL second agent has a different resistance profile to the initial
clinical guidelines) failing agent. This is particularly important since drug
Peg-IFN Entecavir Tenofovir resistant mutants that have been selected by previous
HBeAg positive
treatments are thought to be archived in viral cccDNA
HBV DNA 30–40% 60% 76% reservoirs in the liver [14,15]. The add-on strategy with
suppression NUCs having complementary cross-resistance profiles is
HBeAg loss 30–35% 20–25% 20% mandatory when using drugs with a low barrier to resis-
HBeAg 30–35% 20% 20%
tance. However, although there is a strong virologic
seroconversion
Normalization 35–50% 70–80% 70% rationale for an add-on strategy with a complementary
of ALT drug to prevent the emergence of multi-drug resistant
HBsAg loss 5% (6 mo post-Tx) 3% (1 yr) 3% (1 yr) strains and raise the barrier to resistance, the current trend
11% (3 yrs post-Tx) 5% (2 yrs) 8% (3 yrs) is to recommend a switch to a complementary drug having
HBeAg negative a high barrier to resistance such as TDF [51,52]. The
HBV DNA 20–40% 90% 90% basic understanding of antiviral drug resistance, and
suppression
treatment management have been recently reviewed in
Normalization 60% 80–90% 80%
of ALT detail [15,53].
HBsAg loss 4% (6 mos post-Tx) 1% (1 yr) 0% (1 yr)
6% (3 yrs post-Tx) Can we do more than viral suppression today?
Combination of currently approved drugs
As peg-IFN and antivirals have different mechanisms of
strains, inadequate drug exposure because of pharmaco- action, it has been hypothesized that combining the 2 drug
logic properties of particular drug(s) and individual ge- classes could improve rates of HBsAg loss [11]. Several
netic variation [2,3,5–7,14,49]. trials have evaluated combination treatment with peg-
IFN and oral antivirals for patients with CHB, but the
The results are summarized in Table 1. results are inconclusive. Despite the observation that
combination of peg-IFN with Lamivudine or Telbivu-
Safety is an issue mainly in patients receiving IFN based dine showed a higher on-treatment virological response, it
therapy. The most common side effects are flu-like did not show a higher rate of sustained off-treatment
symptoms after IFN injections, neutropenia and/or virological or serological response [5,54–56]. None of
thrombopenia, auto-immune syndromes, infections espe- these trials were designed to evaluate serum HBsAg loss
cially in cirrhotics, and depression, a common side effect as a primary end point. A recent study compared the
with IFN. With NUCs, safety is significantly less often an efficacy and safety of TDF and peg-IFN combination
issue. Nevertheless, TDF administration can be associ- therapy for 48 weeks, with TDF for 120 weeks and
ated with kidney function disorders and kidney tubulo- pegIFN alone for 48 weeks in patients with CHB. A
pathy. Both Entecavir and TDF dose should be adapted combination regimen involving a short duration
to kidney function. Entecavir cannot be administered (16 weeks) of peg-IFN was also evaluated to explore
during pregnancy. whether a peginterferon-sparing regimen could affect
rates of HBsAg loss. At week seventy-two, 9% of subjects
Management of antiviral drug resistance receiving the combination for 48 weeks had HBsAg loss
Good adherence to anti-HBV therapies is important for compared with 3% of subjects in patients who received a
maintaining maximal suppression of HBV replication and shorter duration of combined peg-IFN, none of the sub-
decreasing the likelihood of resistance emergence jects in the TDF monotherapy arm, and 3% of subjects in
[14,15]. Investigation of adherence to NUC therapy in the peg-IFN monotherapy group [57]. Overall, less than
patients with CHB has shown that nearly 40% may not be 10% of good candidates lost HBsAg. Based on these
fully adherent; this significantly impacts on the rates of findings and other studies of peg-IFN alone in HBV,
viral suppression [50]. The rapidity of selection of drug patients with genotype A have the best chance of
resistant mutants depends on the barrier to resistance of responding to IFN based therapies. Furthermore, those
the administered NUC, treatment history as sequential with very active liver inflammation evidenced by an ALT
therapy with low barrier to resistance drugs favors the of >10 times the upper limit of normal (ULN) were found
development of resistance, the replication fitness of the in this study (and other studies) to have a higher chance of
variants and selective advantage in the viral quasi-species, responding. Currently, this type of combination is not
and the replication space for virus spreading. Cross-resis- recommended by clinical practice guidelines. Another
tance is defined as resistance to drugs to which a virus has recent study looked at the effect of adding peg-IFN to
never been exposed as a result of changes that have been Entecavir and showed that Peg-IFN add-on led to sig-
selected for by the use of another drug [14,15]. The initial nificantly more decline in serum HBsAg, HBeAg, and

Current Opinion in Virology 2016, 18:109–116 www.sciencedirect.com


HBV DNA; however, the rate of HBsAg loss was not
reported [58].
There are only very few studies of de novo combination of
NUCs with high barrier to resistance in treatment naı̈ve
patients. One randomized trial compared the efficacy and
safety of ETV monotherapy with those of a combination
of ETV and TDF [59]. At week 96, comparable propor-
tions of patients in each study arm achieved the primary
end point of a level of HBV DNA <50 IU/mL. Among
HBeAg-positive patients, a greater proportion given com-
bination therapy achieved levels of HBV DNA <50 IU/
mL than those given ETV alone (80.4% vs 69.8%).
However, this difference was observed only in patients
with baseline levels of HBV DNA 10(8) IU/mL (79% vs
62%) and not in those with baseline levels of HBV DNA
<10(8) IU/mL (83% in both arms). Rates of HBeAg loss
and HBeAg seroconversion were comparable between
groups. The combination therapy could provide an incre-
mental benefit to HBeAg-positive patients with baseline
levels of HBV DNA 10(8) IU/mL [59]. In the same trial,
mean HBsAg changes from baseline at Weeks 12, 48, and
96 were more pronounced in HBeAg-positive than in
HBeAg-negative patients, in patients with genotype A
than in those with genotypes C or D, and in patients with
elevated baseline ALT, but were similar between treat-
ment groups and between patients of different age cate-
gories. Overall, during the study observation time, the
kinetics of HBsAg decline were slow even in the group of
patients who received the combination of TDV and ETV
[60]. Another recent trial evaluated the effects of single
therapy with TDF and combination therapy with TDF
and Emtricitabine in immune-tolerant patients [61]. At
week 192, 55% of patients in the TDF + placebo group
and 76% of patients in the TDF + Emtricitabine group
had levels of HBV DNA <69 IU/mL. No patients were
found to have viral resistance to therapy. The rate of
HBeAg seroconversion was low and no patient had loss of
hepatitis B surface antigen. In multivariate analysis, fe-
male sex and TDF + Emtricitabine treatment were asso-
ciated with a favorable response. It was therefore
concluded that in this patient population with high viral
load the combination of TDF and Emtricitabine provided
better viral suppression than TDF alone [61]. Although
the results of these two trials showed that combination of
NUCs could induce a more profound viral suppression,
this strategy is not yet recommended by international
guidelines.
Stopping NUC therapy
Several reasons prompted clinicians to stop prolonged
NUC administration after achieving long-term viral sup-
pression. The first was to determine whether long-term
viral suppression (associated with HBeAg seroconversion
in previously HBeAg positive patients or not in the
HBeAg negative CHB patients), could lead to HBV
specific immune restoration that would allow treatment
www.sciencedirect.com
Antiviral therapy of hepatitis B Zoulim, Lebossé and Levrero 113
cessation and leave patients in a status of inactive carrier.
Many studies have addressed this question but were
mainly disappointing as most patients presented a relapse
of viral replication often associated with an increase in
ALT levels and sometimes with severe flares. Therefore,
most clinical practice guidelines do not recommend this
strategy [21,38]. A recent, sophisticated immunological
study performed at the time of NUC cessation suggested
that patients who maintained a control of viral replication
and did not present flares after treatment cessation had
the most vigorous HBV specific T cells (Kennedy et al.,
AASLD abstract 2015). However, this type of analysis will
be challenging to implement in clinical practice as a guide
for treatment management.
Another reason to attempt stopping NUC strategies was
to investigate whether a relapse of viral replication fol-
lowed by an ALT exacerbation could trigger HBV spe-
cific immunity to clear infected hepatocytes and induce
HBsAg clearance. This came from the pioneering study
from Hadzyiannis et al, who observed 33 HBeAg-nega-
tive patients with CHB, undetectable serum HBV DNA,
and normal levels of aminotransferases after 4–5 years
treatment with adefovir dipivoxil [62]. During the first
few months of the post-discontinuation period, all
patients experienced virological and 25 (76%) had bio-
chemical relapse. During the follow-up period, 18 patients
(55%) who had discontinued antiviral therapy achieved
sustained response with HBV DNA level <2000 IU/L
and persistently normal level of ALT. Among these, 13
(39%) cleared HBsAg. Fifteen patients (45%) with viro-
logical and/or biochemical relapse were re-treated with
oral antiviral agents (11 during the first 18 months and
4 after the third year) [62]. A recent study investigated the
biochemical, serologic and virologic effects in patients
who received antiviral treatment for at least 8 years with
HBV DNA <29 IU/mL and subsequently stopped TDF
for 24 weeks (Buti et al., AASLD Abstract 2015).
41 patients completed the 24 weeks follow-up. Among
them, 32 had a virological relapse >2000 UI/mL, 25 had
elevated ALT at the end of observation, 15 (27%) pre-
sented peak ALT >5  ULN. Only 11 maintained HBV
DNA < 2000 IU/mL and normal ALT levels, and 3 out of
the 41 (7%) patients lost HBsAg (Buti et al., AASLD
abstract 2015). Overall, all these results suggest that NUC
interruption should not be performed outside of clinical
trials and careful post-treatment monitoring as antiviral
rescue may be needed in many patients. It is also clearly
contra-indicated in cirrhotic patients.
Prevention of HCC — should patients with
mild liver disease be treated?
Current international treatment guidelines recommend
delaying therapy until patients show clear signs of active
liver disease extending over several months, including
persistent ALT elevations and, when biopsies are avail-
able, evidence of inflammation and/or fibrosis [3,6,7,21].
Current Opinion in Virology 2016, 18:109–116
114 Antiviral strategies
Application of the guidelines can block the progression of
fibrosis and cirrhosis and may reduce the rate of progres-
sion to HCC [22–25]. Several clinical trials, cohort studies,
and meta-analysis showed that antiviral therapy of CHB
can decrease the major complications of chronic infection,
including decompensation of cirrhosis and HCC devel-
opment [47,48,63,64]. There is still a debate regarding the
stage of the disease in which antiviral therapy with NUCs
provides the best benefit in terms of HCC prevention and/
or delay. These differences in results or interpretation
could be due to the duration of observation on treatment
and bias in patients selection for these studies with
heterogeneity in terms of ethnicity, duration of infection,
viral genotypes, and co-factors of HCC (alcohol, aflatoxin,
tobacco, metabolic syndrome, etc.) [44,65,66]. It is impor-
tant to remember that in all studies the HCC incidence in
these patients treated with NUCs was significantly de-
creased but not eliminated [22–25,66]. Another important
concern is that HCC risk factors in HBV carriers are not
well understood. Current thinking favors the notion that
the HCC risk begins, in the vast majority of cases, with the
immune reactive phase, but there is no proof that it does
not begin much earlier [44,67]. The current information
on long-term antiviral treatment efficacy and safety allows
to consider earlier treatment intervention in patients with
chronic HBV infection. A change in treatment practices is
much more feasible now as much better drugs have
become available with a better antiviral potency and a
higher barrier to resistance. It is interesting to see that the
results of the first clinical trial of NUCs in immune
tolerant patients has recently been published [68] and
showed a significant drop in viremia levels in the majority
of patients, although no HBsAg seroconversion occurred
and the impact on HCC development could not be
determined due to the short duration of follow-up. In
theory, it would be best to initiate NUC treatment as early
as possible, to suppress viral replication and thereby
decrease the integration events and molecular damage
in infected hepatocytes [67], as this was demonstrated for
HIV infection with the treatment of HIV infected patients
with high CD4 count despite a high viral load. When
biopsies are available, attempts should be made to estab-
lish hepatocyte infection levels and identify low-level
inflammatory activity and/or fibrosis. The presence of
some degree of inflammatory activity associated with
lower levels of HBV DNA in serum (less than
8 log 10 IU/mL, but higher than 4 log 10 IU/mL) would
suggest a high level of accumulated hepatocyte damage/
change even in the absence of other indicators of histo-
logical change, and treatment would seem strongly war-
ranted [67]. This is also supported by the observation that
HBV specific T cell functions are conserved in patients in
the so-called ‘immune tolerance’ phase [69]. An addition-
al, unappreciated, cause of clonal hepatocyte repopulation
occurs in non-cirrhotic liver as well [70]. Immune killing
of infected hepatocytes is the strongest known pressure
on the infected hepatocyte population in the non-cirrhotic
Current Opinion in Virology 2016, 18:109–116
liver and, analogous to cirrhosis, should lead to emergence
of HBV resistant hepatocytes that are able to avoid
immune killing. Indeed, most analyses of long-term car-
riers suggest that 50% or more of hepatocytes no longer
support HBV infection and/or support much reduced
levels of replication [71].
Perspectives
Currently the rate of ‘functional cure’ of infection defined
by HBsAg clearance and HBsAb seroconversion, despite
the lack of complete cccDNA eradication [72], remains
very low with NUCs and peg-IFN. There is therefore a
need for more effective antiviral treatments to increase
the rate of HBsAg seroconversion allowing treatment
cessation in more patients. Furthermore, the loss of
HBsAg may also enhance the beneficial effect of current
treatments on the prevention of HCC.
To define new therapeutic options and head toward
treatments with finite duration, it is therefore necessary
to develop new molecules acting on novel targets to set
true combination therapies [72]. These novel approaches
are discussed in the following paper by Levrero et al. exact
reference to be added by the publisher; it is in the same
issue of the journal !
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