Chronic Hepatitis C Infection: Clinical and Societal Evaluations

Chronic hepatitis C virus infection (HCV) affects 180 million people worldwide. Chronic HCV can cause hepatic decompensation, hepatocellular carcinoma (HCC), and portal hypertension1. Nowadays, chronic HCV is the leading indication for liver transplantation in developed countries. HCV is an enveloped single-stranded RNA virus that is transmitted in humans through blood-to-blood contact2. Acute infection leads to chronic infection in 50-80%3. In most cases, chronic HCV infection remains relatively asymptomatic until complications of disease present. Natural course of chronic HCV infection is highly variable with serious liver disease developing in one third of persons 20 years or less after infection and no progression in another third for 30 years or longer. Factors that accelerate clinical progression include alcohol intake, which has a pronounced effect on the course of the disease, co-infection with HIV or HBV, male sex, and older age at infection. Once cirrhosis is established, the risk of HCC is approximately one to four percent per year. HCC can occur without cirrhosis but is rare. For this reason, antiviral treatment is ideally provided in pre-cirrhotic liver disease. Furthermore, antiviral treatment is more effective in non-cirrhotic and, preferably less fibrotic stages of chronic HCV infection

Unexplained Hyponatremia: Seek and You Will Find

Background: Hyponatremia is a common diagnostic challenge. Methods: An index case is presented to discuss the diagnostic approach to chronic and unexplained hyponatremia. Results: The index case concerns a 60-year-old man with chronic hepatitis C and previous alcohol use who was referred because of weight loss, poor dietary intake, dizzy spells, and unexplained hyponatremia (serum sodium 124-129 mmol/l). A low urine sodium concentration (20 mmol/l) and a low fractional sodium excretion (0.07%) were observed repeatedly, while urine osmolality was high (>400 mosm/kg). The central questions in this case are: what is the differential diagnosis, which tests are needed to confirm or exclude a diagnosis, and how would you proceed if no obvious cause is found? Conclusions: The diagnosis of this case of unexplained hyponatremia was unexpected, but important because it was treatable. The challenges and caveats of the diagnostic approach to hyponatremia are discussed. A diagnostic algorithm to guide clinicians who are confronted with similar cases is presented. Copyright (C) 2011 S. Karger AG, Base

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design

Background: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design. Methods: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily). Results: Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA declin Conclusions: An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design

Background: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design. Methods: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily). Results: Oral administration of PHX1766 was safe and well tolerated at all dose levels wit

Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7

Background: ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. Methods: The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. Results: Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log 10 IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-αwas induced in non-responders. Conclusions: These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation

Hepatitis C Virus Infection Epidemiology among People Who Inject Drugs in Europe: A Systematic Review of Data for Scaling Up Treatment and Prevention

Background: People who inject drugs (PWID) are a key population affected by hepatitis C virus (HCV). Treatment options are improving and may enhance prevention; however access for PWID may be poor. The availability in the literature of information on seven main topic areas (incidence, chronicity, genotypes, HIV co-infection, diagnosis and treatment uptake, and burden of disease) to guide HCV treatment and prevention scale-up for PWID in the 27 countries of the European Union is systematically reviewed. Methods and Findings: We searched MEDLINE, EMBASE and Cochrane Library for publications between 1 January 2000 and 31 December 2012, with a search strategy of general keywords regarding viral hepatitis, substance abuse and geographic scope, as well as topic-specific keywords. Additional articles were found through structured email consultations with a large European expert network. Data availability was highly variable and important limitations existed in comparability and representativeness. Nine of 27 countries had data on HCV incidence among PWID, which was often high (2.7-66/100 person-years, median 13, Interquartile range (IQR) 8.7-28). Most common HCV genotypes were G1 and G3; however, G4 may be increasing, while the proportion of traditionally ‘difficult to treat’ genotypes (G1+G4) showed large variation (median 53,IQR 43-62). Twelve countries reported on HCV chronicity (median 72, IQR 64-81) and 22 on HIV prevalence in HCV-infected PWID (median 3.9%, IQR 0.2-28). Undiagnosed infection, assessed in five countries, was high (median 49%, IQR 38-64), while of those diagnosed, the proportion entering treatment was low (median 9.5%, IQR 3.5-15). Burden of disease, where assessed, was high and will rise in the next decade. Conclusion: Key data on HCV epidemiology, care and disease burden among PWID in Europe are sparse but suggest many undiagnosed infections and poor treatment uptake. Stronger efforts are needed to improve data availability to guide an increase in HCV treatment among PWID