RESUMO
BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).
Assuntos
Antivirais/administração & dosagem , Desoxicitidina/análogos & derivados , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios , Administração Oral , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Área Sob a Curva , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Muco , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Vírus Sinciciais Respiratórios/fisiologia , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. METHODS: This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults (n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout. RESULTS: Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration-time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were â¼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. CONCLUSIONS: Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.
Assuntos
Capsídeo , Vírus da Hepatite B , Adulto , Antivirais/farmacocinética , Área Sob a Curva , Voluntários Saudáveis , HumanosRESUMO
The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.
Assuntos
Alanina/análogos & derivados , Antivirais/farmacocinética , Variação Biológica da População , Hepatite C Crônica/tratamento farmacológico , Uridina/análogos & derivados , Administração Oral , Alanina/administração & dosagem , Alanina/farmacocinética , Antivirais/administração & dosagem , Antivirais/metabolismo , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada/métodos , Voluntários Saudáveis , Humanos , Indóis/administração & dosagem , Fosforamidas , Simeprevir/administração & dosagem , Uridina/administração & dosagem , Uridina/farmacocinéticaRESUMO
The aim of this study was to characterize the pharmacokinetic drug-drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. The dual effect of simeprevir and odalasvir on their pharmacokinetic parameters was explored. Simulations were performed to assess the impact of the DDI on exposure parameters. In presence of odalasvir, the relative bioavailability of simeprevir increased by 26% and the apparent clearance was reduced following competitive inhibition depending on odalasvir plasma concentrations, with an inhibitory constant (Ki) estimated to be 1610 ng/mL. The apparent odalasvir clearance was reduced by simeprevir plasma concentrations following an Imax model, characterized by a maximum inhibitory effect of 46.7% and an IC50 of 257 ng/mL. Model-based simulations indicated that both Cmax and AUC24h increased for both drugs, when co-administered. The pharmacokinetic model adequately describes the time course of plasma concentrations and their variability when simeprevir and/or odalasvir were orally administered. This model can be used as a first step to predict the exposures of concomitant administration of simeprevir and odalasvir in HCV-infected subjects. Data from study AL355-602 (NCT02512562) were used for this analysis.
Assuntos
Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Carbamatos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Indóis/farmacocinética , Modelos Biológicos , Simeprevir/farmacocinética , Adulto , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Disponibilidade Biológica , Carbamatos/administração & dosagem , Interações Medicamentosas , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Voluntários Saudáveis , Hepatite C/tratamento farmacológico , Humanos , Indóis/administração & dosagem , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Simeprevir/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. METHODS: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. RESULTS: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. CONCLUSIONS: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.
Assuntos
Alanina/análogos & derivados , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Uridina/análogos & derivados , Adulto , Alanina/efeitos adversos , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Genótipo , Meia-Vida , Hepacivirus/genética , Hepatite C/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Fosforamidas , Efeito Placebo , RNA Viral/sangue , Uridina/efeitos adversos , Uridina/farmacocinética , Uridina/uso terapêuticoRESUMO
This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
Assuntos
Alanina/análogos & derivados , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Carbamatos/farmacocinética , Quimioterapia Combinada/efeitos adversos , Indóis/farmacocinética , Pró-Fármacos/farmacocinética , Simeprevir/farmacocinética , Uridina/análogos & derivados , Administração Oral , Adulto , Alanina/efeitos adversos , Alanina/farmacocinética , Antivirais/efeitos adversos , Área Sob a Curva , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Esquema de Medicação , Feminino , Voluntários Saudáveis , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fosforamidas , Pró-Fármacos/efeitos adversos , Simeprevir/efeitos adversos , Uridina/efeitos adversos , Uridina/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto JovemRESUMO
Analyses of drug susceptibility and replication capacity for clinical HBV isolates have been hampered by the limitations of available in vitro culture systems. Site-directed mutagenesis has been used to study the effects of point mutations in recombinant laboratory HBV strains, however, the validity of such analyses are compromised since mutations are removed from their natural genetic context. Here we report the development of a new plasmid vector that facilitates the cloning and expression of full-length HBV genomes amplified from the sera of chronic hepatitis B patients. Using this vector, we cloned a total of 28 full-length HBV isolates from nine different patients. The majority of cloned HBV genomes ( approximately 70%) replicated in vitro and were suitable for further phenotypic characterization. Adefovir susceptibility was measured for clones from all nine patients. IC(50) values were similar to those previously obtained with standard laboratory HBV strains and did not vary significantly between individual patient isolates (mean IC(50)=0.24+/-0.08 microM). The vector described here enables the efficient phenotypic analysis of full-length HBV isolates from patients and will be useful in future studies including resistance surveillance, cross-resistance analyses, and novel drug-discovery.
Assuntos
Adenina/análogos & derivados , Antivirais/farmacologia , Clonagem Molecular/métodos , Vetores Genéticos , Vírus da Hepatite B/efeitos dos fármacos , Organofosfonatos , Adenina/farmacologia , Linhagem Celular , DNA Viral/isolamento & purificação , Farmacorresistência Viral , Genoma Viral , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE: This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. RESULTS: Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. CONCLUSION: The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.
Assuntos
Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Progressão da Doença , Esquema de Medicação , Humanos , Lenalidomida , Pessoa de Meia-Idade , Recidiva , Talidomida/administração & dosagem , Talidomida/análogos & derivadosRESUMO
BACKGROUND/AIMS: In contrast to lamivudine, adefovir dipivoxil (ADV) therapy is associated with delayed and infrequent selection of drug resistant hepatitis B virus (HBV). METHODS: A 52 year-old man was treated with lamivudine for an HBV recurrence on his liver graft. A viral breakthrough was observed and the patient received ADV. Serum HBV DNA decreased rapidly and lamivudine was discontinued while ADV monotherapy was maintained. Serum HBV DNA levels remained suppressed until a second breakthrough was observed. Lamivudine was then reintroduced together with ADV, and serum HBV DNA became undetectable by polymerase chain reaction. RESULTS: Sequence analyses of the HBV polymerase gene revealed a sequential selection of lamivudine resistance mutations L180M+M204V, followed by a reversion to wild-type, and subsequently the selection of a novel adefovir resistance mutation N236T. Phenotypic analyses in cell culture assays demonstrated that the HBV isolates at the time of ADV breakthrough had reduced susceptibility to ADV. This mutant remained sensitive to lamivudine, entecavir and emtricitabine in vitro. CONCLUSIONS: We describe the first case of sequential selection of lamivudine and adefovir resistant strains of HBV in a liver transplantation patient. The selection of the N236T polymerase mutant was associated with resistance to ADV but remained sensitive to lamivudine in vitro and in vivo.
Assuntos
Adenina/análogos & derivados , Adenina/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/cirurgia , Transplante de Fígado , Organofosfonatos , Inibidores da Transcriptase Reversa/administração & dosagem , Sequência de Aminoácidos , Terapia Combinada , Farmacorresistência Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
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.
Assuntos
Adenina/análogos & derivados , Adenina/administração & dosagem , Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos , Adenina/química , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Antivirais/química , Sequência de Bases , Sequência Conservada , DNA Viral/análise , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos ProspectivosRESUMO
Therapy of chronic hepatitis B virus (HBV) infection with the polymerase inhibitor lamivudine frequently is associated with the emergence of viral resistance. Genotypic changes in the YMDD motif (reverse transcriptase [rt] mutations rtM204V/I) conferred resistance to lamivudine as well as reducing the in vitro replication efficiency of HBV. A second mutation, rtL180M, was previously reported to partially restore replication fitness as well as to augment drug resistance in vitro. Here we report the functional characterization of a third polymerase mutation (rtV173L) associated with resistance to lamivudine and famciclovir. rtV173L was observed at baseline in 9 to 22% of patients who entered clinical trials of adefovir dipivoxil for the treatment of lamivudine-resistant HBV. In these patients, rtV173L was invariably found as a third mutation in conjunction with rtL180M and rtM204V. In vitro analyses indicated that rtV173L did not alter the sensitivity of wild-type or lamivudine-resistant HBV to lamivudine, penciclovir, or adefovir but instead enhanced viral replication efficiency. A molecular model of HBV polymerase indicated that residue rtV173 is located beneath the template strand of HBV nucleic acid near the active site of the reverse transcriptase. Substitution of leucine for valine at this residue may enhance polymerization either by repositioning the template strand of nucleic acid or by affecting other residues involved in the polymerization reaction. Together, these results suggest that rtV173L is a compensatory mutation that is selected in lamivudine-resistant patients due to an enhanced replication phenotype.
Assuntos
2-Aminopurina/análogos & derivados , Vírus da Hepatite B/enzimologia , Lamivudina/uso terapêutico , Mutação , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Seleção Genética , 2-Aminopurina/farmacologia , 2-Aminopurina/uso terapêutico , Sequência de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral , Famciclovir , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Lamivudina/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Dados de Sequência Molecular , Inibidores da Transcriptase Reversa/farmacologia , Replicação ViralRESUMO
Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug. To determine whether extended treatment with ADV led to the emergence of drug-resistant populations of HBV, we analyzed virus isolated from patients currently enrolled in a long-term open-label study. The reverse transcriptase domain of HBV polymerase was amplified and sequenced from patients that had received a cumulative exposure of up to 60 weeks of ADV. During our analyses, several previously unreported amino acid substitutions were observed in the reverse transcriptase domain of HBV. Importantly, none of the observed mutations occurred in more than 1 patient, nor were they associated with an adefovir-resistant phenotype in vitro. Furthermore, none of the patients from whom these mutant viruses were isolated had evidence of virologic rebound. In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy.
Assuntos
Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos , Adulto , Sequência de Bases , Carcinoma Hepatocelular , Sequência Conservada , DNA Viral/análise , DNA Polimerase Dirigida por DNA/genética , Farmacorresistência Viral , Feminino , Seguimentos , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas , Masculino , Pessoa de Meia-Idade , Mutagênese , Fenótipo , Análise de Sequência de DNA , Células Tumorais Cultivadas , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.