Comparison of INSTI vs INSTI in HIV Treatment Studies
This content provides a detailed comparison of Raltegravir taken once daily versus twice daily with TDF/FTC in various HIV treatment studies, including key findings, patient characteristics, treatment responses, and safety profiles at week 48.
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Comparison of INSTI vs INSTI QDMRK Study SPRING-2 Study ONCEMRK Study GS-US-380-1489 Study GS-US-380-1490 Study
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Design Randomisation* 1 : 1 Double-blind W48 W96 RAL 400 mg BID + RAL 800 mg QD placebo N = 389 > 18 years ARV-na ve TDF/FTC fdc QD HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to TDF or FTC RAL 800 mg QD + RAL 400 mg BID placebo TDF/FTC fdc QD N = 386 *Randomisation was stratified by baseline HIV RNA (< or > 100,000 c/mL) and viral hepatitis co-infection status Objective Non inferiority of RAL QD: % HIV RNA < 50 c/mL by ITT, NC=F (lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power) Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Baseline characteristics and patient disposition RAL BID RAL QD Randomised and received treatment, N Median age, years Female White/Black/Other HIV RNA (log10c/mL), median HIV RNA > 100,000 c/mL CD4 cell count (/mm3), median CD4 < 200 per mm3 HBsAg+ or HCV Ab+ Discontinuation by W48 For lack of efficacy For adverse event Lost to follow-up Other reasons 388 38 18% 382 38 23% 70% / 15% / 16% 4.8 38% 278 26% 6% 25 (6.4%) N = 5 N = 2 N = 7 N = 11 72% / 13% / 15% 4.9 37% 285 23% 7% 42 (11.0%) N = 18 N = 3 N = 7 N = 14 Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Response to treatment at week 48 HIV RNA < 50 c/mL RAL BID HIV RNA < 50 c/mL at W48 (NC=failure analysis) by baseline factors RAL QD % Primary analysis 100 91.0 Baseline RAL BID RAL QD 88.9 86.6 83.2 RNA < 5 log10c/mL RNA > 5 log10c/mL 91.9%* 84.2% 89.1%* 74.3% 75 CD4 > 200/mm3 CD4 < 200/mm3 91.6% 80.8% 87.0% 70.8% 50 HIV-1 B subtype Non-B subtype 90.3% 96.3% 88.5% 90.9% 25 * 95% CI for the difference = - 8.3 ; 2.7 N = 386 382 377 367 0 Mean CD4/mm3increase at W48 (observed-failure analysis): + 196 (RAL BID) vs + 210 (RAL QD) Per protocol, observed-failure* 95% CI for the difference = (- 9.0 ; 0.2) ITT NC = F 95% CI for the difference =( - 10.7 ; -0.8) * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Safety at W48 RAL BID RAL QD Clinical adverse events Drug-related AE Serious drug-related AE Treatment discontinuation due to AE Laboratory adverse events Drug-related AE Treatment discontinuation due to AE Moderate to severe adverse events of any cause Diarrhoea Headache Depression Vomiting Grade 3 or 4 laboratory abnormality in > 2% of patients in either group Fasting LDL-cholesterol > 190 mg/dL (4.9 mmol/L) Creatine kinase ALT / AST 24.2% 0.5% 1.0% 26.4% 0.3% 1.0% 2.3% 0 48% 4% 4% 2% 3% 1.3% 0.3% 45% 4% 3% 3% 2% 2.0% 5.4% 1.4% 3.9% 3.4% / 3.4% 2.9% / 1.8% Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Virologic failure: definition Non-response = never achieved 2 consecutive HIV RNA < 50 c/mL by week 24 or at time of premature study discontinuation or rebound = after an initial response, confirmed HIV RNA > 50 c/mL RAL BID N = 388 RAL QD N = 382 Emergence of resistance in virologic failure Protocol-defined virologic failure 35 (9%) 53 (14%) Non-response 14 22 Rebound 21 31 Assessed for emergence of resistance mutations * 16 30 No result available (technical issue) 2 2 Raltegravir resistance mutations + M184I/V 2/12 9/27 M184I/V alone 4/13 11/28 No resistance 8/14 8/28 * Genotyping was done only in patients with HIV RNA > 400 c/mL 2/2 (RAL BID) and 7/9 (RAL QD) patients who had emergence of RAL resistance had baseline HIV RNA > 100 000 c/mL Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Pharmacokinetic Data Trough raltegravir concentrations were more than six times higher with twice-daily dosing than they were with once-daily dosing Although an association between trough RAL concentrations and efficacy was evident in the once-daily group, no clear threshold could be identified Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
QDMRK Study: raltegravir QD vs BID, with TDF/FTC Conclusion At 48 weeks of treatment, RAL QD was not non-inferior to RAL BID, in combination with TDF/FTC Virologic failure was more common with once-daily dosing especially in patients with baseline HIV RNA > 100 000 c/mL More patients in the once-daily group than in the twice-daily group had resistance emergence to both RAL and FTC at the time of virological failure Patients in the once-daily group with low pharmacokinetic values and high baseline viral loads were at particular risk of treatment failure Despite a high response rate, RAL at 800 mg QD cannot be recommended in place of twice-daily dosing for first-line antiretroviral therapy Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK
