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Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.
Kim, Manbok,Hansen, Kristina K,Davis, Lesley,van Marle, Guido,Gill, Michael John,Fox, Julie D,Hollenberg, Morley D,Rancourt, Derrick E,Lee, Patrick W K,Yun, Chae-Ok,Johnston, Randal N International Medical Press 2010 ANTIVIRAL THERAPY Vol.15 No.6
<P>BACKGROUND: Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy. METHODS: Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors. RESULTS: We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK-treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice. CONCLUSIONS: Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.</P>
Ko, Soon Young,Kwon, So Young,Choe, Won Hyeok,Kim, Byung Kook,Kim, Kyun-Hwan,Lee, Chang Hong International Medical Press 2009 ANTIVIRAL THERAPY Vol.14 No.4
<P>A previous clinical study of oral clevudine monotherapy for 24 weeks demonstrated that it has potent sustained antiviral effects without inducing drug resistance. The aim of this study was to evaluate the antiviral effects and safety of clevudine monotherapy for 12 months.</P>
Choe, Won Hyeok,Hong, Sun Pyo,Kim, Byung Kook,Ko, Soon Young,Jung, Young Kul,Kim, Ji Hoon,Yeon, Jong Eun,Byun, Kwan Soo,Kim, Kyun-Hwan,Ji, Seung Il,Kim, Soo-Ok,Lee, Chang Hong,Kwon, So Young International Medical Press 2009 ANTIVIRAL THERAPY Vol.14 No.7
<P>BACKGROUND: The efficacy of entecavir (ETV) monotherapy in treatment-experienced patients with chronic hepatitis B (CHB) is debatable. METHODS: A total of 22 hepatitis B e antigen (HBeAg)-positive CHB patients who had shown viral breakthrough or suboptimal response with lamivudine (3TC) and adefovir disoproxil (ADV) therapy were treated with 1.0 mg of ETV. Clinical and virological parameters were monitored every 3 months. Restriction fragment mass polymorphism assays were used to detect antiviral resistance. RESULTS: During 3TC and ADV therapy, 11 patients had rtM204V/I mutations, 2 had rtA181V/T or rtN236T, 7 had both and 2 had no 3TC- or ADV-related mutations. After switching to ETV monotherapy, the median change in serum hepatitis B virus (HBV) DNA level was -2.1 log(10) copies/ml. Virological response (HBV DNA<300 copies/ml) was achieved in 1 of 18 patients with pre-existing rt204 mutations, whereas it was achieved in all 4 patients without pre-existing rt204 mutations regardless of the presence of rt181 or rt236 mutations. Changes in mutational patterns during ETV therapy showed that rt204 mutations persisted or re-emerged. Relative abundances of rtM204V/I mutations in total viral populations gradually increased under ETV rescue, whereas those with rtA181V/T and rtN236T mutations decreased. ETV resistance mutations (rtL180M+rtT184I/L[rtS202G]+rtM204V) were detected in five patients with pre-existing rt204 mutations. CONCLUSIONS: ETV monotherapy resulted in a limited virological response in patients who had previously failed 3TC and ADV rescue therapy. The limited efficacy might be associated with residual or reselected rtM204V/I mutations leading to ETV resistance. Combination treatment including potent antiviral agents should be recommended for patients with pre-existing rtM204V/I mutations.</P>
Lee, Jung Min,Park, Jun Yong,Kim, Do Young,Nguyen, Tin,Hong, Sun Pyo,Kim, Soo Ok,Chon, Chae Yoon,Han, Kwang-Hyub,Ahn, Sang Hoon International Medical Press 2010 ANTIVIRAL THERAPY Vol.15 No.2
<P>BACKGROUND: Large clinical studies assessing long-term adefovir dipivoxil salvage monotherapy in patients with lamivudine-resistant chronic hepatitis B (CHB) are lacking, particularly in patients positive for hepatitis B e antigen (HBeAg). We assessed the efficacy and resistance profile of adefovir dipivoxil monotherapy for up to 5 years in a large cohort of Korean patients with lamivudine-resistant CHB. METHODS: A total of 320 patients (81.3% HBeAg-positive; 100% genotype C) with confirmed genotypic lamivudine-resistant CHB were switched to adefovir dipivoxil 10 mg once daily. Liver function tests and HBV DNA were monitored every 3 months. Genotypic resistance to adefovir dipivoxil was performed in patients with detectable HBV DNA. RESULTS: The overall cumulative virological response rate at 5 years of adefovir dipivoxil therapy was 48.8%. The virological response rate was significantly higher in HBeAg-negative patients (62.0% versus 45.9%; P=0.010). Most cases of virological response (131/134, 97.8%) occurred within the first 36 months of therapy. The 5-year cumulative probability of genotypic resistance and virological breakthrough was 65.6% and 61.8%, respectively. Predictive factors for a virological response included baseline HBeAg seronegativity, HBV DNA< or =8 log(10) copies/ml and achievement of an on-treatment initial virological response. CONCLUSIONS: Adefovir dipivoxil salvage monotherapy for lamivudine-resistant CHB resulted in a modest cumulative virological response rate at 5 years, which was associated with progressive antiviral resistance. Consequently, adefovir monotherapy is not preferable as a first-line strategy for lamivudine resistance where combination lamivudine plus adefovir dipivoxil therapy is available.</P>
Han, Kyung Ho,Hong, Sun Pyo,Choi, Seo Hee,Shin, Soo-Kyung,Cho, Sung Won,Ahn, Sang Hoon,Hahn, Ji-Sook,Kim, Soo-Ok International Medical Press 2011 Antiviral therapy Vol.16 No.1
<P>Drug resistance is a major limitation to the long-term efficacy of controlling chronic hepatitis B (CHB). There is a growing need to analyse multiple mutations associated with drug resistance because sequential or combinational use of antivirals is increasingly being used in treatment. In this study, we introduced a multiplex restriction fragment mass polymorphism (RFMP) assay for detecting mutations conferring entecavir and lamivudine resistance, and compared its performance with direct or clonal sequencing assays.</P>
HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B.
Kim, Beom Kyung,Revill, Peter A,Ahn, Sang Hoon International Medical Press 2011 Antiviral therapy Vol.16 No.8
<P>Although chronic HBV infection is the leading cause of chronic liver disease and death worldwide, there are substantial differences in its clinical courses regarding prevalence, mode of transmission, characteristics of each phase, responses to antiviral therapy, and development of cirrhosis and hepatocellular carcinoma, according to geographical areas (Asia versus Western Europe and North America versus Africa). Furthermore, the clinical course in infected individuals depends on a complex interplay among various factors including viral, host, environmental and other factors. Recently, understanding of molecular characteristics of the prevailing HBV genotypes, frequently accompanied mutations and their clinical implications might explain these geographical differences more pertinently. Hence, in this article, we review the global epidemiology and the natural history of HBV infection, with emphasis on summarizing the different HBV genotypes according to regions.</P>
Shin, Jung Woo,Jung, Seok Won,Park, Bo Ryung,Kim, Chang Jae,Eum, Jun Bum,Kim, Byung Gyu,Du Jeong, In,Bang, Sung-Jo,Park, Neung Hwa International Medical Press 2012 ANTIVIRAL THERAPY Vol.17 No.2
<P>The aim of this study was to investigate the relationship between HBV DNA levels at baseline and on-treatment and the virological response at 96 weeks after adefovir add-on therapy in chronic hepatitis B (CHB) patients with lamivudine resistance.</P>
Kim, Hye-Young,Eo, Eun-Young,Park, Hyun,Kim, Youn-Chul,Park, Sun,Shin, Ho-Joon,Kim, Kyongmin International Medical Press 2010 ANTIVIRAL THERAPY Vol.15 No.5
<P>BACKGROUND: Cimicifuga rhizome, Meliae cortex, Coptidis rhizome and Phellodendron cortex have been previously shown to exhibit anti-coronavirus activity. Here, an additional 19 traditional medicinal herbal extracts were evaluated for antiviral activities in vitro. METHODS: A plaque assay was used to evaluate the effects of 19 extracts, and the concentration of extract required to inhibit 50% of the replication (EC(50)) of mouse hepatitis virus (MHV) A59 strain (MHV-A59) was determined. The 50% cytotoxic concentration (CC(50)) of each extract was also determined. Northern and western blot analyses were conducted to evaluate antiviral activity on viral entry, viral RNA and protein expression, and release in MHV-infected DBT cells. RESULTS: Sophorae radix, Acanthopanacis cortex and Torilis fructus reduced intracellular viral RNA levels with comparable reductions in viral proteins and MHV-A59 production. The extracts also reduced the replication of the John Howard Mueller strain of MHV, porcine epidemic diarrhoea virus and vesicular stomatitis virus in vitro. Sanguisorbae radix reduced coronavirus production, partly as a result of decreased protein synthesis, but without a significant reduction in intracellular viral RNA levels. The EC(50) values of the four extracts ranged from 0.8 to 3.7 mug/ml, whereas the CC(50) values ranged from 156.5 to 556.8 mug/ml. Acanthopanacis cortex and Torilis fructus might exert their antiviral activities in MHV-A59-infected cells by inducing cyclooxygenase-2 expression via the activation of extracellular signal-related kinase (ERK) and p38 or ERK alone, respectively. CONCLUSIONS: Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus might be considered as promising novel anti-coronavirus drug candidates.</P>
Paik, Yong-Han,Han, Kwang-Hyub,Hong, Sun Pyo,Lee, Hyun Woong,Lee, Kwan Sik,Kim, Soo-Ok,Shin, Ji Eun,Ahn, Sang Hoon,Chon, Chae Yoon,Moon, Young Myoung International Medical Press 2006 ANTIVIRAL THERAPY Vol.11 No.4
<P>The early emergence of lamivudine (3TC)-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutants has been reported during 3TC therapy in patients with chronic hepatitis B (CHB) in hepatitis B virus (HBV)-endemic areas; however, its clinical impact during long-term 3TC therapy is unknown. This study was performed to investigate the impact of the early emergence of YMDD mutants 3 months after the initiation of treatment on the outcomes of long-term 3TC therapy in HBV e antigen (HBeAg)-positive CHB. We analysed YMDD genotypes in consecutive samples from 30 patients with HBeAg positive CHB throughout 3TC treatment using both restriction fragment length polymorphism and mass spectrometric assays. Long-term outcome was compared between patients who had YMDD mutations detected at 3 months and those who had no mutations. YMDD mutation was detected in 16 (53.3%) out of 30 patients at 3 months and only the rtM2041 mutation was found. Cumulative HBeAg loss rates at 3 years was 12.5% and 57.4% in patients who had the rtM2041 mutant and wild-type virus at 3 months, respectively (P=0.010). Cumulative viral breakthrough rates at 3 years was 75.0% and 14.3% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively (P=0.002). Logistic regression revealed that YMDD mutation at 3 months was significantly related to viral breakthrough within 24 months (P=0.003). In conclusion, early detection for HBV YMDD mutation at 3 months may be useful to predict the long-term outcomes of 3TC therapy in patients with HBeAg-positive CHB in HBV-endemic areas.</P>
Lee, Jung Min,Kim, Hyung Joon,Park, Jun Yong,Lee, Chun Kyon,Kim, Do Young,Kim, Ja Kyung,Lee, Hyun Woong,Paik, Yong Han,Lee, Kwan Sik,Han, Kwang-Hyub,Chon, Chae Yoon,Hong, Sun Pyo,Nguyen, Tin,Ahn, Sang International Medical Press 2009 ANTIVIRAL THERAPY Vol.14 No.5
<P>BACKGROUND: The efficacy of adefovir dipivoxil (ADV) or entecavir (ETV) rescue monotherapy has not been directly compared in hepatitis B e antigen (HBeAg)-positive patients with lamivudine (3TC)-resistant chronic hepatitis B (CHB). We compared the efficacy of ADV and ETV rescue monotherapy in HBeAg-positive patients with confirmed genotypic 3TC resistance. METHODS: A total of 160 HBeAg-positive patients with confirmed 3TC resistance underwent switch therapy (91 ADV and 59 ETV). Parameters assessed included alanine aminotransferase (ALT) normalization, HBeAg seroconversion, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower detection limit <300 copies/ml), virological breakthrough and initial virological response (IVR) at 3 (IVR-3) and 6 (IVR-6) months. RESULTS: Following 52 weeks of treatment in the ADV and ETV groups, serum HBV DNA became undetectable in 25 (27.5%) and 21 (35.6%; P=0.292) patients, ALT normalization occurred in 67/78 (85.9%) and 43/47 (91.5%; P=0.351), HBeAg seroconversion in 4 (4.4%) and 1 (1.7%; P=1.000), IVR-3 in 19 (20.9%) and 18 (30.5%), IVR-6 in 40 (44.0%) and 25 (42.4%) and virological breakthrough in 2 (2.2%) and 1 (1.7%; P=1.000) patients, respectively. CONCLUSIONS: ADV and ETV revealed comparable efficacy after 52 weeks of treatment in HBeAg-positive patients with 3TC resistance. Undetectable HBV DNA in serum following 52 weeks of treatment was predictable with IVR-3 and IVR-6 in both groups.</P>