Chronic hepatitis C virus (HCV) infection is a frequent cause of cirrhosis and hepatocellular carcinoma. Improvement in not only liver fibrosis, even reversal of cirrhosis, but also a lower risk of decompensated liver disease and liver-related death are observed among HCV-infected individuals who attain sustained virological response (SVR) after antiviral therapy.1–9 Short-term liver fibrosis changes have been mainly assessed with paired biopsies obtained before antiviral treatment and shortly afterwards.1–3 A single clinical trial has provided data on liver biopsy changes over longer periods of follow-up in patients with advanced liver fibrosis who did not reach SVR.10 Repeated liver biopsies after antiviral therapy are difficult to obtain outside clinical trials, particularly in patients achieving HCV clearance. This fact accounts for the paucity of data on long-term liver damage changes in patients treated against HCV infection.

On the contrary, liver fibrosis evaluated through liver stiffness measurement (LSM) by transient elastometry is easily repeated.11 In addition, LSM fulfills other characteristics that make the technique very adequate for follow-up determinations as high reproducibility,11–14 accurate diagnosis of cirrhosis11 and good performance to detect and exclude significant fibrosis.11 Moreover, LSM correlates with the hepatic venous pressure gradient15 and, as a consequence, can predict esophageal varices16 and liver-related events.17–20 Because of this, changes in LSM are important from a clinical point of view, in addition to the variations in histology that they reflect.

Sequential LSM have been applied to follow patients during anti-HCV therapy.21–24 LSM decrease significantly among patients with chronic HCV infection who achieve SVR with antiviral treatment.21,23,24 The rates of improvement in fibrosis stage between paired liver biopsies in clinical trials, with second biopsy performed 24 weeks after the end of treatment, are similar to those observed with follow-up LSM.1–3 However, the time between paired assessments of liver fibrosis has also been short in studies on LSM21–24 after treatment with pegylated interferon (Peg-IFN) plus ribavirin (RBV). Due to the lack of long-term studies both with biopsies and LSM, there are very limited data on the rates of histology or LSM normalization among patients treated with interferon-based antiviral therapy, since fibrosis regression is a very slow process.25

The objective of this study was to assess the probability of return of LSM to normal values in HCV-infected patients who received Peg-IFN plus RBV and the factors associated with LSM normalization.

LSM normalizations during Peg-IFN plus RBV treatment are significantly more likely and occur earlier among patients with SVR. In addition, LSM normalizations continue beyond 24 weeks after the scheduled end of therapy only among individuals who reach SVR. Patients with baseline cirrhosis are more unlikely to return to normal LSM. Moreover, individuals with cirrhosis normalize LSM mainly after SVR is achieved. Thus, sequential LSM could be useful to follow patients after SVR is attained.

In the present study, about one third of the patients normalized LSM after starting Peg-IFN plus RBV. Independent predictors of LSM normalization were achievement of SVR and absence of baseline cirrhosis. During the follow-up after the SVR evaluation date, LSM normalizations were only detected in subjects with SVR. Thus, no significant benefit could be observed among patients without SVR after completing therapy. This was particularly important for patients with baseline cirrhosis. A small proportion of them showed reductions below 7kPa after starting Peg-IFN plus RBV. All patients with cirrhosis and normalization of LSM had attained SVR. This result is in agreement with previous data on paired liver biopsies in patients receiving anti-HCV therapy.1 In the present study, most LSM normalizations among patients with cirrhosis were seen throughout the follow-up after reaching SVR.

The LSM threshold that we selected to define normal LSM values was derived from two large studies on healthy adults.26,27 One of them examined individuals attending a systematic free medical check-up26 and the other blood donors.27 Similar median LSM values were reported in both studies.26,27 We chose the value of 7kPa because it was close to the 95th percentile value in both studies.26,27 The use of a stringent category to define the outcome variable, as LSM below 7kPa, is a strength of the present study. Small decreases in LSM 24 weeks after the scheduled end of treatment date have been reported.21–23 The clinical meaning of small variations in LSM is not clear. On the contrary, reductions of LSM below values seen in the majority of healthy adults are more easily interpretable. Indeed, since lower values of LSM are associated with lower portal pressure,15 reduced likelihood of esophageal varices16 and, in turn, a smaller rate of clinical events,17–19 it is conceivable that normal LSM could be associated with no further risk of liver-related complications. In the present study, we found that liver decompensations were only observed in the short-term among individuals with cirrhosis without LSM normalization. However, the relationship between LSM decreases to normal values and clinical outcomes needs to be investigated.

Higher levels of liver inflammation may increase LSM to some extent.11,31 Given that antiviral treatment improves both liver fibrosis and inflammatory activity, improvements in liver inflammation during treatment might also decrease LSM. In the present study, baseline ALT levels showed no association with LSM reductions below 7kPa. Due to this, baseline ALT levels and, hence, in initial liver inflammatory activity, was not a confounder for LSM normalization. This suggests that decreases in LSM actually reflect improvements in fibrosis, rather than reductions in liver inflammation.

This study has a few limitations. First, the proportion of patients who end up reaching normal LSM values is likely to be higher than that found herein, especially for patients with cirrhosis at baseline. Surely, a much longer follow-up is needed to see more cases of cirrhosis reversion. However, we provide relevant data on LSM normalization in patients receiving Peg-IFN plus RBV therapy. Thus, this study clearly shows that patients without SVR have few chances of LSM normalization after starting antiviral treatment. For patients with SVR and with LSM equal or greater than 7kPa at 24 weeks after the end of therapy, the likelihood of LSM normalization after two years of follow-up is nearly 70%. Individuals with cirrhosis and SVR do show reversions of cirrhosis, but clearly a longer follow-up is needed for them. Second, the study population was not homogeneous, as it was composed of HCV-infected individuals with and without HIV coinfection. HIV infection was associated with a lower probability of LSM normalization. However, this association was confounded by the lower rates of SVR and higher proportion of subjects with cirrhosis among HIV-coinfected patients. After adjustment in the multivariate analysis, SVR and cirrhosis were the only independent predictors of LSM normalization and HIV-coinfection did not remain associated with LSM return to normality anymore.

In conclusion, LSM normalization is a continuous phenomenon during Peg-IFN plus RBV treatment and afterwards in patients who attain SVR. This fact led us to believe that eventually most, if not all, patients with SVR will achieve a normal LS, if sufficient time goes by, perhaps as an expression of a normalization in liver histology. Patients without SVR do not show LSM normalization after the SVR evaluation time point. If normal LSM were associated with lack of liver complications in patients with SVR, sequential LSM could be used to identify patients with and without continued risk of liver decompensations after anti-HCV therapy. In this way, repeated LSM could aid targeting screening and preventive measures at those patients who previously had LS indicative of cirrhosis.

This study was partly financed by the Health Research Fund (PI10/01631), by the Andalusion Regional Health Department (PI-0429) and the ISCIII-RETIC (Carlos III Health Institute-Research NetworksRD06/006. JAP is an investigator in the Intensification of Research Activities Program of the Spanish National Health Service (Reference; I3SNS). AR receives an intensification grant from the Progress and Health Foundation of the Andalusion Regional Health Department (Reference; AI-0011-2010). KN is the beneficiary of an advanced “Sara Borrell” Post-Doctorate course contract of the Carlos III Health Institute (SCO/523/2008). CC is the beneficiary of a Research Support Tecnician contract by the Spanish Ministry of Science and Innovation (Reference; PTA 2011-5503-I).

Juan A. Pineda has carried out consultancy work for GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead, Merck Sharp and Dome, Schering-Plough, Janssen Cilag and Boehringer Ingelheim. He has received research grants from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals y Boehringer Ingelheim and financial compensation for conferences by GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead, Merck Sharp and Dome, Janssen Cilag, Boehringer Ingelheim and Schering-Plough.