Direct-Acting Antiviral Therapy and a Reduction in Extrahepatic Manifestations of HCV

hepatitis C virus, HCV
hepatitis C virus, HCV
Researchers reviewed the effects of direct-acting antiviral therapies on the extrahepatic manifestations of HCV.

Studies have demonstrated an association between direct-acting antiviral therapy and a reduction in both the incidence and severity of extrahepatic manifestations of hepatitis C virus (HCV) infection, according to a review article published in the New England Journal of Medicine.

HCV is recognized as the virus most often associated with extrahepatic manifestations, including mixed cryoglobulinemic vasculitis, B-cell non-Hodgkin’s lymphoma (B-NHL), cardiovascular diseases, type 2 diabetes, and renal dysfunction.

It has been five years since approval of the first interferon-alfa–free direct-acting antiviral agents in combination, and widespread access to direct-acting antiviral therapy is now available in most developed countries. Therefore, researchers now have sufficient follow-up data to analyze their effects on most of these extrahepatic manifestations.

In view of well-described pathophysiological processes, the researchers believe it is reasonable to expect a rapid decrease in cases of HCV-related mixed cryoglobulinemic vasculitis. This should also be true, although with a less rapid decrease, for cardiometabolic manifestations.

For B-NHL, such a benefit may take more time because underlying mechanisms include HCV antigen–independent B-cell lymphoproliferation. Thus, patients who have a sustained virologic response to direct-acting antiviral therapy but still have cryoglobulinemia should be followed for a longer period of time, as they appear to be at high risk for the development of B-NHL.

For chronic kidney disease, with a low absolute risk mostly related to sequelae, only stabilization of renal function can be expected in most patients.

The authors concluded, “It seems logical to argue that if millions of chronically infected patients have been cured with the introduction of direct-acting antiviral therapy, extrahepatic manifestations will also disappear in several hundred thousand patients.” They added, “Although HCV eradication is still far from a reality in developing countries, physicians should be aware of the benefits of these agents in improving hepatic and extrahepatic outcomes.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Cacoub P, Saadoun D. Extrahepatic manifestations of chronic HCV infection. N Engl J Med. 2021;384(11):1038-52. doi: 10.1056/NEJMra2033539