The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform
James F Demarest - One of the best experts on this subject based on the ideXlab platform.
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hiv type 1 from a patient with baseline resistance to ccr5 antagonists uses drug bound receptor for entry
AIDS Research and Human Retroviruses, 2010Co-Authors: John C Tilton, James F Demarest, Kathryn M Kitrinos, Heather Amrinemadsen, John L Miamidian, Jennifer M Pfaff, Neelanjana Ray, Jerry Jeffrey, Celia C Labranche, Robert W DomsAbstract:CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist Aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.
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virologic failure in first line human immunodeficiency virus therapy with a ccr5 entry inhibitor Aplaviroc plus a fixed dose combination of lamivudine zidovudine nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: James F Demarest, Heather Amrinemadsen, David M Irlbeck, Kathryn M KitrinosAbstract:The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naive human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to Aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with Aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.
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virologic failure in therapy naive subjects on Aplaviroc plus lopinavir ritonavir detection of Aplaviroc resistance requires clonal analysis of envelope
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Kathryn M Kitrinos, Heather Amrinemadsen, David M Irlbeck, J M Word, James F DemarestAbstract:The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc in combination with lopinavir-ritonavir in drug-naive human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to Aplaviroc or lopinavir-ritonavir was not observed at the population level. However, Aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced Aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with Aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of Aplaviroc and lopinavir-ritonavir may be associated with Aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.
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in vitro and clinical investigation of the relationship between ccr5 receptor occupancy and anti hiv activity of Aplaviroc
The Journal of Clinical Pharmacology, 2008Co-Authors: James F Demarest, Kimberly K Adkison, Lei Fang, Sara S Sparks, Kathleen Schell, Shiro Shibayama, Charlene B Mcdanal, Anne Shachoyclark, Stephen C PiscitelliAbstract:Aplaviroc (GW873140) binds specifically to human cellular CC chemokine receptor 5 (CCR5) and demonstrates potent anti-human immunodeficiency virus activity in vitro in the subnanomolar range. In vitro studies show that Aplaviroc selectively inhibits the binding of a particular monoclonal antibody, 45531, to CCR5. Based on this observation, a flow cytometry-based assay was developed to determine percentage CCR5 receptor occupancy (RO). CCR5 receptor occupancy was Aplaviroc concentration-dependent and related to anti-human immunodeficiency virus activity in vitro. In the clinical setting, CCR5 receptor occupancy in peripheral blood was >98% in all subjects within 2 to 3 hours of dosing, which is consistent with the peak plasma concentrations of drug. Longitudinal analysis in the drug washout period revealed the time to 50% CCR5 receptor occupancy averaged >100 hours, in both human immunodeficiency virus-positive and human immunodeficiency virus-negative subjects, substantially longer than the plasma pharmacokinetic half-life of 3 hours. The duration of CCR5 receptor occupancy appeared to be dose-dependent and associated with antiviral activity as measured by plasma human immunodeficiency virus RNA nadir following 10 days of multiple dose administration. These data demonstrate that the analysis of CCR5 receptor occupancy, in addition to conventional plasma-based pharmacokinetic measures, provides an informative tool to assist in evaluating the pharmacodynamic and antiviral effects of cellular CC chemokine receptor antagonists.
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update on Aplaviroc an hiv entry inhibitor targeting ccr5
Retrovirology, 2005Co-Authors: James F DemarestAbstract:Aplaviroc (873140) is a novel spirodiketopiperazine CCR5 antagonist that binds specifically to human CCR5 and allosterically inhibits HIV entry. Aplaviroc has exhibited potent in vivo antiviral activity (1.66 log decrease in viral load at nadir) following 10 days of monotherapy. In vitro studies of antiviral activity demonstrate that Aplaviroc is active against HIV isolates from a variety of clades as well as those resistant to current HIV therapies targeting RT, PR, and gp41. In vitro studies suggest prolonged CCR5 receptor occupancy (RO) by Aplaviroc with an offset halflife of >100 hours. In vivo studies following short term Aplaviroc administration using CCR5-specific mAb demonstrate substantial and prolonged CCR5 RO (>50%) by Aplaviroc, when plasma drug levels were undetectable, observed for approximately 5 days.
Kathryn M Kitrinos - One of the best experts on this subject based on the ideXlab platform.
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hiv type 1 from a patient with baseline resistance to ccr5 antagonists uses drug bound receptor for entry
AIDS Research and Human Retroviruses, 2010Co-Authors: John C Tilton, James F Demarest, Kathryn M Kitrinos, Heather Amrinemadsen, John L Miamidian, Jennifer M Pfaff, Neelanjana Ray, Jerry Jeffrey, Celia C Labranche, Robert W DomsAbstract:CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist Aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.
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virologic failure in therapy naive subjects on Aplaviroc plus lopinavir ritonavir detection of Aplaviroc resistance requires clonal analysis of envelope
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Kathryn M Kitrinos, Heather Amrinemadsen, David M Irlbeck, J M Word, James F DemarestAbstract:The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc in combination with lopinavir-ritonavir in drug-naive human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to Aplaviroc or lopinavir-ritonavir was not observed at the population level. However, Aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced Aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with Aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of Aplaviroc and lopinavir-ritonavir may be associated with Aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.
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virologic failure in first line human immunodeficiency virus therapy with a ccr5 entry inhibitor Aplaviroc plus a fixed dose combination of lamivudine zidovudine nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: James F Demarest, Heather Amrinemadsen, David M Irlbeck, Kathryn M KitrinosAbstract:The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naive human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to Aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with Aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.
W G Nichols - One of the best experts on this subject based on the ideXlab platform.
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antiviral activity and safety of Aplaviroc a ccr5 antagonist in combination with lopinavir ritonavir in hiv infected therapy naive patients results of the epic study ccr100136
Hiv Medicine, 2009Co-Authors: P Yeni, Adriano Lazzarin, A Lamarca, Daniel S Berger, P J Cimoch, P Salvato, Fiona M Smaill, E Teofilo, Sam J Madison, W G NicholsAbstract:Background This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist Aplaviroc (APL) in antiretroviral-naive patients harbouring R5- or R5X4-tropic virus. Methods A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. Results This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. Conclusions While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.
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hepatotoxicity observed in clinical trials of Aplaviroc gw873140
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: W G Nichols, Kimberly K Adkison, H M Steel, T Bonny, L Curtis, J Millard, K Kabeya, Nathan ClumeckAbstract:Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naive, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.
Nathan Clumeck - One of the best experts on this subject based on the ideXlab platform.
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hepatotoxicity observed in clinical trials of Aplaviroc gw873140
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: W G Nichols, Kimberly K Adkison, H M Steel, T Bonny, L Curtis, J Millard, K Kabeya, Nathan ClumeckAbstract:Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naive, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.
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antiviral activity and safety of Aplaviroc with lamivudine zidovudine in hiv infected therapy naive patients the ascent ccr102881 study
Antiviral Therapy, 2008Co-Authors: Judith S Currier, Nathan Clumeck, Adriano Lazzarin, Louis Sloan, Jihad Slim, Deb Mccarty, Helen C Steel, Jorg Peter Kleim, Tab Bonny, Judith MillardAbstract:Background: This Phase llb study explored the antiviral activity and safety of the investigational CCR5 antagonist Aplaviroc (APL) in antiretroviral-naive patients harbouring R5-tropic virus. Methods: One hundred and forty-seven patients were randomized 2:2:1 to one of two APL dosing regimens or efavirenz (EFV). All dosage arms were administered twice daily and in combination with lamivudine/zidovudine (3TC/ZDV; Combivir, COM). Efficacy, safety, and pharmacokinetic parameters were assessed. Results: This study was prematurely terminated due to APL-associated idiosyncratic hepatotoxicity. The primary endpoint of the study was the proportion of patients with plasma HIV-1 RNA <400 copies/ml who remained on randomized treatment through week 12. Of the 147 patients enrolled, 145 patients received one dose of treatment and were included in the intention-to-treat population. The proportion of patients with HIV-1 RNA <400 copies/ml at week 12 was 53%, 50% and 66% in the APL 600 mg twice daily, APL 800 mg twice daily, and EFV arms, respectively. Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated non-linear pharmacokinetics with high interpatient variability. In addition to the hepatic findings, there was an apparent dose-response relationship in the incidence of diarrhoea. Conclusions: Whereas target plasma concentrations of APL were achieved, the antiviral activity of APL as the third agent in a triple drug regimen did not appear to be comparable to EFV in this treatment-naive patient population.
Heather Amrinemadsen - One of the best experts on this subject based on the ideXlab platform.
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hiv type 1 from a patient with baseline resistance to ccr5 antagonists uses drug bound receptor for entry
AIDS Research and Human Retroviruses, 2010Co-Authors: John C Tilton, James F Demarest, Kathryn M Kitrinos, Heather Amrinemadsen, John L Miamidian, Jennifer M Pfaff, Neelanjana Ray, Jerry Jeffrey, Celia C Labranche, Robert W DomsAbstract:CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist Aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.
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virologic failure in therapy naive subjects on Aplaviroc plus lopinavir ritonavir detection of Aplaviroc resistance requires clonal analysis of envelope
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Kathryn M Kitrinos, Heather Amrinemadsen, David M Irlbeck, J M Word, James F DemarestAbstract:The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc in combination with lopinavir-ritonavir in drug-naive human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to Aplaviroc or lopinavir-ritonavir was not observed at the population level. However, Aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced Aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with Aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of Aplaviroc and lopinavir-ritonavir may be associated with Aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.
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virologic failure in first line human immunodeficiency virus therapy with a ccr5 entry inhibitor Aplaviroc plus a fixed dose combination of lamivudine zidovudine nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: James F Demarest, Heather Amrinemadsen, David M Irlbeck, Kathryn M KitrinosAbstract:The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naive human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to Aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with Aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.