The Benefits of Hepatitis C Virus Cure: Every Rose Has Thorns

D. Salmon; M. U. Mondelli; M. Maticic; J. E. Arends


J Viral Hepat. 2018;25(4):320-328. 

In This Article

Extrahepatic Benefits of HCV Cure

Extrahepatic manifestations are common in patients with chronic HCV infection. They include membranoproliferative glomerulonephritis (usually in a context of type II mixed cryoglobulinaemia), cutaneous disorders like porphyria cutanea tarda and lichen planus, neurologic abnormalities like fatigue or depression, atherosclerosis and type 2 diabetes.[40] These extrahepatic manifestations also increase mortality.[41]

It is thought that these extrahepatic disorders are caused by ongoing inflammation and immune activation due to continuous viral replication.[41] It is therefore reasonable to expect that eradication of the virus will lead to their disappearance. Indeed, in a large nationwide cohort from Taiwan, treatment with P/R was associated with improved extrahepatic outcomes.[42]

The introduction of DAAs has also impacted the extrahepatic symptoms of the disease. The first evidence was a case report concerning a patient with HCV–1–related cryoglobulinaemic membranoproliferative glomerulonephritis, a severe nephritic syndrome and rapidly progressive renal failure.[43] She was treated with a combination of peg–IFN, ribavirin and the first–generation NS3/4a protease inhibitor telaprevir, which resulted in HCV eradication and complete resolution of her acute renal failure. This was followed by a case series of 5 patients with F3F4 fibrosis and mixed cryoglobulinaemia who also received triple therapy with peg–IFN, ribavirin and boceprevir, telaprevir or sofosbuvir.[44] Although all were cured of HCV infection, clearance of plasma cryoglobulin seemed to come after viral load clearance.

In the recently published HCV–CryoVas study, 27 chronic HCV patients with clinically active vasculitis were treated with DAAs (16 with all–oral DAAs).[45] Complete or partial clinical responses were noted in 26 patients (96%), along with a complete/partial immunological response in 17 patients (90%). The durability of the clinical response (ie resolution or improvement of mixed cryoglobulinaemia syndrome was demonstrated by Gragnani et al in their study of 424 HCV–infected Caucasian patients with a mean post–treatment follow–up of 92.5 months after peg–IFN–alpha/RBV therapy.[46] Arthralgia occurs in around 50% of patients with cryoglobulinaemia and is reported to resolve after DAA–induced viral cure.[47]

Hepatitis C virus has been shown to cause kidney dysfunction through direct invasion of the renal parenchyma. Several studies have shown that treatment with DAAs like grazoprevir/elbasvir and paritaprevir/ritonavir/ombitasvir is safe and well tolerated in patients with advanced kidney disease. Moreover, improvements in renal function have been reported after HCV cure.[48]

Another extrahepatic manifestation of HCV infection is type 2 diabetes.[49] The proposed mechanisms involve direct interference of HCV with insulin signalling, resulting in metabolic disturbances, impaired glucose tolerance and hepatic steatosis.[41,50] The first evidence of improved insulin sensitivity after SVR came from an Australian study demonstrating decreased HOMA–IR values.[51] Moreover, a retrospective analysis of a US Veterans cohort, based on Cox proportional hazards regression analysis, showed that patients achieving SVR had a significantly lower risk of developing DM2.[52]

Fatigue is another major problem for chronic HCV patients. P/R therapy has been shown to improve quality of life (QoL) and fatigue,[53,54] irrespective of the severity of liver fibrosis.[55] There are few well–controlled randomized placebo–controlled trials of DAA therapy focusing on fatigue and QoL. The ASTRAL–1 study evaluated the efficacy of sofosbuvir/velpatasvir in a total of 740 HCV genotype 1–, 2–, 4–, 5– and 6–infected patients.[56] Four patient–related outcomes (PROs) were collected, namely general (SF–36) and chronic liver disease–specific QoL (CLDQ–HCV), fatigue (FACIT–F) and work productivity (Work Productivity Activity Index) with only completed PRO items being used for analysis. PROs were similar between SOF/VEL– and placebo–treated patients at baseline. After 12 weeks of post–treatment follow–up, SOF/VEL–treated patients showed a significant improvement in PRO scores compared to placebo–treated patients, who remained at baseline.

Finally, numerous case reports have shown an improvement in symptoms after successful DAA therapy, including remission of erosive lichen planus lesions on the lip,[57] reversal of bilateral anterior optic ischaemic neuropathy[58] and a haematologic response in a patient with splenic marginal zone lymphoma.[59]