A Review on Extrahepatic Manifestations of Chronic Hepatitis C Virus Infection and the Impact of Direct-Acting Antiviral Therapy

Abstract

Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin’s lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

“…DAA regimens are now the drug of choice for HCV-associated MCV. The combination of PEG-IFNα with RBV has been abandoned for their side-effects, including the immune-stimulatory effects[ 84 ]. With DAA therapy, the rate of SVR after 12 months of therapy was the same for HCV patients with and without mixed cryoglobulinemia (MC).…”

“…HCV infection also increases the risk of chronic kidney disease (CKD). The association between chronic HCV infection and CKD is more significant with high HCV viral load and HCV genotype 2[ 84 , 101 , 102 ].…”

“…In addition, HCV infected patients may have an increased risk of insulin resistance, which develops during the inflammation process and exacerbates renal damage[ 105 - 108 ]. In very few cases, viral NS3 was found in the glomerular deposits, capillary walls, and the mesangium[ 84 ].…”

“…HCV replicates in the pancreatic β-cells, causing impairment of their function involved in glucose metabolism. In addition, HCV infection can indirectly induce IR due to oxidative stress, liver steatosis, release of inflammatory cytokines such as TNF-α, interleukin (IL)-1, IL-6, and leptin, phosphorylation of the insulin-1 receptor substrate and protein kinase B, and up-regulation of gluconeogenic genes such as glucose 6 phosphatase and phosphoenolpyruvate carboxy kinase[ 84 , 126 , 127 ].…”

“…This may be due to the presence of the virus in the human salivary glands, where it can replicate. It is characterized by high RF titers, higher-frequency cryoglobulins, low antinuclear antibodies (ANA), hypocomplementemia, and a lower frequency of anti-Ro/SSA and anti-La/SSB autoantibodies[ 84 ]. Myalgia is a common finding in HCV infected patients, and it occurs in about 15% of cases.…”