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Abstract
Introduction The density of hepatitis C virus (HCV) in plasma is heterogeneous but the factors that influence this are poorly understood. Evidence from animal models and cell culture suggest that low-density apolipoprotein B (apoB)-associated HCV lipoviral particles (LVP) are more infectious than high density HCV.
Aim We measured HCV LVP in patients with chronic hepatitis C genotype 1 (CHC-G1) and examined metabolic determinants of LVP load and clinical correlates.
Method Fasting lipid profiles and HOMA-IR (homeostasis model assessment of insulin resistance) were determined in 51 CHC-G1 patients. LVP and non-LVP viral load were quantitated by real-time RT-PCR of plasma at density d<1.07 g/ml and d>1.07 g/ml, respectively, following iodixanol density gradient ultracentrifugation. The LVP ratio was calculated using: LVP/(LVP+non-LVP)=LVP ratio.
Results The mean LVP ratio was 0.241 but varied 25-fold (0.029 to 0.74). When divided above and below the median value of 0.177, those with high LVP ratio had metabolic syndrome characteristics, higher liver stiffness and poorer early virological response rates (EVR) (see Abstract OP14 table 1).
| Low LVP ratio (n=25) | High LVP ratio (n=26) | p-value | |
| Waist circum (cm) | 85.7±11.1 | 92.7±12.2 | 0.037 |
| Liver Stiffness (KPa) | 9.53 | 19.54 | 0.001 |
| Triglycerides mmol/l | 1.08±0.46 | 1.62±0.15 | 0.015 |
| HDL cholesterol mmol/l | 1.36±0.33 | 1.11±0.25 | 0.015 |
| TG/HDL ratio | 0.84±0.4 | 1.62±1.1 | 0.003 |
| HOMA IR | 1.25±0.68 | 2.17±1.3 | 0.008 |
| EVR (%) | 31% | 26% | 0.037 |
High vs low HCV LVP ratio—clinical and metabolic characteristics
Univariate analysis showed LVP ratio correlated with HOMA-IR (p=.004) and triglyceride (TG)/HDL-C ratio (p=0.004), but not with apoB. In multivariate analysis HOMA-IR was the main determinant of LVP load (log10 IU/ml) (p=0.037; R2=16.6%) but TG/HDL-C ratio was the strongest predictor of LVP ratio (p=0.019; R2=24.4%). Higher LVP ratios were associated with non-response to antiviral therapy (p=0.037) and with greater liver stiffness (p=0.001). There was no association between total viral load and host clinical and metabolic parameters.
Conclusion Measurement of HCV LVP is of more direct clinical relevance than total HCV viral load. Insulin resistance and associated dyslipidaemia are the major determinants of low-density apoB-associated LVP in fasting plasma. This provides a novel mechanism to explain why insulin resistance is associated with more rapidly progressive liver disease and poorer treatment outcomes.