An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Viral kinetics of hepatitis C virus RNA in patients with chronic hepatitis C treated with 18 MU of interferon alpha daily.

BACKGROUND: A rapid decrease of hepatitis C virus (HCV) RNA is interferon (IFN) dose-dependent, and a 3-log decline of HCV-RNA is a strong predictor of sustained virological response. In this study, viral kinetics of HCV RNA in patients treated with 18 MU interferon alpha (IFN-alpha) daily for 2 weeks are presented. METHODS: Thirteen treatment-naive patients with chronic hepatitis C received 6 MU of IFN-alpha2a every 8 h for 2 weeks. Samples were obtained daily during the treatment period. HCV-RNA levels were determined using the quantitative VERSANT 3.0 bDNA assay (detection limit 520 IU/ml). When results were below the detection limit, HCV-RNA was measured by qualitative polymerase chain reaction (PCR) using the COBAS AMPLICOR HCV test, version 2.0 (detection limit of 50 IU/ml). RESULTS: In patients infected with genotype non-1, a 3-log decline of viral load was found 2.4 days after the start of induction therapy. Only one of three patients infected with genotype 1 had a 3-log decline in viral load within 14 days of the start of therapy. In four patients, a third phase of viral decline was observed. At the end of treatment, 10/13 (77%) and 7/13 (54%) patients were HCV-RNA-negative in quantitative assay and qualitative PCR, respectively. Only one of 13 patients achieved a sustained virological response (SVR). CONCLUSION: Daily administration of 18 MU IFN-alpha to patients infected with genotype non-1 induces a 3-log decline of viral load within 2.4 days of the start of treatment. In patients infected with genotype 1, only one-third of patients have a 3-log decline at 11 days.

A physician with a positive hepatitis C virus RNA test after a needlestick injury.

Needlestick accidents continue to be a hazard for healthcare workers. We report the development of acute hepatitis C infection in a physician after needlestick injury. Hepatitis C virus (HCV)-RNA, seroconversion and a raised plasma alanine aminotransferase (ALAT) level were found in plasma three months after the accident. Treatment with interferon alfa and ribavirin was started. While the physician was on treatment, HCV-RNA test results from plasma taken the day treatment was started became available. HCV-RNA was undetectable by quantitative bDNA assay, undetectable by qualitative polymerase chain reaction (PCR) and undetectable by transcription mediated amplification (TMA). A dilemma arose at this point: should the patient stop the treatment or continue the planned therapy? The physician decided to continue a 24-week course of treatment. Six months after the end of treatment, the physician was still HCV-RNA-negative and with a normal plasma ALAT level. The rationale of the decision to continue therapy is discussed. This information may be useful for clinicians confronted with a similar dilemma.

Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.

BACKGROUND AND AIMS: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. METHODS: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). RESULTS: Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. CONCLUSIONS: BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.