Regression of fibrosis in chronic hepatitis C after therapy with interferon and ribavirin

Interferon and ribavirin decrease necroinflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established. We evaluated the effect of combination therapy on virological and liver histopathological outcomes in 52 naïve patients and 79 patients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C. One hundred four patients completed interferon and ribavirin treatment after 24–48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in naïve patients and 22% in re-treated patients. In virological responders and nonresponders, fibrosis and necroinflammation scores decreased by –0.91 (P =0.04) and –0.5 (P =0.02) and by –2.8 (P =0.001) and –0.66 (P =0.06), respectively. Interferon and ribavirin had greater benefit on fibrosis when associated with clearance of HCV RNA. Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes.     

Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy

Aim: The aim of this retrospective cohort study is to assess the development incidence and predictive factors for chronic kidney disease (CKD) after the termination of interferon therapy in hepatitis C virus (HCV) positive Japanese patients with liver cirrhosis. Methods: A total of 650 HCV positive, liver cirrhotic patients who were treated with interferon and showed an estimated glomerular filtration rate (eGFR) of ≥60 mL/min per 1.73 m² after the termination of interferon therapy were enrolled. CKD was defined as an eGFR of <60 mL/min per 1.73 m². End‐stage‐CKD was defined as an eGFR of <15 mL/min/1.73 m². The primary goal is the new development of CKD and end‐stage‐CKD. Results: Eighty‐five patients developed CKD, and six patients progressed to end‐stage‐CKD. The development rate of CKD was 5.2% at the 5th year, 14.5% at the 10th year and 30.6% at the 15th year. Multivariate Cox proportional hazards analysis showed that CKD occurred when patients had age increments of 10 years (hazard ratio: 2.32; 95% confidence interval [CI] 1.61–3.35; P < 0.001), eGFR decrements of 10 mL/min per 1.73 m² (hazard ratio: 1.66; 95% CI 1.27–2.16; P < 0.001), hypertension (hazard ratio: 2.00; 95% CI 1.13–3.53; P = 0.017), diabetes (hazard ratio: 1.79; 95% CI 1.02–3.14; P = 0.042), and non‐clearance of HCV (hazard ratio: 2.67; 95% CI 1.34–5.32; P = 0.005). The development rate of end‐stage‐CKD was 0.4% at the 5th year, 1.6% at the 10th year and 2.8% at the 15th year. Conclusions: The annual incidence for CKD among cirrhotic patients with HCV was determined to be about 1.0–1.5%. In addition, the annual incidence for end‐stage‐CKD is one order of magnitude lower than that of CKD.     

Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation

BACKGROUND/AIMS: Steatosis is a frequent histological finding in chronic hepatitis C and is associated with increased hepatic fibrosis. METHODS: We studied 80 patients with untreated chronic hepatitis C to determine whether steatosis contributes to fibrosis through a steatohepatitis-like pathway. RESULTS: Fine sinusoidal and/or central vein fibrosis was present in 52 patients (65%). This was typically located in acinar zone 3 and had a chicken-wire appearance similar to that seen in steatohepatitis. A statistically significant relationship was found between subsinusoidal fibrosis and age (r(s) = 0.33, P = 0.003) and grade of steatosis (r(s) = 0.35, P = 0.001). Mean body mass index was higher in patients with focal (28.4 +/- 4.7 kg/m2) or extensive (29.6 +/- 5.9 kg/m2) subsinusoidal fibrosis than in those patients with no subsinusoidal fibrosis (25.5 +/- 3.7 kg/m2). The extent of alpha-smooth muscle actin staining (as a marker of stellate cell activation) correlated with the degree of portal inflammation and the stage of portal fibrosis, but not with the grade of hepatic steatosis. CONCLUSIONS: These findings suggest that in hepatitis C infection, host factors, particularly adiposity, contribute to both steatosis and acinar fibrosis. The implication of these observations is that weight reduction may provide an important therapeutic strategy for patients with chronic hepatitis C.     

Hepatic stellate cell activation and liver fibrosis are associated with necroinflammatory injury and Thl-like response in chronic hepatitis C

Abstract: Background/Aims: The involvement of a direct viral cytopathic effect or an immune-mediated mechanism in the progression of hepatic damage in chronic hepatitis C is controversial. The type of immune response is itself a matter of controversy, and histological data are lacking. The aim of this study was to identify the factors associated with the progression of liver injury in 30 HCV/RNA-positive untreated patients with chronic hepatitis. Methods: Necroinflammatory and architectural damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC) were visualized by immunohistochemistry for α-smooth muscle actin (αSMA) and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive RT-PCR method. To study the type of immune response involved in the progression of liver injury, interferony (IFNγ)-positive cells (as expression of a Th1-like response) were evaluated by immunohistochemistry and quantitated by morphometry. Results: HSC were mostly detected close to areas of lobular necroinflammation or lining fibrotic septa. The αSMA- and Sirius Red-positive parenchyma correlated significantly with necroinflammatory and architectural scores. IFNγ-positive cells were detected in periportal areas associated with the inflammatory infiltrates and significantly correlated with architectural damage. No relationship was found between the histological features of liver injury and viral load. Conclusions: HSC activation and progression of liver injury are unrelated to viral load but associated with a Th1-like response, a plausible target for the treatment of chronic hepatitis C.     

Quantitative HCV RNA and effect of interferon therapy in chronic hepatitis C

Digestive Diseases and Sciences -     

Hepatic fas antigen expression before and after interferon therapy in patients with chronic hepatitis C

To assess the relationship between hepatitis C virus infection and Fas antigen expression on hepatocytes, we examined changes in hepatic Fas antigen expression in the presence or absence of active hepatitis C virus infection. Twenty patients with chronic hepatitis C infection were treated with interferon and underwent pre- and posttreatment liver biopsies. Patients were classified according to the absence (group A; n=9) or the presence (group B; n=11) of hepatitis C virus RNA (HCV-RNA) in the liver after interferon therapy. An immunohistochemical assay showed Fas antigen staining in hepatocytes membranes and cytoplasm with expression concentrated mainly in periportal areas. The percentage of Fas-positive cells in the liver before treatment was not different between group A (39.5 ± 19.1%) and group B (32.5 ± 15.6%). Hepatic Fas expression was reduced significantly after treatment (24.3 ± 10.6%) compared with the pretreatment values in group A (p < 0.05) but not in group B (25.9 ± 16.9%). There was no significant difference between the two groups in the degree of histologic improvement. These results suggest that hepatic Fas expression is associated with persistent infection of hepatitis C virus.     

Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C

Interferon can induce autoantibodies and autoimmune reactions. This study reviewed the clinical, serological, and HLA phenotypical features of patients who developed autoimmune hepatitis during interferon therapy for chronic hepatitis C, analyzing their response to immunosuppressive treatment. The diagnosis of chronic hepatitis C was based on positivity for viral RNA and a liver biopsy specimen obtained before interferon treatment. Sera were tested for autoantibodies by indirect immunofluorescence assay. HLA typing was performed by applying a standard microlymphocytotoxicity method. Of 144 patients with chronic hepatitis C treated with interferon, 7 women deteriorated during treatment; serum transaminase, γ-globulin, and immunoglobulin G levels increased; and serum autoantibodies became positive. Interferon was interrupted, a diagnosis of autoimmune hepatitis was established, and immunosuppressive therapy was initiated. All patients responded to this treatment. The 7 patients had similar HLA typing to those with autoimmune hepatitis, with DR4 in 2 patients (67%) with type 2 autoimmune hepatitis, and with DR3 and DR52 in 2 (50%) and 4 (100%) patients, respectively, with type 1 autoimmune hepatitis; additionally, 5 patients (71%) had DQ2, and 4 (57%) had both DR52 and DQ2. In female patients with chronic hepatitis C, a genetic susceptibility to autoimmune hepatitis may exist, possibly triggered by immunostimulating effects during interferon therapy. Immunosuppressive treatment has been well tolerated and seems to be effective.     

Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C

Abstract: Background/Aim: Quantitative tests of liver function may be superior to conventional tests to assess the prognosis of patients with liver diseases. There are insufficient data from quantitative testing of liver function (QTLF) for patients with chronic hepatitis B and C, particularly with regard to fibrosis. Therefore, we applied a broad panel of QTLF to these patients. Methods: Three hundred and sixty‐seven consecutive patients with chronic hepatitis B or C underwent liver biopsy and QTLF, which included tests for hepatic metabolism (aminopyrine breath test, galactose elimination capacity) and for hepatic perfusion (sorbitol clearance, indocyanine green clearance). QTLF values were correlated with liver histology (grading and staging for inflammation and fibrosis) and Child–Pugh classification for liver cirrhosis. Results: In patients with no and moderate fibrosis, metabolic liver function was significantly decreased, whereas hepatic perfusion remained normal. Severe fibrosis and cirrhosis showed a significant decline in all QTLFs. Hepatic inflammation only reduced metabolic liver function, irrespective of the inflammatory grade. Viral etiology and HCV genotypes did not change QTLF. Conclusions: In summary, viral damage compromises hepatic metabolism before perfusion. Therefore, tests of metabolic liver function (aminopyrine breath test, galactose elimination capacity) should be useful to search for drugs that restore liver function in viral hepatitis irrespective of the fibrosis stage.     

Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C

BACKGROUND & AIMS: Liver fibrosis is an important prognostic factor in patients with hepatitis C. The effect of pegylated (PEG) interferon alone or its combination with ribavirin on fibrosis has not been established. METHODS: We pooled individual data from 3010 naive patients with pretreatment and posttreatment biopsies from 4 randomized trials. Ten different regimens combining standard interferon, PEG interferon, and ribavirin were compared. The impact of each regimen was estimated by the percentage of patients with at least 1 grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least 1 stage worsening in fibrosis METAVIR score, and by the fibrosis progression rate per year. RESULTS: Necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 73% (optimized PEG 1.5 and ribavirin; P < 0.001). Fibrosis worsening ranges from 23% (interferon 24 weeks) to 8% (optimized PEG 1.5 and ribavirin; P < 0.001). All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis. Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ratio [OR] = 0.12; P < 0.0001), sustained viral response (OR = 0.36; P < 0.0001), age < 40 years (OR = 0.51; P < 0.001), body mass index < 27 kg/m(2) (OR = 0.65; P < 0.001), no or minimal baseline activity (OR = 0.70; P = 0.02), and viral load < 3.5 millions copies per milliliter (OR = 0.79; P = 0.03). CONCLUSIONS: PEG-interferon and ribavirin combination significantly reduces the rate of fibrosis progression in patients with hepatitis C.     

Factors associated with liver steatosis and fibrosis in chronic hepatitis C patients

Liver steatosis is a common finding in patients infected with hepatitis C virus (HCV). Host and viral factors have been associated with steatosis, but their relative contributions have not been clearly addressed. It has been suggested that steatosis plays a role in the progression of liver fibrosis. AIMS: To assess: a) factors associated with steatosis in patients infected with hepatitis C virus; b) their impact on liver fibrosis. PATIENTS AND METHODS: Three hundred and fourteen untreated patients were included. Lifetime alcohol consumption was estimated. Liver fibrosis, inflammation and necrosis were assessed using the METAVIR score. Body mass index (BMI) was determined. The scoring system for steatosis was as follows: 0, no steatosis; 1, less than 10%; 2, 10% to 30%; 3, 30% to 70%; 4, more than 70% of hepatocytes affected. RESULTS: In univariate analysis, steatosis was associated with elevated BMI (P=0.001), excessive alcohol intake (P=0.005), genotype 3 (P<0.001) and moderate to severe histological activity (P=0.01). Multivariate analysis showed that steatosis correlated with two independent factors: genotype 3a (OR=60.7; 95% CI: 7.6-483.4) (P<0.001) and BMI (OR=4.86; 95% CI: 1.8-13.15) (P=0.002). In univariate analysis, severe fibrosis (F2-F3-F4) was associated with older age (P<10(-5)), male gender (P=0.001), disease duration (P<0.006), BMI (P<10(-4)), alcohol intake (P<10(-6)), severity of histological activity (P<10(-5)) and steatosis (P<10(-6)). In multivariate analysis, three independent factors were associated with severe fibrosis: disease duration > 10 years (OR=3.17; 95% CI: 0.65-15.4) (P=0.015), presence of steatosis (OR=3.17; 95% CI: 1-9.99) (P<0.049) and genotype 3a (OR=5.56; 95% CI: 1.4-22.1) (P=0.015). CONCLUSION: In patients with chronic hepatitis C, steatosis is significantly associated with genotype 3 infection and high BMI. Steatosis is an independent risk factor associated with severe fibrosis. These results have major implications for the management of patients with chronic hepatitis C.     

Evolution of liver fibrosis after interferon-based anti-hepatitis C virus therapy failure in 3,049 chronic hepatitis C patients without cirrhosis

Background and study aimsLiver fibrosis is the underlying cause of hepatitis C virus (HCV)-related disease progression to endpoints such as cirrhosis, liver failure, and hepatocellular carcinoma. The aim of our study was to assess changes in hepatic fibrosis in patients with chronic HCV who had a fibrosis evaluation at two time points at least six months apart.Patients and MethodsThis was a retrospective cohort study that included patients who had failed interferon therapy and received HCV retreatment with direct-acting antivirals (DAAs) at least six months later. Patients were evaluated previously for fibrosis according to liver biopsy and fibrosis biomarkers were evaluated before pegylated interferon and ribavirin (PEG/RBV) therapy. Fibrosis was re-evaluated with fibrosis-4 (FIB-4) scores before starting DAAs.ResultsA total of 3,049 patients were included [age 43.47 ± 9.07 years, 55.20 % males] and baseline histopathology showed F1, F2, and F3 in 16.86 %, 46.21 %, and 36.93 %, respectively. The mean time interval between the last dose of previously failed IFN-therapy to the first dose of DAAs was 2.38 (±1.07) years. Overall, there was a significant increase in FIB-4 scores at retreatment times (from 11.71 ± 1.13 to 22.26 ± 1.68, p < 0.001). Patients with baseline FIB-4 < 1.45 (n = 1,569) and between 1.45 and 3.25 (n = 1,237) had significant increases in their FIB-4 at the retreatment time point [median difference; 0.41 (0.91) and 0.24 (1.5), p < 0.001, respectively], whereas patients with FIB-4 > 3.25 had significant reduction of their FIB-4 score at a retreatment timepoint [−0.98 (2.93), p ≤ 0.001].ConclusionFibrosis progressed in most patients, even within six months for some patients, and this indicates retreatment of non-system vascular resistance patients even if they do not have significant fibrosis.     

Evolution of liver fibrosis after interferon-based anti-hepatitis C virus therapy failure in 3,049 chronic hepatitis C patients without cirrhosis

Background and study aimsLiver fibrosis is the underlying cause of hepatitis C virus (HCV)-related disease progression to endpoints such as cirrhosis, liver failure, and hepatocellular carcinoma. The aim of our study was to assess changes in hepatic fibrosis in patients with chronic HCV who had a fibrosis evaluation at two time points at least six months apart.Patients and MethodsThis was a retrospective cohort study that included patients who had failed interferon therapy and received HCV retreatment with direct-acting antivirals (DAAs) at least six months later. Patients were evaluated previously for fibrosis according to liver biopsy and fibrosis biomarkers were evaluated before pegylated interferon and ribavirin (PEG/RBV) therapy. Fibrosis was re-evaluated with fibrosis-4 (FIB-4) scores before starting DAAs.ResultsA total of 3,049 patients were included [age 43.47 ± 9.07 years, 55.20 % males] and baseline histopathology showed F1, F2, and F3 in 16.86 %, 46.21 %, and 36.93 %, respectively. The mean time interval between the last dose of previously failed IFN-therapy to the first dose of DAAs was 2.38 (±1.07) years. Overall, there was a significant increase in FIB-4 scores at retreatment times (from 11.71 ± 1.13 to 22.26 ± 1.68, p < 0.001). Patients with baseline FIB-4 < 1.45 (n = 1,569) and between 1.45 and 3.25 (n = 1,237) had significant increases in their FIB-4 at the retreatment time point [median difference; 0.41 (0.91) and 0.24 (1.5), p < 0.001, respectively], whereas patients with FIB-4 > 3.25 had significant reduction of their FIB-4 score at a retreatment timepoint [−0.98 (2.93), p ≤ 0.001].ConclusionFibrosis progressed in most patients, even within six months for some patients, and this indicates retreatment of non-system vascular resistance patients even if they do not have significant fibrosis.     

Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C.

BACKGROUND/AIM: Quantitative tests of liver function may be superior to conventional tests to assess the prognosis of patients with liver diseases. There are insufficient data from quantitative testing of liver function (QTLF) for patients with chronic hepatitis B and C, particularly with regard to fibrosis. Therefore, we applied a broad panel of QTLF to these patients. METHODS: Three hundred and sixty-seven consecutive patients with chronic hepatitis B or C underwent liver biopsy and QTLF, which included tests for hepatic metabolism (aminopyrine breath test, galactose elimination capacity) and for hepatic perfusion (sorbitol clearance, indocyanine green clearance). QTLF values were correlated with liver histology (grading and staging for inflammation and fibrosis) and Child-Pugh classification for liver cirrhosis. RESULTS: In patients with no and moderate fibrosis, metabolic liver function was significantly decreased, whereas hepatic perfusion remained normal. Severe fibrosis and cirrhosis showed a significant decline in all QTLFs. Hepatic inflammation only reduced metabolic liver function, irrespective of the inflammatory grade. Viral etiology and HCV genotypes did not change QTLF. CONCLUSIONS: In summary, viral damage compromises hepatic metabolism before perfusion. Therefore, tests of metabolic liver function (aminopyrine breath test, galactose elimination capacity) should be useful to search for drugs that restore liver function in viral hepatitis irrespective of the fibrosis stage.