Tuesday, July 8, 2014

Long term changes in liver histology following treatment of chronic hepatitis C virus

Long term changes in liver histology following treatment of chronic hepatitis C virus

Good morning folks, another fun packed research article awaits you, this time by liver specialist Mitchell L. Shiffman, MD., exploring improvements in inflammation as well as fibrosis regression following SVR.

The discussion only is provided below, click here to download the full text, published in Annals of Hepatology; July, August issue. 

Long term changes in liver histology following treatment of chronic hepatitis C virus
Mitchell L. Shiffman,* Richard K. Sterling,** Melissa Contos,*** Sarah Hubbard,** April Long,* Velimir A. Luketic,** R. Todd Stravitz,** Michael Fuchs,** Arun J. Sanyal 

Ann Hepatol. 2014 Jul-Aug;13(4):340-9.

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Background and aims
The histologic hallmarks of chronic HCV include inflammation and fibrosis. The impact of interferon therapy on liver histology was evaluated.

Material and methods
The study population consisted of 348 patients with chronic HCV who underwent a baseline liver biopsy, received either no treatment or a single course of interferon based therapy, were followed for 5 years without any treatment or additional treatment and then underwent a repeat liver biopsy. The patients were divided into 3 groups; deferred treatment (NoTx = 47), received interferon based therapy but failed to achieve SVR (NoSVR = 189) and achieved SVR (SVR = 112).

Patients with NoTx and NoSVR had significant increases in mean inflammation scores (from 4.3 to 6.3 and 5.4 to 6.7 respectively; p < 0.001 for both) and fibrosis scores (from 0.9 to 1.8 and 1.9 to 2.5; p < 0.001 for both). The amounts by which inflammation, fibrosis and rate of fibrosis progression increased were not significantly different between the two groups. Increases in total inflammation and the piecemeal necrosis sub-score over time were strongly associated with fibrosis progression. Patients with SVR had a significant decline in mean inflammation and fibrosis scores (from 6.7 to 2.2 and 3.3 to 1.8; p < 0.001 for both); 40% of patients resolved all fibrosis and 50% of patients resolved cirrhosis.

Increases in inflammation are associated with fibrosis progression and in the absence of SVR interferon treatment does not appear to affect the long term natural history of this process. Patients with SVR have resolution of inflammation and fibrosis and many resolve cirrhosis.

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The results of this study have demonstrated that the vast majority of patients with chronic HCV who achieve SVR and remain HCV RNA undetectable in serum over many years have regression in fibrosis. Overall, about 40% of patients had complete loss of fibrosis and 50% no longer had evidence of cirrhosis 5 years after achieving SVR.

Significant improve ments in non-invasive markers of fibrosis, such as platelet count and APRI were also observed in patients with SVR. The degree of fibrosis improvement was closely linked to changes in the inflammation score. A long term improvement in both inflammation and fibrosis has also been observed in patients who achieved SVR in a previous study. 30 The current study also evaluated the impact of interferon based therapy in patients with chronic HCV who failed to achieve SVR.

Previous studies suggested that these patients also derive histologic benefit and this may reduce the rate of fibrosis progression. 13,14,16,18,19 However, in many of these studies the repeat liver biopsy was performed less than 1 year after discontinuing interferon treatment. None of the previous studies compared the histologic impact of interferon to a control group of untreated patients.

In the HALT-C study, over 800 patients with advanced fibrosis or cirrhosis underwent 2-3 liver biopsies over 4-5 years. 31,32 No significant reduction in fibrosis progression was observed even in patients who had profound virologic suppression during treatment with full-dose peginterferon during the lead-in phase and with low-dose peginterferon maintenance therapy. 32,33

Similar results were observed when a more sensitive technique, morphometric analysis, was utilized to quantitate tissue collagen. 34 The unique aspect of the present study was that changes in liver histology in patients who failed to achieve SVR were compared to patients who deferred HCV treatment. The rate of fibrosis progression observed in the NoTx group, 0.12 Ishak units/year, was very similar to that reported for untreated patients in previous studies, 1,11,12,35 and similar to that observed in patients with “No SVR”.

Thus, although short term improvements in liver histology may be achieved following interferon based therapy in patients without SVR it is unlikely that a single course of HCV treatment significantly impacts the long term natural history of fibrosis progression in the absence of SVR.

The primary limitation of this study was that patients could not be matched for baseline characteristics. Patients with no fibrosis who achieved SVR could not be included because there was no reason for these patients to undergoing a repeat liver biopsy. In addition, patients with more fibrosis rarely deferred treatment or opted for retreatment if they failed to achieve an SVR. This explains why the “SVR” and “No SVR” groups had significantly higher fibrosis scores at baseline than the “No Tx” group (Table 1).

As a result, we only evaluated fibrosis progression in patients with the same degree of fibrosis at baseline (Figure 2).

Another limitation was that biopsies were not rescored and 2 different systems were utilized during the nearly 15 years required to conduct this study. However, all biopsies were scored by the same pathologist during the entire study and the system utilized to convert Knodell to Ishak fibrosis scores was internally validated and tightly correlated.

Liver injury in chronic HCV is composed of two processes; inflammation and fibrosis. Several studies now strongly suggest that inflammation is the driving force for fibrosis progression in patients with chronic HCV. Inflammation increases with increasing fibrosis in chronic HCV 11,12,36 and fibrosis progression is strongly associated with higher inflammation scores. 11,12,36,37

The piecemeal necrosis subscore appears to be the most important part of the inflammation score leading to fibrosis progression. 12 Similar results were observed in the current study. Why inflammation increases in some patients with chronic HCV but remains stable in others remains undefined.

Most likely, this is secondary to host immunologic factors and their response to HCV. 38 Specific genetic polymorphisms may be associated with fibrosis progression because they affect the host immunologic response to HCV and the level of inflammation. 9,10 This possibility is worthy of additional studies.

Previous studies in other liver disorders have demonstrated that reducing the degree of hepatic inflammation can either lead to regression of fibrosis or delay fibrosis progression. Anti-viral therapy in patients with chronic hepatitis B virus, 39,40 and suppressing the immune response in patients with autoimmune hepatitis 41,42 are both associated with a reduction in inflammation and fibrosis.

Suppressing inflammation with maintenance interferon has been shown to prevent fibrosis progression. 43 Although very few patients in the HALT-C trial had suppression of HCV RNA with maintenance peginterferon, those patients in whom HCV RNA was suppressed to low or undetectable levels also had a reduction in inflammation scores and evidence of fibrosis regression. 44

In the present study, a strong linear relationship was observed between the decline in inflammation and fibrosis scores in patients who achieved SVR. Patients with SVR who had no improvement in inflammation also had no improvement in fibrosis. Why some patients with SVR had no improvement in inflammation remains unclear at this time. This observation may explain why some patients who achieve SVR do not resolve cirrhosis and remain at risk for hepatocellular carcinoma.

In summary, the current study has demonstrated that in patients with chronic HCV a strong relationship exists between hepatic inflammation and fibrosis. In patients with ongoing chronic disease, increases in inflammation are associated with fibrosis progression.

In contrast, achieving SVR and eradicating HCV, not just receiving interferon therapy, is associated with a marked reduction in inflammation and fibrosis regression. The future of HCV treatment is to suppress HCV with multiple oral antiviral agents without interferon and/or ribavirin. This approach has already been demonstrated to achieve high rates of SVR with various combinations of antiviral agents. 45-49

The observations of the present study strongly suggest that fibrosis regression including resolution of cirrhosis will occur in the vast majority of patients who will achieve SVR with these future therapies.

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Articles Of Interest
The impact of hepatitis C burden-Viral eradication can improve mortality and quality of life
The researchers noted that the associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence.

The team found strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life.

Dr Younossi's team comments, "The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden."
Alimentary Pharmacology & Therapeutics, March 2014

AASLD - Liver Deaths Cut Once HCV Viral Load Suppressed
Patients who achieved an undetectable viral load of hepatitis C virus (HCV) had decreased hepatic morbidity and mortality long-term, researchers found.
Medscape AASLD coverage , Nov 6, 2013

A ‘Killer’ of a Reason to Treat Hepatitis C
Dr. David Johnson stresses the importance of treating patients with hepatitis C and advanced hepatic fibrosis, given that those with sustained treatment response have a lower all-cause mortality rate. Medscape Gastroenterology, February 15, 2013

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