| 1. |
- Dickinson, Laura, et al.
(author)
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Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial
- 2020
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 75:3, s. 628-639
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Journal article (peer-reviewed)abstract
- Objectives: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5∗3, CYP3A4∗22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression. Results: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively]. Conclusions: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
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| 2. |
- Lambert-Niclot, S., et al.
(author)
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Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: Raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART
- 2016
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 1460-2091 .- 0305-7453. ; 71:4, s. 1056-1062
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Journal article (peer-reviewed)abstract
- Objectives: To describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir). Methods: Genotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32. Results: A resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of TREND = 0.007). Of note, 4/15 participants with IN RAM had a VL <200 copies/mL at time of testing. Conclusions: In the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.
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| 3. |
- Scott, Whitney, et al.
(author)
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Feasibility randomized-controlled trial of online acceptance and commitment therapy for painful peripheral neuropathy in people living with HIV : The OPEN study
- 2021
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In: European Journal of Pain. - : John Wiley & Sons. - 1090-3801 .- 1532-2149. ; 25:7, s. 1493-1507
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Journal article (peer-reviewed)abstract
- Background Neuropathic pain negatively affects quality of life among people living with HIV (PLWH). This study examined the feasibility of conducting a full-scale randomized-controlled trial of online acceptance and commitment therapy ("ACT OPEN") for neuropathic pain in PLWH. Methods Using a parallel-groups design, thirty-eight participants were randomized to ACT OPEN or a waitlist control (2:1). Participants completed standard self-report outcome measures at baseline, and two- and five-months post-randomization. Participants were aware of their allocation, but assessment was blinded. Results Twenty-five participants were randomized to ACT OPEN and 13 to the control (of 133 referrals). ACT OPEN completion was 69% and two-month trial retention was 82%. Treatment credibility and satisfaction scores for ACT OPEN were comparable to scores reported in previous trials of cognitive-behavioural treatments for pain. Four adverse events were reported during the study, including one serious adverse event; all of these were unrelated to the research procedures. Small to moderate effects and 95% confidence intervals suggest that the true effect may favour ACT OPEN for improvements in pain intensity/interference and depression. Conclusions A full-scale RCT of online ACT for pain management in PLWH may be feasible with refinements to trial design to facilitate recruitment. Significance Research on pain management in people living with HIV has primarily focused on pharmacological treatments with limited success. This is the first study to show the potential feasibility of a psychological treatment based on acceptance and commitment therapy delivered online and tailored for pain management in people with HIV ("ACT OPEN"). ACT OPEN may be a promising treatment in this population and further evaluation in a full-scale randomized-controlled trial appears warranted.
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