Comparison of Protease Inhibitors in ARTEMIS Study

This study compares the efficacy and safety of different protease inhibitors (PIs) including ATV, ATV/r, LPV/r, FPV/r, DRV/r, and SQV/r in HIV treatment. The ARTEMIS study specifically focuses on comparing DRV/r and LPV/r in combination with TDF/FTC in ARV-naive patients. Results show non-inferiority of DRV/r over LPV/r at week 48, with superior virologic outcomes and similar safety profiles. Baseline characteristics, patient disposition, and response to treatment are detailed, indicating the potential benefits of DRV/r in HIV therapy.

• Protease Inhibitors
• ARTEMIS Study
• HIV Treatment
• DRV/r
• LPV/r

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1. Comparison of PI vs PI ATV vs ATV/r LPV/r mono vs LPV/r + ZDV/3TC LPV/r QD vs BID BMS 089 MONARK M02-418 M05-730 A5073 GARDEL ALERT ATADAR KLEAN GEMINI CASTLE ARTEMIS LPV/r + 3TC vs LPV/r + 2 NRTI ATV/r vs FPV/r ATV/r vs DRV/r FPV/r vs LPV/r SQV/r vs LPV/r ATV/r vs LPV/r DRV/r vs LPV/r

2. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Design Randomisation* 1 : 1 Open-label W48 W192 N = 343 DRV/r 800/100 mg QD > 18 years ARV-na ve TDF/FTC fdc QD LPV/r 400/100 mg BID or 800/200 mg QD TDF/FTC fdc QD HIV RNA > 5,000 c/mL Any CD4 cell count N = 346 *Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and CD4 (< or > 200/mm3) at screening Objective Non inferiority of DRV/r vs LPV/r at W48: % HIV RNA < 50 c/mL by per-protocol TLOVR analysis (lower margin of the 2-sided 95% CI for the difference = - 12%, 90% power). Superiority tested by ITT if non inferiority established Ortiz R. AIDS 2008;22:1389-97 ARTEMIS

3. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Baseline characteristics and patient disposition DRV/r N = 343 * LPV/r ** N = 346 Mean age, years 36 35 Female 30% 30% Caucasian/Hispanic/Other 40% / 23% / 37% 44% / 21% / 35% HIV RNA (log10c/mL), mean CD4 cell count (/mm3), median 4.86 + 0.64 4.84 + 0.60 228 218 Hepatitis B and/or C coinfection 13% 14% Discontinuation by W48 12% 16% For virologic failure 2 (< 1%) 6 (2%) For adverse event 12 (3%) 24 (7%) * 3 patients excluded for the per-protocol analysis (did not received study medication or received disallowed therapy for more than 1 week) ** LPV/r was administered BID or QD according to investigator and/or patient preference (77% received BID, 15% QD and 8% both; 15% received soft-gel capsules, 2% tablets and 83% switched from SGC to tablets) Ortiz R. AIDS 2008;22:1389-97 ARTEMIS

4. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Response to treatment at week 48 HIV RNA < 50 c/mL (TLOVR) % Per protocol ITT HIV RNA < 50 c/mL at W48 (per-protocol, TLOVR) by baseline stratification factors 100 84 84 78 78 DRV/r (%) LPV/r (%) Baseline 75 RNA < 5 log10c/mL RNA > 5 log10c/mL 86 79 * 85 67 * 50 CD4 > 200/mm3 CD4 < 200/mm3 87 79 84 70 25 * P < 0.05 N = 343 346 343 346 0 DRV/r LPV/r DRV/r LPV/r Median CD4/mm3increase at W48 (ITT, NC = F): 137 (DRV/r) vs 141 (LPV/r) 95% CI 95% CI for the difference = (- 0.1; 11) (P < 0.001) Non inferiority for the difference = (- 0.3; 11) Test for superiority (P = 0.062) Ortiz R. AIDS 2008;22:1389-97 ARTEMIS

5. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Virologic failure at Week 48 Definition: HIV RNA never suppressed below 50 c/mL at W24 or confirmed HIV RNA > 50 c/mL after achieving < 50 c/mL or last observed HIV RNA > 50 c/mL followed by discontinuation Resistance data DRV/r N = 343 LPV/r N = 346 Virologic failure 34 (10%) 49 (14%) Patients in genotypic analysis (HIV RNA > 1,000 c/mL) 10 * 18 Protease inhibitor resistance mutation emergence 0 1 ** M184I/V 1 2 * 1 patient with HIV RNA > 1,000 c/mL did not have genotype available ** A71T and V77I Ortiz R. AIDS 2008;22:1389-97 ARTEMIS

6. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC W48 Safety: DRV/r vs LPV/r Discontinuations for adverse events (AE) were significantly less frequent in the DRV/r group: 3% vs 7% (P < 0.05) Rate of serious AE was not significantly different: 7% vs 12% Incidence of grade 2 to 4 gastrointestinal AE was significantly lower in the DRV/r group: 7% vs 14% (P < 0.01); these were mainly diarrhoea: 4% vs 10% (P < 0.01) Rash incidence was not significantly different: 3% vs 1%; 1 case of Stevens-Johnson occurred in the DRV/r group No patients discontinued because of renal events Mean increases in triglycerides and total cholesterol were less pronounced with DRV/r; grade 2 to 4 elevations in triglycerides and total cholesterol were significantly less frequent with DRV/r: 3% vs 11% and 13% vs 23%, respectively Hepatic safety was similar in both groups Ortiz R. AIDS 2008;22:1389-97 ARTEMIS

7. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Summary Conclusion (W48) DRV/r QD is non inferior to LPV/r, when co-administered with TDF/FTC(1) Greater virologic response, at W48 (HIV RNA < 50 c/mL), of DRV/r as compared with LPV/r in patients with high pre treatment HIV RNA (significant difference) or low CD4 count Lower incidence of diarrhoea with DRV/r vs LPV/r Lipid elevations were less pronounced with DRV/r Ortiz R. AIDS 2008;22:1389-97

8. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Overview at week 96 At W96(2), significantly more DRV/r (79%) than LPV/r (71%) patients had HIV RNA < 50 c/mL confirming non inferiority and superiority (P = 0.012; ITT) in virologic response Safety outcomes confirmed W48 results: more favourable gastrointestinal and lipid profile of DRV/r QD Lipid-lowering agents use by W96: 8% LPV/r vs 7% DRV/r Overall, discontinuation for adverse events occurred in 4% of DRV/r patients vs 9% of LPV/r patients Mills AM. AIDS 2009;23:1679-88

9. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Patient disposition at W96 and W192 DRV/r N = 343 LPV/r N = 346 p Discontinuation by W48 12% 16% For virologic failure 2 (< 1%) 6 (2%) For adverse event 12 (3%) 24 (7%) Discontinuation by W96 17.2% 23.4% Discontinuation by W192 24.8% 32.9% For virologic failure 5 9 For adverse event 16 (4.7%) 44 (12.7%) 0.005 For pregnancy 9 6 Lost to follow-up 21 17 Withdrew consent/non compliance 26 26 Other 8 12 Ortiz R. AIDS 2008;22:1389-97 ; Mills AM. AIDS 2009;23:1679-88 ; Orkin C. HIV Med 2012;14:49-59 ARTEMIS

10. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Final (week 192) analysis % HIV RNA < 50 c/mL (TLOVR) HIV RNA < 50 c/mL (ITT, TLOVR) by baseline stratification factors 100 Per protocol ITT DRV/ r (%) LPV/r (%) 69.1 75 Baseline p 68.8 57.1 57.2 RNA < 5 log10 c/mL RNA > 5 log10 c/mL 50 69.5 67.5 60.2 51.7 0.038 0.012 25 CD4 > 200/mm3 CD4 < 200/mm3 Median CD4/mm3increase at W192 (ITT, NC = F): + 258 (DRV/r) vs + 263 (LPV/r) 71.3 65.2 59.6 54.1 0.014 0.052 N = 340 345 343 346 0 DRV/r LPV/r DRV/r LPV/r Difference (95% CI) = 12.0% (4.8 ; 19.2) (P < 0.001) Superiority Difference (95% CI) = 11.6% (4.4 ; 18.8) (P < 0.001) Superiority Orkin C. HIV Med 2012;14:49-59 ARTEMIS

11. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Resistance data at W192 DRV/r N = 343 LPV/r N = 346 Virologic failure 55 (16.0%) 71 (20.5%) Never suppressed 16 22 Rebounders 39 49 Resistance testing (HIV RNA > 50 c/mL) 43 57 Protease inhibitor resistance mutation emergence* 4** 9 Major PI mutation 0 0 4 7 NRTI resistance mutations * M184I/V = 4 M184I/V K70E = 1 * At endpoint = last time point : with available genotype ** L10V, N = 1 ; V11I, N = 1 ; I13V, N = 1 ; I13V + G16E, N = 1 Orkin C. HIV Med 2012;14:49-59 ARTEMIS

12. ARTEMIS Study: DRV/r QD vs LPV/r (BID or QD), in combination with TDF/FTC Safety W192 analysis Data similar to that seen at W96 No new emerging AE with longer-term follow-up Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003) DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed Orkin C. HIV Med 2012;14:49-59 ARTEMIS