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Barry Bernstein - One of the best experts on this subject based on the ideXlab platform.
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Predictors of loss of virologic response in subjects who simplified to Lopinavir/ritonavir monotherapy from Lopinavir/ritonavir plus zidovudine/lamivudine.
AIDS research and human retroviruses, 2009Co-Authors: Rafael Campo, Laurent Cotte, Charles B. Hicks, Cheri E Klein, Yilin Chiu, Martin S King, Barbara A Da Silva, Joseph Gathe, Brian Gazzard, Barry BernsteinAbstract:Abstract Previous studies have demonstrated that Lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving Lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving Lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a Lopinavir/ritonavir-based combination regimen followed by simplification to Lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4+ T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA
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a 96 week comparison of Lopinavir ritonavir combination therapy followed by Lopinavir ritonavir monotherapy versus efavirenz combination therapy
The Journal of Infectious Diseases, 2008Co-Authors: William D Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Robert Myers, Nicholaos C Bellos, Norbert Gilmore, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started Lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (Lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P = .17; 95% confidence interval [CI] for the difference, −29% to 4%); in noncompletion=failure analysis, 60% (Lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P = .73; 95% CI for the difference, −19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the Lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to Lopinavir/ritonavir monotherapy.Trial registration. ClinicalTrials.gov identifier: NCT00075231.
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A 96-Week Comparison of Lopinavir- Ritonavir Combination Therapy Followed by Lopinavir-Ritonavir Monotherapy versus Efavirenz Combination Therapy
The Journal of infectious diseases, 2008Co-Authors: D. William Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Nicholaos C Bellos, Norbert Gilmore, Robert A. Myers, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels
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pharmacokinetic pharmacodynamic analysis of Lopinavir ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus infected patients
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: Ann Hsu, Scott C. Brun, Jeffrey D Isaacson, Bruce Richards, Barry Bernstein, Wayne Lam, Richard Bertz, Cheryl Foit, Karen Rynkiewicz, Martin S KingAbstract:The steady-state pharmacokinetics and pharmacodynamics of two oral doses of Lopinavir-ritonavir (Lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of Lopinavir/r at 400/100 mg BID; subjects in one arm increased the Lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the Lopinavir/r 400/100 mg BID regimen resulted in lower Lopinavir concentrations in plasma, particularly Cmin, than were observed in previous studies of Lopinavir/r administered without efavirenz. Increasing the Lopinavir/r dose to 533/133 mg increased the Lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC12), Cpredose, and Cmin by 46, 70, and 141%, respectively. The increase in Lopinavir Cmax (33%,) did not reach statistical significance. Ritonavir AUC12, Cmax, Cpredose, and Cmin values were increased 46 to 63%. The Lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with Lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified Lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline Lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no Lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.
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analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor experienced hiv 1 infected patients receiving Lopinavir ritonavir therapy
Antiviral Therapy, 2002Co-Authors: Dale J Kempf, Scott C. Brun, Jeffrey D Isaacson, Martin S King, Jacquelyn Sylte, Bruce Richards, Barry Bernstein, Richard A RodeAbstract:The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with Lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a 'dropouts as censored' analysis, plasma HIV RNA s400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with 40-fold reduced susceptibility to Lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline Lopinavir mutation score of 0-5, 6-7 and ≥8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to Lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to Lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to Iopinavir/ritonavir.
Martin S King - One of the best experts on this subject based on the ideXlab platform.
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predictors of loss of virologic response in subjects who simplified to Lopinavir ritonavir monotherapy from Lopinavir ritonavir plus zidovudine lamivudine
AIDS Research and Human Retroviruses, 2009Co-Authors: Rafael Campo, Charles B. Hicks, Cheri E Klein, Yilin Chiu, Martin S King, Barbara A Da Silva, Joseph Gathe, Brian Gazzard, L Cotte, Barry M BernsteinAbstract:Abstract Previous studies have demonstrated that Lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving Lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving Lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a Lopinavir/ritonavir-based combination regimen followed by simplification to Lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4+ T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA <50 copies/ml prior to simplificat...
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Predictors of loss of virologic response in subjects who simplified to Lopinavir/ritonavir monotherapy from Lopinavir/ritonavir plus zidovudine/lamivudine.
AIDS research and human retroviruses, 2009Co-Authors: Rafael Campo, Laurent Cotte, Charles B. Hicks, Cheri E Klein, Yilin Chiu, Martin S King, Barbara A Da Silva, Joseph Gathe, Brian Gazzard, Barry BernsteinAbstract:Abstract Previous studies have demonstrated that Lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving Lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving Lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a Lopinavir/ritonavir-based combination regimen followed by simplification to Lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4+ T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA
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a 96 week comparison of Lopinavir ritonavir combination therapy followed by Lopinavir ritonavir monotherapy versus efavirenz combination therapy
The Journal of Infectious Diseases, 2008Co-Authors: William D Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Robert Myers, Nicholaos C Bellos, Norbert Gilmore, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started Lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (Lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P = .17; 95% confidence interval [CI] for the difference, −29% to 4%); in noncompletion=failure analysis, 60% (Lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P = .73; 95% CI for the difference, −19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the Lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to Lopinavir/ritonavir monotherapy.Trial registration. ClinicalTrials.gov identifier: NCT00075231.
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A 96-Week Comparison of Lopinavir- Ritonavir Combination Therapy Followed by Lopinavir-Ritonavir Monotherapy versus Efavirenz Combination Therapy
The Journal of infectious diseases, 2008Co-Authors: D. William Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Nicholaos C Bellos, Norbert Gilmore, Robert A. Myers, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels
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selection of resistance in protease inhibitor experienced human immunodeficiency virus type 1 infected subjects failing Lopinavir and ritonavir based therapy mutation patterns and baseline correlates
Journal of Virology, 2005Co-Authors: Martin S King, Scott C. Brun, Kathryn R King, Akhteruzzaman Molla, Dale J KempfAbstract:The selection of in vivo resistance to Lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with Lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to Lopinavir (emergence of new mutation[s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of Lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating Lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to Lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with Lopinavir resistance and/or displayed >60-fold-reduced susceptibility to Lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for Lopinavir-ritonavir.
D M Burger - One of the best experts on this subject based on the ideXlab platform.
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high incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of Lopinavir ritonavir tablets
AIDS, 2008Co-Authors: Hanneke Mj Nijland, Rob E Aarnoutse, Martin J. Boeree, R F A Lhomme, Gerard A Rongen, P Van Uden, R Van Crevel, P P Koopmans, D M BurgerAbstract:OBJECTIVE: Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of Lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to Lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced Lopinavir/ritonavir tablets. METHODS: A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive Lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period. RESULTS: Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of Lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks. CONCLUSIONS: The study showed a high incidence of adverse events when a higher than standard dose of the new Lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and Lopinavir/ritonavir are combined in patients.
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Pharmacokinetics op Iopinavir in HIV type-1 infected children taking the new tablet formulation
Antiviral therapy, 2008Co-Authors: M. Van Der Flier, Gwenda Verweel, L.c. Van Der Knaap, P. Jaarsveld, Gertjan J. Driessen, M. Van Der Lee, Nico G. Hartwig, D M BurgerAbstract:BACKGROUND Recently, a new tablet formulation of the widely used HIV protease inhibitor Lopinavir/ritonavir was licensed. Here, we present a pilot study of the pharmacokinetics of the new adult tablet formulation taken once daily in children. METHODS Lopinavir pharmacokinetics of the new adult tablet formulation were evaluated in 15 HIV type-1-infected children between 4 and 15 years of age. A target dose of 460/115 mg/m2 was administered once daily. Plasma concentrations of Lopinavir over the course of 24 h were determined with a validated HPLC method. RESULTS The median Lopinavir dose was 498 mg/m2 (range 424-548). The mean +/- SD for Lopinavir area under the 24 h curve was 217.9 +/- 44.9 mg/l x h, the maximum concentration was 14.8 +/- 2.4 mg/l and the concentration 24 h after intake was 3.1 +/- 2.6 mg/l. The half-life of Lopinavir was 5.8 +/- 4.5 h and the median time to maximum concentration was 5.8 h (range 1.8-12.2). Overall, the tablet formulation resulted in greater exposure to Lopinavir with less variability compared with the soft-gel capsule formulation. All children treated with the new adult tablet formulation had undetectable viral loads (< 50 copies/ml) during 24 weeks follow-up. CONCLUSIONS The tablet formulation could probably result in improved Lopinavir dosing and increases the feasibility of once-daily Lopinavir/ritonavir-based regimens in children.
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Lopinavir ritonavir plus saquinavir in salvage therapy pharmacokinetics tolerability and efficacy
AIDS, 2003Co-Authors: C.j.l. La Porte, Jan-christian Wasmuth, Jürgen Kurt Rockstroh, K. Schneider, D M BurgerAbstract:Patients receiving a Lopinavir/ritonavir and saquinavir dual protease inhibitor-based antiretroviral salvage regimen were studied to evaluate the pharmacokinetics, tolerability and efficacy of the regimen. Pharmacokinetic curves were obtained for Lopinavir and saquinavir. Patient records were studied for adverse events and efficacy data. The pharmacokinetics of Lopinavir and saquinavir were comparable with literature data, except for the saquinavir 0-12 h area under the curve and maximum concentration. The tolerability of the regimen was good and efficacy was encouraging.
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Lopinavir/ritonavir plus saquinavir in salvage therapy; pharmacokinetics, tolerability and efficacy.
AIDS, 2003Co-Authors: C.j.l. La Porte, Jan-christian Wasmuth, Jürgen Kurt Rockstroh, K. Schneider, D M BurgerAbstract:Patients receiving a Lopinavir/ritonavir and saquinavir dual protease inhibitor-based antiretroviral salvage regimen were studied to evaluate the pharmacokinetics, tolerability and efficacy of the regimen. Pharmacokinetic curves were obtained for Lopinavir and saquinavir. Patient records were studied for adverse events and efficacy data. The pharmacokinetics of Lopinavir and saquinavir were comparable with literature data, except for the saquinavir 0-12 h area under the curve and maximum concentration. The tolerability of the regimen was good and efficacy was encouraging.
Scott C. Brun - One of the best experts on this subject based on the ideXlab platform.
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a 96 week comparison of Lopinavir ritonavir combination therapy followed by Lopinavir ritonavir monotherapy versus efavirenz combination therapy
The Journal of Infectious Diseases, 2008Co-Authors: William D Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Robert Myers, Nicholaos C Bellos, Norbert Gilmore, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started Lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (Lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P = .17; 95% confidence interval [CI] for the difference, −29% to 4%); in noncompletion=failure analysis, 60% (Lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P = .73; 95% CI for the difference, −19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the Lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to Lopinavir/ritonavir monotherapy.Trial registration. ClinicalTrials.gov identifier: NCT00075231.
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A 96-Week Comparison of Lopinavir- Ritonavir Combination Therapy Followed by Lopinavir-Ritonavir Monotherapy versus Efavirenz Combination Therapy
The Journal of infectious diseases, 2008Co-Authors: D. William Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Nicholaos C Bellos, Norbert Gilmore, Robert A. Myers, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels
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the tablet formulation of Lopinavir ritonavir provides similar bioavailability to the soft gelatin capsule formulation with less pharmacokinetic variability and diminished food effect
Journal of Acquired Immune Deficiency Syndromes, 2007Co-Authors: Cheri E Klein, Scott C. Brun, Yilin Chiu, Walid M Awni, Tong Zhu, Renee S Heuser, Thao Doan, Joerg Breitenbach, John B Morris, George J HannaAbstract:Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of Lopinavir. The original solid oral formulation of Lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of Lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of Lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to Lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent Lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent Lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.
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Pharmacokinetics of Lopinavir/Ritonavir in HIV/Hepatitis C Virus–Coinfected Subjects With Hepatic Impairment
The Journal of Clinical Pharmacology, 2006Co-Authors: Joanna Z. Peng, Federico Pulido, Sonja J. Causemaker, Alicia Lorenzo, Concepción Cepeda, Juan A. García Cabanillas, Barbara Dasilva, Scott C. Brun, Jose R. ArribasAbstract:The effect of hepatic impairment on Lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received Lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on Lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, Lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound Lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While Lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.
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selection of resistance in protease inhibitor experienced human immunodeficiency virus type 1 infected subjects failing Lopinavir and ritonavir based therapy mutation patterns and baseline correlates
Journal of Virology, 2005Co-Authors: Martin S King, Scott C. Brun, Kathryn R King, Akhteruzzaman Molla, Dale J KempfAbstract:The selection of in vivo resistance to Lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with Lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to Lopinavir (emergence of new mutation[s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of Lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating Lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to Lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with Lopinavir resistance and/or displayed >60-fold-reduced susceptibility to Lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for Lopinavir-ritonavir.
Jose R. Arribas - One of the best experts on this subject based on the ideXlab platform.
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Switching to Lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudine
The Journal of antimicrobial chemotherapy, 2013Co-Authors: Jose I. Bernardino, Federico Pulido, Esteban Martínez, Julio Arrizabalaga, P. Domingo, Joaquín Portilla, Antonio Ocampo, Jessica Muñoz, R. Torres, Jose R. ArribasAbstract:BACKGROUND Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery. METHODS This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to Lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to Lopinavir/ritonavir plus abacavir/lamivudine versus Lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007). RESULTS Of 95 patients included, 88 were randomized to Lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or Lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the Lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the Lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in Lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the Lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)]. CONCLUSIONS In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to Lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to Lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.
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a 96 week comparison of Lopinavir ritonavir combination therapy followed by Lopinavir ritonavir monotherapy versus efavirenz combination therapy
The Journal of Infectious Diseases, 2008Co-Authors: William D Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Robert Myers, Nicholaos C Bellos, Norbert Gilmore, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started Lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (Lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P = .17; 95% confidence interval [CI] for the difference, −29% to 4%); in noncompletion=failure analysis, 60% (Lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P = .73; 95% CI for the difference, −19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the Lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to Lopinavir/ritonavir monotherapy.Trial registration. ClinicalTrials.gov identifier: NCT00075231.
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A 96-Week Comparison of Lopinavir- Ritonavir Combination Therapy Followed by Lopinavir-Ritonavir Monotherapy versus Efavirenz Combination Therapy
The Journal of infectious diseases, 2008Co-Authors: D. William Cameron, Scott C. Brun, Jose R. Arribas, Martin S King, Barry Bernstein, Barbara A Da Silva, Nicholaos C Bellos, Norbert Gilmore, Robert A. Myers, George J HannaAbstract:Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either Lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels
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Pharmacokinetics of Lopinavir/Ritonavir in HIV/Hepatitis C Virus–Coinfected Subjects With Hepatic Impairment
The Journal of Clinical Pharmacology, 2006Co-Authors: Joanna Z. Peng, Federico Pulido, Sonja J. Causemaker, Alicia Lorenzo, Concepción Cepeda, Juan A. García Cabanillas, Barbara Dasilva, Scott C. Brun, Jose R. ArribasAbstract:The effect of hepatic impairment on Lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received Lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on Lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, Lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound Lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While Lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.
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Lopinavir–Ritonavir versus Nelfinavir for the Initial Treatment of HIV Infection
The New England journal of medicine, 2002Co-Authors: Sharon Walmsley, Jose R. Arribas, Barry Bernstein, Martin T. King, Gildon N. Beall, Peter Ruane, Margaret Johnson, David W. Johnson, Richard G. Lalonde, Anthony J. JapourAbstract:Background Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma Lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50 percent. Methods We conducted a double-blind trial in which 653 HIV-infected adults who had not received antiretroviral therapy for more than 14 days were randomly assigned to receive either Lopinavir–ritonavir (400 mg of Lopinavir plus 100 mg of ritonavir twice daily) with nelfinavir placebo or nelfinavir (750 mg three times daily) with Lopinavir–ritonavir placebo. All patients also received open-label stavudine and lamivudine. The primary efficacy end points were the presence of fewer than 400 HIV RNA copies per milliliter of plasma at week 24 and the time to the loss of virologic response through week 48. Results At week 48, greater proportions of patients treated with Lopinavir–ritonavir than of patients treated with nelfi...
