The Effects of Sustained Virological Response to Direct-Acting Anti-Viral Therapy on the Risk of Extrahepatic Manifestations of Hepatitis C Infection

Hashem B. El-Serag; Israel C. Christie; Amy Puenpatom; Diana Castillo; Fasiha Kanwal; Jennifer R. Kramer


Aliment Pharmacol Ther. 2019;49(11):1442-1447. 

In This Article

Abstract and Introduction


Background: Direct-acting anti-viral (DAA) therapy may have a beneficial role in extrahepatic manifestations of hepatitis C virus (HCV) infection. However, the available data are limited.

Aim: To examine the effects of DAA treatment on the risk of several extrahepatic manifestations of HCV.

Methods: We conducted a retrospective cohort study of patients from the US Department of Veterans Affairs Corporate Data Warehouse who had a positive HCV RNA test and received first course of DAAs between 2012 and 2016. We calculated incidence rates by sustained virological response (SVR) status for six extrahepatic manifestations, and effect of SVR on these conditions was evaluated in adjusted Cox regression models.

Results: Of the 45 260 patients treated with DAA with mean follow-up of 2.01 years, 41 711 (92.2%) experienced SVR. Incidence rates ranged from 0.17/1000 PY for porphyria cutanea tarda to 21.04/1000 PY for diabetes in the SVR group and 0.51/1000 PY for porphyria cutanea tarda to 23.11/1000 PY for diabetes in the no SVR group. The risk was reduced with SVR for mixed cryoglobulinaemia (adjusted HR (aHR) = 0.23; 95% CI 0.10-0.56), glomerulonephritis (aHR = 0.61; 95% CI 0.41-0.90) and lichen planus (aHR = 0.46; 95% CI 0.30-0.70), but not for non-Hodgkin's lymphoma (aHR = 0.86; 95% CI 0.52-1.43) or diabetes (aHR = 0.98; 95% CI 0.81-1.19). Non significant risk reduction was seen for porphyria cutanea tarda (aHR = 0.33; 95% CI 0.11-1.03).

Conclusions: Successful DAA treatment resulting in SVR was associated with significant reductions in the risk of mixed cryoglobulinaemia, glomerulonephritis, lichen planus and possibly porphyria cutanea tarda, but not non-Hodgkin's lymphoma or diabetes.


Hepatitis C virus (HCV) infection affects approximately 185 million individuals around the world. HCV infection leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Chronic HCV infection is also associated with several extrahepatic manifestations, including essential mixed cryoglobulinaemia, some subtypes of B-cell non-Hodgkin lymphoma (NHL), membranoproliferative glomerulonephritis, porphyria cutanea tarda and lichen planus.[1] There is also consistent epidemiological evidence supporting the association of chronic HCV infection with type-2 diabetes mellitus. These conditions have been associated with added morbidity and cost.[2]

HCV anti-viral therapy with attainment of sustained virological response (SVR), which is virological cure, has hepatic benefits, such as normalising liver enzymes, halting the progression of liver disease and reducing the risk of hepatocellular carcinoma. Studies in the interferon-based treatment era showed that SVR was also associated with a reduced risk of mixed cryoglobulinaemia; glomerulonephritis; porphyria cutanea tarda; NHL;[3] and, possibly, diabetes mellitus.[4–7]

With the introduction and increased use of direct-acting anti-virals (DAA) that have much better efficacy in achieving SVR than interferon-containing regimens, we expect a reduction in the risk of some extrahepatic manifestations of chronic HCV infection. These benefits could be important enough to be included in the cost-benefit analyses for overall HCV treatment. However, apart from case reports and case series, there only few systematic studies on the effect of DAA-related SVR on extrahepatic manifestations.[8] We, therefore, conducted the largest to-date retrospective cohort study of HCV-infected patients to evaluate the effect of DAA-induced SVR on the risk of extrahepatic manifestations.