Is it enough to eliminate hepatitis C virus to reverse the damage caused by the infection?

Abstract

Hepatitis C virus (HCV) infection represents one of the major causes of chronic liver disease, hepatocellular carcinoma and morbidity/mortality worldwide. It is also a major burden to the healthcare systems. A complete elimination of the HCV from the body through treatment is now possible. However, HCV not only alters the hepatic function. Several extra-hepatic manifestations are present in HCV-infected patients, which increase the mortality rate. Liver and gut are closely associated in what is called the “gut-liver axis”. A disrupted gut barrier leads to an increase in bacterial translocation and an activation of the mucosal immune system and secretion of inflammatory mediators that plays a key role in the progression of liver disease towards decompensated cirrhosis in HCV-infected patients. In addition, both qualitative and quantitative changes in the composition of the gut microbiota (GM) and states of chronic inflammation have been observed in patients with cirrhosis. Thus, a successful treatment of HCV infection should be also accompanied by a complete restoration of GM composition in order to avoid activation of the mucosal immune system, persistent inflammation and the development of long-term complications. Evaluation of GM composition after treatment could be of interest as a reliable indicator of the total or partial cure of these patients. However, studies focused on microbiota composition after HCV eradication from the body are lacking, which opens unique opportunities to deeply explore and investigate this exciting field.

Key Words: Hepatitis C infection, Inflammation, Virus eradication, Direct-acting antivirals, Gut microbiota

Core tip: Hepatitis C infection represents one of the major causes of chronic liver disease, hepatocellular carcinoma and morbidity/mortality worldwide. A complete elimination of the hepatitis C virus (HCV) from the body through treatment is now possible. However, HCV not only alters the hepatic function. In fact, changes in gut microbiota composition (GM) and gut barrier that leads to an increased bacterial translocation and inflammation have also been observed. Thus, a successful treatment of HCV infection should be accompanied by a complete restoration of GM and inflammation. Studies focused on GM after HCV eradication are lacking, which opens unique opportunities to deeply explore this exciting field.

TEXT

Infection with hepatitis C virus (HCV) is one of the major causes of liver damage and morbidity/mortality worldwide[1]. The spectrum of this disease is quite variable, ranging from acute hepatitis to cirrhosis and hepatocellular carcinoma (HCC). In fact, HCV is considered the most important risk factor for the development of this type of cancer[2], one of the more common cancers in the general population that has substantially increased in recent years.

HCV infection is a major burden to the healthcare systems, as it is the most frequent indication for virus-related liver transplantation in the western world[3]. In addition, patients diagnosed with HCV showed increased morbidity, with higher hospital admission rates[4] and with mortality rates three times higher than that of the general population[5]. In a recent meta-analysis, the number of people with anti-HCV antibodies has been estimated at 185 million in 2005 (2.8% of the human population), with an estimation of 130-170 million people chronically infected[6]. Overall, between 300000-700000 people die every year due to liver diseases associated with HCV-infection[7,8].

Liver is, by far, the most affected organ, but HCV infection is definitely not a liver-limited disease. Actually, HCV infection has been associated with other extra-hepatic manifestations that include thyroid diseases, renal and cardiovascular diseases, eye and skin diseases, lymphomas, mixed cryoglobulinemia, dyslipidemia, diabetes and central nervous system diseases (brilliantly reviewed by several authors)[9-13]. In fact, up to 74% of HCV-infected patients experienced some form of these extra-hepatic manifestations[14]. Therefore, HCV infection showed a higher mortality rate due to the presence of these extra-hepatic complications[15-17]. Several studies have also suggested that HCV may infect other tissues apart from liver. Thus, HCV has been found in peripheral blood mononuclear cell[18,19], kidney, heart, pancreas, and in intestine[20,21]. The infected extra-hepatic tissues might act as potential reservoirs for HCV, and could play a role in both HCV persistence and reactivation of infection but could also contribute to the aforementioned extra-hepatic manifestations associated with HCV infection. Despite the fact that a growing interest has recently emerged concerning the extra-hepatic manifestations of chronic HCV infection, as demonstrated by the increasing number of reviews recently published, there is no scientific evidence that could demonstrate an association between the presence of the virus in other tissues different from liver and the extra-hepatic complications. Therefore, this issue deserves further investigation.

One area of investigation that has been the focus of much recent interest in the last years is the role of intestinal microbiota in health and disease[22]. Microbiota is defined as the collective microbial community inhabiting a specific environment, including bacteria, archaea, viruses, and some unicellular eukaryotes. Microbiota, its evolutive dynamics and influence on host through its protective, trophic and metabolic actions, has a key role in health and opens unique opportunities for the identification of new markers of the physiopathological state of each individual. Recent studies have demonstrated that changes in gut microbiota (GM) contribute to an increased intestinal permeability and, consequently, increased bacterial translocation and endotoxemia, which triggers inflammation and several deleterious actions[23]. In this sense, changes in GM composition is associated with plenty disorders, including liver disorders[22,24-27].

The effects of GM are not limited to the intestine (gut). Indeed, the gut and the liver are closely associated and there is continuous bidirectional communication between these two organs through the bile, hormones and other products of digestion and absorption. This association is known as the “gut-liver axis” and includes transfer of molecules associated with the gut microbiome to the liver and on the other way round[24,28]. Therefore, it is plausible that the composition of the intestinal microbiota could have direct and indirect effects on the function and physiology of the liver and possibly liver disease progression[29-31]. In addition, it has also been suggested that several liver products, such as bile acids, could directly influence the GM composition[30].

A disrupted gut barrier leads to an increase in bacterial translocation and to an activation of the mucosal immune system and secretion of inflammatory mediators that has a key role in the development of several liver disorders associated with HCV-infection, especially in the progression of liver disease towards decompensated cirrhosis in both HCV-mono infected and HCV/HIV co-infected patients[32-36]. In this context, the study carried out by Sandler et al[37] (2011) in HCV-infected patients showed that LPS-induced activation of both circulating monocytes and resident Kupffer cells was associated with severe hepatic fibrosis and failure to respond to therapy (based on interferon or pegylated interferon with or without ribavirin) and predicts progression to end-stage liver disease independent of the degree of fibrosis. In addition, several studies have demonstrated both qualitative and quantitative changes in the composition of the GM in patients with cirrhosis (summarized by Betrapally et al[38]). More specifically, the alteration in GM of cirrhotic patients (with and without HCV infection) is characterized by an overgrowth of potentially pathogenic bacteria (i.e., gram negative species) and a decrease in autochthonous familiae[24]. Significant differences in the microbiota community and metabolic potential have also been detected in the fecal microbiota of patients with hepatitis B liver cirrhosis[39]. Therefore, preservation of GM composition - through the usage of different approaches such as probiotics, prebiotics, etc., arises as a promising tool to prevent and/or to treat the development of these liver disorders[40-44]. However, studies focused on microbiota composition of a large population of HCV patients (over the entire disease spectrum) are lacking and only studies concerning cirrhosis and HCC independently of their etiology can be found.

On the other hand, it is important to mention that one of the main objectives of health professionals when treating infectious diseases is to eliminate the pathogenic microorganism responsible for such disorder. To achieve this, physicians are provided with a large arsenal of antibiotics, antivirals, antiretroviral, etc., that have appeared in the last decades thanks to the spectacular progress of scientific research. In the context of HCV-infection, the last five years have been crucial in the fight against this infection. A few years ago, physicians only had therapies based on the combination of weekly pegylated interferon-α and daily doses of ribavirin to treat this infection. The efficacy of these therapies was not higher than 50%, and their mechanism of action was not direct against the virus, but was based on enhancing the immune system. In 2011, the arrival of first-generation direct-acting antivirals has shown successful rates of virus elimination from the body in more than 75% of the cases. Unlike the previous therapies, these new regimens cause fewer side effects, they do not require monitoring and most of them are pangenotypic. These therapies are also simpler and require a shorter duration. Thus, and despite the fact that there is not an effective vaccine yet, this could be the beginning of the end of hepatitis C disease[1,45]. However, a complete cure of HCV-infection requires not only the elimination of the virus from the body, but also would imply an improvement in liver and in the extra-hepatic manifestations. In this sense, the study from Innes et al[46] (2015), demonstrated a clear association between achievement of HCV cure [as evidenced by sustained viral response (SVR)] and a decrease in both liver-related and all-cause mortality. A large study of HCV-infected patients in the Veteran’s Administration database also demonstrated that non-liver-related mortality was significantly reduced among patients who achieved SVR who had comorbidities that included coronary artery disease, diabetes, and hypertension. It was suggested that decreased chronic inflammation associated with HCV was a key factor in mortality decline[47,48]. It is important to highlight that changes in microbiota composition are present in states of chronic inflammation. Thus, a successful treatment of HCV infection should be also accompanied by a complete restoration of GM composition in order to avoid activation of the mucosal immune system, persistent inflammation and the development of different long-term complications. Thus, evaluation of GM composition after treatment could be of interest as a reliable indicator of the total or partial cure of these patients. Only a very preliminary study has been recently published in this regard[49]. It demonstrated that the pro-inflammatory state and the changes observed in GM composition of HCV-infected patients with cirrhosis were not improved regardless of at least one year of SVR. This persistent dysbiosis could contribute towards varying rates of improvement after HCV eradication in cirrhosis. However, what happen in HCV-infected patients with a lower degree of fibrosis/liver damage? Could HCV have a direct effect on GM composition since the presence of this virus has been demonstrated in intestine? or the changes observed in GM are only secondary to liver damage induced by the virus? These are only a few questions that arise in this exciting field and that deserve further investigation. A deep evaluation of the short, medium and long-term consequences of the new HCV treatments is needed, specially focused on the effects on GM composition, bacterial translocation and inflammation.