The ultimate goal of follow-up in patients who have achieved SVR is prolonged life expectancy with improved quality of life.28 To achieve this goal, it remains unclear how patients should be treated and how long they should be followed after SVR. In addition, many studies have focused only on HCC development,9–15 and few studies have prospectively observed the development of non-HCC malignancies, i.e., other organ malignancies. To our knowledge, only a few reports have been published on cohorts of patients who achieved SVR with interferon.22 Furthermore, there are no prospective studies that have meticulously observed overall survival in patients who achieved SVR. Therefore, we prospectively and in detail observed the occurrence of all malignancies and overall prognosis in all patients who achieved SVR.
The risk of other organ malignancies, unlike HCC, is difficult to predict due to the systemic nature of the disease. However, careful follow-up of patients with SVR makes it possible to diagnose the development of malignancies of other organs at an early stage. In our cohort, we observed a wide range of carcinogenesis, including stomach, colorectal, lung, prostate, breast, and uterus, and the overall 5-year survival rate for non-HCC was 84.2%, suggesting the importance of early detection.
As for HCC carcinogenesis, a history of HCC was identified as a risk factor, and it is known that once SVR is achieved, liver fibrosis resolves and the liver carcinogenesis rate also decreases.9,10 However, patients with cirrhosis prior to DAA treatment or with a high FIB-4 index are known to continue to carcinogenesis 10 years after DAA treatment, and continued follow-up is recommended for these patients.16–18 In our cohort, among these factors, a history of HCC is the strongest risk factor for hepatocarcinogenesis, and these cases should be followed up more carefully with an eye toward hepatocarcinogenesis.
On the other hand, in cases with mild fibrosis or low FIB-4 index, follow-up is not recommended due to cost-effectiveness issues.17,18 These studies discussed only from the perspective of hepatocarcinogenesis, and it remains unclear whether they improved the overall life outcome of patients with SVR.
Hepatitis C virus is known to be associated with malignancies of other organs besides the liver, such as colorectal cancer and lymphoma.19–21 Its incidence is significantly more frequent and at a younger age than in the general population. Furthermore, the risk of other organ carcinogenesis has been reported to persist after SVR.22,23 For this reason, sorting of follow-up with a view only to hepatic carcinogenesis may be one-sided. In fact, in our study cohort, non-HCC malignancies, like HCC, had a linear curve of carcinogenesis and continued to develop at approximately the same rate up to 5 years. Although not significantly different, half of the non-HCC malignancies, especially lung and colorectal cancers, were Stage 3–4, which does not necessarily indicate early detection, and it is also difficult to define high-risk groups. Long-term survival of SVR cases may be the most cost-effective outcome. But that should be debated on solid data.
We compared the actual long-term survival of SVR cases with the SMR of the Japanese population. Our group has previously demonstrated that IFN therapy improves the prognosis of patients with chronic hepatitis C compared to the SMR.29 The overall survival rate in this study had non-inferiority compared to the sex- and age-matched SMR for Japanese patients. Analysis of cause of death showed that 53% of deaths were liver-related, including HCC, while the remaining 47% of deaths were from other causes, including malignancies of other organs. In the analysis of risk factors for life outcome, liver stiffness by elastography (p = 0.0022) and age (0.0501) were extracted. Furthermore, malignant tumor occurrence after DAA treatment was added to the analysis, but these did not affect the life expectancy. This is another finding that has implications for the follow-up of these SVR patients. Therefore, the continuous follow-up of SVR patients is necessary, not only for hepatic carcinogenesis but also for carcinogenesis of all organs, as the aging of SVR patients.
Since this is a prospective study of only 651 Japanese patients at a single institution, bias cannot be completely eliminated. However, we are a cancer center hospital located in an area with a relatively high retention rate of residents in Japan, and we have the advantage of having the cooperation of the government and complete follow-up (100%, live/death catch-up rate).
This study did not calculate the cost of treatment. Therefore, one of the limitations of this study is that cost-effectiveness could not be examined. However, in Japan, the government has a universal health insurance system and a high-cost medical care coverage system, and patients tend to place more emphasis on effectiveness than on cost. We hope that further studies will clarify the cost-effectiveness of SVR in the future.
A careful prospective study of the occurrence of all malignancies and overall survival of patients who have achieved SVR revealed that malignancies of other organs continue to occur as frequently as HCC. Therefore, follow-up of patients who have achieved SVR should focus not only on HCC but also on malignancies of other organs, especially since no clear risk factors for extra hepatic malignancy could be identified and patients are getting older. The lack of clear risk factors for extra hepatic malignancy and the aging of patients may require lifelong follow-up.