Hepatitis C Virus Infection and Non-hepatocellular Malignancies in the DAA Era

A Systematic Review and Meta-analysis

Mario Masarone; Marcello Persico


Liver International. 2019;39(7):1292-1306. 

In This Article

Abstract and Introduction


Background and Aims: Direct antiviral agents have greatly improved therapeutic options for chronic hepatitis C. Indeed, former "difficult-to-treat" patients can now be treated and can achieve sustained response. Hepatitis C virus (HCV) is associated with hepatocellular carcinoma and with B-cell non-Hodgkin lymphoma (B-NHL). Other malignancies have been reported to be associated with HCV infection albeit with various grades of evidence. Antineoplastic treatment is often reduced or suspended in HCV-positive cancer patients to avoid "HCV reactivation." In this setting, antiviral therapy combined with antineoplastic protocols may improve the outcome. For this reason, we conducted a systematic review and a meta-analysis to update the association between HCV infection and non-hepatocellular malignancies, and to shed light on the effects exerted by antiviral treatment on the natural history of oncological diseases.

Methods: Relevant studies were identified by searching PUBMED, EMBASE and MEDLINE up to 1 August 2018. Pooled risk estimates were calculated with random-effects models according to PRISMA guidelines.

Results: A total of 58 studies were included in the analysis: 27 studies of the association between HCV and B-NHL(OR 3.36; 95% CI 2.40-4.72;P < 0.00001);13 studies of the association between sustained virological response and progression-free survival (PFS) in B-NHL patients(OR 9.34; 95% CI 4.90-17.79; P < 0.00001); 13 studies of the association between HCV and intrahepatic-cholangio-carcinoma (OR 3.95;95% CI 2.25-6.94; P < 0.00001); and 5 studies of the association between HCV infection and pancreatic adeno-carcinoma(OR 1.60; 95% CI:1.25-2.04; P = 0.0002).

Conclusions: This study updates the strong association between B-NHL and HCV infection, confirms the association between HCV and non-hepatocellular tumours, and demonstrates a very strong association between viral eradication and a better outcome of HCV-positive B-NHL.


Many therapeutic protocols have been developed for chronic hepatitis C in the last two decades, the efficacy of which has increased exponentially over time. From interferon-based regimens to the so-called "interferon-free" therapies based on direct antiviral agents (DAAs), this resulted in sustained virologic response (SVR) rates exceeding 95%.[1] These agents have a very high safety profile, also in the previously so-called "difficult-to-treat" patients, that is, patients with liver cirrhosis or hepatocellular carcinoma (HCC), patients awaiting liver transplantation, and patients with extrahepatic manifestations. Currently, there is a worldwide trend to remove prescription barriers to antiviral treatment, thereby giving all patients access to treatment.[1,2]

It is well recognized that hepatitis C virus (HCV) has oncogenic potential.[3,4] In fact, HCV infection is one of the most common causes of HCC,[5] but it has also been associated, albeit with various grades of significance, with non-hepatocellular tumours.[6,7] This association has been confirmed at pathophysiological level in onco-hematologic malignancy B-cell non-Hodgkin lymphoma (B-NHL).[8] Consequently, antiviral therapy for HCV has been proposed as first-line therapy for low grade malignant B-NHL.[9,10] Moreover, an SVR can lead to a better progression-free survival (PFS) in intermediate and high-grade B-NHL.[11–14] Finally, an epidemiological association has been reported between HCV and other types of solid tumours.[15,16]

We conducted a systematic review and meta-analysis in the attempt to update information about the association between HCV and non-hepatocellular malignancies and to evaluate the effects of viral eradication on the natural history of these malignancies.