HCV genotype 3: a wolf in sheep’s clothing
DOI:10.1586/14787210.2016.1127757
José-R. Blancoa* &
Antonio Rivero-Juarez
1a Infectious Diseases Area. Hospital San Pedro - Center for Biomedical Research of La Rioja (CIBIR) . Piqueras 98, 26006 Logroño , La Rioja ( Spain ).
2b Infectious Diseases Unit. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) . Hospital Universitario Reina Sofía de Córdoba. Universidad de Córdoba . Avda. Menendez Pidal s/n, 14004 Córdoba , Córdoba ( Spain ).
HCV genotype 3: a wolf in sheep’s clothing
"All truths are easy to understand once they are discovered; the point is to
discover them". Galileo Galilei"
At present, the hepatitis C virus (HCV) is a major cause of morbidity and
mortality affecting over 185 million people worldwide,[1] equivalent to a global
prevalence of about 2.5% in 2015. Genotype 3 (HCV G3) is one of the seven
recognized genotypes.[2] HCV G3 is the second most common genotype
overall and is estimated to account for 54.3 million cases throughout the world
(30.1%).[1] Although three-quarters of them occur in South Asia where it is
endemic, the 3a subtype is an “epidemic subtype“ widely distributed
geographically, probably associated with injecting drug use.[3]
In the last two years, the history of HCV infection has changed radically with the
appearance of the new direct-acting antiviral agents (DAAs).[4] Although HCV
G3 was one of those genotypes who achieved a better sustained viral response
(SVR) using pegylated interferon and ribavirin (PEG-IFN/Rbv) therapy,[5] the
current effectiveness of the new DAAs against HCV G3 leaves a lot to be
desired compared with the results obtained with other genotypes.[6] This is a major problem since, compared to other genotypes, HCV G3 is associated with
faster progression of fibrosis,[7,8] a greater risk for hepatocellular carcinoma
(HCC),[8-10] and a higher mortality.[11] Why is it so pathogenic and resistant to
treatment? The reasons for this “aggressiveness” are without doubt multiple,
complex and not well known.
First, it is important to remember that the host immune response plays an
important role in HCV G3 infection because of its potential to contribute to viral
clearance. So, acutely HCV-infected patients are much more likely to
spontaneously clear HCV if they are infected with HCV G3 than HCV G1.[12]
Indeed, chronically infected HCV G3 patients had higher SVR rates after shorter
treatment with PEG-IFN/Rbv therapy when compared to those with chronic
HCV G1 infection.[13] One of the possible reasons could be that in monocytic
cell and plasmacytoid dendritic cell lines and in macrophages differentiated from
monocytes with macrophage colony-stimulating factor, HCV G3 induces greater
interferon transcription than either genotype 1a or 1b.[14] However, this
apparent benefit may backfire because of the increased rate of fibrosis
progression of HCV G3, probably due to the higher non-parenchymal cell
transcription of IFN genes following intracellular HCV G3 sensing.[14]
It has been reported previously that HCV G3 is associated with a significantly
increased risk of developing cirrhosis and HCC compared to HCV G1, and
association that is independent of the patients’ age, diabetes, body mass index,
or antiviral treatment.[8] The high viremia observed in HCV G3-infected patients
may be a marker of rapid disease damage, reflecting either the inability of the
immune system to control the infection or the existence of some escape
mechanisms in HCV G3 which prevents the immune system response from
being effective.[15]
Secondly, another problem that is not well understood is the interaction
between HCV and lipid metabolism.[16] So, HCV G3 selectively interferes with
the late cholesterol synthesis pathway,[17] although this interference is resolved
after the SVR. Other mechanisms that alter lipid metabolism are increased the
novo lipogenesis and the inhibition of mitochondrial fatty acid degradation.[18]
At what level of lipid metabolism does HCV G3 work? Is the damage the consequence of the virus or of its proteins in infected hepatocytes? Given that,
in previous studies, the variables independently associated with SVR were high
LDL levels,[19,20] low HDL levels [19] and statin use,[19] one might think that
statins would be a useful option for such patients. Nonetheless, this is not
actually the case with HCV G3. In one analysis of patients with HCV 1-3
genotypes who received combination therapy with PEG-IFN/Rbv, the significant
impact of statin use was only observed among the HCV G1 patients.[20] Similar
findings were reported by Selic Kurincic et al.[21]
Steatosis is a common histologic finding in patients infected by HCV G3,
independently of the presence of fibrosis, diabetes, hepatic inflammation,
ongoing alcohol abuse, higher body mass index, and older age.[22] Indeed,
steatosis in HCV G3 infected patients is not the result of overexpression of
genes involved in lipogenesis.[23] The higher rates of hepatic steatosis in HCV
G3 patients, even in absence of other metabolic complications, suggest that
some specific viral sequences may be involved in the etiology of steatosis.[18]
In fact, after reaching SVR, hepatic steatosis in these patients had
disappeared.[24,25] Another possible explanation for the high presence of
steatosis could be that HCV G3 steatosis induces the liberation of
proinflammatory chemokines that increase the recruitment of inflammatory cells
to the liver.[14] In support of this idea, the depletion of liver Kupffer cells
prevents the development of diet-induced hepatic steatosis and insulin
resistance.[26]
It is important to bear in mind that there is a significant correlation between the
steatosis score and the titer of intrahepatic HCV RNA in patients with HCV G3,
providing virological and some clinical evidence that steatosis is the
morphological expression of a viral cytopathic effect in patients infected with this
genotype.[27] This finding has important implications, such as lower SVR rates
or higher relapse rates after HCV treatment.[28,29] Is steatosis a marker of
rapid progression or bad prognosis in HCV G3 infected patients?
Non-alcoholic fatty liver disease (steatosis/steatohepatitis) is similarly
recognized as the hepatic manifestation of metabolic syndrome (MS). HCV
virus genotype 3 infection increases the risk of insulin resistance and diabetes,
probably due to the direct effect of the virus on intracellular insulin signaling.[30]
This situation not only increases the cardiovascular risk but also reduces the
likelihood of achieving a SVR.[31] Another common manifestation of MS is
obesity, a problem that also increases the expression of some inflammatory
cytokines and activates several signaling pathways involved in the
pathogenesis of insulin resistance.[32] The inflammation may also contribute to
the pathogenesis of liver damage.[33] Obesity has also been correlated with a
lower SVR rate.[34] Once again, this opens up an interesting way to research
the mechanisms involving MS and SVR in these patients. Are insulin resistance
and/or obesity indicators of the the existence of an established liver damage,
even though we are unable to diagnose it? Is there some symbiotic relationship
between the adipocytes and HCV G3 that reduces the efficacy of the DAAs? In
view of the higher rates of SVR using the new DAAs, is the presence of MS still
important in chronic HCV infection?.[35] Probably not, but there is as yet no
concrete answer for this question and so the controversy about steatosis and
HCV remains. Valenti et al also reported that the rs738409 genotype, a
polymorphism that influences liver fat without affecting insulin resistance and
body composition, was associated with severe hepatic steatosis in patients
infected with a non-3 HCV genotype, and also with fibrosis stage and cirrhosis
(OR = 1.47; P = 0.002).[36] Similarly, Cai et al [37] reported that rs738409 was
associated with an increased risk of steatosis in patients infected with a non-3
HCV genotype. These results suggest distinct pathogenic mechanisms in the 3
and non-3 genotypes.
Moving on to the third point, and so concluding this topic, it is necessary to
understand the clinical implications of the different HCV G3 subtypes (in other
words, immunity, inflammation, prognosis, response to DAAs). This is
something we already known for HCV G1a and 1b.[38] At least 10 HCV G3
subtypes have been described so far.[39] Are some of these HCV G3 subtypes
able to evade the immune response? Can we expect the same SVR for
different subtypes? The correct identification of HCV G3 subtypes would
probably be necessary because they are crucial in clinical trials evaluating the
new DAAs. No data have so far stratified the response of HCV G3 to the new
DAAs, which could be an essential issue that requires further investigation.
In summary, given the aggressiveness of HCV G3, it is increasingly necessary
to initiate antiviral treatment as soon as possible in all patients, including those
with steatosis and/or MS. In these patients, even those with SVR, continued
surveillance is necessary, paying careful attention to patients with cirrhosis.
There is no doubt that better knowledge of HCV G3 should be a priority for us
all.
Financial & competing interests disclosure
JR Blanco has carried out consulting work for Abbvie, Bristol-Myers Squibb,
Gilead Sciences, Janssen, Merck, and ViiV Healthcare; has received
compensation for lectures from Abbvie, Bristol-Myers Squibb, Gilead Sciences,
Janssen, Merck, and ViiV Healthcare, as well as grants and payments for the
development of educational presentations for Gilead Sciences and BristolMyers
Squibb. A Rivero-Juarez is the recipient of a Postdoctoral Perfection
Grant from Fundación Progreso y Salud, Consejería de Salud y Políticas
Sociales, Junta de Andalucia (0024-RH-2013). He has received compensation
for lectures from Bristol-Myers Squibb, Janssen, Merck, and ViiV
Healthcare.The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript apart
from those disclosed.
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"
All truths are easy to understand once they are discovered
; the point is to
discover them
"
.
Galileo Galilei
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