Mini review
Hepatitis C virus and lipids in the era of direct acting antivirals (DAAs)

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Summary

The six different HCV-genotypes have marked differences in response to therapy with pegylated interferon-α and ribavirin. The introduction of the direct acting antiviral (DAA) protease inhibitors, telaprevir and boceprevir in combination with pegylated interferon-α and ribavirin has become the new standard of care for genotype 1 infection. Several host factors associated with response to pegylated interferon-α and ribavirin are not as important in predicting response to triple therapy, and yet low-density lipoprotein cholesterol (LDLC) and statin use remain important associations of outcome with DAAs. This review focuses on the clinical associations between lipids and treatment response to interferon based antiviral treatments. We consider how understanding the interactions of HCV and host lipid metabolism remains relevant in the era of DAAs for genotype 1 infection and for treatment of non-genotype 1 chronic hepatitis C.

Section snippets

Factors associated with response to peginterferon-α + ribavirin and triple therapy

Host and viral factors known to be associated with response to PR alone and combination triple therapy with boceprevir and telaprevir in treatment naïve and experienced patients with HCV-genotype 1 infection are summarised in the table. Data on factors associated with SVR in response to boceprevir and telaprevir has been reported from post hoc analyses of the landmark phase 3 trials in treatment naïve (Sprint-2 [9], Advance [10], Illuminate [11]) and PR treatment experienced (Respond-2 [12],

Why is low-density lipoprotein cholesterol favourable to treatment response?

The continued association of LDLC and treatment outcome to triple therapy (PR + DAAs) implies that factors involved in regulation of plasma LDLC concentrations affect the interaction of HCV and the host. These interactions may occur at the stages of entry, replication, assembly or remodelling in the vascular compartment. The major steps of the HCV lifecycle have been unravelled by experiments utilising Japanese Fulminant Hepatitis virus 1 (JFH1), a genotype 2a strain of HCV that is able to

Hepatitis C virus association with lipoproteins in the vascular compartment

HCV particles in the circulation are associated with lipoproteins. Association with lipoproteins of varying triglyceride and cholesterol composition determines the density distribution of HCV RNA in plasma [41]. HCVcc particles of low-density have higher specific infectivity in vitro [31], [42]. Low-density HCV particles associated with apoB containing lipoproteins (VLDL, IDL, LDL) have been termed ‘lipoviral particles’ (LVP) [43], [44]. We have shown that levels of LVP (HCV RNA at density < 1.07 

Hepatitis C virus-genotype specific differences in lipid metabolism

It is apparent that there are HCV-genotype specific differences in lipid and metabolic phenotypes between HCV-genotypes 1 and 3. HCV-genotype 3 in particular is associated with low LDLC, apoB and hepatic steatosis, thought to be due to viral inhibition of microsomal triglyceride transfer protein (MTP) [53]. Our data supports reduced endogenous cholesterol synthesis in both HCV-genotype 1 and genotype 3. However, in HCV-genotype 3 there is evidence of selective preservation of desmosterol, and

Clinical studies of lipid modulation in hepatitis C virus

A number of retrospective and prospective studies have shown an association of increased LDLC and favourable response to PR therapy [8], [58]. In HCV-genotype 1 infection, statins have shown limited antiviral efficacy when used as monotherapy [59], [60], [61], [62], [63], although in small numbers appear well tolerated [64]. Statin use in combination with PR may improve outcome. In a retrospective study of US veterans [65], statin use in diabetics and non diabetics was associated with increased

Conclusions

The intimate interaction of HCV and lipid pathways continues to provide possible therapeutic avenues in the post DAA era, because of the association of lipids with interferon sensitivity. Remarkably LDLC and statin use are associated with favourable outcomes in the phase 3 DAA trials. Further data of factors associated with non-response to DAAs in ‘real world’ use needs to be reported. A mass of in vitro data emphasises the importance of lipid metabolism to the viral lifecycle, and there are

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Funding: Funding supported by the Medical Research Council (G0502028) and the Newcastle upon Tyne Healthcare Charity.

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