Hepatitis C Eradication With Direct-acting Anti-virals Reduces the Risk of Variceal Bleeding

Andrew M. Moon; Pamela K. Green; Don C. Rockey; Kristin Berry; George N. Ioannou


Aliment Pharmacol Ther. 2020;51(3):364-373. 

In This Article

Abstract and Introduction


Background: The real-world, long-term benefits of sustained virologic response (SVR) on the risk of variceal bleeding remain unclear.

Aim: To assess the association between DAA-induced SVR and post-treatment variceal bleeding

Methods: We identified patients who initiated DAA-only anti-viral treatments in the United States Veterans Affairs healthcare system from 2013 to 2015. We followed patients until 1 January 2019 for the development of gastro-oesophageal variceal bleeding defined by diagnostic codes. We used multivariable Cox proportional hazards regression to assess the association between SVR and development of variceal bleeding, adjusting for potential confounders.

Results: Among 33 582 DAA-treated patients, 549 (1.6%) developed variceal bleeding after treatment (mean follow-up 3.1 years). Compared to no SVR, SVR was associated with a significantly lower incidence of variceal bleeding among all patients (0.46 vs 1.26 per 100 patient-years, adjusted hazard ratio [AHR] 0.66, 95% CI 0.52–0.83), among patients with pre-treatment cirrhosis (1.55 vs 2.96 per 100 patient-years, AHR 0.73, 95% CI 0.57–0.93) and among patients without pre-treatment cirrhosis (0.07 vs 0.29 per 100 patient-years, AHR 0.33, 95% CI 0.17–0.65). The risk of variceal bleeding after treatment was lower in those who achieved SVR vs no SVR among patients who had non-bleeding varices (3.5 vs 4.9 per 100 patient-years) or bleeding varices (12.9 vs 16.4 per 100 patient-years) diagnosed before treatment, but these differences were not statistically significant in adjusted analyses.

Conclusion: DAA-induced SVR is independently associated with a lower risk of variceal bleeding during long-term follow-up in patients with and without pre-treatment cirrhosis. These findings demonstrate an important real-world benefit of DAA treatment.


Gastro-oesophageal varices are a common complication of cirrhosis that can lead to substantial morbidity and mortality.[1–3] Hepatitis C virus (HCV) infection is a leading cause of cirrhosis in the US.[4] With the advent of direct-acting anti-viral agents (DAA), HCV cure rates have increased dramatically and the majority of patients with HCV are now expected to achieve sustained virologic response (SVR).[5] Furthermore, SVR can now be achieved in the majority of patients with established cirrhosis, including patients with advanced or decompensated cirrhosis, such as those with a history of ascites, encephalopathy, varices and variceal bleeding.

Since all available randomised, placebo-controlled trials of anti-viral treatment have very short follow-up, some have argued that the long-term clinical benefits of anti-viral treatment and sustained virologic response (SVR) have not yet been demonstrated.[6] As such, some insurance providers and states require that significant fibrosis be present before covering HCV anti-viral treatment.[7] This may lead to inappropriate withholding or delay in HCV treatment in patients without cirrhosis or portal hypertension. It is therefore imperative to evaluate the long-term benefits of DAA-induced SVR among patients with and without significant fibrosis in adequately powered and designed observational studies. DAAs have now led to eradication of HCV in unprecedented numbers of patients with cirrhosis and decompensated cirrhosis and we now have long-term follow-up data, enabling us to address these questions.[8]

We hypothesised that HCV eradication may lead to a reduced risk of variceal bleeding both in patients with and those without pre-treatment cirrhosis during long-term follow-up. In patients without pre-treatment cirrhosis, HCV eradication may reduce the risk of progressing to cirrhosis or developing portal hypertension, thereby reducing the risk of developing varices and variceal bleeding. HCV eradication in patients with cirrhosis may stop fibrosis progression or even cause fibrosis regression, leading to improved portal hypertension and reduced risk of variceal bleeding.[9] Finally, HCV eradication might reduce the risk of variceal bleeding even in the highest risk patients, that is, those who with known varices or variceal bleeding prior to SVR.

In this study, we used Veterans Affairs Healthcare System (VAHS) data to examine the associations between DAA-induced HCV eradication and the risk of variceal bleeding, in clinically relevant subgroups such as the ones outlined above. Furthermore, we aimed to investigate other characteristics that are associated with variceal bleeding in patients who received anti-viral treatment and achieved SVR.