CROI 2017 Review: Novel ART Strategies

Transcription

1 Mountain West AIDS Education and Training Center CROI 2017 Review: Novel ART Strategies Brian R. Wood, MD Assistant Professor of Medicine Medical Director, Mountain West AETC ECHO Telehealth March 2, 2017 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient.

2 Outline Dolutegravir/rilpivirine dual therapy for maintenance coming soon! Dolutegravir + lamivudine dual therapy for maintenance promising! Dolutegravir monotherapy don t do it!

3 Background Why study dual or mono ART strategies? Potential to: - Reduce pill burden and side effects - Reduce cost Dolutegravir + second agent offers high barrier to resistance and high tolerability

4 SWORD 1&2: Dolutegravir + Rilpivirine 2-Drug Maintenance Therapy Abstract 44LB Llibre JM et al. Barcelona, Spain.

5 Methods Study Design: SWORD 1&2 Early switch phase Late switch phase Background: Identical randomized, multinational, openlabel, industry-sponsored, parallel-group, non-inferiority studies Inclusion Criteria: - On stable 3-drug ART (2 NRTI s + INSTI, NNRTI, or boosted PI) for >6 months - 1 st or 2 nd regimen with no prior change due to virological failure - HIV RNA <50 for > 12 months - No HBV co-infection DTG + RPV (n = 513) Continue 3-Drug ART (n = 511) 48 weeks DTG + RPV (n = 513) Primary endpoint: week 48 HIV RNA <50 copies/ml by snapshot analysis Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

6 Baseline Characteristics (Pooled Across SWORD 1&2) DTG + RPV (n=513) Age (mean) Drug ART (n=511) Age >50 years 147 (29%) 142 (28%) Female 120 (23%) 108 (21%) Race, non-white 92 (18%) 111 (22%) CD4 count (median) Baseline PI 133 (26%) 136 (27%) Baseline NNRTI 275 (54%) 278 (54% Baseline INSTI 105 (20%) 97 (19%) Baseline TDF 374 (73%) 359 (70%) ART duration (median) 51 months 53 months Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

7 % with HIV RNA <50 copies/ml Results 48-Week Virologic Response by Intention-to-Treat 100 DTG + RPV 3-Drug ART *DTG + RPV met criteria for non-inferiority *2 virologic failures in each arm; 1 in DTG + RPV arm had K101K/E Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

8 Results and Conclusions Adverse Events: - More grade 1-2 AE s in 2-drug arm (17% vs 2%) Also more AE s leading to study withdrawal (4% vs <1%) - Neutral effect on lipids (small decrease TG s & TC:HDL ratio) - Significant improvement in bone biomarkers; substudy ongoing Conclusions: - DTG + RPV 2-drug maintenance non-inferior for select persons - Regulatory FDA filing for DTG/RPV (co-formulated single-tablet) Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

9 LAMIDOL: DTG + 3TC 2-Drug Maintenance Therapy Abstract 458 Joly V et al. Paris, France.

10 Methods Study Design: LAMIDOL Background: Non-comparative, open-label, single-arm, multicenter trial Inclusion Criteria: - Nadir CD4 count >200 cells/ml - HIV RNA <50 for >2 years - First-line 3-drug ART: 2 NRTI s + NNRTI, boosted PI, or INSTI - Max 2 modifications of ART for simplification or intolerance - Wild type HIV-1 on genotype - No HBV co-infection Phase 1 Phase 2 DTG + 2 NRTI s (n = 110) DTG + 3TC (n = 104) 8 weeks 48 weeks Primary endpoint: proportion with HIV RNA <50 copies/ml at week 48 Source: Joly V et al. Abstract 458. CROI Seattle, WA.

11 Baseline Characteristics Participants who Entered Phase 2 N = 104 Age (median) 45 Male 89 (85.6%) MSM 73 (70.2%) Duration since HIV diagnosis (median) 6.3 years Time on current ART (median) 4.0 years Nadir CD4 count (median) 399 Current CD4 count (median) 743 Baseline NNRTI 58 (55.8%) Baseline PI 24 (23.1%) Baseline INSTI 22 (21.2%) Source: Joly V et al. Abstract 458. CROI Seattle, WA.

12 % with HIV RNA <50 copies/ml Results and Conclusions 100 DTG + 3TC 101/104 had HIV RNA <50 copies after 40 weeks of DTG + 3TC dual therapy Those with RNA >50 copies mostly had LLV (<200 copies) and suppressed after re-introduction of 3- drug ART; no resistance occurred Results promising and add to PADDLE ACTG 5353 & GEMINI enrolling tx-naïve patients Source: Joly V et al. Abstract 458. CROI Seattle, WA.

13 DOLUMONO: DTG for Maintenance Monotherapy Abstract 451LB Wijting IEA et al. Rotterdam, The Netherlands.

14 Methods Study Design: DOLUMONO Background: Randomized, open-label, multicenter, noninferiority trial Inclusion Criteria: - On 3-drug ART - HIV RNA <50 for >6 months - HIV RNA zenith <100k - CD4 count nadir >200 - No baseline resistance, no h/o virologic failures - No HBV co-infection Immediate Monotherapy DTG (n = 51) Continue 3-Drug ART (n = 53) Delayed Monotherapy DTG (n = 104) 24 weeks 48 weeks Primary endpoint: HIV RNA <200 copies/ml week 24 Secondary: HIV RNA <200 and <50 weeks 24 & 48 Post-hoc analysis: add in 152 more 3-drug controls Source: Wijting IAE, et al. Abstract 451LB. CROI Seattle, WA.

15 % with HIV RNA <50 copies/ml Results and Conclusions 48-Week Virologic Response; DOLUMONO and Controls p = DTG Drug ART 80 The genetic barrier against resistance of DTG is insufficient to allow 70 for maintenance monotherapy. Future studies should evaluate DTG + 3TC rather than DTG monotherapy *Study stopped early; 9 VF s in DTG arm, 3 with INSTI resistance (N155H, R263K, S230R) *RNA at failure mostly 1-5k copies with one exception ( 70k); all reported >95% adherence; all suppressed with re-initiation of cart Source: Wijting IAE, et al. Abstract 451LB. CROI Seattle, WA.

16 Summary Avoid dolutegravir monotherapy Dolutegravir + second agent (RPV or 3TC or perhaps boosted darunavir) promising for simplified maintenance therapy for select individuals Question: would you consider 2-drug maintenance therapy for your patients? If so, in what circumstances?