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

Media Coverage Of This Article
March 17, 2017
Liver Inflammation Lingers in Some Patients After Hepatitis C Is Eradicated
About one-third of patients who were successfully treated to eliminate the hepatitis C virus continued to exhibit liver inflammation, a German study showed. The findings include people who took direct-acting antiviral (DAA) drugs, the current preferred therapy for the virus.

“This is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of hepatitis C,” wrote Christoph Welsch, MD, and colleagues at the J. W. Goethe-University Hospital in Frankfurt am Main, Germany.
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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 [13–14], 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 [20–21], 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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CNIO scientists decipher how the immune system induces liver damage during hepatitis

CNIO scientists decipher how the immune system induces liver damage during hepatitis

Viral infections are the primary cause of liver inflammation or hepatitis, affecting hundreds of millions of people all over the world, and they represent a public health problem worldwide. The acute condition can cause irreversible damage to the liver, and if not cured can become chronic, leading to serious diseases such as cirrhosis or cancer.

A study published today in the online edition of The Journal of Clinical Investigation, and carried out by Erwin Wagner's team, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme and holder of an ERC Advanced Grant, shows how the immune system 'attacks' liver cells during hepatitis by using the AP-1 gene JunB.

Latifa Bakiri, one of the study's authors and a researcher in Wagner's laboratory details: "The activation of the JunB/AP-1 gene in a subset of immune cells, called NK cells, increases the production of interferon-gamma that attacks liver cells while the organ is suffering from hepatitis".

 

With this discovery, the study's authors propose a new mechanism by which AP-1 acts as a double-edged sword in the liver: it's a first line of defence against viruses that cause the disease, but also encourages liver damage depending on the diet or genetics of the patient.

"The balance of these signals is fundamental to the understanding of the pathogenesis of inflammatory liver disease and to design new therapeutic approaches to reverse this disease", says Wagner.

NK-type immune cells are also part of the micro-environment surrounding tumours. Researchers point out in the discussion of the article that a better knowledge of these cells may be vital for designing immune-therapies that specifically target tumour cells.

Source: Centro Nacional de Investigaciones Oncologicas (CNIO)

Inflammation of the Liver

The word "hepatitis" literally means "inflammation of the liver." Inflammation is the body's response to injury or infection in vascular tissue (tissue with blood vessels).

Although the "classic signs" of inflammation are redness, swelling, heat, pain, and the formation of exudate (such as pus), in hepatitis C infection, there may be no visible signs of inflammation.

So what is it about infection with the hepatitis C virus (HCV) that actually damages the liver? In fact, the virus itself does relatively little damage. For the most part, it's the body's own inflammatory response to infected liver cells that results in the tissue damage characteristic of chronic HCV infection.

Inflammation and Immunity: What's the Difference?

There are significant difference between the immune response and the inflammatory response. Additionally, there are differences between the acute inflammatory response and chronic inflammation.

The first response of the body to an antigen (foreign invader) such as the hepatitis C virus is the inflammatory response. The inflammatory response is:

Rapid. The inflammatory response can begin within seconds of injury or invasion

Nonspecific. The response is the generally the same regardless of the type of antigen

Self-Limiting. The inflammatory process stops after the antigen is eliminated.
Because the inflammatory response is rapid, nonspecific and can be perpetuated by different factors, an exaggerated or prolonged inflammatory response can be difficult to control and can cause significant tissue damage.

The immune response also begins after the detection of an antigen, and complements the activity of the inflammatory response. However, the immune response has significant differences from the inflammatory response, in that it is:

Slow. The immune response can develop over days to weeks

Specific. The immune system creates antibodies which target individual types of antigens

Ongoing. With a few exceptions, the persistence of antibodies after the resolution of infection provides protection against future infection by the same antigen.
The hepatitis C virus is an example of an antigen that is able to defeat the immune system's ability to provide lasting immune protection. People who "clear" hepatitis C infection, either spontaneously or with medications, are not immune and can be reinfected if subsequently exposed.

Triggering the Inflammatory Response

The hepatitis C virus seems to have a preference for infecting liver cells (hepatocytes). Once HCV binds to a hepatocyte, it injects its genetic material (RNA) into the cell. The viral RNA takes control of the cell's metabolic processes, and causes the cell to assemble more copies of the virus (a process called viral replication).

The infected liver cell is doomed, but it performs one last service - it generates cytokines, which are chemical signals that attract the attention of the body's immune system. Cytokines warn nearby cells of the infection and also play a role in initiating the inflammatory and immune responses.

One of the cytokines expressed by infected cells is interferon. Interferon communicates with nearby cells, instructing them to begin producing proteins that prevent the virus from replicating. In addition, interferon acts as a regulator of body's immune response to infection, increasing and decreasing the immune response as needed.

The Role of the White Blood Cell

The "soldiers" of immune defense are white blood cells (WBC's), also called leukocytes.

When a physician orders a laboratory blood test called a "CBC with Diff" (complete blood count with differential), the tests results report a breakdown of the WBC count by different WBC types, such as:

Neutrophils. These fast-acting WBC's are usually the first to arrive at the site of an infection, and specialize in attacking and digesting bacteria. They have a life-span of about 12 hours.

Eosinophils. These cells also phagocytize (ingest) foreign particles, but specialize in digesting antigens that have attached to antibodies, which are proteins produced by other specialized WBC's that bind with and neutralize antigens. Eosinophils are also highly active during allergic reactions and parasitic infections.

Basophils. These rare cells migrate to the site of injury or infection and release substances (histamines) that increase the inflammatory response by attracting other leukocytes.

Monocytes. These cells, also called macrophages (literally "big eaters") can either circulate freely in the blood stream or become lodged in tissues. Moncytes ingest foreign particles, secrete chemicals to attract other leukocytes, and initiate the process of scar tissue formation to isolate and repair the damaged or infected region.

Lymphocytes. While the types of WBC's mentioned above all contribute to the inflammatory response, lymphocytes are critical to the immune response. They are programmed to respond to specific threats by analyzing foreign particles and creating responses that will protect the person from future infection - the phenomenon of immunity. The subtypes of lymphocytes include:

Cytotoxic T lymphocytes. These cells act directly against the infectious agent

Helper and Suppressor T lymphocytes. These cells work to either stimulate the immune response or decrease it as the infection resolves


B lymphocytes. When triggered, these cells produce antibodies, proteins that neutralize antibodies by binding with them, and provide long term protection against future infection.
The Process of Inflammation

The interplay of immune and inflammatory response is extremely complex, involving a large number of chemical and mechanical processes. What follows is a very abbreviated description of the process.

Once infected with the hepatitis C virus, the infected hepatocytes release cytokines. These chemical messengers trigger a series of changes in the walls of blood vessels that allows various leukocytes to pass through the vessel wall and migrate to the site of infection, attracted by the cytokines released by the infected cells.

When leukocytes arrive at the infected cell, they release chemicals onto the surface of the cell that causes it to swell and burst. Fragments of the destroyed cells are engulfed by the leukocytes and digested.

Additionally, changes in the vascular wall allows fluid in the blood vessels to "leak" through the wall of the vessel into surrounding tissue, transporting plasma proteins and fluids to the site of injury, resulting in edema and exudate, or pus.

These fluids and plasma proteins assist to control the inflammatory and immune response, and flush away cellular fragments from destroyed cells.

So What Goes Wrong?

If the immune and inflammatory responses are so effective at eliminating infections, why does hepatitis C infection become chronic in 85% of cases?

The answer is that although the hepatitis C virus is a very simple "organism," over time it has developed traits that allow it to effectively resist the body's immune and inflammatory defense systems.

Once the virus attaches to the surface of a cell, it inserts its RNA (the genetic material of the virus) into the cell. Inside the cell, the viral RNA is acted upon by substances called proteases, which begin to make copies of the RNA.

The rate at which new viruses are replicated is staggering - it is estimated that between 100 billion (1011) and 1 trillion (1012) viruses are replicated per day.

The process of copying the viral RNA is imperfect, and tends to introduce variations into the RNA sequence at the rate of one error per genome per replication cycle.

The result of this rapid, error-prone replication process is a subtle variation in the genome, or genetic blueprint, of newly-produced HCV viruses. These genetic mutations are called genotypes and quasispecies.

Although the immune system is capable of producing an effective immune response to HCV infection, the response is highly specific, that is, the immune cells are not able to defend against a wide variety of slightly different HCV particles.

Since the replication process rapidly generates virus particles with many subtle genetic variations, some of the virus variants can escape the host’s immune response.

The strength of the host’s immune response is sometimes referred to as “immune pressure.” People who generate a stronger immune response exert more immune pressure on the virus, and this tends to drive the virus to develop a broader range of quasispecies than those who have a weaker immune response.

In addition, there is study evidence to suggest that when HCV infects a cell it is capable of regulating some of the cellular responses to infection. The hepatitis C virus appears to be able to modify the infected cell's reaction, causing an increase in the expression of factors that favor viral reproduction, and decreasing the production of chemical factors which could lead to its destruction.

The Progression to Fibrosis

The liver has an amazing ability to heal itself. For example, when a liver is transplanted in to a recipient, it can grow to nearly full size in a few weeks. However, when the inflammatory response progresses and worsens, there can be damage to the reticulum, or supporting framework of the liver.

When the supporting framework is damaged, the repair must be accomplished by the formation of scar tissue. The presence of scar tissue on liver biopsy indicates the development of liver fibrosis. In time, scar tissue can cause changes to the physical architecture of the liver - a condition called cirrhosis.

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