Comparison of INSTI vs PI

Comparison of INSTI vs PI
ARV-trial.com Comparison of INSTI vs PI FLAMINGO GS ACTG A5257 WAVES 1

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC
ARV-trial.com ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Design Randomisation* 1 : 1 : 1 Open label N = 603 N = 605 W96 N = 601 > 18 years ARV-naïve (< 10 days of ART) HIV RNA > 1,000 c/mL Any CD4 cell count No resistance to NRTI or PI ATV/r 300/100 mg QD + TDF/FTC RAL 400 mg BID + TDF/FTC DRV/r 800/100 mg QD + TDF/FTC *Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening, participation in cardiovascular sub-study, and 10-year Framingham risk score Objective Evaluate regimen equivalence regarding virologic efficacy and tolerability over 96 weeks, by intention-to-treat analysis. Equivalence = 2-sided 97.5% CI on the pairwise difference in 96-week cumulative incidence of each individual or composite endpoint falling between - 10% and 10%, 90% power. If equivalence was not shown, superiority was defined as exclusion of 0 from the 97.5% CI ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71 2

Endpoints Virologic failure: confirmed HIV-1 RNA > 1,000 c/mL at or after W16, or > 200 c/mL at or after W24 Tolerability failure: time from randomisation to discontinuation of the randomised regimen component for toxicity (substitution of TDF or FTC not considered as tolerability failure) Composite endpoint: virologic or tolerability failure, whichever occurred first ITT-TLOVR, with HIV-1 RNA threshold of 200 c/mL HIV-1 RNA < 50 c/mL at W96 by ITT, snapshot Sensitivity analysis: as-treated (virologic failure including treatment discontinuation as a competing event) Key toxicity secondary endpoint: time from initiation of treatment to the first grade 2, 3, or 4 sign or symptom (grade 3 or 4 if after week 48) or any grade 3 or 4 laboratory abnormality while the patient was receiving the randomized treatment (as-treated) Prespecified sensitivity analysis excluded hyperbilirubinemia and elevated CK levels Further sensitivity analysis included all qualifying adverse events regardless of status on randomized treatment (ITT analysis) ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

ARV-trial.com ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Baseline characteristics and patient disposition ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + N = 603 Median age, years 37 36 Female 24% 25% HIV RNA (log10 c/mL), median 4.60 4.61 4.66 HIV RNA > 100,000 c/mL 32% 27.8% HIV RNA > 500,000 c/mL 6.9% 6.0% 8.3% CD4 cell count (/mm3), mean 309 310 304 CD4 < 200 per mm3 28.9% 29% 31% Hepatitis B / hepatitis C coinfection 2.5% / 7.8% 3% / 7.5% 2.7% / 8.1% Never started ART, N 5 4 Discontinuation by W96 8.1% 9.1% 7.1% Death 10 13 6 Lost to follow-up 29 34 23 ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71 4

Cumulative incidence of virologic failure (primary end point) Virologic failure (ITT) Virologic failure (as-treated) ATV/r RAL DRV/r 24 48 64 80 96 112 128 144 0.00 0.25 0.50 0.75 1.00 -20 20 10 -10 ATV/r (12.6%) vs. RAL (9.0%) 3.4% (-0.7% to 7.4%) DRV/r (14.9%) vs. RAL (9.0%) 5.6% (1.3% to 9.9%) ATV/r (12.6%) vs. DRV/r (14.9%) -2.2% (-6.7% to 2.3%) Week 578 574 585 605 603 601 541 552 530 493 517 484 369 390 364 ATV/r RAL DRV/r ≠ (97.5% CI) 24 48 64 80 96 112 128 144 0.00 0.25 0.50 0.75 1.00 -20 20 10 -10 ATV/r (10.7%) vs. RAL (8.0%) 2.4% (-1.4% to 6.2%) DRV/r (13.1%) vs. RAL (8.0%) 4.7% (0.7% to 8.7%) ATV/r (10.7%) vs. DRV/r (13.1%) -2.3% (-6.5% to 2.0%) Week 536 574 559 605 603 601 494 545 520 427 511 470 317 387 358 ATV/r RAL DRV/r ≠ (97.5% CI) Cumulative probability of virologic failure by W96 ATV/r 12.6% DRV/r 14.9% RAL 9.0% Equivalence of the 3 regimens ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Cumulative incidence of tolerability failure (primary end point) Favors RAL Favors DRV/r 24 48 64 80 96 112 128 144 0.00 0.25 0.50 0.75 1.00 Week 548 585 576 605 603 601 522 562 553 467 534 517 349 411 392 ATV/r RAL DRV/r 20 10 -10 -20 ATV/r (13.9%) vs. RAL (0.9%) 12.7% (9.4% ; 16.1%) DRV/r (4.7%) vs. RAL (0.9%) 3.6% (1.4% ; 5.8%) ATV/r (13.9%) vs. DRV/r (4.7%) 9.2% (5.5% ; 12.9%) ≠ (97.5% CI) ATV/r RAL DRV/r RAL equivalent to DRV/r RAL superior to ATV/r DRV/r superior to ATV/r Greater tolerability benefit of RAL vs ATV/r in patients with baseline HIV RNA < 100,000 c/mL RAL vs DRV/r in women ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Discontinuations of randomised antiretroviral therapy for toxicity ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Any toxicity/discontinuations 95 (15.7%) 32 (5.3%) 8 (1.3%) Jaundice or hyperbilirubinemia 47 Nausea or other gastrointestinal toxicities 25 14 2 Hepatic toxicity 4 5 1 Skin toxicity 7 5 (1 Stevens-Johnson) Metabolic toxicity 6 Renal toxicity Abnormal chemistry/hematology findings Other 3 ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Cumulative incidence of virologic or tolerability failure (preplanned composite failure) 24 48 64 80 96 112 128 144 0.00 0.25 0.50 0.75 1.00 Week 536 574 559 605 603 601 494 545 520 427 511 470 317 307 358 ATV/r RAL DRV/r Participants in the risk set, N Favors RAL Favors DRV/r -20 20 10 -10 ATV/r (24.1%) vs. RAL (8.6%) 14.9% (10.2% ; 19.6%) DRV/r (16.6%) vs. RAL (8.6%) 7.5% (3.2% ; 11.8%) ATV/r (24.1%) vs. DRV/r (16.6%) 7.5% (2.3% ; 12.7%) ≠ (97.5% CI) ATV/r inferior to DRV/r and to RAL DRV/r inferior to RAL ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

HIV-1 RNA level ≤ 50 copies/mL, regardless of ART change (ITT analysis) HIV-1 RNA level ≤ 50 copies/mL and receiving randomized ART (ITT, snapshot analysis) ATV/r RAL DRV/r 24 48 64 80 96 120 144 0.0 1.0 563 566 564 605 603 601 553 555 542 515 526 518 394 410 387 ATV/r RAL DRV/r Participants contributing data, N 0.8 0.6 0.4 0.2 Week 93.9% 89.4% 88.3% 24 48 64 80 96 605 603 601 471 483 468 ATV/r RAL DRV/r Participants contributing data, N 0.0 1.0 0.8 0.6 0.4 0.2 120 144 Week 79.8% 72.7% 62.6% ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Genotypic analysis for resistance at virologic failure ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Virologic failure 95 115 85 Genotype available 75 99 65 Any resistance detected 9 4 18 PI resistance NRTI-only resistance 8 3 7 - FTC - TDF - FTC and TDF 5 2 1 3 0 0 7 0 0 INI-only resistance 1 NRTI and INI resistance 10 - FTC and RAL - FTC, TDF and RAL 7 3 Patients may not have been on their randomised treatment at time of failure ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Grade 2 or higher adverse events in ≥ 5% of participants in either group ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Grade, N Total 2 3 4 Diarrhea 35 11 46 (7.6) 46 6 52 (8.6) 26 10 36 (6.0) Nausea 36 8 1 45 (7.4) 29 12 41 (6.8) 21 33 (5.5) Vomiting 22 7 30 (5.0) 32 (5.3) 15 9 24 (4.0) Abdominal pain 13 17 31 (5.1) 14 29 (4.8) 17 (2.8) Headache 23 35 (5.8) 30 44 (7.3) 42 (7.0) Pain in extremity 27 42 (6.9) 18 31 45 (7.5) Arthralgia 25 (4.1) 28 (4.7) 22 (3.6) Back pain 18 (3.0) 21 (3.5) Fatigue 32 39 (6.4) 5 Cough 33 40 (6.6) Dyspepsia 16 26 (4.3) 23 (3.8) 28 (4.6) Pyrexia 27 (4.5) 25 Hyperbilirubinemia 217 47 286 (47.3) 4 (< 1) 5 (< 1) Hypophosphatemia 34 (5.6) 37 (6.2) 24 Hyperglycemia ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Other safety data ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 96-week cumulative incidence of the 1st clinical or laboratory AE Any AE 80.3% 64.9% 59.5% Excluding bilirubin and CK 62.3% 59.3% Fasting LDL-cholesterol increase p ≤ 0.001* - Fasting triglycerides increase Grade 3-4 elevation in creatinine N = 7 N = 12 N = 4 Substitution of TDF and/or FTC N = 20 N = 23 N = 9 * vs RAL ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71

Mean (95% CI) changes from baseline in fasting lipids, mg/dL 24 48 96 144 weeks -20 20 602 600 595 541 527 529 521 542 507 490 505 364 397 363 Total cholesterol p<0.001 HDL-cholesterol ATV/r RAL DRV/r 5,0 10 24 48 96 144 7,5 2,5 p>0.05 weeks Triglycerides LDL-cholesterol p<0.001 -5 5 10 15 24 48 96 144 596 593 581 529 518 508 512 531 486 480 493 468 360 395 346 weeks p<0.001 -20 20 24 48 96 144 602 600 595 542 527 528 522 507 490 505 364 397 363 weeks ACTG A5257 Ofotokun I, CID 2015;60:

Mean percentage change in bone mineral density over 96 weeks -3.9 -3.7 -3.4 -2.4 -5 -4 -3 -2 -1 ATV/r vs DRV/r PI/r vs RAL Total hip p=0.36 p=0.005 Lumbar spine -4.0 -3.8 -3.6 -1.8 -5 -4 -3 -2 -1 ATV/r vs DRV/r PI/r vs RAL p=0.42 p<0.001 Total body -2.9 -1.7 -1.6 -4 -3 -2 -1 ATV/r vs RAL vs DRV/r p=0.004 p=0.72 p=0.001 ATV/r (N = 109) RAL (N = 106) DRV/r (N = 113) Combined PI/r ACTG A5257 Brown TT, JID 2015; 212:1241-9

Effect of Baseline CD4 count and HIV RNA Load on Bone Loss After adjustment for age, sex, race/ethnicity, baseline HIV RNA and BMI : no associations between lower baseline CD4 count and bone loss at the lumbar spine or total hip After multivariable adjustment, higher baseline HIV RNA was associated with bone loss at both sites (spine, −1.53% [95% CI: −2.28% to − 0.77%] for each log10 c/mL increase [p < 0.001]; total hip, −0.82% [95% CI, −1.51% to − 0.14%] for each log10 cmL increase [p = 0.02]) Multivariable analyses of BMD loss at W96 Baseline factors associated with total hip BMD loss higher baseline concentrations of hsCRP, IL6, and sCD14 Baseline factors associated with lumbar spine BMD loss Markers of CD4+ T-cell senescence and exhaustion (CD4+CD28−CD57+PD1+) Markers of CD4+ T-cell activation (CD4+CD38+HLA-DR+) ACTG A5257 Brown TT, JID 2015; 212:1241-9

Mean (97.5%) % of body composition change at W96, ITT : limb fat, trunk fat and lean mass (DXA scan), visceral and subcutaneous abdominal fat (CT abdomen) ATV/r RAL DRV/r 10 20 30 Baseline W96 109 105 113 98 94 97 Number of subjects ATV/r : 11 % RAL : 20 % DRV/r : 14 % Limb fat SAT 10 20 30 40 Baseline W96 108 104 112 97 95 94 Number of subjects ATV/r : 23 % RAL : 25 % DRV/r : 20 % Trunk fat VAT 10 20 30 40 Baseline W96 108 103 113 98 94 97 Number of subjects ATV/r : 16 % RAL : 29 % DRV/r : 21 % 10 20 30 40 50 Baseline W96 108 105 112 97 95 94 Number of subjects ATV/r : 31 % RAL : 33 % DRV/r : 29 % All p values (ATV/r vs DRV/r, PI/r vs RAL) not significant Larger increases in waist circumference were observed with the RAL arm compared to DRV/r arm at weeks 48 and 96 (all p ≤ 0.023) but not compared with the ATV/r arm (p ≥ 0.07) ACTG A5257 Mc Comsey GA, CROI 2015, Abs. 140 ; Ofotokun I, CID 2015;60:

Effect of baseline HIV RNA on fat changes at W96 in the 3 groups Changes in central fat correlated with changes in peripheral fat (r = 0.67 ; p < 0.001) No change in VAT:TAT ratio within or between regimens Greater gains in VAT associated with : Lower baseline leptin Higher baseline adiponectin HIV RNA level Greater gains in SAT associated with the same baseline factors , with in addition higher IL-6 Greater gains in lean body mass associated with : Higher HIV RNA, IL-6 and D-dimer, and lower CD4 at baseline HIV-1 RNA > c/ml SAT VAT 25 50 75 100 DRV/r Change from baseline (%) ATV/r RAL HIV-1 RNA < c/ml SAT VAT 25 50 75 100 DRV/r Change from baseline (%) ATV/r RAL ACTG A5257 Mc Comsey GA, CROI 2015, Abs. 140

Changes in Inflammation and Immune activation Substudy A5260S (328 patients) : 234 included (HIV RNA < 50 c/mL at W24) : 68 on ATV/r, 84 on DRV/r and 82 on RAL Plasma biomarkers of inflammation and coagulation : hsCRP, IL-6, GlycA, D-dimer, sCD14, sCD163, and sIL-2r Blood cellular markers : %CD38+DR+ of T-cell subsets and %CD14+CD16+ and%CD14(dim)CD16+ monocyte subsets Changes in biomarkers varied by regimen during the 96 weeks of follow-up : hsCRP declined with ATV/r and RAL IL-6 declined only with RAL GLycA decreased in all groups D-dimer declined with ATV/r and DRV/r and was unchanged with RAL Markers of T-cell activation and sCD163 (but not sCD14 and CD14-+CD16+) declined in all groups Conclusion : no consistent evidence that the reduction of inflammation and immune activation with ART initiation was different between RAL and PI-based regimens ACTG A5257 Kelesidis T. CID 2015;61:651-60

ARV-trial.com ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Conclusion ATV/r, RAL, and DRV/r were equivalent for virologic efficacy, when given with TDF/FTC ATV/r + TDF/FTC was less-well tolerated than DRV/r + TDF/FTC or RAL + TDF/FTC A composite assessment of virologic efficacy and tolerability found that RAL + TDF/FTC was superior to both PI-containing regimens DRV/r + TDF/FTC was superior to ATV/r + TDF/FTC Tolerability result was caused primarily by jaundice for ATV/r and gastrointestinal toxicity for both PI/r ATV/r was less tolerated than DRV/r and RAL across all sub-groups RAL tolerability benefit over DRV/r was greater in women Limitations: open-label design, switch to another arm for tolerability or toxicity allowed When tolerability and virologic response are considered together, RAL + TDF/FTC was superior overall to both PI-based therapies and DRV/r was superior to ATV/r. An advantage of PI/r over RAL is the reduced likelihood of drug resistance if virologic failure occurs ACTG A5257 Lennox JL. Ann Intern Med 2014;161:461-71 19

Comparison of INSTI vs PI

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