Cirrhosis, High Age and High Body Mass Index Are Risk Factors for Persisting Advanced Fibrosis After Sustained Virological Response in Chronic Hepatitis C

M. Hedenstierna; A. Nangarhari; A. El-Sabini; O. Weiland; S. Aleman

Disclosures

J Viral Hepat. 2018;25(7):802-810. 

In This Article

Discussion

The long–term effect of achieved SVR on liver fibrosis in patients with HCV–induced advanced fibrosis has not been extensively investigated. To study this, fibrosis in our patients was assessed by LSM during long–term follow–up over more than 5–10 years. Our study shows that the vast majority of our 269 patients with pretreatment advanced fibrosis or cirrhosis improved their fibrosis during long–term follow–up after SVR. A minority, however, continued to have advanced fibrosis even after more than 5–10 years of follow–up. In this subset of patients, a point of no return for advanced liver fibrosis might have been reached, where improvement is not possible. Other possible explanations are contributing cofactors such as liver steatosis with inflammation and alcohol use as driving forces to maintain or even progress liver fibrosis. In this study, we identified pretreatment cirrhosis, high age and high BMI as the main risk factors for lack of improvement. The proportion of patients who maintained advanced fibrosis decreased among patients with longer follow–up time, indicating that fibrosis regression is a slow process that continues over time.

Several studies with varying follow–up times have compared pre– and post–treatment fibrosis stages.[10,19–27] Studies based on liver biopsies have all shown that fibrosis and also cirrhosis can improve after achievement of SVR in a majority of patients, but also that fibrosis will persist or progress after SVR in a subset of 1%–14%, confirming the results in our study.[19–23] In a large study including more than 3000 biopsied patients with a mean follow–up time of 20 months, a low baseline fibrosis stage, age below 40 and BMI below 27 were all factors strongly associated with lack of significant fibrosis at follow–up in patients with SVR.[19] The risk factors identified to be associated with persisting fibrosis found were the same as in our long–term study.

More recent studies have investigated fibrosis regression after SVR with LSM and biochemical markers. The diagnostic accuracy of these methods to detect persisting cirrhosis after SVR, however, has been questioned.[10,24] In a study comparing LSM with follow–up biopsies 61 months after achieved SVR, the sensitivity of LSM to detect cirrhosis after SVR was only 61% when standard pretreatment cut–offs were used.[10] On the other hand, the specificity for diagnosing cirrhosis with LSM after treatment reached 95%. As LSM measures both fibrosis and inflammation, rapid early improvement of liver stiffness after SVR could be explained by a reduction in liver inflammation, and not by fibrosis regression. This could suggest that patients with pretreatment cirrhosis defined by LSM, including some with severe inflammation and less advanced fibrosis, would have lower liver stiffness at follow–up than patients with biopsy–proven cirrhosis. Surprisingly, in our study, we observed the opposite. The difference was not significant, but could be explained by the fact that patients with cirrhosis defined by LSM had shorter follow–up times. This supports our conclusion that cirrhosis regression is a process that continues over time. Recently published studies with repeated LSM up to 2 years after achieved SVR have shown a rapid initial improvement of liver stiffness, but also a continued slower reduction, better reflecting true fibrosis regression.[25–27] The follow–up times in these studies were relatively short, but the findings support the results generated in our study. Another possible explanation for the initial rapid and later slower improvement of liver stiffness levels after SVR could be the remaining presence of nodular architecture in the liver, despite decreased amount of fibrosis.[21] Nodules are the hallmark for a histopathological definition of cirrhosis.[5] This implies that the persisting advanced fibrosis in our study, measured by LSM, probably is accurate, while we might have misclassified the stage of fibrosis in some of the cirrhotic patients that still had nodular architecture.

Although this study was not designed to assess the correlation between LSM and the risk to develop HCC, there were patients in our study with improved fibrosis who later developed HCC up to 15 years after SVR. This finding supports that surveillance for HCC should continue even in patients where cirrhosis has regressed after achieved SVR. The duration for such surveillance needs to be further studied. We have earlier found that diabetes and the presence of pretreatment cirrhosis were risk factors for the development of HCC after SVR had been achieved.[13] No direct correlation between diabetes mellitus and persisting advanced fibrosis was noted in this study. On the other hand, high BMI, known to be associated with diabetes, was found to be a risk factor for persisting advanced fibrosis.

There are several limitations to this study. It had a cross–sectional and retrospective design and lacked sequential LSMs for the included patients. However, in a preliminary prospective study on LSM data collected at 6–month intervals after SVR in 100 patients with F3–F4 fibrosis at baseline, 31% had persisting advanced fibrosis, similar to the results in our study.[28] Furthermore, in our study, a third of the eligible patients were excluded or lost to follow–up, which could introduce a selection bias. Baseline characteristics for the nonincluded patients were, however, comparable to the studied patients, reducing this bias. The clinical outcome was worse in the excluded group with higher occurrence of HCC and death, but the causes of death were not liver related in a majority of the cases.

Assessment of fibrosis after SVR with transient elastography and not liver histology may have caused us to underestimate the extent of advanced fibrosis at follow–up. However, the identified patients with maintained advanced fibrosis are probably correctly classified. As all our patients were treated with IFN–based regimens, we do not know if our findings are relevant for patients treated with IFN–free regimens. One recently published study, however, showed a statistically similar median change in LSM levels 24 weeks after the end of treatment in patients with SVR after IFN–containing and IFN–free regimens.[25]

To conclude, we found that the liver fibrosis after achievement of SVR improved in the vast majority of our patients after long–term follow–up. Our data indicate that fibrosis regression is an ongoing long–term process over years. Risk factors for lack of such improvement during follow–up were pretreatment cirrhosis, older age and high body mass index. Lifestyle intervention to decrease weight in obese persons and treatment before establishment of cirrhosis at a younger age should therefore be recommended to avoid persistence of advanced fibrosis after SVR.

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