Peripheral blood toll-like receptor 4 correlates with rapid virological response to pegylated-interferon and ribavirin therapy in hepatitis C genotype 1 patients.

BACKGROUND: Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS: We enrolled 79 treatment-naïve patients with HCV genotype 1. Patients completed a 24- to 48-week course of response-guided therapy. Peripheral blood monocyte (PBMC) expression of mRNA for TLRs 2, 3, 4, 7, and 9 was quantified by real-time PCR before therapy. TLR mRNA expression is shown as a log ratio relative to GAPDH mRNA (log 2 (-(∆Ct))). RESULTS: Forty-five patients (57.0 %) showed a rapid virological response (RVR). Univariate analysis revealed that TLR 2, 3, 4, 7, and 9 were significantly lower in the RVR group than in the non-RVR group (P = 0.001, 0.014, < 0.001, 0.008, and 0.001, respectively). Multivariate analysis revealed that TLR 4 < -2 log (OR: 7.17, 95 % CI: 1.70-30.34, P = 0.007) was an independent predictor for RVR. In addition, levels of TLR 2, 3, 4, 7, and 9 were positively correlated with HCV viral load (P = 0.009, 0.013, < 0.001, 0.007, and 0.001, respectively). CONCLUSIONS: A low level of TLR 4 mRNA in PMBCs was correlated with RVR, which indicates that TLR4 may play a critical role in HCV recognition and activation of innate immunity. TLR expression levels were correlated with HCV viral load, indicating that TLR activation upon exposure to HCV may subsequently limit HCV replication.

Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts.

BACKGROUND: Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN: 2 prospective observational cohort studies. SETTING & PARTICIPANTS: From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS: Peginterferon alfa-2b monotherapy, 1.0 µg/kg/wk, versus peginterferon alfa-2b, 1.0 µg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS: End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS: Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS: Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS: Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Hepatitis B virus genotype B results in better immediate, late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients.

BACKGROUND AND AIMS: This study investigated outcome predictors in hepatitis-B-e-antigen (HBeAg)-positive chronic hepatitis B patients treated with peginterferon alfa-2a. METHODS: A total of 88 HBeAg-positive patients receiving peginterferon alfa-2a for 6 months and followed up for at least 24 weeks were prospectively analyzed. Precore and core promoter genes of hepatitis B virus (HBV) were sequenced from the serial serum samples of 88 patients. RESULTS: After 24 weeks of follow up, 38.6% and 28.4% of patients achieved HBeAg clearance and combined response, respectively. Multivariate analysis disclosed that pretreatment HBeAg sample to cut-off (S/Co) ratio ≤ 200, alanine aminotransferase > 200 IU/mL, HBV genotype B and T1846 were independent factors for HBeAg clearance, and HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for combined response. HBeAg S/Co ratio ≤ 10 at week 12 of therapy was the useful factor for treatment response and had a greater power (P = 0.012) to predict HBeAg clearance than HBV DNA. Patients with HBeAg clearance had a higher frequency of A1896 mutation at baseline and during therapy than those without HBeAg clearance, and the frequency of A1896 decreased during treatment. During follow up, delayed HBeAg seroconversion and reactivation of HBV after HBeAg clearance were observed in eight non-responders and 20 patients with HBeAg clearance, respectively. HBV genotype B was a significant factor to predict both responses. CONCLUSIONS: Pretreatment HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for treatment response to peginterferon. Genotype-B-infected patients had higher probability of delayed HBeAg clearance and sustained response. Rapid decrease of HBeAg titer was useful on treatment predictor.

Reversal of hypolipidemia in chronic hepatitis C patients after successful antiviral therapy.

BACKGROUND/PURPOSE: Chronic infection with the hepatitis C virus (HCV) is associated with impaired lipid metabolism. The aim of this study was to determine the impact of antiviral response on the serial change of serum lipids in chronic HCV patients. METHODS: A total of 165 consecutive patients with HCV infection were prospectively enrolled. Serum total cholesterol (TC) and triglyceride (TG) levels in these subjects were compared with age, sex and body mass index-matched healthy individuals and 55 patients with chronic infection with hepatitis B virus (HBV). Serum lipid levels were measured in 143 patients with chronic HCV infection receiving pegylated interferon plus ribavirin therapy at baseline, at the end of treatment, and at week 24 after the end of treatment. RESULTS: Patients with chronic HCV infection had significantly lower total TC and TG levels than normal controls (both p < 0.001). Serum TC levels were lower in HCV patients than in those infected with HBV (p < 0.001). Pretreatment serum lipid levels were not independent factors associated with sustained virological response (SVR). Among patients achieving a SVR, serum TC and TG levels significantly increased from 165 ± 30 mg/dL and 100 ± 47 mg/dL at baseline to 191 ± 36 mg/dL (p < 0.001) and 116 ± 77 mg/dL (p = 0.029) at week 24 posttreatment, whereas no evident change in lipid profile occurred in the non-SVR group. CONCLUSION: Our data suggest that chronic HCV infection is associated with hypocholesterolemia and hypotriglyceridemia, which can be reversed by successful eradication of HCV. The clinical significance of hypolipidemia reversal among SVR patients, such as the risk of coronary artery or cerebral vascular disease, should be further investigated.

HBsAg profiles in patients receiving peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses.

BACKGROUND: With use of peginterferon alfa-2a and ribavirin combination therapy in patients with dual chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, 11.2% of patients achieved clearance of hepatitis B surface antigen (HBsAg) at 6 months after treatment; however, reactivation of HBV DNA was observed in 36.3%. We investigated the predictive potential of HBsAg quantification. METHODS: HBsAg quantification was performed in 120 e antigen-negative patients dually infected with HBV and hepatitis C virus and treated with peginterferon alfa-2a/ribavirin for 48 weeks (HCV genotype 1; n = 74) or 24 weeks (HCV genotype 2/3; n = 46). HBsAg was quantified at baseline, week 4, week 12, end of treatment, and 24 weeks after treatment. RESULTS: The baseline median serum HBsAg level was 120 IU/mL and decreased gradually during treatment. Low baseline HBsAg was significantly associated with HBsAg clearance (40% for HBsAg level 20 IU/mL vs 2.2% for HBsAg level >20 IU/mL; P < .05). A decrease in HBsAg level from baseline to week 12 of 50% was associated with a reduced likelihood of HBV DNA reactivation in patients with baseline undetectable serum HBV DNA (positive predictive value, 89.5%). CONCLUSIONS: HBsAg quantification appears to be a useful indicator of posttreatment outcome in patients dually infected with HBV and hepatitis C virus.

Sustained virological response to hepatitis C therapy does not decrease the incidence of systemic lupus erythematosus or rheumatoid arthritis.

In patients with chronic hepatitis C (CHC), the effects of baseline characteristics, virological profiles, and therapeutic outcome to pegylated interferon plus ribavirin (PR) therapy on autoimmune diseases are unknown. Taiwanese Chronic Hepatitis C Cohort is a nationwide hepatitis C virus registry cohort comprising 23 hospitals of Taiwan. A total of 12,770 CHC patients receiving PR therapy for at least 4 weeks between January 2003 and December 2015 were enrolled and their data were linked to the Taiwan National Health Insurance Research Database for studying the development of 10 autoimmune diseases. The mean follow-up duration was 5.3 ± 2.9 years with a total of 67,930 person-years, and the annual incidence of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) was 0.03%. Other autoimmune diseases were not assessable due to few events. Body mass index ≥24 kg/m2 was an independent predictor of the low incidence of SLE or RA (hazard ratio 0.40, 95% confidence interval 0.17-0.93, p = 0.034). A sustained virological response (SVR) to PR therapy was not associated with the low incidence of SLE or RA in any subgroup analysis. CHC patients achieving SVR to PR therapy did not exhibit an impact on the incidence of SLE or RA compared with non-SVR patients.

Successful antiviral and antituberculosis treatment with pegylated interferon-alfa and ribavirin in a chronic hepatitis C patient with pulmonary tuberculosis.

Pulmonary tuberculosis is a rare side effect of antiviral treatment for chronic hepatitis C. We present the case of 55-year-old woman with chronic hepatitis C, who developed pulmonary tuberculosis after receiving 8 weeks of peginterferon alfa-2a plus ribavirin therapy. Antituberculous treatment was started and antiviral agents were given continually at adjusted doses. Her symptoms of cough with blood-tinged sputum improved 1 month after antituberculous therapy. Treatment for hepatitis C and pulmonary tuberculosis were completed after 6 months. At 6 months after antiviral therapy, a sustained virological response was achieved and follow-up chest radiography showed a marked regressive change. This is believed to be the first case report of complete remission from hepatitis C and pulmonary tuberculosis treated concurrently with antiviral and antituberculous agents.

Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels.

BACKGROUND AND AIMS: Patients with chronic hepatitic C (HCV) infection and normal serum alanine transaminase (ALT) levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN) based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels. METHODS: We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186) while those with elevated ALT levels were group B (n = 3055). RESULTS: At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR) rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993). But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032). No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non-HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development. CONCLUSIONS: HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression.

Neutrophil-to-lymphocyte ratio as a predictor of response to peginterferon plus ribavirin therapy for chronic hepatitis C.

We aimed to determine whether neutrophil-to-lymphocyte ratio (NLR) could be a predictor of antiviral response in chronic hepatitis C patients. A total of 602 consecutive patients (genotype 1, n = 263; genotype 2, n = 297; others/unknown, n = 42) receiving response-guided therapy with peginterferon plus ribavirin were recruited. NLR was related to clinical and virological features and to treatment outcome. Rapid virological response (RVR) and sustained virological response (SVR) were achieved in 436 (73%) and 458 (76%) of the patients, respectively. Higher NLR (≥1.42) was found to be associated with higher prevalence of DM (P = 0.039) and higher hepatitis C viral load (P = 0.002) and white cell count (P < 0.001). NLR was significantly lower in patients with RVR and SVR compared to those without (P = 0.032 and 0.034, resp.). However, NLR was not an independent factor by multivariate analysis. In the subgroup analysis, higher NLR (≥1.42) (odds ratio, 0.494, P = 0.038) was an independent poor predictor of SVR in genotype 2 patients but was not in genotype 1 patients. In conclusion, NLR is a simple and easily accessible marker to predict response to peginterferon plus ribavirin therapy for chronic hepatitis C genotype 2.

A double-blind randomized controlled study to evaluate the efficacy of low-dose oral interferon-alpha in preventing hepatitis C relapse.

Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500 IU/day (n=59), 1,500 IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4-1.7, relapse occurred in 1/12 (8.3%) 500 IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500 IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500 IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500 IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy.

Sustained HCV clearance by interferon-based therapy reduces hepatocellular carcinoma in hepatitis B and C dually-infected patients.

BACKGROUND: Recent studies have indicated that interferon (IFN) or pegylated interferon (PEG-IFN) plus ribavirin therapy can achieve sustained virological response (SVR) against HCV equally in dual HBV-HCV infection and in HCV monoinfection. Whether these therapies can reduce hepatocellular carcinoma (HCC) development in dual HBV-HCV infection remains unclear. METHODS: A total of 135 dually-infected patients with active hepatitis C receiving IFN or PEG-IFN plus ribavirin therapy were enrolled. The cumulative incidence of HCC was compared to that in 1,470 HCV-monoinfected patients. RESULTS: Based on the Cox proportional hazards model, dual infection was an independent factor for HCC development in all 1,605 chronic hepatitis C patients with or without positive hepatitis B surface antigen receiving IFN or PEG-IFN plus ribavirin (hazard ratio (HR)=1.864, 95% CI 1.052-3.303; P=0.033). In dually-infected patients, HCC developed in 4 of 96 with HCV SVR and 11 of 39 without HCV SVR (P < 0.001) after a median follow-up of 4.6 years. Age (HR=1.175, 95% CI 1.070-1.291; P=0.001) and non-HCV-SVR (HR=7.874, 95% CI 2.375-26.32; P=0.001) were independent factors for HCC development. Subgroup analysis showed that HCC occurrence was lower in patients with HCV SVR and HBV DNA levels < 2,000 IU/ml at the end of treatment or follow-up compared to those with HCV SVR and HBV DNA levels ≥ 2,000 IU/ml (P=0.034) and those without HCV SVR (P<0.001). CONCLUSIONS: Sustained HCV clearance by IFN or PEG-IFN plus ribavirin therapy may significantly reduce HCC in HBV-HCV dually-infected patients, whereas persistence or reactivation of HBV decreases the benefit of HCV SVR.

Prevalence and clinical relevance of serum autoantibodies in patients with chronic hepatitis C.

BACKGROUND: Chronic hepatitis C (CHC) is frequently associated with the presence of serum autoantibodies. The prevalence and clinical relevance of serum autoantibodies in CHC patients and their influence on antiviral treatment have not been well established. METHODS: From February 1999 to July 2004, 460 consecutive adult patients with CHC were studied. Antinuclear antibody (ANA) and smooth muscle antibody (SMA) were determined by indirect immunofluorescence. The presence of these antibodies was related to patient characteristics and to the outcome of 24 weeks of therapy with interferon (IFN) alfa-2b (n=376) or pegylated- IFN alfa-2b (n=84) plus ribavirin. RESULTS: The prevalence of ANA and SMA was 7.4% and 19.3%, respectively. Seropositivity for ANA and/or SMA was associated with old age and high aspartate aminotransferase (AST) levels. The rates of sustained virological response and early withdrawal of therapy were comparable between autoantibody- positive and -negative patients. None of the autoantibody-positive patients experienced a flare-up of transaminase during treatment, or developed severe systemic autoimmune disease. CONCLUSION: Serum ANA and/or SMA-positive HCV-infected patients are older, and have higher disease activity and severity than their negative counterparts. However, the presence of ANA or SMA did not influence the response to combination antiviral therapy, which is safe and effective in autoantibody--positive CHC patients.

Hepatitis C virus genotypes: clinical relevance and therapeutic implications.

The incidence of hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) has been increasing in several countries including Taiwan. There are six main genotypes, each of which contains closely related subtypes. Molecular epidemiological studies have shown marked differences in the genotype distribution by geographical region and between patient groups. HCV genotype 1 may play a role in the development of HCC, although some studies have argued against this. A sustained virological response secondary to interferon monotherapy or interferon/ribavirin combination therapy may reduce the risk of HCC and improve survival in chronic hepatitis C patients. The HCV genotypes are associated with therapeutic response. Rapid virological response is also a predictor of therapeutic response. Although viral characteristics have consistently been shown to be important predictors of treatment response, identification of additional host immune and genetic factors involved in determining the outcome of antiviral therapy is necessary. Newly developed bio-techniques (microarray, proteomes, bioinformatics), drugs, and treatment strategies may elucidate the pathogenesis and improve the therapeutic response in HCV infection.

Anemia associated with antiviral therapy in chronic hepatitis C: incidence, risk factors, and impact on treatment response.

BACKGROUND: One major side effect of combination antiviral therapy is the development of anemia, which is more severe among the Asian population. We conducted this large-scaled study to explore the incidence, risk factors, and impact on treatment response of anemia in chronic hepatitis C patients receiving combination antiviral therapy. METHODS: Four hundred and sixty-six chronic hepatitis C patients were treated with interferon-alpha-2b (IFN-alpha-2b) three or five million units thrice weekly, or pegylated-IFN-alpha-2b 1-1.5 microg/kg weekly plus ribavirin (1000-1200 mg/day) for 24 weeks. Severe anemia was defined as hemoglobin concentration <10 g/dl. RESULTS: The mean decrease of hemoglobin was 3.9+/-1.3 g/dl. Thirty-nine percent of patients had developed severe anemia during therapy. Stepwise logistic regression analysis revealed that old age (> or =50 years) (odds ratio [OR]=1.935, P=0.001) and baseline hemoglobin level (> or =14 g/dl) (OR=2.975, P<0.001) were significantly correlated with maximal decreases in hemoglobin. Using Cox's regression analysis, pretreatment platelet counts (<150 000/mm(3)) (OR=1.821, P<0.001), old age (> or =50 years) (OR=1.789, P=0.001), female gender (OR=1.739, P<0.001), and low body weight (<65 kg) (OR=1.493, P=0.027) were independent factors contributing to severe anemia. There was a significant linear correlation between the sustained virological response (SVR) rate and the time of severe anemia during therapy (r=0.774, P=0.003), especially among genotype 1 patients (r=0.960, P<0.001). CONCLUSION: Careful monitoring of hemoglobin level is necessary in patients who are old, female and have low body weight and platelet counts. Development of severe anemia was significantly correlated with the SVR.