Fredric Regenstein

Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus

BACKGROUND & AIMS Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS Twenty-six patients were treated at five medical centers. Five patients had Childs class A status, 15 had Childs B status, and 6 had Childs C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS All patients with Childs A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Childs B (33%) and no patients with Childs C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Childs A status.

Morbidity of chronic hepatitis C as seen in a tertiary care medical center.

We studied the morbidity of chronic hepatitis Cin patients referred to a tertiary care medicalfacility. The medical records of 500 consecutive casesof chronic hepatitis C were examined for the following: (1) source and time of exposure, (2) signs andsymptoms of liver disease, (3) degree of alcohol intake,(4) liver biopsy findings, (5) extrahepatic diseasemanifestations, and (6) coexisting illnesses that could have an impact on morbidity. Morbidityand histologic findings were evaluated in relation tothe duration of hepatitis C. The onset of infectioncould be determined in 376 patients (75%). A close relationship between the length of infectionand disease features was not observed. Fatigue wascommon at all stages of infection. Whereas cirrhosisoccurred more frequently in patients with disease of long duration, 15-24% of patients had signs ofadvanced liver disease (ascites, encephalopathy,thrombocytopenia) within six years of exposure. Overtextrahepatic manifestations of chronic hepatitis Coccurred infrequently, and depression was reported in24% of untreated patients. In conclusion, in patientsreferred to a tertiary care setting, chronic hepatitisC is often associated with significantmorbidity.

Interferons α, β, γ each inhibit hepatitis C virus replication at the level of internal ribosome entry site-mediated translation

Abstract: Interferon (IFN)‐α is the standard therapy for the treatment of chronic hepatitis C, but the mechanisms underlying its antiviral action are not well understood. In this report, we demonstrated that IFN‐α, ‐β and ‐γ inhibit replication of the hepatitis C virus (HCV) in a cell culture model at concentrations between 10 and 100 IU/ml. We demonstrated that the antiviral actions each of each these IFNs are targeted to the highly conserved 5′ untranslated region of the HCV genome, and that they directly inhibit translation from a chimeric clone between full‐length HCV genome and green fluorescent protein (GFP). This effect is not limited to HCV internal ribosome entry site (IRES), since these IFNs also inhibit translation of the encephalomyocardititis virus (EMCV) chimeric mRNA in which GFP is expressed by IRES‐dependent mechanisms (pCITE‐GFP). These IFNs had minimal effects on the expression of mRNAs from clones in which translation is not IRES dependent. We conclude that IFN‐α, ‐β and ‐γ inhibit replication of sub‐genomic HCV RNA in a cell culture model by directly inhibiting two internal translation initiation sites of HCV‐ and EMCV‐IRES sequences present in the dicistronic HCV sub‐genomic RNA. Results of this in vitro study suggest that selective inhibition of IRES‐mediated translation of viral polyprotein is a general mechanism by which IFNs inhibits HCV replication.

Mechanisms of Interferon Action and Resistance in Chronic Hepatitis C Virus Infection: Lessons Learned from Cell Culture Studies

Alpha interferon, usually in combination with ribavirin, is currently the standard care for patients infected with hepatitis C virus. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The molecular details concerning the failure of many patients to achieve sustained clearance of the virus infection after interferon therapy are currently unknown. The primary focus of this chapter is to provide an overview of interferon action and resistance against hepatitis C virus (HCV) based on our understanding developed from in vitro experiments. Interferon first binds to receptors on the cell surface; this initiates a cascade of signal transduction pathways leading to the activation of antiviral genes. Using a cell culture model, we determined that the activation of an interferon promoter (interferon inducible genes) is important for a successful antiviral response against HCV. The level of activation of the IFN promoter by exogenous interferon appears to vary among different replicon cell lines. It was observed that a replicon cell line showing low activation of the IFN promoter frequently develops resistant phenotypes compared to cell lines with higher activation. Furthermore, interferon-alpha, -beta, and -gamma are each found to inhibit replication of HCV in the cell culture. The antiviral action of interferon is targeted to the highly conserved 5’ untranslated region (5’ UTR) utilized by the virus to translate protein by an internal ribosome entry site (IRES) mechanism. This effect is the same among HCVs of other genotypes. Interferon inhibits translation of HCV by blocking at the level of formation of polyribosomes on the IRES containing mRNA. These in vitro studies suggest that differences in the regulation of IRES-mediated translation by interferon among hepatic cell clones may be directly related to the development of interferon resistance in chronic HCV infection.

The impact of an educational program on HCV patient outcomes using boceprevir in community practices (OPTIMAL trial)

Objectives: Although effective, direct acting antiviral (DAA) therapies for genotype 1 (GT 1) hepatitis C virus (HCV) have been associated with compliance challenges. Additionally, treatment at predominantly community-based centers has been associated with low retention of patients on treatment and higher dropout rates. The OPTIMAL Phase IV interventional trial (ClinicalTrials.gov Identifier: NCT01405027) was designed to evaluate the impact of an education program for community investigator (CI) sites participating in a Chronic Liver Disease Foundation study treating chronic GT 1 HCV patients. Methods: This physician educational program was administered by 22 Hepatology Centers of Educational Expertise (HCEE) academic sites to 33 CI sites asked to participate from December 2011 to July 2012. The HCEE mentors from DAA-experienced academic sites educated those at CI sites on therapeutic management, practice, and patient outcomes through a series of four standardized educational sequence visits regarding the use of first generation HCV protease inhibitors and the overall treatment of HCV. Results: Treatment duration compliance rates for patients treated at CI sites versus those treated at HCEE academic sites were evaluable in 77 of 84 HCEE academic site patients, 102 of 113 patients treated at CI sites, and 179 of 197 overall patients. The treatment duration compliance rates for patients treated at HCEE academic sites, CI sites and overall were 85.4 ± 25.39%, 83.8 ± 27.37%, and 84.5 ± 26.48%, respectively, and did not differ statistically between the groups (p = 0.49). Almost half (47%) of the patients in the study achieved a sustained virological response for 24 weeks (SVR24) regardless of the type of site (p = 0.64). Safety profiles were similar at both HCEE and CI sites. Conclusions: These results demonstrated that education of CI sites unfamiliar with DAAs resulted in patient outcomes consistent with those observed at DAA-experienced academic sites.