Risk Of Developing Liver Cancer After HCV Treatment

Friday, January 20, 2012

Hepatitis C-From Clinical Guidelines to Clinical Practice

From Clinical Guidelines to Clinical Practice
Is Expanding Access to Treatment Cost-effective?

  1. E. Degasperi,
  2. A. Aghemo
Article first published online: 10 JAN 2012
DOI: 10.1111/j.1365-2893.2011.01517.x

Journal of Viral Hepatitis
Special Issue: How to Optimize Treatment of Hepatitis C
Volume 19, Issue Supplement s1, pages 3–6, January 2012

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Summary.
Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths.

Abbreviations:
ESRDend-stage renal disease
HCChepatocellular carcinoma
HCVhepatitis C virus
PegIFNPegInterferon
SAEserious adverse events
SVRsustained virological response

Hepatitis C virus (HCV) infection is a major health problem that affects over 170 million people worldwide and represents a leading cause of cirrhosis and liver transplantation. The goal of antiviral therapy is to achieve viral eradication to prevent fibrosis progression in chronic hepatitis [1] and liver-related complications in cirrhotic patients [2]. While a sustained virological response (SVR) can positively impact on the natural history of liver disease, antiviral therapy with PegInterferon (PegIFN) and Ribavirin (Rbv) is associated with many side effects, which in rare cases can be serious and ultimately interfere with treatment outcome because of reduced adherence to therapy. For these reasons, most scientific societies do not currently recommend a broad treatment approach, advocating instead a patient selection process where a multitude of baseline factors are considered as clinical drivers.

From Clinical Guidelines to Clinical Practice

Current international guidelines advise treating those patients who could benefit greatly from therapy, based on liver disease severity and likelihood of treatment response, while minimizing serious adverse events. While this approach seems reasonable from a theoretical point of view, its application in everyday clinical practice is problematic and controversial.

Concerning liver disease severity, the AASLD recommendations suggest that, if a liver biopsy is available, treatment should be started in patients with compensated cirrhosis or bridging fibrosis (Metavir score F > 2) [3].

In fact the outcome of compensated HCV cirrhosis is influenced by complications such as hepatocellular carcinoma (HCC), ascites, variceal bleeding, portosystemic encephalopathy and jaundice, which have an annual incidence estimated between 0.5% and 3.5%, and which eventually lead to liver transplantation or death [4]. The beneficial impact of antiviral therapy is well established: SVR to PegIFN and Rbv improves survival in patients with advanced fibrosis or cirrhosis by reducing liver-related complications and liver-related death [5]. However, although treating advanced liver disease is clearly indicated, it is difficult to define a cut-off for mild-moderate disease to identify the best candidates for treatment. Liver biopsy, the current gold standard for assessing fibrosis stage, may underscore fibrosis by one point in at least 30% of patients because of sampling problems or heterogeneous liver architecture [6]; moreover, fibrosis progression does not follow a linear pattern during the natural history of chronic hepatitis C infection. Some authors have hypothesized that patients can be categorized as slow, intermediate, or rapid progressors, based on a time to cirrhosis of <20, 20–50, and >50 years [7]. Others have elaborated models where fibrosis progression is a linear process with an abrupt acceleration during the natural course of liver disease [8]. A number of factors have been identified as accelerators of fibrosis progression, including male sex, co-infections (e.g., HBV, HIV), comorbidities, and even genetic factors; however, prediction of fibrosis progression at the individual level is not currently possible.

Moreover, the many extrahepatic manifestations of HCV infection have led some to consider it a systemic disease [9]. Indeed a pathogenic role for HCV has been established in mixed cryoglobulinemia, a disease that can lead to impaired kidney function and polyneuropathy. Moreover, higher prevalences of B-cell non-Hodgkin lymphoma, monoclonal gammopathies and dermatological diseases (lichen planus) have been observed in HCV patients. While anecdotal reports of other associations, for example, with autoimmune thyroiditis, sicca syndrome, diabetes, non-cryoglobulinemic nephritis, psoriasis, neuropathies, arthritis, dermatomyositis, vitiligo, and cardiopathies require confirmation [9].

Recently, Tsui et al. [10] reported that HCV infection increased the risk of developing end-stage renal disease (ESRD) in a cohort of 52 874 patients infected with HCV compared with 421 495 uninfected patients, with a median follow-up of 3.6 years. A decline of estimated glomerular filtration rate >10 mL/min was observed in 14% of HCV+ patients, compared with 9% of HCV− patients (P < 0.01), indicating that HCV is associated with progressive impairment of renal function (OR for ESRD 1.68).

Hepatitis C virus (HCV) has long been assumed to play a pathogenic role in the development of B-cell lymphomas through polyclonal immune stimulation that eventually leads to monoclonal proliferation. Results from a murine model expressing the full genome of HCV in B-cells have recently suggested a direct role for HCV in the pathogenesis of B-cell lymphomas: Kasama et al. [11] observed a significant increase in spontaneous B-cell lymphomas in rzCD19Cre mice, in which the CD19 gene drives constitutive B-cell-specific expression of the full HCV genome. No significant increases were noted when the HCV genome was integrated but not expressed.

These results have two important implications: first, they demonstrate that HCV infection can lead to B-cell lymphoma in a murine model; secondly, lymphoma is a direct consequence of the presence of the virus and not purely an effect of immune stimulation, because expression of HCV genes at an early embryonic stage results in immunological tolerance to virus. This reinforces the concept that HCV eradication may prevent B-cell lymphomas. This hypothesis is supported by the findings of Kawamura et al.[12], who reported a lower cumulative incidence of malignant lymphoma after 15 years in patients achieving HCV eradication compared with patients who did not (0% for SVR vs 2.6% for persistent infection; Log-rank test P = 0.0159).

Therefore, treating HCV infection and eradicating the virus would impact not only on liver disease, but also on extrahepatic complications, suggesting that treatment decisions should also consider the risk of developing HCV-related diseases during the course of the infection.

According to the AASLD guidelines, eligibility for antiviral therapy should depend also on the likelihood of achieving an SVR to antiviral therapy. Unfortunately, this recommendation has several weak points: not only does it partially contradict the concept of treating only patients with advanced fibrosis, because liver fibrosis is a strong negative predictor of success in antiviral therapy, with SVR decreasing from 70% in patients with a baseline staging of F0 to 10% in stage F4 [13] but also most of the other predictors of treatment failure in chronic hepatitis C, such as genotype 1 or 4, age, race and genetic polymorphisms, are nonmodifiable factors. The matter is further complicated by the fact that the factors considered modifiable, such as obesity, steatosis, insulin-resistance, are either very hard to modify (obesity and steatosis) or their modification has not been shown to improve SVR rates. Attempts to combine baseline moderators of treatment outcome have also been quite disappointing: SVR is estimated at 97% in young, noncirrhotic, normal weight patients with low viral loads, and at 7% in 60-year-old, cirrhotic patients with BMI > 30 kg/m2 and high viral loads [14], demonstrating again that the patients most in-need (i.e. cirrhotic) are also the most difficult to cure, because of unfavourable predictors deriving from liver stage, age and comorbidities that enhance disease progression. Further doubt is cast on the value of baseline predictors by the fact that, independent of negative baseline factors, the probability of achieving SVR soars to roughly 80% in patients who attain undetectable HCV-RNA levels at week 4 [15].

The last key guidance issue when selecting patients for anti-HCV treatment is the risk of side effects. Indeed, therapy must not be administered to certain categories of patients at high risk for serious adverse events, such as those with major uncontrolled depressive illness, autoimmune hepatitis, pregnancy, severe concurrent diseases, solid organ transplant (kidney, lung and heart) or known hypersensitivity to PegIFN or Ribavirin.

Moreover, some categories of patients are potentially exposed to many side effects, such as those with kidney failure, on haemodialysis or with decompensated liver disease. In these patients, treatment is not contraindicated but requires expert clinical management (Table 1). In all other patients, therapy may be complicated by side effects such as flu-like syndrome, anaemia and mood alteration, but these are usually mild. The rate of discontinuation for adverse events is generally between 10% and 15%, while serious adverse events (SAE) are observed in 3–4% of patients [16–18]. Although these numbers are low, it is important to note that most SAEs require expert and multidisciplinary management. For example in the IDEAL study, the most common SAEs were neuro-psychiatric symptoms (28%), infections (22%) and gastro-intestinal disorders (21%) [18]. Therefore, the availability of support from experienced colleagues is critical, especially in case of psychiatric symptoms, suggesting that the evaluation of eligibility for treatment should consider also the local potential for managing side effects and the availability of professional advice in other clinical fields, factors that can reduce discontinuation rates and optimize treatment outcomes.

Table 1. Patients contraindicated for antiviral therapy according to AASLD guidelines and categories of patients in whom therapy should be managed in expert centres ESRD, end-stage renal disease; OLT, orthotopic liver transplantation.

Contraindications to antiviral treatment
Major uncontrolled depressive illness
Solid organ transplant (heart, lung and kidney)
Autoimmune hepatitis
Pregnancy or unwilling to comply with contraception
Severe concurrent medical diseases
Age <2 years
Known hypersensitivity to drugs used in antiviral therapy
Patients requiring expert clinical management
ESRD
Patients on haemodialysis
Decompensated liver disease
Post-OLT patients

Is Expanding Access to Treatment Cost-effective?

For the above reasons, it seems appropriate that all motivated patients not presenting contraindications be considered for antiviral therapy, provided that the clinical centre can manage rare potential SAEs. However, such an aggressive treatment algorithm could lead to over-treatment and potentially have a negative impact on healthcare costs. Surprisingly, in contrast to this, European data on treatment for HCV reveal a general under-treatment of patients, with 1–16 patients treated with PegIFN per 100 prevalent cases [19]. The same is true also in the USA, where only 22% of patients diagnosed with HCV infection are given therapy.

Concerning costs, Volk et al. [20] have assessed public health impact of antiviral therapy in the United States, comparing costs deriving from management of treated or untreated patients: an estimated 50% increase in the number of treated patients could prevent 30% of liver-related deaths from HCV by 2030; the percentage of deaths prevented over that period would increase to 50% with a 75% increase in treated patients and a modest increase in the rate of SVR.

In conclusion, treating more HCV-infected patients could positively impact on public health in terms of deaths prevented, reducing also social costs derived from the management of chronically infected patients (follow-up, surveillance and hospitalization) thus optimizing public expenditures.

Patient eligibility for antiviral therapy requires a complex and extended evaluation, which should consider not only liver staging, but also patient characteristics, baseline predictors of disease progression and the probability of treatment success. Treating chronic hepatitis C could prevent extrahepatic HCV-related manifestations, thus reducing also non-liver-related complications. However, management of treatment requires clinical experience in dealing with side effects, and, for some cases, therapy can be administered only in expert centres. Although treating more patients increases costs, viral eradication is cost-effective in terms of reducing public expenses deriving from the care of chronically infected patients.

Disclosures

Alessio Aghemo participated in Advisory Committees supported by Roche and received travel support from Bristol-Myers Squibb, Roche, Glaxo-Smith-Kline. Elisabetta Degasperi has no financial disclosure to declare.



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