Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy

Abstract

Direct-acting antivirals (DAAs) efficiently eradicate the hepatitis C virus (HCV). Low-density lipoprotein (LDL) levels increase rapidly upon DAA treatment. Proprotein convertase subtilisin/kexin 9 (PCSK9) induces degradation of the hepatic LDL receptor and thereby elevates serum LDL. The aim of this study was to determine serum PCSK9 concentrations during and after DAA therapy to identify associations with LDL levels. Serum PCSK9 was increased in 82 chronic HCV-infected patients compared to 55 patients not infected with HCV. Serum PCSK9 was low in HCV patients with liver cirrhosis, but patients with HCV-induced liver cirrhosis still exhibited higher serum PCSK9 than patients with non-viral liver cirrhosis. Serum PCSK9 correlated with measures of liver injury and inflammation in cirrhotic HCV patients. In patients without liver cirrhosis, a positive association of serum PCSK9 with viral load existed. Serum PCSK9 was not different between viral genotypes. Serum PCSK9 did not correlate with LDL levels in HCV patients irrespective of cirrhotic status. Serum PCSK9 was reduced, and LDL was increased at four weeks after DAA therapy start in non-cirrhotic HCV patients. Serum PCSK9 and LDL did not changeupon DAA treatment in the cirrhotic group. The rapid decline of PCSK9 after the start of DAA therapy in conjunction with raised LDL levels in non-cirrhotic HCV patients shows that these changes are not functionally related.

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

“…Most studies used commercially available ELISAs to determine systemic PCSK9 levels, and could not discriminate between the active and less active isoforms. In contrast to the abovementioned report, total serum PCSK9 concentrations declined 4 weeks after therapy initiation and remained low up to 12 weeks post-treatment [129]. Reduced circulating PCSK9 levels were also detected in a cohort of 48 HCV-infected patients after successful DAA therapy [126] (Figure 2), while posttreatment plasma PCSK9 concentrations were induced in 27 HCV patients who achieved sustained virologic response [121].…”

“…These findings implied HCV genotypedependent effects on plasma PCSK9 levels, but while other studies confirmed HCV-induced PCSK9 serum levels, a link to HCV genotypes was not described [126][127][128][129]. HCV infection also elevated serum PCSK9 levels in noncirrhosis and cirrhosis patients as well as HIVinfected patients [129,130]. On the other hand, LDL levels did not correlate with plasma PCSK9 concentrations in chronic HCV [125,127,129].…”

“…Six different genotypes of HCV exist, and in another study, patients with the major HCV genotype 1 displayed the highest PCSK9 levels, followed by noninfected controls and patients carrying the second most common HCV genotype 3 [127]. These findings implied HCV genotypedependent effects on plasma PCSK9 levels, but while other studies confirmed HCV-induced PCSK9 serum levels, a link to HCV genotypes was not described [126][127][128][129]. HCV infection also elevated serum PCSK9 levels in noncirrhosis and cirrhosis patients as well as HIVinfected patients [129,130].…”

“…HCV infection also elevated serum PCSK9 levels in noncirrhosis and cirrhosis patients as well as HIVinfected patients [129,130]. On the other hand, LDL levels did not correlate with plasma PCSK9 concentrations in chronic HCV [125,127,129]. Taken together, HCV infection is associated with high PCSK9 and low circulating LDL levels, suggesting that the functional relationship between the LDL-R and PCSK9 is disturbed (Figure 2).…”

“…Increased systemic PCSK9 levels were identified in patients with higher viral load [125,127,129]. HCV genotype-related associations may exist between plasma PCSK9 levels and the amount of HCV associated with lipoproteins in 'lipoviral' particles (which may also resemble infectious HCV particles) in genotype 3, but not genotype 1 infected patients [127].…”