Interferon therapy for chronic hepatitis B.

This article summarizes the results obtained with interferon alfa and pegylated interferon alfa, as monotherapy and in combination with lamivudine, in the treatment of chronic hepatitis B.

Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-alpha2b plus ribavirin treatment in a patient with hepatitis B and C coinfection.

In hepatitis B or hepatitis C endemic areas, the number of patients with dual infections is substantial. In such patients, interferon-alpha plus ribavirin can achieve sustained hepatitis C virus (HCV) clearance and hepatitis B e antigen (HBeAg) seroconversion. Pegylated interferon (PegIFN), an established treatment for hepatitis C, is currently increasingly recognized as an efficient therapy for hepatitis B. No case of successful use of PegIFN plus ribavirin has yet been reported, however, in hepatitis B virus (HBV) and HCV coinfection. We report on a 32-year-old man, of Kampuchean origin, with chronic hepatitis B, as documented by the presence of hepatitis B surface antigen with HBeAg, who was coinfected with HCV genotype 1. On therapy with PegIFN-alpha2b plus ribavirin, HCV RNA became undetectable at week 17. At the end of the 48 weeks of treatment, HCV RNA was still undetectable, HBV DNA was reduced and HBeAg remained positive. Twelve weeks after the end of treatment, HBV DNA reduction was followed by HBeAg to anti-HBe seroconversion. Two years after the end of treatment, HCV RNA and HBV DNA were still undetectable, and HBeAg to anti-HBe seroconversion was maintained. We conclude that the combination of PegIFN plus ribavirin may induce suppression of both viral infections.

Lipoprotein lipase mediates hepatitis C virus (HCV) cell entry and inhibits HCV infection.

The host-virus interactions leading to cell infection with hepatitis C virus (HCV) are not fully understood. The tetraspanin CD-81 and human scavenger receptor SR-BI/Cla1 are major receptors mediating virus cell entry. However, HCV in patients' sera is associated with lipoproteins and infectious potential of the virus depends on lipoproteins associated to virus particles. We show here that lipoprotein lipase (LPL), targeting triglyceride-rich lipoproteins (TRL) to the liver, mediates binding and internalization of HCV to different types of cells, acting as a bridge between virus-associated lipoproteins and cell surface heparan sulfate proteoglycans (HSPG). The dimeric structure and catalytic activity of LPL are required for LPL-mediated HCV uptake to cells. Unexpectedly, exogenous LPL significantly inhibits HCVcc infection in vitro. This effect is prevented by anti-LPL antibodies and by tetrahydrolipstatin (THL) a specific inhibitor of LPL enzymatic activity. In addition, we show that antibodies directed to apolipoprotein B (ApoB)-containing lipoproteins efficiently inhibits HCVcc infection. Our findings suggest that LPL mediates HCV cell entry by a mechanism similar to hepatic clearance of TRL from the circulation, promoting a non-productive virus uptake. These data provide new insight into mechanisms of HCV cell entry and suggest that LPL could modulate HCV infectivity in vivo.

Serum proteome to predict virologic response in patients with hepatitis C treated by pegylated interferon plus ribavirin.

BACKGROUND & AIMS: Surface-enhanced laser desorption ionization time-of-flight mass spectrometry is a proteomic technique that enables the global profiling of proteins. We used this approach to monitor the kinetics of serum proteome in patients with chronic hepatitis C virus infection receiving a standard bitherapy regimen to predict treatment response. METHODS: Ninety-six patients with chronic hepatitis C were retrospectively selected. All patients received complete treatment with pegylated interferon in combination with ribavirin. Patients had serum sampling before starting treatment and at the end of treatment. Results were validated in an independent cohort of 51 patients. RESULTS: Comparison of protein profiles in pretreatment and after-treatment serum allowed us to characterize 50 protein peaks, the level of which significantly varied. In the group of patients with sustained virologic response, 37 peaks displayed significant variation during treatment, whereas only one peak differed in nonresponders. A logistic regression analysis allowed us to define an algorithm composed of 2 protein peaks (fibrosis stage and genotype) that correctly predicted, in pretreatment serum, response to treatment in 89% of all patients with an area under the receiver operating characteristic curve of 0.92. In the independent testing group, the same difference in proteome kinetics was observed between sustained responders and nonresponders. The algorithm correctly predicted treatment response in 81% of patients in the testing group. CONCLUSIONS: This study suggests that the kinetics of proteome are significantly different in serum of patients according to treatment response. Serum protein profiling allows prediction of response to antiviral treatment in a significant proportion of patients.

Treatment of hepatitis C virus genotype 4-related cirrhosis: ribavirin and interferon combination compared with interferon alone.

BACKGROUND: Response to treatment with interferon alfa, with or without concomitant ribavirin, varies with the viral genotype and the degree of fibrosis in patients with chronic hepatitis C virus (HCV). GOALS: To determine the response of HCV type 4-related cirrhosis to interferon and ribavirin combination treatment compared with interferon alone. STUDY: Patients living in Kuwait were assigned to take either interferon alone at a dosage of 5 million units thrice weekly (26 patients) or interferon 5 million units thrice weekly combined with ribavirin 1,000 mg/d (21 patients) for 24 weeks. Biochemical response was defined as normal alanine aminotransferase (ALT) at end of therapy. Sustained biochemical response was defined as normal ALT 6 months after the end of therapy. Sustained virologic response was defined as negative serum HCV RNA 6 months after the end of therapy. RESULTS: Only 2 (8%) of 26 patients showed biochemical response after interferon alone, whereas 11 (52%) of 21 showed biochemical response after interferon combined with ribavirin (p < 0.01). Only 2 (8%) of 26 patients showed sustained biochemical response after interferon alone, whereas 5 (23%) of 21 showed sustained biochemical response after interferon combined with ribavirin (not significant, p > 0.1). None of the 26 patients showed virologic response after interferon alone, whereas 3 (14%) of 21 showed sustained virologic response after interferon combined with ribavirin (not significant, p > 0.1). CONCLUSION: These results suggest that patients with cirrhosis caused by HCV type 4 show no response to interferon alone and only slightly better response to 24 weeks of interferon combined with ribavirin.

The predictive value of core antigen testing for the management of hepatitis C patients receiving pegylated interferon/ribavirin treatment.

A new quantitative marker of HCV viremia based on the detection of the core antigen of the virus has recently become commercially available in Europe. The usefulness of this test was examined for the management of patients treated with pegylated interferon/ribavirin. One hundred twenty-eight pegylated interferon/ribavirin treated patients were studied. Serum samples were available at baseline, week 4 and week 12 time-points, respectively. Core antigen was quantified using the trak-C assay (Ortho Clinical Diagnostics, Raritan, NJ). For all genotypes at week 4, the positive and negative predictive values of HCV core antigen were 81.4 and 92.9%, respectively, while at week 12 they were 67.9 and 100%, respectively. These predictive values varied substantially according to viral genotype. Among patients with a negative core antigen level (<1.5 pg/ml) at week 12, only 33% of those who were positive at week 4 achieved a sustained virological response whereas 85% of those who were already negative did (P < 0.001). The core antigen assay may be used at week 4 and week 12 to distinguish patients who will achieve a sustained virological response from those who will relapse/breakthrough. This assay is a new reliable alternative for early prediction of virological non-response in patients treated with pegylated interferon/ribavirin.

Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B.

BACKGROUND & AIMS: The outcome of chronic hepatitis B and the efficacy of interferon alfa (IFN-alpha) remain controversial in human immunodeficiency virus (HIV)-positive patients. We analyzed the influence of HIV coinfection on the response to IFN-alpha therapy, long-term virologic status, progression to cirrhosis, and mortality. METHODS: This was a retrospective follow-up cohort study of 141 consecutive hepatitis B e antigen-positive patients (69 HIV positive) followed up for 45 months. RESULTS: The short-term response to IFN-alpha therapy was not significantly different in HIV-positive and HIV-negative patients (28% vs. 51%; P = 0.06) but was poorer in cases of low CD4 cell count (P = 0.038). The hepatitis B virus (HBV) reactivation rate was higher in HIV-positive patients (P = 0.033) and was associated with low CD4 cell count. The risk of cirrhosis was higher in HIV-positive patients with a CD4 cell count <200/mm(3) (relative risk [RR], 4.57; P = 0.007), in IFN-alpha-untreated patients (RR, 2.63; P = 0.041), in patients older than 33 years (RR, 4.59; P = 0.008), and in cases of high necroinflammatory score at baseline (RR, 1.27; P = 0.010). Cirrhosis-related death was more frequent in HIV-positive patients with low CD4 cell count at baseline (P = 0.041), in alcohol consumers (P = 0.001), in IFN-alpha-untreated patients (P = 0.052), and in patients with high histology activity index at baseline (P = 0.005). CONCLUSIONS: HIV coinfection was associated with poorer response to IFN-alpha therapy, more frequent HBV reactivations, and increased incidence of cirrhosis and cirrhosis-related death in cases of low CD4 count. IFN-alpha therapy decreased the incidence of HBV cirrhosis regardless of HIV status or serologic response.