Dataset Information

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

ABSTRACT:

Background

Drug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection.

Methods

A randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF.

Results

157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32 mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74 mmol/l (95% CI -1.00, -0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86 mmol/l (p < 0.001) compared with +0.01 mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (-0.47 mmol/L [-0.70, -0.25]), HDL cholesterol (-0.15 mmol/L [-0.21, -0.08]), triglycerides (-0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (-0.56 mmol/L [-0.80, -0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of -0.73 mmol/L (p < 0.001).

Conclusions

Switching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters.

Trial registration

ClinicalTrials.gov NCT00615810.

SUBMITTER: Moyle GJ

PROVIDER: S-EPMC4319732 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

Moyle Graeme J GJ Orkin Chloe C Fisher Martin M Dhar Jyoti J Anderson Jane J Wilkins Edmund E Ewan Jacqueline J Ebrahimi Ramin R Wang Hui H

PloS one 20150206 2

<h4>Background</h4>Drug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection.<h4>Methods</h4>A randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension ...[more]

PMID: 25658097

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Project description:The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks).A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Project description:Abstract Background Doravirine (DOR) is a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI). In the phase 3 DRIVE-AHEAD trial in HIV-1-infected treatment-naïve adults, DOR demonstrated noninferior efficacy to efavirenz (EFV) and favorable profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. Methods DRIVE- AHEAD (Clinical Trials Registration: NCT02403674) is a phase 3, multicenter, double-blind, noninferiority trial that compared DOR with EFV. Eligible participants were HIV-1-infected treatment-naïve adults with pre-treatment HIV-1 RNA ?1,000 copies/mL. Participants were randomized (1:1) to a fixed-dose regimen of DOR 100 mg, lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) QD or EFV 600 mg, emtricitabine 200 mg and TDF 300 mg (EFV/FTC/TDF) QD for up to 96 weeks. Randomization was stratified by screening HIV-1 RNA (?/>100,000 copies/mL) and hepatitis B/C co-infection (yes/no). The efficacy endpoint of interest at week 96 was HIV-1 RNA <50 copies/mL with predefined noninferiority margin of 10%. Safety endpoints of interest included occurrence of pre-specified neuropsychiatric adverse events and mean change from baseline in fasting lipid levels at week 96. Results Of 734 participants randomized, 728 received study drug and were included in analyses (mean age 33 years, 85% male, 48% white, 19% black, 34% Hispanic). At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF recipients vs. 73.6% of EFV/FTC/TDF recipients (difference 3.8%, 95%CI [?2.4, 10.0]). No additional phenotypic resistance to DOR was observed between weeks 48 and 96, while two additional participants in the EFV/FTC/TDF group developed resistance to EFV. Dizziness, sleep disorders/disturbances, altered sensorium, and rash were less frequent in DOR/3TC/TDF recipients than in EFV/FTC/TDF recipients. Fasting LDL-C and non-HDL-C increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group, while change in total cholesterol/HDL-C ratio was similar. Conclusion Week 96 results support non-inferiority of DOR/3TC/TFD to EFV/FTC/TDF established at Week 48 with no additional DOR resistance between week 48 and 96. DOR/3TC/TDF was safe and well-tolerated with fewer neuropsychiatric and rash events and favorable lipid profile compared with EFV/FTC/TDF. Disclosures C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Grant Investigator and Research Contractor, Research grant and Research support. K. Squires, Merck & Co., Inc.: Ad Board, Ad Board. Gilead Sciences: Grant, Ad Board. VIIV: Ad Board, Ad Board. Bristol Myers Squibb: Ad Board, Ad Board. Janssen: Ad Board, Ad Board. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee. P. Sax, Gilead: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Merck: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Janssen: Consultant, Consulting fee. BMS: Grant Investigator, Grant recipient and Research grant. W. Wong, Merck & Co., Inc.: Research Contractor, Research grant. G. Lin, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee and Shareholder, May hold stock/stock options in the company and Salary. S. Kumar, Merck & Co., Inc.: Employee and Shareholder, Salary. G. Hanna, Merck & Co., Inc.: Employee and Shareholder, Salary. C. Hwang, Merck & Co., Inc.: Employee and Shareholder, Salary. E. Martin, Merck & Co., Inc.: Employee and Shareholder, Salary. H. Teppler, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA: Employee, May hold stock/stock options in the company and Salary.

Project description:BackgroundWe compare the effect of 4 different antiretroviral regimens on limb and visceral fat.MethodsA5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥ 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test.ResultsA5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT.ConclusionsABC-3TC- and TDF-FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT.Clinical trials registrationNCT00118898.

Project description:Therapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV.Dual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups.Participants taking tenofovir at baseline had lower section modulus (-107.3 mm2, p?=?0.001), lower cross-sectional area (-15.01 mm3, p?=?0.001), and lower cross-sectional moment of inertia (-2,036.8 mm4, p?=?0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p?=?0.008) and cross-sectional area (p?=?0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p?=?0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p?=?0.025), and higher osteoprotegerin (p?=?0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine.In this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation.ClinicalTrials.gov NCT00192634.

Dataset Information

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

Background

Methods

Results

Conclusions

Trial registration

Publications

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

Similar Datasets

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