Dolutegravir-Lamivudine Dual Therapy in ARV-Naïve HIV Patients: 48-Week Results of PADDLE Trial

The PADDLE trial evaluated the efficacy, safety, and tolerability of a Dolutegravir-Lamivudine regimen as initial therapy in HIV-infected, treatment-naïve patients. This pilot study demonstrated comparable viral load changes to triple therapy, supporting the use of this dual regimen. The study design, baseline characteristics, and primary endpoint of achieving plasma HIV-1 RNA levels

• HIV
• Dual therapy
• Dolutegravir
• Lamivudine
• ARV

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1. abstract number FRAB0104LB Dolutegravir-Lamivudine as initial therapy in HIV-Infected, ARV na ve patients 48 Week Results of the PADDLE trial. ClinicalTrials.gov : # NCT02211482 Pedro Cahn, Mar a J Rol n, Mar a I. Figueroa, Ana Gun, Patricia Patterson, Omar Sued

2. Background Dual therapy is an emerging concept that might result in lower cost, toxicity and pill burden. Dolutegravir is a potent antiviral compound with proven clinical efficacy, high genetic barrier and excellent safety profile. Lamivudine is a well-tolerated, cheap, once daily NRTI, without known drug- drug interactions. The GARDEL study demonstrated that a 2 drug regimen was non-inferior to triple therapy in naive patients* The 24 weeks preliminary results of the PADDLE study provided evidence to continue with this pilot trial** Viral load change was of similar magnitude after a dual therapy regimen DTG/3TC compared to 2 DTG-based triple therapy regimens.*** * Cahn et al: Lancet Inf Dis, 2015 ** Figueroa et al: EACS 2015 *** Sued et al : CROI 2016

3. Objective and Primary Endpoint To evaluate the antiviral efficacy, safety and tolerability of a 2-drug regimen with 3TC and DTG in HIV-1 infected, treatment- na ve individuals. Proportion of subjects with plasma HIV-1 RNA levels <50 copies/mL at week 48 using the FDA snapshot algorithm (Missing, Switch or Discontinuation = failure) for the ITT- exposed population.

4. PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE): Study design Phase IV, pilot, open-label, single arm exploratory trial 1stcohort (n= 10) 2ndcohort (n= 10) ARV- na ve patients, 18 years HIV-1 RNA >5,000 copies/mL and <100,000 copies/mL CD4 count 200 cells/mL HB(s)Ag negative (n= 20) DTG 50 mg QD 3TC 300 mg QD DTG 50 mg QD 3TC 300 mg QD Second cohort enrolled after confirming success of first cohort at week 8 Viral load was measured at baseline, days 2,4,7,10, and weeks 2,3,4,6,8,12, 24, 36 and 48* * 96 week extension ongoing

5. Baseline Characteristics Baseline Characteristics DTG/3TC n=20 19/1 34 (31-43) Gender (male: female) Age, years, median (IQR) Mode of transmission (n) MSM Heterosexual 15 5 HIV RNA (copies/mL), median (IQR) 24,128 (11,686-36,794) CD4 count, cells/mm3, median (IQR) 507 (296-517) CDC stage (%) A/B/C 90/10/0

6. Viral load at Screening and baseline # 1 2 3 4 5 6 7 8 9 SCR 5.584 8.887 67.335 99.291 34.362 16.024 37.604 25.071 14.707 10.679 50.089 13.508 28.093 15.348 23.185 11.377 39.100 60.771 82.803 BSL 10.909 10.233 DAY 2 3.701 5.671 37.604 11.797 4.680 3.754 2.948 6.264 Not done 5.671 160.974 3.496 37.350 3.994 15.830 370 11.879 31.170 35.517 DAY 4 383 318 1.565 3.303 1.292 1.634 819 1.377 516 318 68.129 3.296 26.343 791 4.217 97 1.970 2.174 2.902 DAY 7 101 < 50 1.178 432 570 162 61 Not done 202 < 50 3.880 135 539 198 192 143 460 692 897 DAY 10 71 < 50 266 179 168 < 50 < 50 268 43 < 50 2.247 351 268 98 69 < 50 147 358 352 W.2 < 50 < 50 97 178 107 < 50 < 50 105 47 < 50 784 351 61 < 50 49 < 50 52 156 168 W.3 < 50 < 50 53 55 < 50 < 50 < 50 < 50 < 50 < 50 290 84 < 50 61 < 50 < 50 < 50 < 50 76 W.4 < 50 < 50 < 50 < 50 44 < 50 < 50 < 50 < 50 < 50 288 67 < 50 64 < 50 < 50 < 50 < 50 < 50 W.6 < 50 < 50 < 50 46 < 50 < 50 < 50 < 50 < 50 < 50 147 < 50 < 50 < 50 W.8 < 50 < 50 < 50 42 < 50 < 50 < 50 < 50 < 50 < 50 48 < 50 < 50 < 50 < 50 < 50 W.12 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.24 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 151.569 148.370 20.544 14.499 18.597 24.368 10.832 7.978 10 11 12 13 14 15 16 17 18 19 At 273.676 64.103 33.829 15.151 23.500 3.910 25.828 73.069 < 50 Not done < 50 < 50 < 50 < 50 < 50 106.320 20/06/201 5 20/09/201 5 20 5.190 7.368 3.433 147 56 < 50 < 50 < 50 < 50 < 50 4 patients had 100,000 copies/mL at baseline

7. Viral suppression at week 24 # 1 2 3 4 5 6 7 8 9 SCR 5.584 8.887 67.335 151.569 99.291 148.370 34.362 16.024 37.604 25.071 14.707 10.679 50.089 273.676 68.129 13.508 64.103 28.093 33.829 15.348 15.151 23.185 23.500 11.377 3.910 39.100 25.828 60.771 73.069 82.803 106.320 5.190 7.368 BSL 10.909 10.233 DAY 4 383 318 1.565 3.303 1.292 1.634 819 1.377 Not done 516 318 DAY 7 101 < 50 1.178 432 570 162 61 W.2 < 50 < 50 97 178 107 < 50 < 50 105 < 50 < 50 784 351 61 < 50 < 50 < 50 52 156 168 < 50 W.3 < 50 < 50 53 55 < 50 < 50 < 50 < 50 < 50 < 50 290 84 < 50 61 < 50 < 50 < 50 < 50 76 < 50 W.4 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 288 67 < 50 64 < 50 < 50 < 50 < 50 < 50 < 50 W.6 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 147 < 50 < 50 < 50 W.8 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.12 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.24 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.36 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.48 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 20.544 14.499 18.597 24.368 10.832 7.978 202 < 50 3.880 135 539 198 192 143 460 692 897 56 SAE 10 11 12 13 14 15 16 17 18 19 20 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3.296 26.343 791 4.217 97 1.970 2.174 2.902 147 Not done < 50 < 50 < 50 < 50 < 50 PDVF < 50 < 50

8. Viral suppression at week 48 # 1 2 3 4 5 6 7 8 9 SCR 5.584 8.887 67.335 151.569 99.291 148.370 34.362 16.024 37.604 25.071 14.707 10.679 50.089 273.676 68.129 13.508 64.103 28.093 33.829 15.348 15.151 23.185 23.500 11.377 3.910 39.100 25.828 60.771 73.069 82.803 106.320 5.190 7.368 BSL 10.909 10.233 DAY 4 383 318 1.565 3.303 1.292 1.634 819 1.377 Not done 516 318 DAY 7 101 < 50 1.178 432 570 162 61 W.2 < 50 < 50 97 178 107 < 50 < 50 105 < 50 < 50 784 351 61 < 50 < 50 < 50 52 156 168 < 50 W.3 < 50 < 50 53 55 < 50 < 50 < 50 < 50 < 50 < 50 290 84 < 50 61 < 50 < 50 < 50 < 50 76 < 50 W.4 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 288 67 < 50 64 < 50 < 50 < 50 < 50 < 50 < 50 W.6 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 147 < 50 < 50 < 50 W.8 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.12 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.24 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.36 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 W.48 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 20.544 14.499 18.597 24.368 10.832 7.978 202 < 50 3.880 135 539 198 192 143 460 692 897 56 SAE 10 11 12 13 14 15 16 17 18 19 20 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3.296 26.343 791 4.217 97 1.970 2.174 2.902 147 Not done < 50 < 50 < 50 < 50 < 50 PDVF < 50 < 50 CD4 increase: Median (IQR) : 267 (180-462)

9. Results: Viral load decay 5.0 4.5 4.0 Viral Load (Log 10) 3.5 3.0 -2.54 0.27* 2.5 2.0 1.5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 (W24) (W12) Days *Day 14: Early evolution of viral load (log 10) (mean standard deviation).

10. Adverse Events at 48 weeks Adverse Events possibly related to DTG GRADE I AE GRADE II ( 8 AEs / 6 pts ) 1 Somnolence 1 Epigastric pain 2 1 Headache 1 Diarrhea 2 Nausea All AEs were reported at the first week of treatment Three Grade 2-3 laboratory toxicities were reported in 3 patients through 48 weeks: Proteinuria, CPK ( both at baseline) and hematuria. One SAE * : One patient committed suicide between w24 and w36 , in the context of a stressful - traumatic life event. His last pVL at week 24 was < 50 copies. * SAE Not deemed related to study medication

11. Protocol-Defined Virologic Failure 106,320 40,000 82,803 GENOTYPE RT : NO MUTATIONS; DIDNT AMPLIFY TO INTEGRASE AND PROTEASE 4,000 400 246 168 99 76 61 40 40 40 40 40 40 40 SCR BSL W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 retest W.48 DV DTG 50mg/d plus 3TC 300 mg /d Jan 2016 Feb 2016 Mar 2016 Dec 2015 Patient was discontinued from study an counted as a failure, but followed up to week 48. He resuppressed without changes in ARV regimen.

12. Conclusions This is the first study exploring an InSTI/lamivudine-based 2 drug regimen in ARV-na ve patients. In this pilot, proof of concept study, dual therapy with DTG plus lamivudine induced rapid virologic suppression with a favorable safety/tolerability profile in HIV-1 infected, treatment-na ve individuals. At week 48, 18/20 (90%) of subjects achieved the primary endpoint. Observed virologic failure rate was 5%. If confirmed in a well powered randomized clinical trial, this 2-drug regimen might be considered as a simple, potent, well tolerated and potentially cheap strategy for HIV treatment initiation.

13. Acknowledgments All study participants and their families Fundacion Huesped : Valeria lvarez, Agustina Arg ello, Fabiana Enjamio, Agustina Enz, Mariano de Stefano Marcelo De las Heras, Carina Cesar, Valeria Fink, Claudia Frola, Danisa James, Horacio Beylis , Emanuel Fojo, Leandro Cahn, Adriana Corera, Kurt Frieder, Edgardo Szyld and Santiago Perez Lloret ViiV Healthcare: Michael Aboud, Dannae Brown, Kimberley Smith, Omar Marin This study was an investigator initiative, funded by ViiV Healthcare