The Experts below are selected from a list of 13701 Experts worldwide ranked by ideXlab platform

David W Haas - One of the best experts on this subject based on the ideXlab platform.

  • pharmacogenetic interactions of rifapentine plus isoniazid with Efavirenz or nevirapine
    Pharmacogenetics and Genomics, 2021
    Co-Authors: David W Haas, Richard E Chaisson, Anthony T. Podany, Noluthando Mwelase, Khuanchai Supparatpinyo, Yajing Bao, Susan Swindells, Lerato Mohapi, Amita Gupta, Constance A Benson
    Abstract:

    OBJECTIVES The effect of rifapentine plus isoniazid on Efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS A subset of HIV-positive individuals receiving Efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to Efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed. RESULTS Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with Efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in Efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma Efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater Efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS Among HIV-positive individuals receiving Efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma Efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

  • pharmacokinetics and drug drug interactions of isoniazid and Efavirenz in pregnant women living with hiv in high tb incidence settings importance of genotyping
    Clinical Pharmacology & Therapeutics, 2020
    Co-Authors: Kamunkhwala Gausi, David W Haas, Lubbe Wiesner, Jennifer Norman, Carole L Wallis, Carolyne Onyangomakumbi, Tsungai Chipato, Renee Browning, Nahida Chakhtoura
    Abstract:

    The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and Efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received Efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and Efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased Efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and Efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

  • pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives
    Pharmacogenetics and Genomics, 2020
    Co-Authors: David W Haas, Francesca T Aweeka, Yoninah Cramer, Catherine Godfrey, Susan L Rosenkranz, Baiba Berzins, Robert W Coombs, Kristine Coughlin, Laura Moran
    Abstract:

    Objective In AIDS Clinical Trials Group study A5316, Efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. Methods In A5316, women with HIV enrolled into control (no antiretrovirals), Efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. Results The 72 participants in this analysis included 25, 24 and 23 in the control, Efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the Efavirenz group, CYP2B6 genotype was associated with increased plasma Efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, Efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. Conclusion CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of Efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

  • brain neurotransmitter transporter receptor genomics and Efavirenz central nervous system adverse events
    Pharmacogenetics and Genomics, 2018
    Co-Authors: David W Haas, Yuki Bradford, Anurag Verma, Shefali S Verma, Joseph J Eron, Roy M Gulick, Sharon A Riddler, Eric S Daar, Gene D Morse
    Abstract:

    OBJECTIVE: We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to Efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. PARTICIPANTS AND METHODS: Four clinical trials randomly assigned treatment-naive participants to Efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma Efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. RESULTS: Analyses included 167 cases with grade 2 or greater Efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 Efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate Efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10(-4)). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10(-27)). CONCLUSION: Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to Efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

  • brain neurotransmitter transporter receptor genomics and Efavirenz central nervous system adverse events
    Pharmacogenetics and Genomics, 2018
    Co-Authors: David W Haas, Yuki Bradford, Anurag Verma, Shefali S Verma, Joseph J Eron, Roy M Gulick, Sharon A Riddler, Paul E. Sax, Eric S Daar
    Abstract:

    OBJECTIVE We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to Efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. PARTICIPANTS AND METHODS Four clinical trials randomly assigned treatment-naive participants to Efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma Efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. RESULTS Analyses included 167 cases with grade 2 or greater Efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 Efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate Efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10(-4)). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10(-27)). CONCLUSION Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to Efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

Marita Stevens - One of the best experts on this subject based on the ideXlab platform.

  • week 96 analysis of rilpivirine or Efavirenz in hiv 1 infected patients with baseline viral load 100 000 copies ml in the pooled echo and thrive phase 3 randomized double blind trials
    Hiv Medicine, 2014
    Co-Authors: Jeanmichel Molina, Simon Vanveggel, Nathan Clumeck, Chloe Orkin, Lt Rimsky, Marita Stevens
    Abstract:

    Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving rilpivirine or Efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or Efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the rilpivirine (n = 368) and Efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for Efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for Efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the rilpivirine group than in the Efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the rilpivirine group and by 206 (188–225) cells/μL in the Efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for Efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of Efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the Efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than Efavirenz.

  • rilpivirine vs Efavirenz in hiv 1 patients with baseline viral load 100 000 copies ml or less week 48 phase iii analysis
    AIDS, 2013
    Co-Authors: Jeanmichel Molina, Laurence T. Rimsky, Simon Vanveggel, Nathan Clumeck, Karla Redant, Marita Stevens
    Abstract:

    OBJECTIVES To compare efficacy, resistance development, and safety between rilpivirine and Efavirenz in treatment-naive, HIV-1-infected adults with baseline viral load 100,000 copies/ml or less in the pooled 48-week dataset of the ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) and THRIVE (TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz) trials. DESIGN Phase III, double-blind, double-dummy, randomized trials. METHODS Patients received rilpivirine 25 mg once daily (q.d.) or Efavirenz 600 mg q.d. with two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. This analysis considers the subpopulation of 368 rilpivirine and 330 Efavirenz patients with baseline viral load 100,000 copies/ml or less. RESULTS Significantly higher 48-week response rates (viral load <50 copies/ml, intent-to-treat-time-to-loss-of-virological response) were observed with rilpivirine vs. Efavirenz [90 vs. 84%, respectively; difference 6.6% (95% confidence interval 1.6-11.5%)]. The proportion of patients experiencing virological failure (VF(res)) was 5% in each treatment group. A comparable proportion of VF(res) patients in each group developed nonnucleoside reverse transcriptase inhibitor resistance-associated mutations (RAMs) [rilpivirine: 6/16 (38%) vs. Efavirenz: 5/12 (42%)]. A numerically higher proportion of rilpivirine VF(res) patients developed N(t)RTI RAMs [7/16 (44%)] vs. Efavirenz [2/12 (17%)]; P = 0.2232. A significantly lower incidence for rilpivirine vs. Efavirenz was observed for the following events: treatment-related grade 2-4 overall adverse events (17 vs. 30%; P <0.0001), rash (any type; 2 vs. 12%; P <0.0001), and neurological adverse events (19 vs. 40%; P <0.0001), including dizziness (10 vs. 29%; P <0.0001). There was no significant difference between groups in the total cholesterol/high-density lipoprotein cholesterol ratio. CONCLUSION In treatment-naive patients with baseline viral load 100,000 copies/ml or less, rilpivirine along with two N(t)RTIs achieved a high response, with a comparable frequency of VF(res) and more favorable tolerability than Efavirenz.

  • efficacy and safety of rilpivirine in treatment naive hiv 1 infected patients with hepatitis b virus hepatitis c virus coinfection enrolled in the phase iii randomized double blind echo and thrive trials
    Journal of Antimicrobial Chemotherapy, 2012
    Co-Authors: Mark Nelson, Marita Stevens, Pablo Tebas, Annemie Buelens, Nathan Clumeck, Gerardo Amaya, Clovis Arns Da Cunha, Dushyantha T Jayaweera, Patrice Junod, Simon Vanveggel
    Abstract:

    OBJECTIVES The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and Efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. METHODS Patients received 25 mg of rilpivirine once daily or 600 mg of Efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels ≤5× the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. RESULTS HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the Efavirenz group. At baseline, 49 rilpivirine and 63 Efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; Efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; Efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; Efavirenz: 79.4%) (rilpivirine, P = 0.04 and Efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus Efavirenz: 6.6%) and was higher in HBV/HCV-coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). CONCLUSIONS Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or Efavirenz than in those who were not coinfected.

Roy M Gulick - One of the best experts on this subject based on the ideXlab platform.

  • brain neurotransmitter transporter receptor genomics and Efavirenz central nervous system adverse events
    Pharmacogenetics and Genomics, 2018
    Co-Authors: David W Haas, Yuki Bradford, Anurag Verma, Shefali S Verma, Joseph J Eron, Roy M Gulick, Sharon A Riddler, Eric S Daar, Gene D Morse
    Abstract:

    OBJECTIVE: We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to Efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. PARTICIPANTS AND METHODS: Four clinical trials randomly assigned treatment-naive participants to Efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma Efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. RESULTS: Analyses included 167 cases with grade 2 or greater Efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 Efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate Efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10(-4)). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10(-27)). CONCLUSION: Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to Efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

  • brain neurotransmitter transporter receptor genomics and Efavirenz central nervous system adverse events
    Pharmacogenetics and Genomics, 2018
    Co-Authors: David W Haas, Yuki Bradford, Anurag Verma, Shefali S Verma, Joseph J Eron, Roy M Gulick, Sharon A Riddler, Paul E. Sax, Eric S Daar
    Abstract:

    OBJECTIVE We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to Efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. PARTICIPANTS AND METHODS Four clinical trials randomly assigned treatment-naive participants to Efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma Efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. RESULTS Analyses included 167 cases with grade 2 or greater Efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 Efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate Efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10(-4)). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10(-27)). CONCLUSION Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to Efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

  • impact of Efavirenz on neuropsychological performance and symptoms in hiv infected individuals
    Annals of Internal Medicine, 2005
    Co-Authors: David B Clifford, Karen T Tashima, Edward P Acosta, Heather J Ribaudo, Scott R Evans, Yijun Yang, Karl Goodkin, David M Simpson, David M Dorfman, Roy M Gulick
    Abstract:

    Highly active antiretroviral therapy (HAART) regimens often include Efavirenz. Physicians caring for HIV-infected patients have attributed adverse neuropsychological effects to Efavirenz. In this s...

  • pharmacogenetics of Efavirenz and central nervous system side effects an adult aids clinical trials group study
    AIDS, 2004
    Co-Authors: David W Haas, Roy M Gulick, Grant R Wilkinson, David B Clifford, Catia Marzolini, Heather J Ribaudo, Camlin Tierney, Todd Hulgan, Edward P Acosta
    Abstract:

    Objectives: Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with Efavirenz central nervous system side effects and pharmacokinetics. Design: Twenty-four week cohort from a randomized study. Methods: Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and Efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing. Results: Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (Gln 172 His) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater Efavirenz plasma exposure (P < 0.0001). The median Efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n=78), 60 (n=60), and 130 (n=14) μg.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P=0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied. Conclusions: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater Efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to Efavirenz central nervous system side effects.

Gary Maartens - One of the best experts on this subject based on the ideXlab platform.

  • cyp2b6 genotype and weight gain differences between dolutegravir and Efavirenz
    Clinical Infectious Diseases, 2020
    Co-Authors: Rulan Griesel, Gary Maartens, Maxwell Chirehwa, Simiso Sokhela, Godspower Akpomiemie, Michelle Moorhouse, Francois Venter, Phumla Sinxadi
    Abstract:

    Background Dolutegravir is associated with more weight gain than Efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher Efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting Efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the Efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the Efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the Efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the Efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the Efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting Efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the Efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with Efavirenz observed in ADVANCE and other studies.

  • effect of mid dose Efavirenz concentrations and cyp2b6 genotype on viral suppression in patients on first line antiretroviral therapy
    International Journal of Antimicrobial Agents, 2016
    Co-Authors: Catherine Orrell, Andrzej Bienczak, Gary Maartens, Karen Cohen, David R Bangsberg, Robin Wood, Paolo Denti
    Abstract:

    Abstract The therapeutic range for Efavirenz plasma concentrations is unclear and some studies found no correlation with viral non-suppression. Efavirenz concentrations are variable, driven in part by polymorphisms in CYP2B6 . We hypothesised that Efavirenz mid-dosing concentrations, together with CYP2B6 metaboliser genotype, could predict viral non-suppression. Participants starting first-line Efavirenz-based antiretroviral therapy were monitored for 48 weeks. HIV-RNA and Efavirenz mid-dose interval concentrations were determined at Weeks 16 and 48. CYP2B6 metaboliser genotype status was determined by 516G→T and 983T→C polymorphisms. Cox proportional hazards modelling was used to predict viral non-suppression and to determine the most predictive Efavirenz mid-dosing concentration threshold. In total, 180 participants were included. Median Efavirenz concentrations were 2.3 mg/L (IQR 1.6–4.6 mg/L) and 2.2 mg/L (IQR 1.5–3.9 mg/L) at Weeks 16 and 48, respectively. Moreover, 49 (27.2%), 84 (46.7%) and 39 (21.7%) participants had extensive, intermediate or slow CYP2B6 metaboliser genotype, respectively. Log 2 Efavirenz concentrations [adjusted hazard ratio (aHR) = 0.77, 95% CI 0.67–0.89] and baseline CD4 cell count (aHR = 0.994, 95% CI 0.989–0.998), but not CYP2B6 genotype, were predictive of viral non-suppression. For every doubling of Efavirenz concentration there was a 23% decrease in the hazard of non-suppression. A threshold of 0.7 mg/L was found to be the Efavirenz mid-dosing concentration that was most predictive of non-suppression. Mid-dosing Efavirenz concentrations are predictive of viral non-suppression, but the currently recommended lower therapeutic limit (1 mg/L) is higher than our finding. Knowledge of CYP2B6 metaboliser genotype is not required for prediction of virological outcomes.

  • pharmacogenetics of plasma Efavirenz exposure in hiv infected adults and children in south africa
    British Journal of Clinical Pharmacology, 2015
    Co-Authors: Phumla Sinxadi, Helen Mcilleron, Gary Maartens, Pete Smith, Paul Leger, Joel A Dave, Naomi S Levitt, David W Haas
    Abstract:

    Aims Genetic factors, notably CYP2B6 516GT [rs3745274] and 983TC [rs28399499], explain much of the interindividual variability in Efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma Efavirenz concentrations in HIV-infected Black South African adults and children. Methods Steady-state mid-dosing interval Efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to Efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. Results Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516GT, 983TC, and 15582CT [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose Efavirenz concentrations were 1.44 (1.21–1.93) µg ml–1, 2.08 (1.68–2.94) µg ml–1 and 7.26 (4.82–8.34) µg ml–1 for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted Efavirenz concentrations (β = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10–11). Among individual CYP2B6 polymorphisms, 516GT best predicted Efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10−6). There was also associations with 983TC (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582CT (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with Efavirenz concentrations. Conclusions Composite CYP2B6 genotype based on CYP2B6 516GT, 983TC, and 15582CT best described Efavirenz exposure in HIV-infected Black South African adults and children.

  • effect of rifampicin based antitubercular therapy and the cytochrome p450 2b6 516g t polymorphism on Efavirenz concentrations in adults in south africa
    Antiviral Therapy, 2009
    Co-Authors: Karen Cohen, Helen Mcilleron, Alison D Grant, Collet Dandara, Lindiwe Pemba, Katherine Fielding, Salome Charalombous, Gavin J Churchyard, Pete Smith, Gary Maartens
    Abstract:

    BACKGROUND: Rifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes Efavirenz. The CYP2B6 516G>T polymorphism impairs Efavirenz metabolism and occurs more commonly in Africans than in Caucasians. We explored the effect of rifampicin-based antitubercular therapy and the 516G>T polymorphism on Efavirenz concentrations in HIV-infected patients in South Africa. METHODS: Between-patient and within-patient comparisons were made of mid-dosing interval Efavirenz plasma concentrations in adults on antiretroviral therapy including Efavirenz 600 mg daily, with and without antitubercular therapy. RESULTS: There were 142 participants (40 were on antitubercular therapy and 102 were controls), the mean weight was 66 kg. Median Efavirenz concentration was 2.4 mg/l (interquartile range [IQR] 1.3-3.1) and 1.8 mg/l (IQR 1.4-4.4) in participants on antitubercular therapy and controls, respectively (P=0.734). Paired Efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar (P=0.113). Genotyping results were 60 (49%) G/G homozygotes, 46 (38%) G/T heterozygotes and 16 (13%) T/T homozygotes. In a multivariate logistic regression model adjusted for sex, weight and concomitant antitubercular therapy, the 516G>T polymorphism was strongly associated with high (>4 mg/l) Efavirenz concentrations: odds ratio (OR) 4.4 (95% confidence interval [CI] 1.3-14.9) for G/T versus G/G and 31.1 (95% CI 6.6-146.6) for T/T versus G/G. High Efavirenz concentrations were associated with severe sleep disturbance (P=0.048). Low ( CONCLUSIONS: Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G>T polymorphism occurred commonly and was associated with high Efavirenz concentrations.

  • effect of rifampicin based antitubercular therapy and the cytochrome p450 2b6 516g t polymorphism on Efavirenz concentrations in adults in south africa
    Antiviral Therapy, 2009
    Co-Authors: Karen Cohen, Helen Mcilleron, Alison D Grant, Collet Dandara, Lindiwe Pemba, Katherine Fielding, Salome Charalombous, Gavin J Churchyard, Pete Smith, Gary Maartens
    Abstract:

    BackgroundRifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes Efavirenz. The CYP2B6 516G>T polymorphism impairs Efavirenz metabolism and occurs more commo...

Gene D Morse - One of the best experts on this subject based on the ideXlab platform.

  • brain neurotransmitter transporter receptor genomics and Efavirenz central nervous system adverse events
    Pharmacogenetics and Genomics, 2018
    Co-Authors: David W Haas, Yuki Bradford, Anurag Verma, Shefali S Verma, Joseph J Eron, Roy M Gulick, Sharon A Riddler, Eric S Daar, Gene D Morse
    Abstract:

    OBJECTIVE: We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to Efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. PARTICIPANTS AND METHODS: Four clinical trials randomly assigned treatment-naive participants to Efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma Efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. RESULTS: Analyses included 167 cases with grade 2 or greater Efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 Efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate Efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10(-4)). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10(-27)). CONCLUSION: Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to Efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

  • secondary metabolism pathway polymorphisms and plasma Efavirenz concentrations in hiv infected adults with cyp2b6 slow metabolizer genotypes
    Journal of Antimicrobial Chemotherapy, 2014
    Co-Authors: David W Haas, Gene D Morse, Awewura Kwara, Danielle M Richardson, Paxton Baker, Ioannis Papageorgiou, Edward P Acosta, Michael H Court
    Abstract:

    Objectives Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define Efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma Efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval Efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.

  • pharmacogenetics of long term responses to antiretroviral regimens containing Efavirenz and or nelfinavir an adult aids clinical trials group study
    The Journal of Infectious Diseases, 2005
    Co-Authors: David W Haas, Gene D Morse, Laura M Smeaton, Robert W Shafer, Gregory K Robbins, Line Labbe, Grant R Wilkinson, David B Clifford, Richard T Daquila, Victor De Gruttola
    Abstract:

    BACKGROUND Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive Efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS The 504 participants in the genetic study included 340 Efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both Efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to Efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among Efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of Efavirenz-resistant virus but not with plasma Efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS Genetic variants predict plasma exposure to Efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

  • comparison of four drug regimens and pairs of sequential three drug regimens as initial therapy for hiv 1 infection
    The New England Journal of Medicine, 2003
    Co-Authors: Robert W Shafer, Gene D Morse, Laura M Smeaton, Gregory K Robbins, Richard T Daquila, Victor De Gruttola, Sally Snyder, Victoria A Johnson, Mostafa Nokta, Ana Martinez
    Abstract:

    BACKGROUND It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS In this multicenter trial we compared initial therapy involving four-drug regimens containing Efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either Efavirenz or nelfinavir. RESULTS A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and Efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and Efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and Efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and Efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and Efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and Efavirenz (hazard ratio, 1.21). CONCLUSIONS There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and Efavirenz is the optimal choice.