Wednesday, February 15, 2017

Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response

Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response
Christoph Welsch , Mira Efinger, Michael von Wagner, Eva Herrmann, Stefan Zeuzem, Tania M. Welzel , Christian M. Lange Published: February 14, 2017

Published: February 14, 2017
http://dx.doi.org/10.1371/journal.pone.0171755

Abstract
Background
Novel direct-acting antiviral DAA combination therapies tremendously improved sustained virologic response (SVR) rates in patients with chronic HCV infection. SVR is typically accompanied by normalization of liver enzymes, however, hepatic inflammation, i.e. persistently elevated aminotransferase levels may persist despite HCV eradication. Aim: To investigate prevalence and risk factors for ongoing hepatic inflammation after SVR in two large patient cohorts.

Methods
This post-hoc analysis was based on prospectively collected demographic and clinical data from 834 patients with SVR after HCV treatment with either PegIFN- or DAA-based treatment regimens from the PRAMA trial (n = 341) or patients treated at our outpatient clinic (n = 493).

Results
We observed an unexpected high prevalence of post-SVR inflammation, including patients who received novel IFN-free DAA-based therapies. Up to 10% of patients had ongoing elevation of aminotransferase levels and another 25% showed aminotransferase activity above the so-called healthy range. Several baseline factors were independently associated with post-SVR aminotransferase elevation. Among those, particularly male gender, advanced liver disease and markers for liver steatosis were strongly predictive for persistent ALT elevation. The use of IFN-based antiviral treatment was independently correlated with post-SVR inflammation, further supporting the overall benefit of IFN-free combination regimens.

Conclusion
This is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of HCV. Our data show a high proportion of patients with ongoing hepatic inflammation despite HCV eradication with potential implications for the management of approximately one third of all patients upon SVR.

Discussion Only
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Sustained virological response is the major goal in antiviral treatment for chronic hepatitis C which to date is achieved for most patients with novel treatment regimens. Typically accompanied by normalization of aminotransferase levels, SVR is considered a patient relevant endpoint. Some patients in particular those with advanced liver disease and cirrhosis, however, show persistent liver injury even years after HCV cure [9]. Despite obvious clinical importance, the prevalence of elevated aminotransferase levels upon achievement of SVR and characteristics of respective patient populations are unknown. Here we present data from an observational study on post-SVR aminotransferase activity from two large cohorts with overall 834 patients after antiviral treatment with or without interferon (IFN).

The major finding from our study is the high prevalence of post-SVR elevated ALT levels despite viral eradication, including patients that have been treated with novel IFN-free direct-acting antiviral-based therapy. This observation supports our notion that ongoing aminotransferase elevation upon SVR is not a rare clinical event. Up to 10% of our patients were observed with persistently elevated ALT levels. Importantly, only approx. 65% of SVR patients showed healthy ALT levels upon viral cure, whereas another approx. 25% of SVR patients showed normal ALT levels that are below the upper limit of normal but above the so-called healthy range and hence require further surveillance [8]. Although baseline ALT activity showed significant correlation with ongoing ALT elevation, the correlation was only weak, and hence is not considered a reliable predictor for post-SVR aminotransferase activity.

In line with previous observations on the natural course of CHC infection, we found that male gender significantly correlated with post-SVR elevated ALT. A similar finding was previously reported in a study of chronic HCV patients from the Observatoire de i'Hépatite C-(OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpêtrière (DOSVIRC) population, and the original METAVIR population. In this study several host factors were identified with strong association to fibrosis progression prior to IFN treatment, in particular male gender [10]. The authors, however, were unable to explain this association, but found male gender associated with a younger age at infection, shorter duration of infection, and daily alcohol consumption of more than 50 g, as well as a history of intravenous drug use. Such confounders on the course of disease are difficult to assess but potentially also relate to the gender-specific prevalence of persistently elevated ALT levels upon virus eradication that we report in our study albeit patients with significant alcohol consumption were excluded from our analysis.

Post-SVR inflammation in our study was observed in patients irrespective of being treated with IFN-based of IFN-free regimens. According to our data, IFN-based treatment per se can be considered as independent risk factor for persistently elevated ALT levels after SVR. We observed a strong correlation of IFN-based therapy with elevated ALT levels at week 24 and week 48 post SVR, further supporting the clinical benefits of novel IFN-free treatment regimens. Hence our data provide novel details on long-term adverse effects of IFN. Importantly, we also observed post-SVR inflammation in patients upon IFN-free all-DAA combination treatment. However no correlation between post-SVR ALT activity and any specific DAA or DAA combination is found, although NS3 protease inhibitors are reported previously to be associated with hepatotoxicity and elevated aminotransferase levels [11].

Moreover, we found body mass index and GGT significantly correlated with ongoing ALT elevations in our study. Serum ALT activity was already previously reported as independently related to body mass index [7]. The body mass index is associated with hepatic steatosis in CHC and known to affect the natural course of HCV infection [12], i.e. fibrosis progression [1314], and is also a possible mediator of increased risk to develop type 2 diabetes [15]. A recent study reported a significant weight gain in 44% of patients with SVR12 upon IFN-free antiviral therapy [16]. Weight-gain after SVR potentially leads to deterioration of liver steatosis and might underlie elevated aminotransferase levels upon viral eradication. Further prospective investigations are needed to investigate a potential association between weight-gain after SVR and development of NASH or worsening of pre-existing NASH in patients with high normal or elevated BMI at baseline. Given the high prevalence of NASH in the western world, this would have important clinical implications for the post-SVR management of those HCV patients with liver steatosis.

Baseline platelet counts that are considered as predictors of a fibrotic stage in liver disease [17] were observed with a significant inverse correlation with post-SVR elevated ALT levels both in uni- and multivariate analyses. Hence, laboratory markers for fatty liver disease and/or advanced liver disease are independently related with serum ALT activity. A recent paper by York et al. reported that type I IFN-signaling impairs the balance in metabolism of cholesterol and long chain fatty acids [18]. The study reveals an important metabolic-inflammatory circuit that links cholesterol biosynthesis with activation of innate immunity, which might relate to our clinical observations with elevated aminotransferase levels in the long-term follow up of patients upon SVR. Our data can be interpreted as another argument in support of treating CHC patients early in order to avoid advanced stages of liver disease, not only to reduce the higher risk of treatment failure in cirrhotic patients but also to avoid potential disease progression upon SVR [19].

Strengths of the study are the large patient number and good data quality. Recall bias (e.g. for self-reported variables such as alcohol consumption) is unlikely as data were prospectively collected. Our study, however, has potential limitations. Follow-up data to explore the long-term impact of ALT elevations on morbidity (i.e. fibrosis progression, HCC risk) and mortality of patients enrolled into the PRAMA trial were not available. The follow-up of DAA-treated patients is currently ongoing but yet too short to evaluate clinical long-term outcomes, however, some studies suggested an increased risk of mortality in patients with elevated liver enzymes independent of etiology [4]. As liver biopsy is not standard of care for the management of most patients with chronic hepatitis C virus infection as well as due to the retrospective nature of our study, a comparison of pre-/post-treatment histologies was not possible within this large patient cohort. Also, body-weight was not routinely collected during follow-up in most patients.

Our study is the first clinical characterization of post-SVR aminotransferase elevation with an unexpected high prevalence that affect approximately one third of all patients upon viral eradication. Since CHC is both a virologic and fibrotic disease [2021], the high prevalence of ongoing liver inflammation likely impact the future course of disease, cirrhosis progression and cancer development in thousands of patients with so far unrecognized burden to public health worldwide. Baseline factors that were (i) significantly associated and (ii) strongly correlated with ongoing elevation of ALT levels after SVR were male gender, the use of IFN in antiviral treatment regimens, and markers of advanced liver disease or steatosis. We observed body weight as significant baseline predictor that justify clinical concerns as high body weight might favor the development or worsening of pre-existing fatty liver disease or steatohepatitis (NASH) upon successful antiviral treatment. Due to the enormous implications for patient management after SVR, prospective studies are currently ongoing to further investigate the possible association between SVR and worsening of metabolic liver disease, as indicated herein.

In summary, this is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of HCV. Our data show a high proportion of patients with ongoing hepatic inflammation despite HCV eradication with potential implications for the management of approximately one third of all patients upon SVR.

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