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The association between chronic hepatitis C infection and

cardiovascular risk
P. Pateria,1 G. P. Jeffrey,1,2 G. MacQuillan,1,2 D. Speers,3 H. Ching,1,2 M. A. Chinnaratha,1 G. F. Watts2,4 and
L. A. Adams1,2
1
Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, 2School of Medicine and Pharmacology, University of Western
Australia, 3PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre and 4Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth
Hospital, University of Western Australia, Perth, Western Australia, Australia

Key words Abstract

chronic hepatitis C, atherosclerosis, insulin
resistance, pulse wave velocity, carotid
intima-media thickness.
Correspondence
Leon Adams, School of Medicine and
Pharmacology M503, QEII Medical Centre
Unit, Harry Perkins Institute of Medical Re-
search, 6 Verdun Street, Nedlands, WA 6009,
Australia.
Email: leon.adams@uwa.edu.au;
leon.adams@health.wa.gov.au
Received 22 June 2015; accepted 10 October
2015.
doi:10.1111/imj.12936
Background: Vascular disease is a common cause of death in patients with chronic
hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is
unclear.
Aims: To determine whether patients with CHC have increased subclinical vascular
disease and whether genotype or antiviral treatment modies this risk.
Methods: Fifty CHC patients and 22 age-matched and sex-matched healthy controls
underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular
risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-
femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery ow-
mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid
intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12)
undergoing antiviral treatment 18 months after initiation of treatment.
Results: Baseline vascular risk factors and measures of arterial stiffness, endothelial dys-
function and CIMT were not different between cases and controls (P > 0.2 for all). Genotype
1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 3.5% vs 10.9
5.2%, P = 0.03) and higher right CIMT (0.6 0.1 mm vs 0.5 0.07 mm, P = 0.04) compared
with non-genotype 1. Patients who achieved sustained virological response (7/12) showed
signicant improvement in insulin resistance (homeostasis model of assessment of insulin
resistance 2.3 1.2 vs 1.8 0.8, P = 0.02) and arterial stiffness (PWV 7.4 1.1 m/s vs
6.5 0.6 m/s, P = 0.04).
Conclusions: Subclinical vascular disease is not greater in CHC subjects compared with
controls. However, among CHC subjects, genotype 1 infection is associated with greater en-
dothelial dysfunction and increased carotid-intima medial thickness compared with non-
genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial
stiffness.

Introduction in the absence of signicant liver injury.4 Thus, CHC persists

The global prevalence of hepatitis C has been estimated at
23%, which equates to 150170 million people living with
hepatitis C infection worldwide.1,2 Chronic hepatitis C
(CHC) infection is generally asymptomatic until end-stage
liver disease occurs, and thus, many individuals have the
condition for decades before presenting for treatment.3 Fur-
thermore, treatment may be unsuccessful or is not initiated
Funding: This work was supported by National Heart Foundation
Grant in Aid 634390.
Conict of interest: None.
in a signicant proportion of the infected population for
many years.
A meta-analysis including more than 32 000 patients
suggested that only 16% patients with CHC infection de-
veloped cirrhosis3,5 with only a proportion of these indi-
viduals dying from their liver disease. Vascular disease is
the third leading cause of death in patients with CHC.6,7
However, whether CHC is associated with an increased
risk of death from atherosclerotic vascular disease is un-
known. Determination of an increased vascular risk
would have clear implications on the management of
these patients with potential to reduce future morbidity
and mortality.

2016 Royal Australasian College of Physicians 63

Pateria et al.
CHC may potentially lead to atherosclerosis by several
mechanisms, namely increasing circulating levels of pro-
atherogenic inammatory cytokines, increasing systemic
oxidative stress levels and increasing insulin resistance.811
Clinical studies examining the association between CHC
and vascular disease are conicting. The majority of studies
performed to date have had several limitations in
methodology including small, non-representative study
samples, reliance on hepatitis C virus (HCV) antibodies for
the diagnosis of CHC, failure to match control patients
appropriately, inability to control confounding vascular risk
factors and limited vascular assessment of one modality and
organ.6,1216 Similarly, the effect of HCV genotype on
vascular risk, which impacts on the degree of insulin
resistance, has not been examined.17,18 Last, the majority
of studies has employed a cross-sectional design and
consequently has not assessed the association between
vascular risk over time or in response to antiviral therapy,
limiting conclusions regarding causality. Therefore, the
association between CHC infection and vascular risk re-
mains inconclusive.
The primary objective of this study was to investigate
whether subjects with CHC are at increased risk of
subclinical vascular disease and atherosclerosis. We also
investigated the effect of hepatitis C viral eradication on
subclinical atherosclerotic disease among patients undergoing
antiviral therapy.
Methods
Study design and patients
The study was designed in two parts: rst, a cross-sectional,
case-controlled examination of CHC patients and age-
matched and gender-matched healthy controls and second,
an 18-month longitudinal study of CHC subjects under-
going antiviral treatment. All subjects underwent clinical
assessment for vascular risk factors, biochemical assessment
and non-invasive assessment of subclinical vascular
disease. Assessment was repeated in a subset of CHC
patients undergoing treatment, 18 months after initiation
of treatment. A period of 18 months allowed sufcient
time to assess adequacy of antiviral treatment and to
measure any effect of viral eradication on subclinical
vascular disease.
Cases were recruited from the hepatitis clinic at Sir Charles
Gairdner Hospital. CHC was dened as HCV polymerase
chain reaction (PCR) positive for more than 6 months.
Healthy controls were recruited from relatives/associates
accompanying patients to the viral hepatitis clinic and from
the general public. Healthy controls were dened by the
presence of normal liver enzymes and absence of medical
64
conditions requiring medications. Cases and controls were
matched by age (5 years) and sex. All procedures followed
were in accordance with the ethical standards of Sir Charles
Gairdner Hospital Human Research Ethics Committee and
with the Helsinki Declaration of 1975, as revised in 2008.
Informed consent was obtained from all patients for being
included in the study.
Inclusion criteria for study were positive hepatitis C PCR
for >6 months, alanine transaminase (ALT) > 40 U/L and
duration of infection >10 years. Exclusion criteria were
HIV co-infection, symptomatic cryoglobulinaemic vasculitis
or vasculitis due to any other cause (cryoglobulins in the
absence of clinical vasculitis were not an exclusion criteria),
cirrhosis (due to its possible protective effect on vascular
disease), liver transplantation, current antiviral treatment,
systemic inammatory disease (inammatory arthritis, in-
ammatory bowel disease, chronic infections, autoimmune
conditions), end-stage renal failure, overt vascular disease
(previous myocardial infarction, angina, cerebrovascular
event or peripheral vascular disease) and type 2 diabetes
mellitus requiring hypoglycaemic agents or insulin.
Assessment
Clinical assessment was performed by structured question-
naire for vascular risk factors (smoking, hypertension,
diabetes, family history, hypercholesterolaemia, low high-
density lipoprotein (HDL) cholesterol, alcohol intake),
medications, duration of viral infection (calculated from
date of last potential exposure), previous antiviral treat-
ment, viral serological and genotype status. Clinical exami-
nation of all subjects was performed including height,
weight, waist and hip circumference and blood pressure.
Biochemical assessment was performed by venepuncture
after overnight fast for insulin, HDL and low-density
lipoprotein (LDL) cholesterol, triglycerides, liver function test,
cryoglobulin and cryocrit (possible confounding factors).
Insulin resistance was calculated by the homeostasis model
of assessment (HOMA = insulin (mU/L) glucose (mmol/L)/22.5)
after an overnight fast. Glucose was measured by a
hexokinase method (Bayer Diagnostics, Melbourne, Australia)
and insulin by an enzyme-linked immunosorbent assay
(Boehringer Mannheim, Germany). Hepatic inammation
was assessed non-invasively using standard hepatic
aminotransaminases (ALT, aspartate transaminase (AST)) as
well as Hepascore (combination of bilirubin, gamma glutamyl
transferase, hyaluronate, 2-macroglobulin, age and gender),
which we have demonstrated to be correlated with
necroinammatory grade on liver biopsy.19
Non-invasive vascular assessment
Vascular assessment was comprehensively assessed using
three non-invasive and complementary methods: (i) by
2016 Royal Australasian College of Physicians

measuring arterial stiffness (aortic augmentation index (AIx)
and carotid-femoral pulse wave velocity (PWV)); (ii) endo-
thelial dysfunction (brachial artery ow-mediated dilatation
(FMD) and dilatation post-glycerol trinitrate administration
(GTNMD)); and (iii) carotid intima-media thickness (CIMT).
Importantly, each modality reects different aspects of car-
diovascular (CV) risk including traditional CV risk factors
such as lipid proles, as well as anatomical and functional
pre-clinical vascular abnormalities. Thus, the combination
of non-invasive tests improves the prediction of CV morbidity
to a greater extent than each modality alone.20 Each
non-invasive assessment was performed by a single trained
operator in standardised conditions in keeping with consensus
recommendations (controlled temperature, resting for
10 min in recumbent position, similar time of the day,
refraining from eating and smoking for 3 h and drinking
alcohol for 10 h prior, refraining from speaking during
assessment, supine position).21
Measures of arterial stiffness (AIx and PWV)
Arterial stiffness reects a functional and structural change
associated with arteriosclerosis and arterial remodelling.20
AIx and PWV are independent predictors of coronary artery
disease (CAD) and CV mortality in a wide variety of
populations.21,22 The aortic pressure wave is composed of
a forward travelling wave generated by ventricular
contraction and a later arriving reected wave from the
periphery. The transmission of both forward and reected
wave increases, as the aortic and arterial stiffness increase,
which causes the reected wave to arrive earlier in the
aorta and to augment pressure in late systole. Therefore,
augmentation of the aortic pressure wave is a manifestation
of wave reection and can be expressed as a percentage of
central pulse pressure (PP) as AIx.22 AIx was determined
using a Sphygmocor pulse wave analysis system (SCOR-Px;
AtCor Medical, Sydney, NSW, Australia). A radial artery
blood pressure waveform was obtained for 13 s. An aortic
artery waveform was derived from the radial artery
waveform using a generalised transfer function and
calibrated using a single simultaneously recorded brachial
artery CV measurement (Dinamap, 1846 SX; Critikon,
Tampa, FL, USA) from the left arm.23 Diastolic and mean
arterial pressures were assumed to remain constant
throughout the arterial tree. AIx was calculated as the ratio
of the pressure difference between the shoulder of the
wave and peak systolic pressure (AP) and PP according
to the formula AIx = (AP/PP) 100.
Carotid-femoral PWV is considered to be gold standard
non-invasive assessment of arterial stiffness.21 Carotid-
femoral PWV was determined by simultaneous applanation
tonometry of the carotid and femoral arteries. The time of
travel between applanation points (t) was calculated from
2016 Royal Australasian College of Physicians
Hepatitis C and cardiovascular risk
the foot of each waveform, detected as the maximum of
the second derivative, and was averaged over four to six
cardiac cycles. The distance traversed (L) between sam-
pling sites on the body surface was measured as straight
lines with a tape measure. PWV was calculated as L/t.
Arterial function of brachial artery
Endothelial dysfunction represents an early functional
disturbance of vessel homeostasis, which is intimately related
to inammatory stimuli, oxidative stress and insulin
resistance.24 Brachial artery FMD is an endothelium-
dependent function, whereas GTNMD is an endothelium-
independent function. FMD is related to the prevalence
and extent of coronary atherosclerosis and is an independent
predictor of future CV disease.25,26 Brachial artery FMD was
assessed by 12-MHz high-sensitivity ultrasound with an
internal electrocardiogram monitor (Acuson Aspen 128
ultrasound device; Acuson Corp, Mountain View, CA,
USA) and assessed using edge-detection software as pre-
viously validated by us.27 FMD was assessed by occluding
the brachial arterial inow by a cuff inated to 50 mmHg
above systolic pressure for 5 min, whereas GTNMD was
assessed after 400 g of sublingual GTN. Brachial artery
diameter was measured at baseline and 4560 s after cuff
release or GTN administration. FMD and GTNMD were
expressed as the change in post-stimulus diameter as a
percentage of the baseline diameter.
Measure of carotid intima thickness
CIMT is a structural marker of chronic vascular thickening
and correlates strongly with the extent of atherosclerotic
burden documented by coronary angiography and predicts
incident coronary and cerebrovascular events indepen-
dently of traditional vascular risk factors.28,29 B-mode
ultrasound of both common carotid arteries was performed
by a single trained ultrasonographer using 10-MHz, multi-
frequency linear array probe attached to a high-resolution
ultrasound machine (Acuson Sequoia, Mountain View,
CA, USA). CIMT was measured on multiple end-diastolic
image frames from both common carotid arteries using
validated Digital Imaging and Communications in Medi-
cine-based software. Measurements were taken bilaterally
in the 1-cm segment proximal to the dilatation of the
carotid bulb, and three maximum readings of the anterior,
lateral and posterior projection of the near and far wall were
averaged. Carotid plaques were dened as a focal thickening
of 1.0 mm at the level of the common carotid artery.
Longitudinal study
Patients eligible and willing to undergo treatment were
given standard antiviral treatment with pegylated
65
Pateria et al.
interferon and ribavirin for either 6 or 12 months depending
on their genotype. Protease triple therapy was not available
at the time of the study. Patients were reassessed at month
18. CHC responders were dened as individuals who have
had a sustained virological response (SVR) (negative HCV
PCR during therapy and at 18 months), and non-responders
were dened as individuals who have had a positive HCV
PCR at 18 months.
Statistical analysis
Comparison of demographic, clinical characteristics, bio-
chemical assessment and subclinical vascular disease
(PWV, AIx, CIMT, FMD) was assessed between groups by
KruskalWallis analysis for continuous variables and chi-
squared test for categorical variables. Analysis was repeated
after stratication for CHC viral genotype. To account for
possible confounding factors, separate multivariate linear
analysis (CIMT, PWV, AIx and FMD as dependent
variables) was performed on the pooled group with CHC
and controls included as categorical variables with adjustment
for established CV risk factors.
Change in subclinical vascular disease/risk over time
(PWV, AIx, FMD) at baseline and 18 months was
analysed within responders and non-responders using
Wilcoxon signed-rank test. Comparison at baseline and
18 months of subclinical vascular disease/risk (measured
by PWV, AIx and FMD) was directly compared between
responders and non-responders using KruskalWallis
analysis.
Sample size and statistical power
Based on a mean (standard deviation) PWV in the general
population of 11.8 (3.6) m/s,30 50 subjects with CHC
matched to 25 healthy controls would provide 80% power
to detect a difference in mean PWV between subgroups of
2.5 m/s, with a two-sided P-value of 0.05. An increase in
PWV of 3.4 m/s is independently predictive of an increased
risk of future CV events in the general population.30
Results
Baseline characteristics
Fifty cases with CHC were matched to 22 healthy controls
(Table 1). Thirty-three cases (57.5%) had CHC genotype 1
infection. Baseline vascular risk factors (blood pressure,
body mass index (BMI), waist circumference, serum triglyc-
erides, HDL cholesterol, LDL cholesterol, high-sensitivity
C-reactive protein (hs-CRP), glucose, HOMA) were not
signicantly different between cases and controls (Table 1).
Compared with controls, cases had evidence of hepatic
inammation and brosis, as evidenced by high ALT
66
(109.1 74.7 vs 28.64 14, P < 0.001), AST (69.6 35.8
vs 27.3 6.1, P < 0.001) and Hepascore (0.4 0.2 vs 0.1
0.1, P < 0.001).
Vascular assessment in cases and controls
Measures of arterial stiffness, endothelial dysfunction and
carotid thickness were not different between cases and
controls (P > 0.2 for all, Table 2). Similarly, clinical risk
factors for vascular disease (history of smoking, family
history of CAD and use of medications) were not different
between cases and controls (Table 1).
Genotype-specic differences in vascular
assessment
Among CHC patients, those with genotype 1 infection
had greater endothelial dysfunction with lower FMD
compared with non-genotype 1 (8.2 3.5% vs 10.9
5.2%, P = 0.03) and evidence of subclinical atherosclero-
sis with higher right CIMT (0.6 0.1 mm vs 0.5
0.07 mm, P = 0.04). Vascular changes were not related
to the presence of cryoglobulins. No signicant difference
in AIx (26.4 12.6 vs 25.4 9.6, P = 0.7), PWV (8.2
1.8 vs 7.9 1.5, P = 0.5) or GTNMD (19.2 7.3 vs 21
9.5, P = 0.4) was noted between different genotypes
of CHC infection (Table 3).
Vascular risk modication post-treatment
Twelve patients, six patients each with genotype 1 and non-
genotype 1 infection, received antiviral treatment, and
seven (58%) patients achieved SVR. Thirty-three per cent
(n = 2) of patients with genotype 1 infection were re-
sponders, whereas 83% (n = 5) of non-genotype 1 infection
successfully cleared the virus.
There was a trend towards improvement in vascular
stiffness in patients undergoing treatment (PWV 7.9
1.6 m/s vs 7.3 1.8 m/s, P = 0.07) (Table 4), and this
improvement was signicant in patients who achieved
SVR (PWV 7.4 1.1 m/s vs 6.5 0.6 m/s, P = 0.04)
but not in those who did not (PWV 8.5 1.9 m/s vs
8.3 2.4 m/s, P = 0.07) (Tables 5, 6). PWV reduced in
patients who underwent treatment and achieved SVR
but not in those without SVR, suggesting an effect
related to viral eradication rather than treatment per se.
Insulin resistance determined by HOMA, also improved in
patients who achieved SVR (2.3 1.2 vs 1.8 0.8, P = 0.02)
but did not improve in non-responders (1.8 1.4 vs. 2.2
0.7, P = 0.4). There was no signicant difference in AIx
(27.9 14.7, 27.6 4.3, P = 0.8), FMD (7.8 3.7, 8.2 3.2,
P = 0.5) or GTNMD (20 6 vs 21.2 7.2, P = 0.2) with treat-
ment or its response. CIMT was not assessed post-treatment
as it is unlikely to change/improve over a period of
2016 Royal Australasian College of Physicians
 Hepatitis C and cardiovascular risk

Table 1 Baseline characteristics of cohort

HCV Control Geno 1 Non-geno 1

Variables (n = 50) (n = 22) P-value (n = 33) (n = 17) P-value
Gender (male, %) 54 54.5 1 57.5 47 0.5
Age (years) 47.4 9 46.6 10 0.7 48.7 7.1 45 11.7 0.1
2
BMI (kg/m ) 26.5 5.3 25.9 3.2 0.6 26.4 5.9 26.8 4 0.7
Waist (cm) 92.4 14 87.6 9.3 0.2 92.2 16 92.7 11 0.2
Alcohol (drinks/week) 16.5 22 8.5 6.3 0.2 12 11.6 25.2 35 0.2
Smoke (pack years) 16.2 14 4.5 0.4 20.2 15 10.9 12 0.1
Family history of CAD (n, %) 7 (14) 3 (14) 1.0 3 (9) 4 (24) 0.2
SBP (mmHg) 124 12 125 12 0.8 124 12 124 13 0.8
DBP (mmHg) 76 8 76 7 0.7 77 8 74 9 0.2
Pulse pressure (mm Hg) 47.6 9.9 48.9 10 0.6 43.6 9.9 50 9.9 0.3
Heart rate (per minute) 61 11 57 9.6 0.1 61 11 62 11 0.6
ALT (IU/L) 109 74 28.6 14 <0.001 95 70.2 136 77 0.06
AST (IU/L) 69.6 35 27.3 6.1 <0.001 62 32.2 85.5 38 0.02
Creatinine (g/L) 70.6 10 71.5 8.7 0.7 71.8 12 68.4 6.9 0.3
hs-CRP 2 4.5 2.1 2.8 0.9 1.5 4.3 2.9 5.1 0.3
TGL (mmol/L) 1.1 0.6 1 0.4 0.5 1.2 0.6 1 0.6 0.4
HDL (mmol/L) 1.4 0.4 1.4 0.2 0.5 1.3 0.3 1.5 0.4 0.1
Non-HDL (mmol /L) 2.8 1.1 3.2 0.7 0.08 2.9 0.8 2.5 1.4 0.3
Hepascore 0.4 0.2 0.1 0.1 <0.001 0.4 0.2 0.3 0.9 0.4
HOMA 1.6 1.3 1.2 1.9 0.3 1.6 1.3 1.6 1.3 0.9
Cryoprecipitate 0.34 0.5 0 0.02 0.25 0.5 0.5 0.6 0.1

Results reported as mean standard deviation. Comparisons performed using independent sample t-test and non-parametric tests (independent
sample KruskalWallis and independent sample MannWhitney test). ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass
index; CAD, coronary artery disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein;
HOMA, homeostasis model of assessment; LDL, low-density lipoprotein; SBP, systolic blood pressure; TGL, triglycerides.

Table 2 Estimates of subclinical vascular disease of HCV versus control

Variables HCV (n = 50) Control (n = 22) P-value Mean difference (95% CI)
AIx (%) 26.1 11 22.9 15 0.3 3.2 (3.39.7)
PWV (m/s) 8.1 1.7 7.8 1.3 0.4 0.3 (0.51.1)
FMD (%) 9.2 4.3 8.2 3.1 0.3 0.9 (13)
GTNMD (%) 19.8 8.1 21.5 8.3 0.4 1.7 (2.66.1)
FMD/GTNMD ratio 0.4 0.2 0.4 0.18 0.3 0.05 (0.050.1)
CIMT Lt (mm) 0.62 0.1 0.61 .1 0.7 0.03 (0.060.08)
CIMT Rt (mm) 0.62 0.1 0.62 0.1 0.9 0.03 (0.060.07)

Results reported as mean standard deviation and mean difference and 95% condence interval. Comparisons performed using independent sample
t-test and non-parametric tests (independent sample KruskalWallis and independent sample MannWhitney test). AIx, aortic augmentation
index; CIMT, carotid intima-media thickness; FMD, ow-mediated dilatation; GTNMD, glyceryl trinitrate-mediated dilatation; HCV, hepatitis C
virus; PWV, pulse wave velocity.

18 months.31 There was no signicant difference in BMI, Discussion

waist circumference, blood pressure, hs-CRP or lipid prole
with treatment or its effect. We did not observe a universal
improvement in all measures of CV risk. This may reect
our study being underpowered or may suggest that the vas-
cular risk mediated by hepatitis C is mediated predominately
through vascular stiffness, which was reduced with viral
eradication, or through endothelial dysfunction in the case
of genotype 1 disease.
In this study, we comprehensively assessed vascular struc-
ture and function in patients with CHC and well-matched
controls and found CHC patients had genotype-specic dif-
ferences in endothelial dysfunction and subclinical athero-
sclerosis. Furthermore, successful eradication of the HCV
was associated with an improvement in arterial stiffness
and insulin resistance. Despite this, baseline measures of

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Pateria et al.

Table 3 Estimates of subclinical vascular disease of genotype 1 versus non-genotype 1

Genotype 1 Non-genotype 1 Mean difference

Variables (n = 33) (n = 17) P-value (95% CI)
AIx (%) 26.4 12 25.4 9.6 0.7 1 (6.18.2)
PWV (m/s) 8.2 1.8 7.9 1.5 0.5 0.3 (0.71.3)
FMD (%) 8.2 3.5 10.9 5.2 0.03 2.6 (0.15.1)
GTNMD (%) 19.2 7.3 21 9.5 0.4 1.7 (3.47)
FMD/GTNMD ratio 0.43 0.2 0.52 0.28 0.2 0.08 (0.060.2)
CIMT Lt (mm) 0.6 0.1 0.6 0.1 0.6 0.03 (0.050.09)
CIMT Rt (mm) 0.6 0.1 0.5 0.07 0.04 0.03 (0.0030.1)

Results reported as mean standard deviation and mean difference and 95% condence interval. Comparisons performed using independent sample
t-test and non-parametric tests (independent sample KruskalWallis and independent sample MannWhitney test). AIx, aortic augmentation index;
CIMT, carotid intima-media thickness; FMD, ow-mediated dilatation; GTNMD, glycerol trinitrate-mediated dilatation; PWV, pulse wave velocity.

Table 4 Subclinical vascular disease in the subject with HCV before and after antiviral treatment

Patients pre-Rx Patients post-Rx Mean difference

Variables (n = 12) (n = 12) P (95% CI)
AIx (%) 27.9 14 27.6 14.3 0.8 0.25 (5.76.2)
PWV (m/s) 7.8 1.5 7.2 1.7 0.07 0.57 (0.21.4)
FMD (%) 7.8 3.7 8.2 3.2 0.5 0.46 (1.42.3)
GTNMD (%) 20 6 21.2 7.2 0.2 1.18 (1.23.5)
FMD/GTNMD ratio 0.38 0.19 0.38 0.15 0.8 0.004 (0.060.007)
HOMA 2.1 1.2 1.9 0.8 0.5 0.18 (0.30.7)
ALT (IU/mL) 126 81 60 61 0.02 79.5 (27.2131.7)

Results reported as mean standard deviation and mean difference with 95% condence interval of the difference. Comparisons performed using
paired sample t-test and non-parametric test (related sample Wilcoxon signed-rank test). AIx, aortic augmentation index; FMD, ow-mediated di-
latation; GTNMD, glycerol trinitrate-mediated dilatation; HCV, hepatitis C virus; HOMA, homeostasis model of assessment; PWV, pulse wave velocity;
Rx, treatment.

Table 5 Subclinical vascular disease in the subject with HCV (responders) before and after antiviral treatment

Responders pre-Rx Responders post-Rx Mean difference

Variables (n = 7) (n = 7) P (95% CI)
AIx (%) 22.4 12.6 26.7 12.8 0.2 4.2 (412.6)
PWV (m/s) 7.4 1.1 6.5 0.6 0.04 0.84 (0.051.6)
FMD (%) 8.8 3.8 8.6 3.2 0.8 0.19 (2.52.9)
GTNMD (%) 23 5.7 23.5 6.5 0.6 0.48 (2.53.4)
FMD/GTNMD ratio 0.36 0.1 0.34 0.12 0.7 0.018 (0.10.2)
HOMA 2.3 1.2 1.8 0.8 0.02 0.57 (0.081.05)
ALT (IU/mL) 145 90 27 14 0.01 114.1 (31.7196.4)

Results reported as mean standard deviation and mean difference with 95% condence interval. Comparisons performed using paired sample t-test
and non-parametric test (related sample Wilcoxon signed-rank test). AIx, aortic augmentation index; FMD, ow-mediated dilatation; GTNMD,
glycerol trinitrate-mediated dilatation; HCV, hepatitis C virus; HOMA, homeostasis model of assessment; PWV, pulse wave velocity; Rx, treatment.

subclinical atherosclerosis and vascular risk factors were
similar in cases and control.
Studies examining the association between CHC infec-
tion and vascular disease are conicting.32,33 Hospital-
based and population-based studies have found both
positive and negative associations between CHC infection
and the prevalence and incidence of cardiovascular and
cerebrovascular morbidity and mortality.34 One potential
explanation for the disparate results may be related to
genotypic differences in vascular risk. Genotype 1 is associated
with more severe insulin resistance, whereas genotype
3 is associated with lower serum cholesterol levels.18,35
Concordantly, we found genotype 1 subjects had more severe
endothelial dysfunction and carotid intima thickening

68 2016 Royal Australasian College of Physicians

 Hepatitis C and cardiovascular risk

Table 6 Subclinical vascular disease in the subject with HCV (non-responders) before and after antiviral treatment

Variables Non-responders pre-Rx (n = 5) Non-responders post-Rx (n = 5) P Mean difference (95% CI)

AIx (%) 35.6 15 29 17.7 0.06 6.6 (0.713.9)
PWV (m/s) 8.5 1.9 8.3 2.4 0.8 0.2 (22.4)
FMD (%) 6.3 3.4 7.7 3.4 0.3 1.3 (2.35.1)
GTNMD (%) 16.5 4.4 18.5 7.8 0.3 2 (3.47.5)
FMD/GTNMD ratio 0.4 0.28 0.43 0.18 0.5 0.03 (0.10.9)
HOMA 1.8 1.4 2.2 0.7 0.4 0.36 (0.81.5)
ALT (IU/mL) 103 69 104 75 0.9 31 (19.581.5)

Results reported as mean standard deviation and mean difference with 95% condence interval. Comparisons performed using paired sample
t-test and non-parametric test (related sample Wilcoxon signed-rank test). ALT, alanine transaminase; AIx, aortic augmentation index; FMD,
ow-mediated dilatation; GTNMD, glycerol trinitrate-mediated dilatation; HCV, hepatitis C virus; HOMA, homeostasis model of assessment;
PWV, pulse wave velocity; Rx, treatment.

thannon-genotype 1 patients. Notably however, we did not
nd any difference in vascular assessments between CHC sub-
jects and healthy controls. This could have been due to the
presence of undiagnosed non-alcoholic fatty liver disease in
control subjects, which is associated with increased vascular
risk, or to type 2 error. Further studies are needed to ascertain
the reasons of increased subclinical vascular risk factors in ge-
notype 1 infection as compared with non-genotype 1
infection.
Interestingly, we found a strong association between vi-
ral clearance on arterial stiffness among CHC patients who
were treated as reected in reduction in PWV in responders
as compared with non-responders. Notably, other vascular
risk factors such as BMI and blood pressure did not alter
over the course of treatment, whereas viral mediated
alterations in serum ALT and insulin resistance both im-
proved. Other inammatory mediators of atherosclerosis
such as platelet-activating factor have also been found to
improve with successful clearance of CHC infection. Thus,
eradication of CHC infection may reduce the risk of future
atherosclerotic disease.
A strength of our study was the thorough assessment of
vascular risk, structure and function. Importantly, each mo-
dality of assessment reects different aspects of the athero-
sclerosis process. Thus, the combination of non-invasive
tests improves the prediction of CV morbidity to a greater
extent than each modality alone.20
The present study has some limitations. First, we cannot
exclude the possibility of the study being underpowered as
small number of patients underwent treatment. Second, at
the time of the present study, triple therapy with protease
inhibitors was not the standard of care for genotype 1 infec-
tion resulting in low rate of SVR. This decreases our ability
to analyse the improvement in vascular risk over time,
based on viral genotype.
Conclusion
We found among CHC patients that genotype 1 CHC has
evidence of increased subclinical vascular disease as suggested
by higher insulin resistance, endothelial dysfunction and
carotid thickness. Further studies examining the association
between vascular morbidity and CHC should take genotype
into account. Successful viral eradication in CHC may im-
prove insulin resistance and arterial stiffness, and further
studies are required to clarify this effect. Attention to vascular
risk factors should be considered among genotype 1 patients
who defer treatment or who do not successfully eradicate
the virus with treatment.

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