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

Disclosures

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

In This Article

Discussion

Variceal bleeding is a life-threatening complication of cirrhosis. In this large cohort of 33 582 US Veterans who underwent DAA treatment and were followed for a mean of 3.1 years after treatment, we extend our knowledge of the associations between SVR and variceal bleeding in several ways. First, we have shown that DAA-induced SVR was clearly associated with a reduced risk of variceal bleeding both among patients with established cirrhosis and among those without cirrhosis prior to anti-viral treatment. Second, our results suggest that even among patients with a prior history of varices or variceal bleeding, which are the highest risk groups, DAA-induced SVR was associated with a lower risk of variceal bleeding (although this difference did not reach statistical significance in our multivariable models). Finally, we found that although in cirrhotic patients SVR reduces the risk of variceal bleeding, a substantial residual risk remains and several important predictors of variceal bleeding are evident. Taken together, our results point to a beneficial effect of DAA-induced SVR with regard to the potentially deadly complication of variceal bleeding and add to the growing literature demonstrating the clinical benefits of HCV eradication with DAAs.[32–34]

Our results demonstrate that DAAs reduced the risk of variceal haemorrhage among patients without cirrhosis or pre-treatment varices, underscoring the importance of "early" HCV treatment. Given the nature of this study, although we do not know the histological stage of fibrosis of the cohort, natural history studies demonstrate that, among all-comers with untreated HCV, cirrhosis will develop in approximately 15% over 5 years[35] and, among patients with compensated cirrhosis, varices will occur in 7% annually.[36] Many patients in our cohort were followed for several years during which cirrhosis or portal hypertension could have developed. However, it is possible that some of the patients without diagnosed cirrhosis in our cohort had undetected significant fibrosis or portal hypertension. Nonetheless, these data still suggest the likelihood of variceal haemorrhage can be substantially reduced with early treatment of HCV—in our study, successful treatment of HCV prior to the development of cirrhosis nearly eliminated the risk of future variceal bleeding (incidence 0.07 per 100 person-years). These findings provide further support for calls to expand of HCV screening[37] and for treatment of all patients with HCV regardless of fibrosis stage.[38]

We have also shown that SVR is associated with reduction in the risk of variceal bleeding among patients with cirrhosis, whether varices are present or not, and that the absolute reduction in risk is greater than among patients without cirrhosis. This may be due to fibrosis reversion after successful DAA therapy, resulting in reduced portal pressures. Biologic plausibility for this is provided by studies showing that HCV treatment is associated with fibrosis reversion,[39–42] improvement in portal hypertension,[43–46] and decreased the risk of oesophageal varices in compensated cirrhosis.[47] Not surprisingly, in our multivariable model low platelet count, an indirect measure of portal hypertension, and other sequelae of portal hypertension (eg ascites, SBP) were associated with an increased risk of variceal bleeding.

Despite SVR, certain patients developed variceal bleeding, including 4.8% of patients with pre-treatment cirrhosis. These data suggest that while some patients may have an improvement in portal hypertension (we speculate as a result of reduced fibrosis) with a concomitant reduction in the risk of variceal bleeding, this does not occur in all patients. This finding has several implications. First, the data suggest that there are likely highly specific biologic responses to SVR—leading to a reduction in portal pressure in some, but not all, patients. Further study to better understand these biologic responses, and the predictors of them, will be essential. Our multivariable model identified some known predictors of variceal bleeding including the history of varices, other decompensation events and low platelet count. NSBB use was also associated with an increased risk of variceal bleeding, as expected since these medications are preferentially used in patients with high-risk varices (eg large, red wale signs). Lastly, black race was associated with a lower risk of variceal bleeding, which has previously been reported and deserves more study.[48] Second, it suggests that it is important to continue endoscopic surveillance for varices and prophylaxis for variceal bleeding if indicated following SVR. This was particularly true among patients with pre-treatment varices. Conversely, it may be that cirrhosis patients without varices who achieve SVR may be able to safely receive screening endoscopies less frequently than every 2–3 years, as is currently recommended by the American Association for the Study of Liver Diseases (AASLD).[49] Future prospective and cost-effectiveness studies could help answer these questions.

This study is strengthened by its large, geographically distributed cohort of HCV patients with prolonged follow-up after treatment with DAAs. The inclusion of data from a national, comprehensive health system decreases the potential for selection bias. However, this study has some potential limitations. First, all patients were derived from a single, national healthcare system with fairly uniform anti-viral treatment practices and guidelines across its facilities. Second, data were derived from the national VA healthcare system where male sex predominates, which may limit generalisability to other populations. Third, since this is by necessity an observational study, we cannot exclude the possibility that residual confounding may have contributed to the associations we observed between SVR and variceal haemorrhage. However, the associations persisted after careful adjustment for > 20 baseline characteristics known or suspected to be associated with SVR and variceal bleeding. Fourth, as mentioned above, there is a possibility of information bias via misclassification of exposures (eg classifying those with cirrhosis as noncirrhotic) or outcomes (eg variceal bleeding events).

In conclusion, these findings demonstrate that successful treatment of HCV with DAAs is associated with a reduced risk of subsequent variceal bleeding. This provides further evidence supporting the real-world benefits of DAAs in patients with and without cirrhosis and emphasises the importance of early identification and treatment of HCV-infected patients.

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