Studies on Switching to DTG + RPV in HIV Treatment
This study explores the efficacy of switching to DTG + RPV regimen in HIV patients who are on stable cART. The primary endpoint is to maintain HIV RNA levels below 50 c/mL at W48. Baseline characteristics, virologic outcomes, and patient disposition are analyzed. The results show non-inferiority of DTG + RPV compared to continuation of cART. Virologic outcomes and resistance mutations are also discussed.
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Switch to DTG + RPV Switch to DTG + RPV SWORD Study Switch to CAB LA + RPV LA IM LATTE-2 Study
SWORD-1 & 2 Studies: Switch to DTG + RPV Design Randomisation 1:1 Open-label W48 W148 HIV+ 18 years On stable cART 6 months (2 NRTI + INSTI or PI/r or NNRTI) 1stor 2ndcART with no prior change for virologic failure HIV RNA < 50 c/mL 12 months HBs Ag negative DTG 50 mg QD + RPV 25 mg QD N = 513 DTG 50 mg QD + RPV 25 mg QD Continuation of cART N = 511 Endpoint Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (ITT-exposed, snapshot) ; non-inferiority if lower margin of a two-sided 95% CI for the difference = - 8% for pooled studies (- 10% for each individual study) Llibre JM. Lancet. 2018;391:839-49 SWORD
SWORD-1 & 2 Studies: Switch to DTG + RPV Baseline characteristics and patient disposition DTG + RPV N = 513 43 23 18 611 Continuation cART N = 511 43 21 22 638 Mean age, years Female, % Race: non white, % CD4/mm3, median Baseline cART, % PI-based NNRTI-based INSTI-based With TDF Duration of cART prior to Day 1, median months Discontinuation by W52, N (%) Adverse event Lack of efficacy Investigator decision Consent withdrawal Lost to follow-up Protocol deviation Protocol-defined stopping criteria 26 54 20 73 51 27 54 19 70 53 29 (5.7%) 17 3 0 5 2 1 1 34 (6.7%) 3 3 3 14 3 7 1 Llibre JM. Lancet. 2018;391:839-49 SWORD
SWORD-1 & 2 Studies: Switch to DTG + RPV Virologic outcome at W48 (ITT-E, snapshot) Other virologic results at W48 HIV RNA < 50 c/mL (ITT-E snapshot) SWORD-1 95% DTG + RPV 96% continuation cART Adjusted : - 0.6% (95% CI: - 4.3 to + 3.0) SWORD-2 94% DTG + RPV 94% continuation cART Adjusted : 0.2% (95% CI: - 3.9 to + 4.2) DTG + RPV Continuation cART % 100 94.9 94.7 80 60 40 20 Confirmed virologic failure: HIV RNA 50 c/mL, retest 200 c/mL DTG + RPV, N = 2 Emergence of NNRTI resistance mutation (K101K/E) Continued cART, N = 2 No mutations 4.7 3.9 0.6 Virologic non-response 1.2 0 Success No virologic data HIV RNA < 50 c/mL Difference (95% CI) = - 0.2% (- 3.0 to 2.5) Llibre JM. Lancet. 2018;391:839-49 SWORD
80 SWORD-1 & 2 Studies: Switch to DTG + RPV HIV RNA of subject with NNRTI-resistant mutation 41-year-old female Pre-cART HIV RNA > 2 millions c/mL ; 1stcART: TDF/FTC/EFV Randomised to DTG + RPV Documented non-adherence before W36 K101K/E on genotype (fold change RPV = 1.2) ; phenotype: sensitive to RPV HIV RNA, c/mL 10,000,000 1,059,771 1,000,000 100,000 10,000 1018 1,000 100 <50 <50 W24 <50 <50 D1 <50 W4 <50 W8 <50 W12 10 Screening W36 W39 W45 1 Resuppressed on DTG + RPV Llibre JM. Lancet. 2018;391:839-49 SWORD
SWORD-1 & 2 Studies: Switch to DTG + RPV Adverse events at W48, % DTG + RPV N = 513 Continued cART N = 511 Adverse events related to study drug Grade 1-2 Grade 3-4 17 2 2 < 1 Serious adverse event 5 4 Adverse event leading to discontinuation CNS adverse event leading to withdrawal 4.1 (N = 21 *) N = 9 0.6 (N = 3) N = 1 Most common adverse events ( 5% of patients) Nasopharyngitis Headache Upper respiratory tract infection Diarrhea Back pain 10 8 5 6 3 10 5 7 5 6 * (some participants have more than 1 AE) ; anxiety (N = 4), depression (N = 3), insomnia (N = 2), depressed mood (N = 1), headache (N = 1), panic attack (N = 1), suicidal ideation (N = 1), tremor (N = 1), drug-induced liver injury (N = 1), eosinophilic pneumonia, acute (N = 1), abdominal distension (N = 2), dyspepsia (N = 2), peptic ulcer (N = 1), gastrointestinal haemorrhage (N = 1), pancreatitis, acute (N = 1), Hodgkin s disease (N = 1), Kaposi sarcoma (N = 1), plasmablastic lymphoma (N = 1) Llibre JM. Lancet. 2018;391:839-49 SWORD
SWORD-1 & 2 Studies: Switch to DTG + RPV Fasting lipids at baseline and W48 DTG + RPV Continuation cART mg/dL Baseline Baseline 5 200 187.6 188.1 W48 W48 185.9 186 4 3.8 3.8 150 3.7 3.7 133.1 132.0133.1 121.3 3 107.1108.1 108.3107.3 100 2 53.6 54.9 52.7 54.2 50 1 0 0 Total HDL LDL Triglycerides Total cholesterol: HDL ratio cholesterol cholesterol cholesterol, calculated Llibre JM. Lancet. 2018;391:839-49 SWORD
SWORD-1 & 2 Studies: Switch to DTG + RPV Conclusion at W48 A switch to a novel, once-daily 2 drug-regimen of DTG + RPV demonstrated high efficacy and was non-inferior to the continuation of a combined antiretroviral therapy in virologically suppressed HIV-1 infected adults The safety profiles of both DTG and RPV were consistent with their respective labels Switching to DTG + RPV had a neutral effect on lipids, while significantly improving bone turnover biomarkers Llibre JM. Lancet. 2018;391:839-49 SWORD
90 SWORD-1 & 2 Studies: Switch to DTG + RPV (W100 results) HIV RNA < 50 c/mL at W100, ITT snapshot % 93 95 95 100 89 80 DTG + RPV (N = 513) 60 Continuation cART (N = 511) 40 20 0 DO-W48 D0-W100 Deferred Switch DTG + RPV W52-W100 (N = 477) Confirmed virologic failure: 2 consecutive HIV RNA 50 c/mL, with HIV RNA 200 c/mL on confirmation sample 10/990 (1 %) patients on DTG + RPV between D0 and W100 No emergence of resistance mutation to INSTI Emergence of resistance mutation to NNRTI: 3/10 Aboud M, IAC 2018, Abs. THPEB047 SWORD
91 SWORD-1 & 2 Studies: Switch to DTG + RPV (W100 results) Virologic failure on DTG + RPV between D0 and W100, N = 10 * Resistance mutations Previous ARV regimen HIV RNA, c/mL DNA genotype at baseline Plasma genotype at failure Failure Fold Change NNRTI INSTI INNTI INSTI W24 EFV/TDF/FTC 88 ; 466 0 G193E 0 G193E DTG : 1.02 W36 EFV/TDF/FTC 1059 ; 771 0 0 K101K/E 0 RPV : 1.21 N155N/H, G163G/R Amplification failure W64 DTG/ABC/3TC 833 0 ? ND W76 ATV/ABC/3TC 79 ND ND ND ND - RPV : 1.61 DTG : 0.72 W88 DTG/ABC/3TC 278 0 0 E138E/A 0 W88 RPV/TDF/FTC 147 ND ND NR NR - K101E, E138A, M230M/L K101E, E138A Amplification failure RPV : 31 DTG : ND W100 EFV/TDF/FTC 651 G193E W100 ATV/r/TDF/FTC 280 0 0 0 0 - * Results available for 8/10 patients In red: emerging mutations Aboud M, IAC 2018, Abs. THPEB047 SWORD
90 SWORD-1 & 2 Studies: Switch to DTG + RPV (W100 results) Cumulative adverse events, % DTG + RPV N = 513 D0-W100 Deferred DTG + RPV N = 477 W52-W100 Adverse events related to study drug 20 12 Drug-related adverse events in 2% Headache Nausea 2 2 2 1 Serious adverse event 11 6 Adverse event leading to discontinuation Psychiatric disorders 7 (N = 34 *) 2.3 3 (N = 15 *) 1.0 Adverse events leading to DTG + RPV discontinuation: 49/990 (5%) at W100 including 17 for psychiatric disorders: suicidal ideation (N = 5), suicide (N = 1), anxiety (N = 4), depression (N = 5), depressed mood (N = 1), insomnia (N = 5), nightmare (N = 1), affective disorder (N = 1), abulia (N = 1), confusional state (N = 1), loss of libido (N = 1) Bone, atherogenesis and inflammation biomarkers: no change on DTG + 3TC between W48 and W100 Renal tubular proteinuria (RBP/creatininuria and 2M/creatininuria): improvement maintained in immediate switch group at W100 Aboud M, IAC 2018, Abs. THPEB047 SWORD
