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Carol L Brosgart - One of the best experts on this subject based on the ideXlab platform.
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extended treatment with lamivudine and Adefovir dipivoxil in chronic hepatitis b patients with lamivudine resistance
Hepatology International, 2011Co-Authors: Robert P Perrillo, Carol L Brosgart, Susan Dixon, Mary Woessner, Bernard Willems, Hie-won Hann, Nancy Leung, David Mutimer, Lynn D CondreayAbstract:Purpose We and others have reported that adding Adefovir dipivoxil (Adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV.
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long term therapy with Adefovir dipivoxil for hbeag negative chronic hepatitis b for up to 5 years
Gastroenterology, 2006Co-Authors: Stephanos J Hadziyannis, Carol L Brosgart, G Kitis, Tingtsung Chang, Nicolaos C. Tassopoulos, Jenny E Heathcote, Mario Rizzetto, Zachary Goodman, Patrick Marcellin, Katyna Borroto EsodaAbstract:Background & Aims: Treatment with Adefovir dipivoxil for 48 weeks resulted in clinical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B that was lost when treatment was discontinued. We investigated the efficacy, safety, and resistance profile of Adefovir dipivoxil treatment for up to 240 weeks. Methods: HBeAg-negative patients were treated double blind with placebo or Adefovir dipivoxil 10 mg once daily for 48 weeks, followed by Adefovir dipivoxil from week 49 to 96. At week 97, 125 patients enrolled in a 144-week, open-label phase. Patients received Adefovir dipivoxil for up to 192 or 240 weeks. Results: Serum hepatitis B virus (HBV) DNA levels were less than 1000 copies per milliliter in 67% of patients, and alanine aminotransferase (ALT) levels normalized in 69% after 240 weeks. After 192 or 240 weeks of treatment, over 83% of patients had improvement in necroinflammation, and over 73% had improvement in fibrosis. Ishak fibrosis scores improved compared with baseline in 35%, 55%, and 71% of patients after 48, 192, and 240 weeks of Adefovir dipivoxil, respectively. After 240 weeks, the cumulative probability of HBV polymerase mutations was 29%, but the cumulative probability of mutations with virologic resistance was 20% and of mutations, virologic resistance, and ALT elevations was 11%. Slight elevations in creatinine were confirmed in 4 (3%) patients. Conclusions: Treatment with Adefovir dipivoxil for up to 240 weeks was well tolerated and produced significant, increasing improvement in hepatic fibrosis, durable suppression of HBV replication, normalization of liver enzymes, and delayed development of resistance.
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safety and efficacy of Adefovir dipivoxil in patients infected with lamivudine resistant hepatitis b and hiv 1
Journal of Hepatology, 2006Co-Authors: Yves Benhamou, Vincent Thibault, M H Fievet, Chuy G Chang, Lu Biao, Shelly Xiong, Anne-geneviève Marcelin, Vincent Calvez, Graeme Currie, Carol L BrosgartAbstract:BACKGROUND/AIMS: Adefovir dipivoxil (10 mg once-daily) was added to antiretroviral therapy including lamivudine in 35 HIV/HBV co-infected patients. METHODS: Parameters evaluated included alanine aminotransferase (ALT), HBV DNA and serological markers, HIV-1 RNA, and CD4+ cell count. RESULTS: Twenty-nine patients (83%) completed 144 weeks. Serum HBV DNA declined from a baseline 9.76 log10 copies/mL (median) to 4.68, 5.24, and 5.90 log10 copies/mL at weeks 48, 96, and 144, respectively (P<0.0001 at all time points). Seven patients (25%) achieved HBV DNA<2.3 log10 copies/mL. No Adefovir-associated resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were detected. ALT declined from 81 IU/L (median) at baseline by -16.0, -44.5, and -46.0 IU/L at week 48, 96 and 144, respectively (P=<0.05, respectively), and normalized in 71% of patients (20 of 28) by week 144. Two patients developed antibodies against HB 'e' antigen by week 48. No serious adverse events related to Adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable. CONCLUSIONS: Treatment with Adefovir dipivoxil for 144 weeks was well tolerated and resulted in significant and sustained reductions in HBV DNA and ALT in HIV/HBV co-infected patients. Efficacy increased with treatment duration, with no loss of viral suppression.
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Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis b with ymdd mutant hepatitis b virus
Gastroenterology, 2004Co-Authors: Robert P Perrillo, Mary Woessner, Bernard Willems, Hie-won Hann, Nancy Leung, David Mutimer, Alison Moorat, Stephen D Gardner, Eric J Bourne, Carol L BrosgartAbstract:Abstract Background & Aims: Prolonged lamivudine therapy is associated with treatment-resistant YMDD mutant hepatitis B virus (HBV). We evaluated the efficacy and safety of adding Adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV. Methods: Ninety-five patients with compensated CHB (group A) were randomized to Adefovir 10 mg daily (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post-liver transplantation (group B) received Adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10 5 copies/mL or a >2 log 10 reduction from baseline at weeks 48 and 52. Results: HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone ( P P 10 copies/mL, respectively). Normalization of alanine aminotransferase levels occurred in 31% of patients (14 of 45) receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone ( P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of −4.6 log 10 copies/mL) and improved liver chemistries ( P ≤ 0.001). Both treatment regimens were well tolerated, and renal function abnormalities were not observed in either group. Conclusions: The addition of Adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to YMDD mutant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated.
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resistance to Adefovir dipivoxil therapy associated with the selection of a novel mutation in the hbv polymerase
Gastroenterology, 2003Co-Authors: Peter W Angus, Carol L Brosgart, William E Delaney, Craig S Gibbs, S Da-xiong, Huiling Yang, Rhys B Vaughan, Danielle Colledge, Rosalind Edwards, Anna AyresAbstract:Abstract Background & aims: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize Adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. Methods: HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. Results: Following the commencement of treatment with Adefovir dipivoxil, the patient initially responded with a 2.4 log 10 decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to Adefovir. Conclusions: The development of this novel mutation in the HBV polymerase confers resistance to Adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.
Tomas Cihlar - One of the best experts on this subject based on the ideXlab platform.
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nonsteroidal anti inflammatory drugs efficiently reduce the transport and cytotoxicity of Adefovir mediated by the human renal organic anion transporter 1
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Andrew Mulato, Tomas CihlarAbstract:Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with Adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that Adefovir is efficiently transported by the human renal organic anion transporter 1 (hOAT1), a membrane transport protein localized in the kidney, that presumably mediates the accumulation of Adefovir in renal proximal tubules. In an effort to look for novel inhibitors of this transport process, we used a cell line stably expressing hOAT1 to demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) efficiently inhibit hOAT1-specific transport of Adefovir at clinically relevant concentrations. Diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen were equally or more effective (IC50 = 0.85–8 μM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC50 = 8 and 6 μM, respectively) with in vivo nephroprotective effects. Importantly, NSAIDs significantly reduced the shift in Adefovir cytotoxicity observed upon hOAT1 expression with ketoprofen and naproxen being 2- to 3-times more effective than probenecid. Transport experiments with [3H]ketoprofen and [3H]ibuprofen revealed that NSAIDs themselves were not efficiently transported by hOAT1. None of the NSAIDs tested showed any interference with the anti-HIV activity of Adefovir. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of Adefovir nephrotoxicity.
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cytotoxicity of antiviral nucleotides Adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1
Journal of The American Society of Nephrology, 2000Co-Authors: Deborah C. Lin, Dirk B. Mendel, Tomas CihlarAbstract:The transport of organic anions in proximal convoluted tubules plays an essential role in the active secretion of a variety of small molecules by the kidney. In addition to other anionic substrates, the human renal organic anion transporter 1 (hOATI) is capable of transporting the nucleotide analogs Adefovir and cidofovir. To investigate the involvement of hOATI in the mechanism of nephrotoxicity associated with these two clinically important antiviral agents, Chinese hamster ovary (CHO) cells were stably transfected with hOATI cDNA. The resulting CHOhOAT cells showed probenecid-sensitive and pH-dependent uptake of p-aminohippurate (Km = 15.4 FtM, V,,, ..ax = 20.6 pmol/106 cells min), a prototypical organic anion substrate. In addition, the stably expressed hOATI mediated efficient transport of Adefovir (Km, = 23.8 tLM, V, a,, = 46.0 pmol/106 cells min) and cidofovir (K, = 58.0 /iM, Vt,ax = 103 pmol/106 cells * min) such that the levels of intracellular metabolites of both nucleotides were > 1 00-fold higher in CHOh OAT cells than in parental CHO. Consequently, Adefovir and cidofovir were approximately 500-fold and 400-fold more cytotoxic, respectively, in CHOh OAT cells compared to CHO. The cytotoxicity of both drugs in CHOh OAT cells was markedly reduced in the presence of hOATI inhibitors. The cyclic prodrug of cidofovir, which exhibits reduced in vivo nephrotoxicity, was a poor substrate for hOATI and showed only marginally increased cytotoxicity in CHOh OAT cells. In conclusion, these studies demonstrate that hOATI plays a critical role in the organ-specific toxicity of Adefovir and cidofovir, and indicates that CHOh OAT cells may represent a useful in vitro model to investigate the potential nephrotoxicity of clinically relevant organic anion agents.
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The antiviral nucleotide analogs cidofovir and Adefovir are novel substrates for human and rat renal organic anion transporter 1.
Molecular pharmacology, 1999Co-Authors: Tomas Cihlar, John B. Pritchard, Deborah C. Lin, Michael D. Fuller, Dirk B. Mendel, Douglas H. SweetAbstract:Nephrotoxicity is the dose-limiting clinical adverse effect of cidofovir and Adefovir, two potent antiviral therapeutics. Because renal uptake likely plays a role in the etiology of cidofovir- and Adefovir-associated nephrotoxicity, we attempted to identify a renal transporter capable of interacting with these therapeutics. A cDNA clone was isolated from a human renal library and designated human organic anion transporter 1 (hOAT1). Northern analysis detected a specific 2.5-kilobase pair hOAT1 transcript only in human kidney. However, reverse transcription-polymerase chain reaction revealed hOAT1 expression in human brain and skeletal muscle, as well. Immunoblot analysis of human kidney cortex demonstrated that hOAT1 is an 80- to 90-kilodalton heterogeneous protein modified by abundant N-glycosylation. Xenopus laevis oocytes expressing hOAT1 supported probenecid-sensitive uptake of [(3)H]p-aminohippurate (K(m) = 4 microM), which was trans-stimulated in oocytes preloaded with glutarate. Importantly, both hOAT1 and rat renal organic anion transporter 1 (rROAT1) mediated saturable, probenecid-sensitive uptake of cidofovir, Adefovir, and other nucleoside phosphonate antivirals. The affinity of hOAT1 toward cidofovir and Adefovir (K(m) = 46 and 30 microM, respectively) was 5- to 9-fold higher compared with rROAT1 (K(m) = 238 and 270 microM, respectively). These data indicate that hOAT1 may significantly contribute to the accumulation of cidofovir and Adefovir in renal proximal tubules and, thus, play an active role in the mechanism of nephrotoxicity associated with these antiviral therapeutics.
Stephanos J Hadziyannis - One of the best experts on this subject based on the ideXlab platform.
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2015Co-Authors: Stephanos J Hadziyannis, George V. PapatheodoridisAbstract:New antiviral agents currently evaluated for the treatment of HBeAg–negative chronic hepatitis B include Adefovir, entecavir and some other newer nucleoside analogues. Adefovir, a nucleotide analogue of adenosine, is expected to be soon available in clinical practice. The recommended 10 mg daily dose is safe and well tolerated. In a phase III clinical trial, a 48-week course of Adefovir was recently shown to achieve histologic improvement, inhibition of HBV replication and biochemical remission in the majority of HBeAg– negative chronic hepatitis B patients. Adefovir is also effective against lamivudine resistant HBV strains, while no evidence of resistance to Adefovir has been detected to date. Entecavir, a guanosine analogue, has initially been shown to suppress HBV replication given even in a low dose of 0.1 mg daily. In a recent phase III trial including lamivudine resistant HBV patients, a 24-week course of entecavir at daily doses of 0.5 mg or 1.0 mg achieved significantly greater reduction of serum HBV-DNA levels than the low 0.1 mg entecavir dose or continuation of lamivudine. Entecavir was safe and well tolerated and is currently under evaluation within several phase III trials. Preliminary data for emtricitabine, clevudine, and L-deoxythymidine suggest that all these agents are probably effective against both HBeAg-positive and HBeAg–negative chronic hepatitis B. However, whether any of these new agents as monotherapy or in combination therapies can induce sustained off-therapy responses in the patients with long-standing HBeAg–negative chronic hepatitis B is currently unknown
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long term therapy with Adefovir dipivoxil for hbeag negative chronic hepatitis b for up to 5 years
Gastroenterology, 2006Co-Authors: Stephanos J Hadziyannis, Carol L Brosgart, G Kitis, Tingtsung Chang, Nicolaos C. Tassopoulos, Jenny E Heathcote, Mario Rizzetto, Zachary Goodman, Patrick Marcellin, Katyna Borroto EsodaAbstract:Background & Aims: Treatment with Adefovir dipivoxil for 48 weeks resulted in clinical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B that was lost when treatment was discontinued. We investigated the efficacy, safety, and resistance profile of Adefovir dipivoxil treatment for up to 240 weeks. Methods: HBeAg-negative patients were treated double blind with placebo or Adefovir dipivoxil 10 mg once daily for 48 weeks, followed by Adefovir dipivoxil from week 49 to 96. At week 97, 125 patients enrolled in a 144-week, open-label phase. Patients received Adefovir dipivoxil for up to 192 or 240 weeks. Results: Serum hepatitis B virus (HBV) DNA levels were less than 1000 copies per milliliter in 67% of patients, and alanine aminotransferase (ALT) levels normalized in 69% after 240 weeks. After 192 or 240 weeks of treatment, over 83% of patients had improvement in necroinflammation, and over 73% had improvement in fibrosis. Ishak fibrosis scores improved compared with baseline in 35%, 55%, and 71% of patients after 48, 192, and 240 weeks of Adefovir dipivoxil, respectively. After 240 weeks, the cumulative probability of HBV polymerase mutations was 29%, but the cumulative probability of mutations with virologic resistance was 20% and of mutations, virologic resistance, and ALT elevations was 11%. Slight elevations in creatinine were confirmed in 4 (3%) patients. Conclusions: Treatment with Adefovir dipivoxil for up to 240 weeks was well tolerated and produced significant, increasing improvement in hepatic fibrosis, durable suppression of HBV replication, normalization of liver enzymes, and delayed development of resistance.
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hepatitis b e antigen negative chronic hepatitis b natural history and treatment
Seminars in Liver Disease, 2006Co-Authors: Stephanos J Hadziyannis, George V. PapatheodoridisAbstract:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B evolves in the natural history of chronic hepatitis B virus (HBV) infection linked with selection of nonproducing HBeAg but replication-competent HBV mutants, and may have a potentially severe and progressive course. Effective suppression of HBV replication is the main therapeutic target. Sustained off-therapy responses are rare with treatment of finite duration, except perhaps for interferon-based therapies, which induce such responses in a sizeable, yet small proportion of patients. Eventually, the majority of patients will be treated with long-term oral antiviral therapy, which improves patients' outcome but is associated with progressively increasing rates of viral resistance. The long-term resistance profile of Adefovir is significantly better than that of lamivudine (LMV), whereas data for entecavir currently are limited to 2 years, with resistance developing in LMV-resistant but not in treatment-naive patients. Combination therapy with Adefovir added to LMV in LMV-resistant patients is extremely effective; cases of Adefovir-resistance have not been reported to date.
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long term therapy with Adefovir dipivoxil for hbeag negative chronic hepatitis b
The New England Journal of Medicine, 2005Co-Authors: Stephanos J Hadziyannis, G Kitis, S Arterburn, Tingtsung Chang, Nicolaos C. Tassopoulos, Jenny E Heathcote, Mario Rizzetto, Zachary Goodman, Patrick Marcellin, S Da-xiongAbstract:Background Treatment with Adefovir dipivoxil for 48 weeks resulted in histologic, virologic, and biochemical improvement in patients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B. We evaluated the effect of continued therapy as compared with cessation of therapy. Methods One hundred eighty-five HBeAg-negative patients with chronic hepatitis B were assigned to receive 10 mg of Adefovir dipivoxil or placebo once daily for 48 weeks (ratio, 2:1). After week 48, patients receiving Adefovir dipivoxil were again randomly assigned either to receive an additional 48 weeks of the drug or to switch to placebo. Patients originally assigned to placebo were switched to Adefovir dipivoxil. Patients treated with Adefovir dipivoxil during weeks 49 through 96 were subsequently offered continued therapy. The primary end points were changes in hepatitis B virus (HBV) DNA and alanine aminotransferase levels. Results Treatment with Adefovir dipivoxil resulted in a median decrease in serum HBV DNA of 3.47 log ...
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hepatitis b virus genotypes and virologic response in 694 patients in phase iii studies of Adefovir dipivoxil
Gastroenterology, 2003Co-Authors: Chris Westland, Carol L Brosgart, William E Delaney, Craig S Gibbs, Stephanos J Hadziyannis, Robert G. Gish, Huiling Yang, Patrick Marcellin, Shanshan Chen, Michael D. MillerAbstract:Abstract Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of Adefovir dipivoxil. Antiviral efficacy of Adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of Adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of Adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.
Michael D. Miller - One of the best experts on this subject based on the ideXlab platform.
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hepatitis b virus genotypes and virologic response in 694 patients in phase iii studies of Adefovir dipivoxil
Gastroenterology, 2003Co-Authors: Chris Westland, Carol L Brosgart, William E Delaney, Craig S Gibbs, Stephanos J Hadziyannis, Robert G. Gish, Huiling Yang, Patrick Marcellin, Shanshan Chen, Michael D. MillerAbstract:Abstract Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of Adefovir dipivoxil. Antiviral efficacy of Adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of Adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of Adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.
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week 48 resistance surveillance in two phase 3 clinical studies of Adefovir dipivoxil for chronic hepatitis b
Hepatology, 2003Co-Authors: Christopher Westland, Michael Wulfsohn, Carol L Brosgart, William E Delaney, Craig S Gibbs, Michael D. Miller, Huiling Yang, Shelly XiongAbstract:Seven hundred nucleoside treatment-naive patients were enrolled in two phase 3 trials of Adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B. To monitor for the emergence of potential Adefovir resistance mutations over the first 48 weeks, all intent-to-treat patients (467 ADV-treated and 228 placebo patients) were included in a prospectively defined, treatment-blinded, virology substudy. The study protocol mandated genotypic analysis for all patients with detectable hepatitis B virus (HBV) DNA by Roche Amplicor polymerase chain reaction (PCR) at baseline and week 48, and in vitro phenotypic analyses for patients with conserved site substitutions in HBV polymerase or 1.0 log10 or greater increase in HBV DNA from nadir. Paired sequences of the entire HBV reverse transcriptase were obtained for 271 ADV-treated and 227 placebo patients by using a sequencing method that detects down to 30% of minor species present within mixtures. Four substitutions (rtS119A, rtH133L, rtV214A, and rtH234Q) developed once each at conserved sites in HBV polymerase in 4 ADV-treated patients. Seven conserved site substitutions developed in 6 placebo patients. HBV mutants encoding the 4 substitutions that emerged in ADV-treated patients remained fully susceptible to Adefovir in vitro. Furthermore, these 4 ADV-treated patients had HBV-DNA reductions of 3.3 to 5.9 log10 copies/mL by week 48 with no rebound. All other substitutions occurred at very low frequencies (<1.6%) at polymorphic sites and were not associated with HBV-DNA increases in patients or Adefovir resistance in vitro. In conclusion, no Adefovir resistance mutations were identified in a large group of chronic hepatitis B patients treated with ADV for 48 weeks. (Hepatology 2003;38:96-103.)
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week 48 resistance surveillance in two phase 3 clinical studies of Adefovir dipivoxil for chronic hepatitis b
Hepatology, 2003Co-Authors: Christopher Westland, Michael Wulfsohn, Carol L Brosgart, William E Delaney, Craig S Gibbs, Michael D. Miller, Huiling Yang, John Fry, Shelly XiongAbstract:Seven hundred nucleoside treatment-naive patients were enrolled in two phase 3 trials of Adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B. To monitor for the emergence of potential Adefovir resistance mutations over the first 48 weeks, all intent-to-treat patients (467 ADV-treated and 228 placebo patients) were included in a prospectively defined, treatment-blinded, virology substudy. The study protocol mandated genotypic analysis for all patients with detectable hepatitis B virus (HBV) DNA by Roche Amplicor polymerase chain reaction (PCR) at baseline and week 48, and in vitro phenotypic analyses for patients with conserved site substitutions in HBV polymerase or 1.0 log(10) or greater increase in HBV DNA from nadir. Paired sequences of the entire HBV reverse transcriptase were obtained for 271 ADV-treated and 227 placebo patients by using a sequencing method that detects down to 30% of minor species present within mixtures. Four substitutions (rtS119A, rtH133L, rtV214A, and rtH234Q) developed once each at conserved sites in HBV polymerase in 4 ADV-treated patients. Seven conserved site substitutions developed in 6 placebo patients. HBV mutants encoding the 4 substitutions that emerged in ADV-treated patients remained fully susceptible to Adefovir in vitro. Furthermore, these 4 ADV-treated patients had HBV-DNA reductions of 3.3 to 5.9 log(10) copies/mL by week 48 with no rebound. All other substitutions occurred at very low frequencies (<1.6%) at polymorphic sites and were not associated with HBV-DNA increases in patients or Adefovir resistance in vitro. In conclusion, no Adefovir resistance mutations were identified in a large group of chronic hepatitis B patients treated with ADV for 48 weeks.
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hepatitis b virus genotypes and virologic response in 694 patients in phase iii studies of Adefovir dipivoxil
Gastroenterology, 2003Co-Authors: Chris Westland, Carol L Brosgart, William E Delaney, Craig S Gibbs, Stephanos J Hadziyannis, Robert G. Gish, Huiling Yang, Patrick Marcellin, Shanshan Chen, Michael D. MillerAbstract:Abstract Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of Adefovir dipivoxil. Antiviral efficacy of Adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of Adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of Adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.
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human immunodeficiency virus type 1 expressing the lamivudine associated m184v mutation in reverse transcriptase shows increased susceptibility to Adefovir and decreased replication capability in vitro
The Journal of Infectious Diseases, 1999Co-Authors: Michael D. Miller, Patrick D Lamy, Andrew Mulato, Kristin E Anton, Julie M CherringtonAbstract:In a phase II study of 6-12 months of Adefovir dipivoxil treatment in human immunodeficiency virus (HIV)-infected patients, HIV from 8 of 29 patients developed mutations in reverse transcriptase (RT) potentially attributable to Adefovir dipivoxil therapy. Recombinant HIV from pre- and posttreatment plasma samples from these 8 patients showed no change or minor decreases in Adefovir susceptibility, consistent with the durable antiviral effect observed. Additionally, HIV from 8 patients developed the M184V RT mutation because of concomitant lamivudine use. Recombinant HIV pairs from all 4 patients with zidovudine-resistant HIV showed statistically significant increases in Adefovir susceptibility of 3- to 4-fold (to near wild type IC 50 ), and HIV pairs from 2 of 4 patients with zidovudine-sensitive HIV showed a 2- to 3-fold increase in susceptibility. In growth kinetics studies, expression of the M184V RT mutation resulted in attenuated viral growth in peripheral blood mononuclear cell cultures. These studies suggest that patients possessing HIV with zidovudine and lamivudine resistance mutations may benefit from Adefovir dipivoxil therapy.
William E Delaney - One of the best experts on this subject based on the ideXlab platform.
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progress in the treatment of chronic hepatitis b long term experience with Adefovir dipivoxil
Journal of Antimicrobial Chemotherapy, 2007Co-Authors: William E DelaneyAbstract:Most chronic hepatitis B patients do not undergo a curative response to interferon-a or nucleoside/ nucleotide-based regimens and require long-term therapy. Long-term safety, efficacy and resistance profiles of hepatitis B virus (HBV) drugs are therefore crucial issues for patient management. Adefovir dipivoxil is a nucleotide prodrug indicated for the treatment of patients with hepatitis B e antigen positive or hepatitis B e antigen negative chronic hepatitis B, lamivudine-resistant HBV infection, HBV infection pre- or post-liver transplantation, or HlV co-infection. Long-term data from clinical trials of up to 5 years duration of Adefovir dipivoxil have recently become available and are reviewed here. These data demonstrate that Adefovir dipivoxil therapy results in sustained efficacy and safety in the majority of patients after multiple years of treatment. The efficacy of Adefovir dipivoxil in treating lamivudineresistant HBV and the delayed emergence of Adefovir resistance are key factors contributing to the durable response achieved in broad groups of chronic hepatitis B patients.
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In vitro susceptibility of Adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents.
Antiviral Therapy, 2007Co-Authors: Shelly Xiong, Huiling Yang, Michael Miller, William E DelaneyAbstract:BACKGROUND: Adefovir dipivoxil is a nucleotide prodrug approved for the treatment of chronic hepatitis B. During clinical trials, ADV-associated mutations were observed in 0, 3, 11, 18 and 29% of patients after 48, 96, 144, 192 and 240 weeks of therapy, respectively. Hepatitis B virus (HBV) polymerase mutations associated with virological breakthrough to ADV include rtA181V and rtN236T, which occur alone or in combination. The rtA181T mutation has also been observed at low frequency, alone or in combination with rtN236T. METHODS: To investigate the in vitro activity of Adefovir and other anti-HBV agents against these mutants, we generated five stable cell lines that each expressed one of the following HBV mutants: rtN236T, rtA181V, rtA181V + rtN236T, rtA181T + rtN236T and rtA181T. Using these cell lines, we quantified in vitro changes in drug susceptibility for eight nucleotide/nucleoside analogues. RESULTS: The rtN236T mutant had 7-fold resistance to Adefovir but remained sensitive to entecavir, telbivudine and torcitabine (53.2-fold reduced susceptibility). The A181V mutant had 4.3-fold resistance to Adefovir and had reduced susceptibility to multiple other agents ranging from 3.2-fold (tenofovir) to >191-fold (clevudine). The A181V + rtN236T double mutant was the most highly resistant showing 18-fold resistance to Adefovir and higher levels of resistance to other tested drugs with the exception of tenofovir (10-fold reduced susceptibility). Our results and preliminary clinical data suggest that patients with rtN236T or rtA181V remain susceptible to tenofovir, entecavir and lamivudine. Further clinical data are necessary to precisely define in vitro cutoffs indicative of clinically-relevant resistance, particularly for drugs in development such as emtricitabine, telbivudine, torcitabine and clevudine.
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suppression of lamivudine resistant b domain mutants by Adefovir dipivoxil in the woodchuck hepatitis virus model
Antiviral Research, 2004Co-Authors: James R Jacob, William E Delaney, Brent E Korba, Paul J Cote, John L Gerin, Illia A Toshkov, Bud C. TennantAbstract:Abstract Adult woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus (WHV) were treated orally with lamivudine (15 mg/kg per day) for 57 weeks. After 20 weeks of treatment a 2–3 log reduction in serum WHV DNA was detected. Serum titers of WHV then increased gradually, in the presence of lamivudine treatment, reaching pre-treatment values by week 40. Viral recrudescence was associated with development of mutations in the B domain of the WHV polymerase gene. Mutations observed in the highly conserved FLLA motif of the B domain were L564V, L565M, and A566T, with A566T being the most frequently observed. Beginning on week 57 of lamivudine treatment, one group (n=3) was treated orally with Adefovir dipivoxil at a dose of 15 mg/kg per day plus lamivudine, and a second group (n=3) was treated with H2O placebo plus lamivudine. In woodchucks treated with Adefovir dipivoxil, two had the A566T mutation, and one had both A566T and L565V. In the group maintained on lamivudine monotherapy, A566T alone was present in one animal, another carried both A566T and L565V, and in the third, no B-domain mutations were detected. There was a 4.5 log reduction in serum WHV DNA after 12 weeks of treatment with the Adefovir/lamivudine combination, while in the lamivudine monotherapy controls, WHV DNA decreased by only 0.83 log (P>0.001). A slight recurrence in serum titers of WHV DNA was observed one week after withdrawal of Adefovir treatment but no further increase in viral load was observed during the remainder of the 12-week post-treatment follow-up period. The results demonstrate that supplemental Adefovir dipivoxil treatment is effective in suppressing replication of lamivudine-resistant B-domain mutants in the woodchuck model of hepatitis B virus infection.
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resistance to Adefovir dipivoxil therapy associated with the selection of a novel mutation in the hbv polymerase
Gastroenterology, 2003Co-Authors: Peter W Angus, Carol L Brosgart, William E Delaney, Craig S Gibbs, S Da-xiong, Huiling Yang, Rhys B Vaughan, Danielle Colledge, Rosalind Edwards, Anna AyresAbstract:Abstract Background & aims: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize Adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. Methods: HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. Results: Following the commencement of treatment with Adefovir dipivoxil, the patient initially responded with a 2.4 log 10 decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to Adefovir. Conclusions: The development of this novel mutation in the HBV polymerase confers resistance to Adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.
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hepatitis b virus genotypes and virologic response in 694 patients in phase iii studies of Adefovir dipivoxil
Gastroenterology, 2003Co-Authors: Chris Westland, Carol L Brosgart, William E Delaney, Craig S Gibbs, Stephanos J Hadziyannis, Robert G. Gish, Huiling Yang, Patrick Marcellin, Shanshan Chen, Michael D. MillerAbstract:Abstract Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of Adefovir dipivoxil. Antiviral efficacy of Adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of Adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of Adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.