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Liver Fibrosis in the Post-HCV Era Massimo Pinzani, MD, PhD, FRCP1

Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom Semin Liver Dis 2015;35:157–165.

Abstract

Keywords

► fibrosis ► interferon-free regimens ► hepatitis C virus ► antifibrotic ► noninvasive

Address for correspondence Massimo Pinzani, MD, PhD, FRCP, UCL Institute for Liver and Digestive Health, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, United Kingdom (e-mail: [email protected]).

The introduction of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infection represents a key turn in hepatology because of their extremely high therapeutic efficacy and relatively safe use also in “difficult-to-treat” and/or “difficult-to-cure” HCV subgroups, including patients with cirrhosis. Due to treatment guidelines based on health economics, patients with cirrhosis will likely represent the frontline in the use of the new anti-HCV agents. Accordingly, this article concentrates on the effect of sustained viral response (SVR) following antiviral treatment for HCV on the evolution of tissue fibrosis and cirrhosis, and more importantly, on the clinical consequences of viral eradication, particularly in patients in which SVR has been achieved in an advanced stage of the disease. In this context, the assessment of fibrosis regression and possibly of cirrhosis reversal will represent the diagnostic challenge of the next decade.

It is truly remarkable to observe and enjoy the renewed atmosphere of enthusiasm among hepatologists following the recent introduction of antiviral regimens with an extremely high eradication efficacy for hepatitis C virus (HCV) infection.1,2 Without a doubt, this is an epochal achievement in hepatology with a generation of physicians who have seen both the birth and the potential defeat of a progressive and mortal disease. On the other hand, this also represents a turning point in the fight against liver fibrosis when, despite decades of excellent academic research, no antifibrotic agent has yet reached clinical practice. The success in the fight against HCV follows the not inferior accomplishment in the management of hepatitis B virus (HBV) infection with the introduction of an HBV vaccination and treatment with nucleoside/nucleotide analogues (NUC). Regardless, though the very high cost for individual treatment will limit the use of the new antiviral agents to high-income industrialized countries for at least the next decade,3,4 the defeat of chronic HCV infection and of the related liver disease has become a realistic possibility. With the advent of highly efficient antivirals and remarkable successes in HBV prevention and treatment, challenges for basic and clinical hepatology are drastically changing, putting emphasis on (1) patients with eradicated HCV infec-

Issue Theme Liver Fibrosis; Guest Editors, Robert Schwabe, MD, and Ramon Bataller, MD, PhD

tion and persisting liver cirrhosis as well as (2) nonalcoholic fatty liver disease (NASH) and (3) alcoholic liver disease (ALD), the latter two soon representing the overwhelming majority of patients with advanced liver disease in both Western and developing countries. With detailed reviews on NASH and ALD by Bataller and Gao (“Liver Fibrosis in Alcoholic Liver Disease”), and Angulo and Diehl (“Fibrosis in Nonalcoholic Fatty Liver Disease: Mechanisms and Clinical Implications”) in this issue, the aim of this article is to attempt drawing possible scenarios for the next one to two decades, a period that will eventually lead to a “post-HCV era” in which a large number of patients can be cured and in which HCV-related liver disease has little clinical significance. The analysis will concentrate on the effect of sustained viral response (SVR) following antiviral treatment for HCV on the evolution of tissue fibrosis and cirrhosis, and more importantly, on the clinical consequences of viral eradication, particularly in patients in which SVR has been achieved in an advanced stage of the disease.

Effect of Successful Antiviral Treatments on Liver Fibrosis Since the early 1990s, when interferon α was first introduced for the treatment of HBV and HCV infection, the main

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DOI http://dx.doi.org/ 10.1055/s-0035-1550056. ISSN 0272-8087.

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1 Institute for Liver and Digestive Health, University College London and

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therapeutic goal has been viral suppression in chronic hepatitis B and viral eradication in chronic hepatitis C. Large randomized trials of 10 different interferon- (IFN-) based regimens in patients with chronic HCV infection (biopsies separated by a mean of 20 months) performed more than 10 years ago demonstrated a reduction in the rate of progression of necroinflammation and fibrosis following SVR even in patients with advanced disease.5 In addition, portal hypertension (PH), splenomegaly, and other clinical manifestations of advanced liver disease also improved. Among HCV-infected persons, SVR was shown to be associated with a more than 70% reduction in the risk of hepatocellular carcinoma (HCC) and a 90% reduction in the risk of liver-related mortality and liver transplantation.6–8 Cure of HCV infection also reduces symptoms and mortality of cryoglobulinemic vasculitis,9 and induces complete or partial remission in up to 75% of HCVrelated non-Hodgkin’s lymphoma and other lymphoproliferative disorders.10,11 Treatment of chronic hepatitis B with antiviral agents aims to prevent disease progression and improve survival through the reduction of HBV DNA to undetectable levels. Similarly to chronic HCV infection, there is now considerable evidence to suggest that effective sustained suppression of HBV replication with long-term anti-HBV treatment using NUC can result in measurable improvements in liver fibrosis over time, even in patients with advanced cirrhosis.12,13 Tenofovir treatment for up to 5 years resulted in histologic improvement in 88% of hepatitis B e-antigen-positive and 87% of hepatitis B e-antigen-negative patients treated continuously with Tenofovir, with improvement or stabilization of fibrosis in the majority of patients.14 Similarly, Entecavir treatment of 57 hepatitis B e-antigen-positive and hepatitis B e-antigennegative patients for a median of 6 years resulted in a  1point improvement in the Ishak fibrosis score in 88% of patients, including the patients who had advanced fibrosis or cirrhosis at baseline.15 Overall, the success of antiviral treatments in blocking the fibrogenic progression of chronic liver disease (CLD) has provided key information on the natural history of fibrosis regression, and has established important benchmarks and targets for antifibrotic drugs. Therefore, these results reinforce the need for a more precise understanding of the molecular mechanisms of fibrogenesis to design new treatment approaches effectively leading to fibrosis regression independent of the etiology of CLD.

Mechanisms of Fibrosis Reversal Following SVR The mechanisms regulating the reabsorbtion of scar tissue and leading to tissue regeneration after the elimination of the cause of chronic liver tissue damage, such in the case of patients achieving SVR, can only be extrapolated from the extensive evidence obtained in experimental models. In addition, the sequence and the relevance of different mechanisms involved in fibrosis reversal may differ in precirrhotic liver, in early cirrhosis, and in advanced/established cirrhosis. In basic terms, the process is led by a more or less rapid Seminars in Liver Disease

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switch-off of the chronic wound-healing process and is characterized by the progressive reduction of necroinflammation followed by the reduction of the number of activated hepatic stellate cells (HSCs), which is critical for the reversibility of fibrosis. Three major pathways—reviewed in detail by Ramachandran, Iredale, and Fallowfield (“Resolution of Liver Fibrosis: Basic Mechanisms and Clinical Relevance”) in this issue—help clear fibrogenic, activated HSCs: (1) apoptosis,16 (2) senescence,17 and (3) reversion to quiescence.18,19 In addition, macrophages have been shown to be key cellular determinants of the resolution of liver fibrosis. Along these lines, several studies have indicated that there might be different classes of macrophages that contribute to fibrosis progression and regression, respectively.20 However, when attempting to transfer these concepts to the mechanisms of fibrosis regression following SVR in patients with chronic HCV hepatitis it is very important to stress that these mechanisms have been identified and investigated in animal models where cirrhosis can be established within a few weeks from the initial exposure to the causative agent or surgical procedure, and can be easily and rapidly reverted upon their suspension. Therefore, the relevance and the dynamics of different mechanisms could be rather different in the regression of liver tissue fibrosis in human CLD that develops over decades rather than weeks. Whereas evidence clearly indicates reversibility of fibrosis in precirrhotic disease, the determinants of fibrosis regression in cirrhosis are not sufficiently clear, and the point at which cirrhosis is truly irreversible is not established, either in morphologic or functional terms. Indeed, with a longer duration of liver fibrosis and cirrhosis there is increasing accumulation of high-density fibrillar collagens (e.g., collagens I and III) as well as proteoglycans and other NAFLD constituents.21 Established fibrotic septa are characterized, in addition to extensive collagen crosslinking, by a relative hypocellularity. This raises the intriguing possibility that a degree of ongoing inflammation and thus the influx of macrophages around the fibrotic bands is essential for adequate scar remodeling.22 Collagen crosslinking enhances the resistance of collagen to degradation, and is a critical determinant of fibrosis irreversibility. Elastin, another noncollagenous matrix component, may also contribute to the resistance to fibrosis reversion after SVR. Elastin accumulates in mature cirrhosis and is dependent on macrophage-derived matrix metalloproteinase- (MMP-) 12 for degradation.23,24 In cirrhosis, its synthesis is enhanced while its degradation is decreased, leading to elastin accumulation. The contribution of elastin to fibrosis persistence may be the result of crosslinking of its preform, tropoelastin by the enzymes lysyloxidase or tissue transglutaminase, which also renders the cirrhotic tissue more resistant to degradation and therefore less likely to regress.

The Clinical Assessment of Fibrosis Progression and Regression It is interesting that the awareness about the fibrotic progression in the natural history of chronic viral hepatitis and

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the consequent need for staging have slowly developed in the last two decades along with the expansion of therapeutic options. Although liver biopsy is not indispensable for formulating a diagnosis of chronic viral hepatitis, the definitions of disease grading (necroinflammatory activity) and staging (tissue fibrosis) were initially introduced to justify and prioritize antiviral treatment. This necessity also led to the introduction of semiquantitative scoring systems that were supposed to facilitate the comparison between samples, both in clinical practice and in clinical trials, and the communication of the results according to a global agreement.25 Along these lines, the introduction of staging systems has allowed a reasonable understanding of what is defined disease progression in CLD and has facilitated the communication between clinicians and pathologists. However, sampling error, and most importantly, interobserver variability26 make semiquantitative scores far from precise especially for scoring systems characterized by a limited number of scoring options, such as METAVIR for HCV. In addition, there is increasing awareness that a simple semiquantitative fibrosis score does not adequately represent the complexity of the pathophysiological process leading to cirrhosis and ultimately to life-threatening complications. This inadequacy becomes fully manifested in the stage defined “cirrhosis,” a phase of CLD often lasting several years, lacking appropriate clinicopathological correlates.27 Thus, there is a pressing need to redefine cirrhosis in a manner that better recognizes its underlying relationship to PH and tissue fibrosis, and more faithfully reflects its progression, reversibility, and prognosis.28 These methodological issues represented and still represent a problem in the correct interpretation of fibrosis progression, and even more, fibrosis regression following the removal of the cause of chronic liver tissue damage and particularly in HCV patients achieving SVR. Along these lines, a claim of “cirrhosis reversal” has stimulated animated discussions and the question “Is cirrhosis reversible?” is still unanswered.29 As it will be expanded later, this interrogative is likely due to the lack of a precise framing/classification of the entity that we define as “cirrhosis.”

New Antivirals and Fibrosis Regression: New Interpretative Challenges The novel treatment regimens usually consist of a 12-week course of both a NS5A inhibitor and a NS5B polymerase inhibitor, and result in excellent SVR rates of > 95%. NS5A/ NS5B inhibitor combinations are also highly effective for previously difficult-to-treat and/or difficult-to-cure HCV subgroups including patients with cirrhosis.2 The introduction of the new therapeutic regimens for HCV bears a very high financial burden.30 Indeed, economic barriers will likely represent a major hurdle for the universal use of the novel IFN-free DAA regimens.31 Local policies differ among health care systems and offer/reimbursement for IFN-free treatment regimens is often limited to certain HCV patient groups according to treatment priorities to prevent astronomical costs. The most immediate and high-impact benefits of SVR

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will be realized by populations that are at the highest risk for liver-related complications due to progressive liver disease (advanced fibrosis/cirrhosis: METAVIR F3/F4), transplant recipients, and patients with clinically severe extrahepatic manifestations. Patients at high risk for liver disease progression (METAVIR F2) or with substantial extrahepatic manifestations are also expected to gather appreciable benefits, although the time course for realizing these benefits will be definitely more protracted. In the scenario driven by treatment guidelines based on health economics, patients with cirrhosis will likely represent the frontline in the use of the new anti-HCV agents. This line of strategy is dictated not only by health economics, but also by the success in reaching SVR independently of disease severity and by the very limited side effects associated with the use of new agents when compared with the IFN-based regimens, even in cirrhotic patients.30 However, it is likely that achieving SVR in patients with cirrhosis represents a virological “cure,” but does not necessarily prevent decompensation and/or completely abolish the risk of HCC development. In practical terms, the interpretative problems emerged by the relatively uncommon and beyond the label indications treatment of cirrhotic patients with IFN-based regimens will be significantly amplified. Indeed, the effect of SVR at different times of progression once cirrhosis is already established is very poorly characterized due to the heterogeneity of expression of the disease.27,32 In addition, there is still no clear-cut demonstration of the effect of the stage of cirrhosis before antiviral treatment on the benefit ensured by SVR, that is whether the benefit on hard endpoints, such as reduction of liver-related death, need for transplant, and HCC development, are equally reduced irrespective of the stage of cirrhosis. At this point it is natural to ask: Is there a staging system of cirrhosis that adequately reflects the pathophysiology of the disease or simply the impact of tissue fibrosis, together with neoangiogenesis, necroinflammation, and attempted regeneration, on the often life-threatening clinical manifestations? The answer is unfortunately negative. Undeniably, it is increasingly clear that the term “cirrhosis” identifies an advanced phase of CLD that per se is neither morphologically or clinically an end stage, particularly with the prospective of novel treatments able to stabilize or even reduce tissue fibrosis. Regardless, patients with cirrhosis are classified along with the appearance of major clinical manifestations with little or no ability to predict these often life-threatening events (so-called expectant algorithm).33 Accordingly, the currently used classification of cirrhosis includes stage 1 (compensated with no esophageal varices) with an estimated 1% mortality rate per year, and stage 2 (compensated with esophageal varices), stage 3 (ascites), and stage 4 (gastrointestinal bleeding) with an annual mortality rate that increases from 3.4% to 20% to 57%, respectively.34 A fifth stage characterized by infections35 and renal failure36 with a 67% one-year mortality rate further refines this classification. The first large study on the effect of SVR in patients with HCV cirrhosis analyzed 479 patients with advanced fibrosis/ cirrhosis (Ishak score, 4–6) treated with an IFN-based Seminars in Liver Disease

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regimen between 1990 and 2003.8 Sustained viral response was achieved in 30% of the patients. The results of the study suggested that the achievement of SVR after treatment with IFN or Peg-IFN with or without ribavirin was associated with a reduction in clinical events, mainly liver failure. However, no information was provided on the effects of SVR on clinical manifestations of PH, which represent the main causes of liver-related death. The results of a more recent study performed in patients with compensated HCV cirrhosis suggested that over an observation period of 12 years, the achievement of SVR prevents the development of esophageal varices (EV) in patients with compensated HCV-induced cirrhosis.37 This observation highlights that SVR obtained in an early stage of cirrhosis, when cirrhosis is still reversible, may arrest the fibrogenic progression and lead to a stabilization or even reduction of portal pressure. A recent prospective study investigated a cohort of 444 patients with compensated HCV cirrhosis treated with Peg-IFN alfa-2b and ribavirin38 to ascertain the role of pretreatment PH and the presence/ absence of EV on the long-term effects of SVR in this condition. All patients were screened for EV before treatment and every 2 years thereafter. Esophageal varices were present at baseline in 51.3% (stage 2 cirrhosis) and 24.3% of the whole cohort achieved SVR. The results show that death due to decompensation is significantly reduced only when SVR occurs in patient in cirrhosis stage 1 and without clinically significant/severe PH. In addition, patients with SVR can still progress from cirrhosis stage 1 to stage 2 because the de novo appearance of EV was observed in 12.3% of patients. Finally, progression in the severity of EV was observed in a large percentage of patients (34.1%). These data suggest that the assessment of portal pressure becomes useful if not indispensable to predict the outcomes following SVR and to organize an adequate follow-up schedule. Considering the immediate prospective of treating efficiently a very large number of cirrhotic patients with the new IFN-free regimens, the key lesson emerging from these studies is that in compensated cirrhotic patients with clinically significant and severe PH, HCV clearance does not induce a significant reduction of PH and that cirrhosis, once advanced, may progress to decompensation even in the absence of HCV replication. In biological terms, this can be explained by the relative autonomy acquired by the fibrogenic process beyond a certain level of development over decades characterized by chronic fibroinflammation and neoangiogenesis. In particular, it is conceivable that at this stage of the disease, two major determinants may condition further clinical progression independently of the reduction of hepatocellular necrosis and inflammation induced by SVR. The first is represented by the remarkable hyperplasia of activated HSCs and myofibroblasts, which is associated by a strong activation of antiapoptotic pathways in these cells.39 The second is due to the extensive changes in hepatic angioarchitecture consequent to neoangiogenesis and to the contraction of scar tissue leading to elevated tissue tension, which are only minimally affected by the reduction of necroinflammation following SVR.40,41 The impact of SVR in patients with decompensated cirrhosis may be even more difficult to define because it encomSeminars in Liver Disease

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passes a wide spectrum of disease, ranging from patients with relatively well-preserved liver function (mild ascites or recent variceal bleeding) to patients with very poor liver function and a short life expectancy (Child–Pugh C > 10 points).42 On the other hand, several studies have found that fibrosis regression/reversal might be more likely in early cirrhosis than established cirrhosis and that the absence of PH may be a determinant of reversibility.43 In this context, PH is simply the pacer of disease severity and the relationship between PH and fibrosis irreversibility reflects the biochemistry of established tissue fibrosis typical of pre-end stage disease (acellular fibrosis, extensive collagen crosslinking, and elastin deposition). In addition, when PH exceeds hepatic venous pressure gradient (HVPG) values of 12 mm Hg, cirrhosis becomes a systemic illness and disease severity is largely independent of liver tissue fibrosis.28 At this stage, the achievement of SVR will lead to minimal clinical advantages with a very high cost and the use of IFN-free regimens should be advised only in patients on the transplant list.44 As mentioned earlier in this article, data from randomized controlled trials have provided direct evidence supporting the positive effect of SVR on the prevention of HCC in patients with chronic HCV infection. Nevertheless, the risk of HCC remains in patients with chronic HCV infection if treatment is initiated after cirrhosis is established.45 Indeed, the presence of cirrhosis and chronic hepatic inflammation is unquestionably important contributing causes to HCV-associated HCC. In addition, while progression to HCC is variable among patients with chronic hepatitis C, suggesting that cancer arises due to a complex interplay between host, viral, and environmental factors, a wealth of studies suggest that epigenetic changes in HCVinfected hepatocytes may underlie the development of HCC.46 The regenerative attempt of infected hepatocytes and the presence of a fibroinflammatory stroma are strong synergic pathways in the pathogenesis of HCC.47,48 In this context, the achievement of SVR will directly prevent the pro-oncogenic changes in hepatocytes and will indirectly tend to reduce/resolve the stromal abnormalities favoring HCC development and progression. However, the prolonged timeframe necessary to obtain these results, and particularly the normalization of the liver microenvironment, will not prevent the emergence of HCC originated before the achievement of HCV clearance with the consequent need of a long follow-up post-SVR. In summary, the achievement of SVR in large cohorts of cirrhotic patients will present clinical challenges related to the relative independence from fibrosis regression of the main causes of liver-related death, in particular the systemic manifestations of decompensated cirrhosis and HCC. In this context, a classification of cirrhosis based on key pathogenetic mechanisms reflecting the complexity of the disease rather than just fibrosis becomes now fundamental.27

The Role of Genetic/Epigenetic Factors and Comorbidities on Fibrosis Regression Following SVR When approaching an effective monitoring of fibrosis regression it is legitimate to think about possible predictors of

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reversibility that would provide a great clinical advantage. It is clinically established that the rate of fibrosis progression is influenced by individual factors with the identification of fast, slow, and intermediate “fibrosers.”49 However, though recent genomic research in the field of liver fibrosis has placed focus on unraveling the genetic architecture of disease susceptibility data on genetic markers anticipating an accelerated fibrogenesis in an individual are still limited.50,51 Along these lines, recent evidence derived from genome-wide association studies or investigating the impact of single nucleotide polymorphisms have identified variants associated with progression of liver fibrosis from HCV infection.52,53 In this context, the identification of fast, intermediate, and slow “regressors” will lead to questions related to the influence of individual genetic and epigenetic factors on the reversibility of fibrosis, for example, Would the presence of genetic/epigenetic determinants of fast progression affect the extent and rapidity of fibrosis regression? Overall, although the answer to this question is likely positive, the precise correlation with individual genetic/epigenetic determinants will need to be established by dedicated studies. The presence of nonalcoholic fatty liver disease (NAFLD), associated with increased body mass index or frank obesity, and the hepatic consequences of alcohol abuse are the most commonly observed profibrogenic cofactors associated with chronic HCV infection. Several reports have shown that excessive alcohol consumption does not affect the response to the standard Peg-IFN/Ribavirin regimen.54,55 and that baseline metabolic factors seem to have a minor, though likely not negligible, role in influencing antiviral response to direct antiviral agent-based treatment in patients with genotype 1 chronic hepatitis C.56 Although there are no definitive data on the influence of these cofactors on the response to the new IFN-free regimens, it is conceivable that the persistence of these key profibrogenic cofactors will negatively impact the extent and rapidity of fibrosis progression despite the achievement of SVR.

Monitoring Fibrosis Regression Following SVR In practical terms, the curative impact of SVR will be monitored by assessing the possible reduction of tissue fibrosis with time. Given the inherent limitations of semiquantitative scoring highlighted earlier, it is unlikely that these systems will be used for assessing fibrosis regression in a cirrhotic liver with sufficient accuracy. Increasing evidence suggests that standardized morphometric analysis of liver tissue fibrosis obtained with computer-assisted morphometry could provide a quantitative measure of hepatic fibrosis on a continuous scale, and when adequately standardized, greatly reduce intra- and interobserver variability. Accordingly, morphometry has been proposed for the characterization of the histopathological features of potential disease regression in patients with HCV cirrhosis achieving a SVR following antiviral treatment.57 Importantly, morphometric analysis using the collagen proportionate area (CPA) system has demonstrated an excellent positive correlation between the amount

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of fibrosis in a cirrhotic liver and the relative HVPG58 with a consistent predictive value for clinical decompensation.59 Further work employing the CPA system or other morphometric methods will hopefully lead to the definition of subcategories of cirrhosis and their relationship with portal pressure, thus providing important information for treatment planning and posttreatment follow-up. The introduction of computer-assisted morphometry could provide additional diagnostic/prognostic elements in the interpretation of disease regression following HCV SVR. Indeed, although fibrosis and even cirrhosis seem to regress significantly in SVR patients, other aspects closely related to the fibrogenic process such as ductular proliferation, loss of lobular zonation, portal inflammation, and sinusoidal capillarization may not regress after viral eradication.57 These observations, although further highlighting the higher discriminative potential of morphometry, suggest that a more comprehensive analysis, that is not limited to the assessment tissue fibrosis, is needed for the characterization of disease progression and regression in patients with cirrhosis. Over the past decade, several methodologies have been proposed for the noninvasive assessment of liver fibrosis, particularly in chronic HCV hepatitis. All these methodologies used the METAVIR scoring system as a gold standard with a consequent poor definition of key endpoints in fibrosis progression: the occurrence of significant fibrosis (F2 METAVIR) and the evolution of cirrhosis (defined as a single endstage F4). Although it would be reasonable to re-evaluate the proposed noninvasive methods for the assessment of disease progression using computer-assisted morphometry, this should be mandatory for the design and the validation of noninvasive methods aimed at monitoring fibrosis regression following SVR. Among noninvasive methods, transient elastography (TE) has reached an established role in clinical practice, particularly in HCV-induced CLD (see also “Diagnosis of Liver Fibrosis: Present and Future” by Patel, Bedossa, and Castera in this issue). There is substantial evidence indicating that TE can be quite effective in detecting patients with a high risk of having (or not having) developed clinically significant elevations of portal pressure or varices.60,61 Recently, studies employing different approaches to measure elastography have highlighted the potential utility of spleen stiffness assessment for the prediction of the presence of EVs and the degree of PH in cirrhotic patients.62,63 With the introduction of IFN-free regimens for HCV, it is conceivable that the monitoring of fibrosis regression following SVR will be largely performed with TE and with analogous methodologies, such as acoustic radiation force impulse imaging (ARFI) and shear wave elastography (SWE), in patients with or without cirrhosis. The studies so far published suggest that even in patients with SVR, a significant decrease of liver stiffness is detected only after 1.5 to 3 years of follow-up and that liver stiffness assessment earlier than 6 months after the end of therapy does not appear to reflect a regression of tissue fibrosis, but rather a decrease in the extent of necroinflammation.64,65 When used to determine the effects of SVR on established fibrosis with extensive collagen crosslinking and elastin Seminars in Liver Disease

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Table 1 Factors conditioning the dynamics of fibrosis regression in cirrhotic liver as assessed by transient elastography Histopathology

Dynamics

Diagnostic value

Biochemistry of cirrhotic tissue: extensive crosslinking/elastin

No changes

Low

Tissue contraction/relaxation

Rapid changes

Low

Necroinflammation/swelling

Rapid changes

Low

Established fibrosis with limited neoangiogenesis

Slow changes

Acceptable

Established fibrosis with extensive neoangiogenesis

Very slow changes

Low

Cholestasis

Very slow changes

Low

deposition, TE is not likely to show significant changes. ►Table 1 summarizes the possible effect of different pathological situations on the measurement of liver stiffness by TE following SVR. Overall, TE would need to be fully reinvestigated and revalidated for the assessment of liver fibrosis regression. This concept is supported by a recent study by D’Ambrosio and coworkers where liver stiffness values were related to quantitative morphometric evaluation of liver fibrosis following therapeutic eradication of HCV.66 They showed that the predictive power of the cutoff of 12 kPa, indicating the presence of cirrhosis, was low as a consequence of complex liver remodeling, representing a key confounding factor for the pure assessment of tissue fibrosis. A large scientific and commercial investment has been made in the past two decades to develop serum markers able to predict the fibrotic stage of CLD (see also review by Patel et al in this issue). Among the proposed markers, some reflect

alterations in hepatic function, but do not directly reflect extracellular matrix metabolism: “indirect markers.” Others are directly linked to the modifications in extracellular matrix turnover occurring during fibrogenesis: “direct markers.”67 When thinking to use these noninvasive methodologies for the assessment of fibrosis regression following SVR, we need to consider that all the proposed algorithms were designed for the assessment of fibrosis progression and not for regression. As shown in ►Fig. 1, none of the single biomarkers, either “direct” or “indirect,” employed in the so far proposed systems would be suitable for reflecting fibrosis regression with a minimum level of accuracy. This means that serum markers for the assessment of fibrosis regression will need to be newly designed and validated for future use. As a final consideration, it is more and more evident that while we are reconsidering the role of liver biopsy in advanced chronic liver disease, a modern assessment of disease

Fig. 1 Changes in the behavior of single components of serum marker algorithms for the assessment of liver fibrosis progression following sustained viral response in patients with chronic hepatitis C virus hepatitis. The bottom black bar indicates different phases of the pathophysiology of chronic liver disease from the initial but constant parenchymal damage to the complications of portal hypertension. α2-MG, α2 macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECM, extracellular matrix; GGT, gamma glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; MMP, metalloproteinase; PI, prothrombin index; PIII NP, procollagen III N-terminal propeptide; TIMP, tissue inhibitor of metalloproteinase. Seminars in Liver Disease

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Fibrosis Regression after SVR: Any Space for Antifibrotic Agents? Before the introduction of the IFN-free regimens and because of the difficulties inherent in the treatment of cirrhotic patients, patients with advanced chronic viral hepatitis nonresponders to Peg-IFN/ribavirin were considered one of the ideal groups for the treatment with antifibrotic drugs once available.68 Clearly, this possibility needs to be reconsidered in the post-HCV era, at least in patients with chronic HCV and also HBV hepatitis. In this context, antifibrotic agents could be employed to favor a more rapid and harmonic remodeling of liver tissue especially in those cirrhotic patients manifesting a tendency to disease progression toward complications of PH after achieving SVR. In other words, an antifibrotic treatment initiated after the completion of antiviral treatment could be aimed at one or more of the following objectives: (1) inhibition of collagen crosslinking and elastin deposition, (2) degradation of collagen and elastin, (3) inhibition of fibrotic tissue contraction and consequently tissue stiffness, and (4) favor HSC/myofibroblast apoptosis. The achievement of these objectives could slow down the SVR-independent disease progression including the development of HCC.

Conclusions At least in the very near future patients with HCV cirrhosis will be at the center of clinical attention with the prioritization of IFN-free regimens. The successful elimination of the cause of chronic hepatocellular damage in thousands of patients will finally shed light on the reversibility of fibrosis and cirrhosis in humans and on the relative mechanisms. In this context, the assessment of fibrosis regression and possibly of cirrhosis reversal will represent the diagnostic challenge of the next decade. It seems likely that in patients with chronic HCV infection, liver biopsy will be proposed in the advanced rather than the early phase of disease to proceed with a morphological classification of cirrhosis based on quantitative/morphometric methods able to provide more precise prognostic information.69 Among the noninvasive methods introduced in clinical practice over the last two

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decades, transient elastography and related techniques will still represent solid and user friendly tools, although caution will be necessary in the interpretation of both rapid and delayed changes in liver tissue stiffness following SVR.

Abbreviations ARFI CLD CPA EV HBV HCC HCV HSCs HVPG IFN MMP NAFLD NUC PH SVR SWE TE

acoustic radiation force impulse imaging chronic liver disease collagen proportionate area esophageal varices hepatitis B virus hepatocellular carcinoma hepatitis C virus hepatic stellate cells hepatic venous pressure gradient interferon matrix metalloproteinase nonalcoholic fatty liver disease nucleoside/nucleotide analogues portal hypertension sustained viral response shear wave elastography transient elastography

Acknowledgments The author wishes to thank Professor Vito di Marco, Universita’ degli Studi di Palermo, Palermo, Italy, for the inspiring discussions on the antiviral treatment in patients with cirrhosis.

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progression and regression should be able to conjugate morphoimaging with the detection of key pathophysiological events (fibrogenesis, angiogenesis, and liver regeneration) and the assessment of different aspects of liver function. Key progression elements, such as hepatocellular necrosis, apoptosis and regeneration, ductular reaction, increasing tissue hypoxia and endothelial dysfunction, scar contraction due to an unbalanced presence of vasoconstrictors, preneoplastic features are not yet fully considered although they could represent optimal tissue biomarkers for the development of advanced bioimaging technologies. Bioimaging together with the implementation of the current imaging techniques (from ultrasound to positron emission tomography-computed tomography) should be one of the top aims of hepatology in the next decade to finally achieve methodologies reflecting the “wounding and the healing” in CLD.

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8 Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic

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Liver Fibrosis in the Post-HCV Era

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