Impact of Hepatitis C Virus Treatment on the Risk of Non-hepatic Cancers Among Hepatitis C Virus-infected Patients in the US

Wei Wang; Vincent Lo Re III; Yi Guo; Hong Xiao; Joshua Brown; Haesuk Park


Aliment Pharmacol Ther. 2020;52(10):1592-1602. 

In This Article


This retrospective cohort study provides real-world evidence of HCV treatment effects on the risk of non-hepatic cancers among US HCV-infected patients. We found that compared to untreated HCV-infected patients, those who received anti-viral therapy had an 11% decreased risk of developing incident non-hepatic cancers. We also found the completion of a minimally effective HCV treatment was associated with slightly higher non-hepatic cancer risk reduction compared to those who initiated the treatment. Among patients with cirrhosis, we found a significant reduction in the risk of non-hepatic cancer only when patients completed a minimally effective treatment.

Although the impact of HCV treatment on extrahepatic manifestations has been studied in recent years, a majority of this evidence focused on type 2 diabetes, renal impairment and cardiovascular diseases.[9,11,13,15,19,37] However, there is little evidence available examining the impact of anti-HCV treatment on risk of non-hepatic cancer. To date, three studies evaluated the association between HCV treatment and rate of haematologic malignancies among HCV-infected veterans.[19,22,38] Evidence indicated that patients who achieved a sustained virologic response with interferon-based anti-viral therapy had a significantly decreased risk of lymphoma of 30%-36%. However, similar to our study, this association was not observed with DAA treatment, due to the short follow-up time for DAA-treated patients (<3 years). Given the growing body of evidence that indicates that chronic HCV infection increases the risk of many non-hepatic cancers,[14,20,26] particularly lung, head/neck and pancreatic cancer, it is important to understand if HCV treatment reduces the incidence of these malignancies among chronically infected HCV patients. In our study, we found that patients who received HCV treatment had a significantly decreased risk of overall non-hepatic cancers, adjusting for patients' age, gender, comorbidities and cancer-related medication uses. However, in the analyses of secondary outcomes, the association was only observed with lung cancer and pancreatic cancer, probably due to decreased power to detect differences between those treated vs not. Future studies with larger sample sizes and longer follow-up may provide more evidence about the long-term benefit of HCV treatment on sub-cancer types.

Another important finding in our study was that patients who received eight to 16 weeks of a minimally effective HCV treatment had a slightly greater reduction in the risk of non-hepatic cancers than patients who initiated the HCV treatment (13% vs 11%). This finding was consistent with previous studies suggesting that patients who achieved SVR through interferon-based anti-viral therapy had reduced risks of developing EHMs compared to patients who had no SVR.[11,19,37] Due to the lack of SVR in our dataset, we used an eight to 16 week treatment duration as a proxy for treatment effectiveness and SVR achievement.[9,10] Nonetheless, this study suggests the importance of completing a minimally effective HCV treatment.

In the subgroup analysis, that association was only observed with dual therapy and not with triple therapy or all-oral therapy. One explanation for this discrepancy in the results is that the short follow-up time for patients in the triple and all-oral therapy groups was insufficient to detect an association.[39] To ascertain comparable follow-up times for treated HCV patients with triple or all-oral therapy compared to untreated HCV patients, we did a subgroup analysis with the truncated datasets from 2011–2016 and 2013–2016. When we minimised the unbalanced follow-up time between treated and untreated patients by using parallel control groups (untreated patients), we found a 24% decreased risk of cancer for patients with minimum effective triple therapy, but not in patients with all-oral DAA therapy. Studies with a longer follow-up will be needed to understand fully the impact of all-oral DAA therapy on cancer risks.

Our study has several potential limitations. First, our study lacks laboratory results (eg SVR). Although we used treatment duration as a proxy, there is still potential misclassification for treatment effectiveness. Second, we had a relatively short follow-up and small sample size for the patients with all-oral DAA therapy (late 2013–2016), which did not allow us to fully explore the effect of DAAs.[39] Third, patient mortality status is not fully captured in the claims database. Potential bias due to competing risk of death may exist. Lastly, although we adjusted for many confounders known to be associated with HCV infection, HCV treatment and cancers (eg hormone therapy for breast cancer, PPIs for gastrointestinal cancer and statins reducing cancer risks) there may have been unmeasured confounders (eg race, fibrosis severity) that may have affected our results.

Our study has several notable strengths. First, this is the first nationally representative population-based cohort study to examine the association between HCV treatment and the risk of non-hepatic cancers. We conducted several subgroup and sensitivity analyses to assess the robustness of our results. Second, by employing time-varying Cox proportional-hazards models, a methodological strength, we were able to account for the changes that occurred over time during the study period including comorbidities and medication use (eg statins, PPI and hormone therapy). Thus, the methods strengthen our interpretation of the associations of these covariates in the development of non-hepatic cancers in patients with chronic HCV infection.

In conclusion, our results investigating outcomes from a large cohort provide evidence that HCV treatment is associated with a decreased risk of developing non-hepatic cancers in patients who are chronically infected with HCV. Although the association is not confirmed for all-oral DAA therapies or sub-cancer types other than lung and pancreatic cancers, these findings highlight that treating HCV can help to change the extrahepatic burden of non-hepatic cancers associated with HCV. Additional studies with longer follow-up are needed to further explore the impact of HCV treatment on sub-cancer types for HCV patients receiving all-oral DAA therapy.