In Vivo Suppression of Precore mRNA Synthesis Is Associated with Mutations in the Hepatitis B Virus Core Promoter

AbstractWe have examined the in vivo effect of hepatitis B virus (HBV) core promoter mutations on the expression of precore mRNA and pregenomic RNA transcripts in the liver of 24 patients with chronic HBV infection, applying a novel transcript-specific RT-PCR assay. The double A1762T/G1764A mutation in the basic core promoter was detected in 11 cases. This mutation was in all cases associated with absence or low levels of precore mRNA transcripts without significantly affecting the levels of total core promoter-directed transcription in the liver of infected patients. Precore mRNA synthesis was suppressed by the A1762T/G1764A mutation regardless of the presence of the precore stop codon mutation G1896A, suggesting that in addition to downregulating an immunomodulatory protein this double basic core promoter mutation may also confer a replication advantage to the virus. Additional mutations detected in the core promoter may also contribute to the observed changes in precore mRNA levels. Our in vivo study shows therefore that the double A1762T/G1764A mutation is associated with the specific suppression of precore mRNA synthesis directed by the HBV core promoter

Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel

Hepatitis C virus (HCV) infection is a serious and growing threat to human health. The current treatment provides limited efficacy and is poorly tolerated, highlighting the urgent medical need for novel therapeutics. The membrane-targeted NS3 protein in complex with the NS4A comprises a serine protease domain (NS3/4A protease) that is essential for viral polyprotein maturation and contributes to the evasion of the host innate antiviral immunity by HCV. Therefore, the NS3/4A protease represents an attractive target for drug discovery, which is tied in with the challenge to develop selective small-molecule inhibitors. A rational drug design approach, based on the discovery of N-terminus product inhibition, led to the identification of potent and orally bioavailable NS3 inhibitors that target the highly conserved protease active site. This review summarizes the NS3 protease inhibitors currently challenged in clinical trials as one of the most promising antiviral drug class, and possibly among the first anti-HCV agents to be approved for the treatment of HCV infection

HBV and HCV Therapy

One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. Following the demonstration of a more potent antiviral effect in terms of sustained virological response (SVR) rates, Pegylated-IFN coupled with Ribavirin has become the standard treatment for chronic hepatitis C, with nearly 65% of all treated patients achieving a SVR. Long-term suppression of HBV and eradication of HCV would halt the progression of chronic hepatitis to cirrhosis, hepatocellular carcinoma and liver decompensation

Clinical Efficacy of a 24-months Course of Lamivudine Therapy in Patients with HBeAg Negative Chronic Hepatitis B: A Long-term Prospective Study

The optimal duration of oral nucleos(t)ide analogue therapy for HBeAg negative chronic hepatitis B (CHB) has not been defined. The aim of this study was to investigate the clinical efficacy of 24-months course of lamivudine therapy in patients with HBeAg negative CHB in Korea. A total of 50 Korean patients with HBeAg negative CHB were prospectively enrolled. The patients received 100 mg/day of lamivudine orally for 24 months. Patients who showed complete response at 24 months to lamivudine therapy stopped treatment, and regular follow-up was done thereafter. The mean follow-up duration after cessation of therapy was 40.8±22.7 (range 12-96) months. The complete response rate at months 12 and 24 were 86.0% (43/50) and 86.0% (43/50), respectively, and the clinical breakthrough at months 12 and 24 were 4.0% (2/50) and 14.0% (7/50), respectively. The expected durability of responses at months 12, 24, and 36 after cessation of lamivudine therapy in 43 complete responders was 79.1%, 64.0%, and 56.9%, respectively. In conclusion, a 24-months course of lamivudine therapy shows high end-treatment response rate and substantial durability of initial response after cessation of therapy in HBeAg negative CHB patients in Korea

Meta‐analysis: oral anti‐viral agents in adults with decompensated hepatitis B virus cirrhosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90203/1/apt4990.pd

Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72882/1/j.1365-2893.2004.00556.x.pd

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon ± RBV and had Ishak fibrosis scores ≥ 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm 3 (n = 559); (B) bridging fibrosis with platelet counts ≤125,000/mm 3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm 3 (n = 198); and (D) cirrhosis with platelet counts ≤125,000/mm 3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively ( P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis ( P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion , disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these “difficult-to-cure” patients. (H EPATOLOGY 2006;44:1675–1684.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55880/1/21440_ftp.pd