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The inhibitory effects of the 9-(2-phosphonylmethoxyethyl)adenine-related compounds (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine, (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine, (R)-9-(2-phosphonylmethoxypropyl)adenine, (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine, and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine on human hepatitis B virus replication in the human hepatoma cell line HepG2 2.2.15 and duck hepatitis B virus infection in primary duck hepatocytes were investigated. (R)-9-(2-phosphonylmethoxypropyl-2,6-diaminopurine had the lowest 50%o inhibitory concentrations against hepatitis B virus and duck hepatitis B virus, 0.22 and 0.06 ,iM, respectively, i.e., two-to fivefold lower concentrations than required for (R)-9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxyethyl)adenine. All compounds were not toxic in vitro at a concentration of 100 ,uM.In chronic hepatitis B virus (HBV) infection the basic therapy is the administration of interferon, although complete disappearance of virus markers is seldom observed. Hepatitis B e antigen seroconversion, reflecting a drastic decline of viral replication, is seen in only 20 to 40% of patients with HBV infections.More potent antiviral drugs are eagerly awaited, and in light of this, the acyclic nucleoside phosphonates described earlier (3, 4) were considered adequate candidates to be further pursued for the treatment of HBV infections.In an earlier study (6) we investigated the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in two hepatoma cell lines and primary duck hepatocytes. The 50% inhibitory concentrations (IC50) for human HBV and duck HBV (DHBV) were found to be 1.2 and 0.2 ,uM as measured in HepG2 2.2.15 cells and primary duck hepatocytes, respectively.Among the acyclic nucleoside phosphonates several other derivatives were found to have high anti-DNA virus activity (herpes group) or antiretrovirus (human immunodeficiency virus [HIV] and Moloney murine sarcoma virus) activity (1). The most effective HIV inhibitors among the acyclic nucleoside phosphonates were evaluated for their anti-HBV activities in the human hepatoma cell line HepG2 2.2.15. Two of the compounds, candidates for application with humans, were also assayed in primary duck hepatocytes infected with DHBV, in anticipation of studies with chronically DHBV-infected ducklings and chronic hepatitis B patients.PMEA, (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine [(S)-FPMPA], (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine [(R)-PMPDAP], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (R)-9-(2-phosphonylmethoxypropyl)adenine [(R)-PMPA], and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine were synthesized by

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BackgroundAs direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment, with the ultimate goal of elimination.MethodsWe retrospectively studied microbiology records from a large UK teaching hospital in order to compare the performance of HCV screening and diagnostic tests (antibody, antigen and HCV RNA detection). Having described a local cohort of adults with active HCV infection, we investigated the proportion who attended hospital appointments, were prescribed direct acting antiviral (DAA) therapy, and cleared HCV RNA following treatment.ResultsOver a total time period of 33 months between 2013 and 2016, we tested 38,509 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag + and/or HCV RNA+) in 353 (positive rate 0.9%). Our in-house HCV-Ab screening test had a positive predictive value of 87% compared to repeat HCV-Ab testing in a reference laboratory, highlighting the potential for false positives to arise using this test. HCV-Ag had 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p < 0.0001). Among the cases of infection, genotype-1 and genotype-3 predominated, the median age was 37 years, 84% were male, and 36% were in prison. Hepatology review was provided in 39%, and 22% received treatment. Among those who received DAA therapy with 12 weeks of follow-up, 93% achieved a sustained virologic response (SVR12).ConclusionsHCV-Ag performs well as a diagnostic test compared to PCR for HCV RNA. Active HCV infection is over-represented among men and in the prison population. DAA therapy is successful in those who receive it, but a minority of patients with a diagnosis of HCV infection access clinical care. Enhanced efforts are required to provide linkage to clinical care within high risk populations.

Rat interferon of relatively high specific activity (about 10(6) units/mg protein) was produced in embryonic rat cells treated with Newcastle disease virus at a high m.o.i. The cells were cultured in serum-free medium and the interferon was precipitated and concentrated with 0.02 M-zinc acetate or with ammonium sulphate at 85% saturation. With both methods the increase in interferon activity was greater than the concentration factor. The rat interferon activity was stable on treatment with 0.15 M-perchloric acid or three cycles of freezing and thawing, but incubation at 37 degrees C for 1 h resulted in a 50% loss in activity. It had no cross activity in human or mouse cells. The sensitivity of different types of rat cells for rat interferon differed widely and was dependent on the challenge virus. Human interferons had no detectable antiviral activity on rat cells and did not block the activity of rat interferon.