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- 1. NEWS & VIEWS
Table 1 | Treatment failure causes and management
Causes
Management
Primary nonresponse or partial response
Antiviral drug potency
Treatment adherence
Drug resistance
Rescue therapy
Treatment counseling
Rescue therapy
Viral breakthrough
Treatment adherence
Drug resistance
their detection might require more sensitive
assays, such as specific hybridization assays
or ultradeep sequencing.3 Furthermore,
the evolution of these replication-impaired
variants might also be sensitive to drug
concentration and treatment adherence.
Monitoring of drug concentration has been
used extensively for the management of HIV
antiretroviral therapy. The reinforcement of
treatment adherence through counseling for
patients during antiviral therapy might also
be of benefit.7 Indeed, monitoring of serum
HBV DNA during therapy is mandatory
to assess virologic response and to counsel
on treatment adherence.3 In addition, viral
genome sequence analysis might help clinicians to choose rescue therapy on the basis
of cross-resistance data.3
The current findings4 might also have
broader implications to optimize treatment response and limit the risk of partial
response in patients who receive nucleoside
analogues with a high barrier to resistance
(such as entecavir and tenofovir). Treatment
adherence might also be an issue in patients
with a suboptimal response to these potent
drugs, especially for individuals who have
already been exposed to several lines of antiviral therapy. Partial virologic response to
antiviral drugs with a high barrier to resistance might be the result of a complicated
interplay between the selection of complex
mutants with low replication fitness and
suboptimal treatment adherence.3,9
The occurrence of viral blips, defined by
transient elevations of viral load, during
antiretroviral therapy is another important
consideration, as has been noted in the field
of HIV therapy.10 This phenomenon might
result from a lack of treatment adherence
or the selection of variants with a low resistance/fitness profile. However, the sensitivity of viral load assays might also have
an effect on the detection of viral blips as
these usually occur at the threshold of viral
genome detection. Viral blips were not
associ ted with the develop ent of resisa
m
tance in patients with HIV who received
combination therapy associated with a high
Treatment counseling
Identification of resistant mutants, rescue therapy
barrier to resistance.10 In chronic hepatitis B
treatment, viral blips can be observed with
entecavir and tenofovir therapy, although
the clinical impact of this phenomenon is
not yet known.
In conclusion, the failure of antiviral
therapy in chronic hepatitis B consists of
different virologic profiles. The main causes
of treatment failure are the selection of drugresistant mutants and suboptimal treatment
adherence. Virologic monitoring and treatment education programs are important for
patients to optimize treatment efficacy and
to prevent disease progression.
INSERM, U1052, Cancer Research Center of
Lyon, 151 cours Albert Thomas, 69003 Lyon,
France.
fabien.zoulim@inserm.fr
Competing interests
F. Zoulim declares associations with the following
companies: Bristol Myers Squibb, Gilead SC,
Novartis, Roche. See the article online for full details
of the relationships.
1.
Soriano, V., Perelson, A. S. & Zoulim, F. Why are
there different dynamics in the selection of
drug resistance in HIV and hepatitis B and C
viruses? J. Antimicrob. Chemother. 62, 1–4
(2008).
2. Werle-Lapostolle, B. et al. Persistence of
cccDNA during the natural history of chronic
hepatitis B and decline during adefovir dipivoxil
therapy. Gastroenterology 126, 1750–1758
(2004).
3. Zoulim, F. & Locarnini, S. Hepatitis B virus
resistance to nucleos(t)ide analogues.
Gastroenterology 137, 1593–1608 (2009).
4. Hongthanakorn, C. et al. Virological
breakthrough and resistance in patients with
chronic hepatitis B receiving nucleos(t)ide
analogs in clinical practice. Hepatology
doi:10.1002/hep.24318.
5. Snow-Lampart, A. et al. No resistance to
tenofovir disoproxil fumarate detected after up
to 144 weeks of therapy in patients
monoinfected with chronic hepatitis B virus.
Hepatology 53, 763–773 (2011).
6. Chang, T. T. et al. Entecavir treatment for up to
5 years in patients with hepatitis B e antigenpositive chronic hepatitis B. Hepatology 51,
422–430 (2010).
7. Osterberg, L. & Blaschke, T. Adherence to
medication. N. Engl. J. Med. 353, 487–497
(2005).
8. Chotiyaputta, W., Peterson, C., Ditah, F. A.,
Goodwin, D. & Lok, A. S. Persistence and
adherence to nucleos(t)ide analogue treatment
for chronic hepatitis B. J. Hepatol. 54, 12–18
(2011).
9. Patterson, S. J. et al. Tenofovir disoproxil
fumarate rescue therapy following failure of
both lamivudine and adefovir dipivoxil in chronic
hepatitis B. Gut 60, 247–254 (2011).
10. Lee, P
. K., Kieffer, T. L., Siliciano, R. F. &
Nettles, R. E. HIV‑1 viral load blips are of
limited clinical significance. J. Antimicrob.
Chemother. 57, 803–805 (2006).
LIVER TRANSPLANTATION
A simple inflammation marker
predicts liver cancer prognosis
Zhao-You Tang
Owing to the shortage of donor organs, improved selection criteria are
needed for allocating patients with hepatocellular carcinoma (HCC) to
receive orthotopic liver transplantation (OLT). A study has found that the
neutrophil:lymphocyte ratio independently predicts tumor recurrence
after OLT for HCC and, therefore, might constitute a simple entry criterion
that measures host inflammation status.
Tang, Z.‑Y. Nat. Rev. Gastroenterol. Hepatol. 8, 367–368 (2011); doi:10.1038/nrgastro.2011.105
The old hypothesis of a link between
inflamma ion and cancer has been cont
firmed by modern molecular biology, and
has consequently been of particular interest to researchers and clinicians in the past
decade. In 2003, Ye et al.1 reported that a
153-gene signature, of which one third of
the top 30 candidate genes were inflamma
tion and/or immune-related ones, from
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
© 2011 Macmillan Publishers Limited. All rights reserved
hepatocellular carcinoma (HCC) tissue
could predict HCC metastasis. However,
efforts to translate this molecular signature
into the clinic have proved both difficult and
costly. In 2006, in collaboration with the
National Cancer Institute, a signature of 17
inflammation and/or immune-related genes
from liver parenchyma surrounding malignant tissue was also found to predict HCC
VOLUME 8 | JULY 2011 | 367
- 2. NEWS & VIEWS
metastasis.2 Indeed, the idea that inflammation has a decisive role in tumor initiation,
promotion, invasion and meta tasis, and
s
affects immune surveillance and response to
treatment has been proposed;3 Mantovani4
has even advocated that inflamma ion
t
should be added as the seventh characteristic
of cancer. Therefore, the use of inflammation markers seems a reasonable approach
to predict HCC metastasis.
Neutrophils are the most abundant type
of leukocytes and constitute the first line of
defense against invading microbes; therefore,
neutrophil count is a sensitive marker of host
inflammation. A study by Bertuzzo et al.5
has found that the neutrophil:lymphocyte
ratio (NLR), a simple laboratory marker,
predicted survival and disease recurrence
in patients who underwent orthotopic
liver transplanta ion (OLT) for HCC. The
t
authors assessed the ability of clinical and
pathological features and three inflammation markers evaluated immediately before
OLT to predict patient prognosis. The three
inflammation markers included C‑reactive
protein (CRP) concentration, erythrocyte
sedimentation rate (ESR) and NLR. Elevated
pretransplantation NLR was associated with
high disease recurrence and mortality rates.
Furthermore, elevated NLR was associated
with the invasiveness of tumors, manifested
by a high incidence of microvessel invasion,
increased serum α‑fetoprotein levels, and
poor differentiation in tumor cells. These
findings concur with those from a study
by Halazun et al.,6 which also showed that
patients with elevated NLR have a poor
prognosis after OLT for HCC.
NLR has been reported to be of prognostic
value in patients with various types of cancer
who have undergone curative surgery.7
In view of its feasibility, therefore, NLR
might be added to the staging systems for
patients entering an OLT waiting list or
for patients receiving adjuvant therapy after
OLT. For patients with unresectable HCC
owing to decompensated liver function, OLT
is the only treatment choice. Milan criteria
are widely used for patient selection and,
unfortunately, post- ransplantation recurt
rence is often observed. Pretransplantation
patient selection mainly involves imaging
methods to evaluate tumor numbers and
total tumor size, whereas the evaluation of
tumor invasiveness is often neglected. In
Bertuzzo et al.’s study, NLR was an independent predictor for prognosis, whereas the
Milan criteria were not5—a result that further
justifies the addition of NLR into the widely
used staging system for patient selection.
368 | JULY 2011 | VOLUME 8
Several lines of evidence suggest that
neutrophils can be recruited by cancer
cells to facilitate proangiogenic and pro
invasive effects. 8 Lymphocytes are comprised of T cells, B cells and natural killer
cells. A reduction in lymphocyte number,
especially CD4+ T cells, is a sign of host
immunodeficiency. The elevation of NLR in
patients with HCC or other cancers might
indicate that inflammation is exacerbated
and host immunity remains low. Elevated
NLR is associated with high mortality rates
in patients with many other nonmalignant
diseases, indicating that patients with severe
inflammation or immune disturbance are in
a critical condition and might not tolerate
major surgical interventions. The mechanism
by which inflammatory or immune disturb
ances can affect tumor recurrence remains
to be determined, although several hypotheses exist. First, in the case of OLT, disease
recurrence might result from the homing of
hematogenously disseminated tumor cells,
and immunological surveillance in patients
with elevated NLR might be extremely
suppressed. Second, host inflamma ory or
t
immune disturbance might lead to the disruption of immune responses in the local
micro nvironment of the subsequently
e
implanted liver, making it hospitable for the
homing tumor cells. Finally, neutrophils that
infiltrate into the tumor microenvironment
might have prometastatic effects by promoting tumor angiogenesis, as demonstrated in a
study in which infiltrating neutrophil counts
were found to predict prognosis for patients
with HCC who underwent curative surgery.9
Neutrophil counts in peripheral blood might
correlate with those that infiltrate into the
tumor microenvironment.
The addition of routinely used inflamma
tion markers into an established system to
evaluate prognosis can be achieved quite
easily. We have previously demonstrated that
the ratio of serum γ‑glutamyl transferase
(GGT) to alanine aminotransferase (ALT)
predicted prognosis for patients with HCC
with compensated liver function who underwent curative liver resection.10 It seems likely
that NLR reflects inflammation disturb
ance in the host, whereas the GGT:ALT
ratio reflects inflammation disturb nce in
a
the liver microenvironment, which is the
main target organ for HCC recurrence or
metastasis. These two markers are both
covered in routine laboratory reports, and
the simple combination of them leads to a
considerable improvement in prognostic
values. Nevertheless, as new molecular biomarkers are developed, the value of existing
prognostic systems that have stood the test
of time should not be neglected.11
Bertuzzo et al. 5 demonstrate a simple
method to measure host inflammation and/
or immune status and, therefore, to predict
a patients’ prognosis after OLT for HCC.
Further molecular studies might help to
clarify how the disruption to host inflamma
tory and immune responses can affect
tumor metastasis and how these imbalances can be addressed thera eutically. In
p
the era of molecular-targeted therapies, we
should not only focus on the tumor cells
and tumor microenvironment, but also the
host environment.
Liver Cancer Institute and Zhongshan Hospital,
136 Yi Xue Yuan Road, Shanghai 200032,
P.R. China.
zytang88@163.com
Competing interests
The author declares no competing interests.
1.
Ye, Q. H. et al. Predicting hepatitis B viruspositive metastatic hepatocellular carcinomas
using gene expression profiling and
supervised machine learning. Nat. Med. 9,
416–423 (2003).
2. Budhu, A. et al. Prediction of venous
metastases, recurrence, and prognosis in
hepatocellular carcinoma based on a unique
immune response signature of the liver
microenvironment. Cancer Cell 10, 1–13
(2006).
3. Grivennikov, S. I., Greten, F. R. Karin, M.
Immunity, inflammation, and cancer. Cell 140,
883–899 (2010).
4. Mantovani, A. Inflaming metastasis. Nature
457, 36–37 (2009).
5. Bertuzzo, V. R. et al. Analysis of factors
affecting recurrence of hepatocellular
carcinoma after liver transplantation with a
special focus on inflammation markers.
Transplantation doi:10.1097/
TP
.0b013e3182187cf0.
6. Halazun, K. J. et al. Negative impact of
neutrophil-lymphocyte ratio on outcome after
liver transplantation for hepatocellular
carcinoma. Ann. Surg. 250, 141–151 (2009).
7. McMillan, D. C. Systemic inflammation,
nutritional status and survival in patients with
cancer. Curr. Opin. Clin. Nutr. Metab. Care 12,
223–226 (2009).
8. Murdoch, C., Muthana, M., Coffelt, S. B.
Lewis, C. E. The role of myeloid cells in the
promotion of tumour angiogenesis. Nat. Rev.
Cancer 8, 618–631 (2008).
9. Li, Y. W. et al. Intratumoral neutrophils: a poor
prognostic factor for hepatocellular carcinoma
following resection. J. Hepatol. 54, 497–505
(2011).
10. Ju, M. J. et al. Preoperative serum gammaglutamyl transferase to alanine
aminotransferase ratio is a convenient
prognostic marker for Child-Pugh A
hepatocellular carcinoma after operation.
J. Gastroenterol. 44, 635–642 (2009).
11. Villanueva, A. et al. Combining clinical,
pathology, and gene expression data to
predict recurrence of hepatocellular
carcinoma. Gastroenterology 140, 1501–1512
(2011).
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© 2011 Macmillan Publishers Limited. All rights reserved