Qué anuncian los nuevos trials?

Transcription

1 Qué anuncian los nuevos trials? XVII Curso Nacional VIH/SIDA Sociedad Chilena de Infectología Agosto 2014 Dr. Carlos Beltrán Hospital Barros Luco Trudeau Universidad de Santiago Grupo SidaChile

2 El presente

3 Recommended ARV 2014 DHHS 1 EACS 2 IAS-USA 3 WHO 4 TDF/FTC EFV TDF/FTC EFV RPV TDF/FTC EFV RPV TDF/FTC TDF/3TC EFV ABC/3TC EFV RPV ABC/3TC EFV TDF/FTC ATV/r DRV/r TDF/FTC ATV/r DRV/r TDF/FTC ATV/r DRV/r ABC/3TC ATV/r DRV/r ABC/3TC ATV/r TDF/FTC DTG EVG/c RAL TDF/FTC ABC/3TC RAL TDF/FTC DTG EVG/c RAL NRTIs NNRTI ABC/3TC DTG TDF/FTC EVG/c ABC/3TC DTG PI/r INI 1. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May EACS Guidelines Version 7.02, June Gunthard HF, et al. IAS Guidelines July WHO guidelines for the use of antiretroviral drugs for treating and preventing HIV infection, June 2013

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5 Key INI trials in treatment-naive pts STARTMRK: RAL noninferior to EFV in HIV-1 RNA < 50 c/ml at Wk 48 (ITT analysis); superior from Wk 192 [1] Study 102: EVG/COBI noninferior to EFV at Wk 48 [2] and through Wk 144 [3] Study 103: EVG/COBI noninferior to ATV/R at Wk 48 [4] and through Wk 144 [5] SINGLE: DTG superior to EFV at Wk 48 [6] and through Wk 96 [7] FLAMINGO: DTG superior to DRV/R at Wk 48 [8] ACTG 5257: Considering both efficacy and tolerability, RAL superior to both ATV/R and DRV/R [9] 1. Rockstroh J, et al. J Acquir Immune Defic Syndr 2013;63: Sax PE, et al. Lancet 2012; 379: Zolopa A, et al. J Acquir Immune Defic Syndr 2013; 63: De Jesus E, et al. Lancet 2012; 379: Rockstroh J, et al. J Acquir Immune Defic Syndr 2013; 62: Walmsley S, et al. N Engl J Med 2013; 369: Walmsley S, et al. CROI Abstract Clotet B, et al. Lancet Epub ahead of print 9. Landovitz R, et al. CROI Abstract 85

6 Percentage of Patients with HIV RNA Levels <50 Copies/mL STARTMRK: Outcomes at 5 Years ITT, NC=F Difference (95% CI): 9.5 (1.7,17.3)* P value (non-inferiority): <0.001 Weeks Number of Contributing Patients Raltegravir 400 mg BID Efavirenz 600 mg QHS Rockstroh J, et al. J Acquir Immune Defic Syndr 2013;63:77-85.

7 Elvitegravir/Cobicistat/FTC/TDF (Quad) vs. EFV and ATV/r + FTC/TDF Phase III Study : ART-naïve subjects HIV RNA >5,000 c/ml (N = 700) Stratification by HIV RNA (> or 100,000 c/ml) Quad QD EFV/FTC/TDF Placebo EFV/FTC/TDF QD Quad Placebo QD Multicenter, international, randomized, blinded 192-week studies Primary Endpoint: VL<50 c/ml W48 (ITT) 12% non-inf Study : ART-naïve subjects HIV RNA >5,000 c/ml egfr > 70ml/min (N = 708) Stratification by HIV RNA (> or 100,000 c/ml) Quad QD ATV/r + FTC/TDF Placebo QD ATV/r + FTC/TDF QD Quad Placebo QD W48 W192 Zolopa A, et al. J Acquir Immune Defic Syndr 2013; 63: Rockstroh J, et al. J Acquir Immune Defic Syndr 2013; 62:

8 Studies 102 & 103: W96 analysis Zolopa A, et al. J Acquir Immune Defic Syndr 2013; 63: Rockstroh J, et al. J Acquir Immune Defic Syndr 2013; 62:

9 SPRING-1 & SPRING-2: Efficacy % DTG 88% % 78% 72% RAL 85% DTG 10mg QD DTG 50mg QD DTG 25mg QD EFV 600mg 10 0 BL BL W4 W8 W12 W16 W24 W32 W40 W48 Week Stellbrink H, et al. CROI Abstract 102LB. Raffi F, et al. Lancet 2013; 381:

10 HIV-1 RNA < 50 copies/ml (%) n/n = 0 DTG + ABC/3TC (n = 414) Δ 7% (2-12; P =.003) / / 419 SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC EFV/TDF/FTC (n = 419) Δ 8.0% ( ; P =.006) / / 419 Wk 48 [1] Wk 96 [2] at Both Wk 48 and 96 Treatment-related study d/c: 3% in DTG vs 11% in EFV arm No new treatment-related AEs in either arm btwn Wks VF at Wk 96: 25 (6%) in each arm 0 pts with resistance in DTG arm; 1 pt with NRTI and 6 pts with NNRTI resistance in EFV arm CD4+ cell count increase at Wk 96 greater with DTG: +325 vs +281 cells/mm 3 (P =.004) Walmsley S, et al. N Engl J Med. 2013;369: Walmsley S, et al. CROI Abstract 543.

11 Patients (%) FLAMINGO: DTG Superior to DRV/r + 2 NRTIs at W48 n = Δ +7.1% (95% CI: +0.9% to +13.2%; P =.025) Virologic Success* DTG + NRTIs DRV/RTV + NRTIs Virologic Nonresponse No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Treatment-related study D/C: 1% in DTG arm vs 4% in DRV/RTV arm More diarrhea with DRV; more headache with DTG 2 pts (< 1%) in each arm met criteria for VF No pts with resistance in either arm Similar increase in CD4+ cell count at Wk 48: +210 cells/mm 3 in each arm Clotet B, et al. Lancet 2014; 383 (9936):

12 Dolutegravir Phase III trials in naïve patients Randomised, non-inferiority Phase III studies Primary endpoint: HIV-1 RNA <50 c/ml at Week 48 Efficacy Failure Resistance (open label) ART-naive patients VL 1,000 c/ml (N=822) 1 ART-naive patients VL 1,000 c/ml HLA-B*5701-neg CrCL >50 ml/min (N=833) 2 ART-naive patients VL 1,000 c/ml (N=484) 3 DTG 50 mg QD + 2 NRTIs* (N=411) RAL 400 mg BID + 2 NRTIs* (N=411) DTG 50 mg QD + ABC/3TC QD (N=414) EFV/TDF/FTC QD (N=419) DTG 50 mg QD + 2 NRTIs* (N=242) DRV/r 800/100 mg QD + 2 NRTIs* (N=242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC 1. Raffi F, et al. Lancet. 2013;381: Walmsley S, et al. N Engl J Med. 2013;369: Clotet B, et al. Lancet 2014;383: % 85% 88% 81% 90% 83% 5% 8% 5% 6% 6% 7% 0.00% 0.97% 0.00% 1.20% 0.00% 0.00%

13 HIV-1 RNA < 50 c/ml at Wk 48 by FDA Snapshot Analysis (%) Similar efficacy of INIs (Ral or DTG) + ABC/3TC or TDF/FTC for high BL VL In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA* ABC/3TC TDF/FTC n/ N = 0 225/ / / 42 72/ 88 13/ 16 29/ 38 < 100k 100K - < 250K 250K - Baseline HIV-1 RNA 500K (c/ml) 13/ 18 18/ 28 > 500K *Pooled data from both INIs Eron J, et al. Glasgow Abstract P204

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15 Patients (%) CD4 Gain (cells/mm 3 ) STaR Study (Week 48): Virologic and Immunologic Outcomes HIV RNA <50 Copies/mL CD4 Cell Gain 85.8% Difference (%): 4.1 (-1.1, 9.2) 81.6% 200 P= FTC/RPV/TDF (n=394) EFV/FTC/TDF (n=392) FTC/RPV/TDF (n=394) EFV/FTC/TDF (n=392) Non-inferiority criteria met. Cohen C. 7th IAS Conference. Kuala Lumpur, Abstract TuPE284.

16 Attributes of ARVs Potency Favorable resistance profile Safe and generally well tolerated Low metabolic impact ARV Simple regimen: Once daily Minimal food requirements Low DDI potential

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18 Probability Risk of Suicidality in Pts Treated With EFV-Containing Regimens EFV EFV-free HR: 2.28 (95% CI ; P =.006) 47 events/5817 PY (8.08/1000 PY) 15 events/4099 PY (3.66/1000 PY) Wks to Suicidality Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials Variable HR (95% CI) P Value Randomly assigned EFV Age category < ( ) ( ) 1.69 ( ) 1.00 (reference).04 Risk of attempted or completed suicide also associated with EFV (HR: 2.58; 95% CI: 0.94 to 7.06; P =.06) EFV also associated with increased risk of death from injury, substance use, or unknown causes Hx IDU 2.18 ( ).02 Psychiatric hx or psychoactive rx 3.90 ( ) <.001 Mollan K, et al. IDWeek Abstract

19 ACTG5257: Diseño Participants Enrolled 1814 Participants Excluded 1 acute illness, 1 prior ART and 3 prior ART + resistance Participants Eligible 1809 ATV/r 605 (5 never started ART) RAL 603 (4 never started ART) DRV/r 601 (4 never started ART) 556 (92%) Completed 96 Weeks 560 (93%) Completed 96 Weeks 546 (91%) Completed 96 Weeks

20 ACTG5257: Fracaso a W96 ITT: - 88% - 94% - 89% Landovitz R et al. CROI 2014; Boston, MA. Abst. 85

21 ACTG5257: W96 Fracaso y switch por tolerancia D/C: - 14% vs 1% y 5% BMD: - Hip: Ral vs PI p= Spine: Ral vs PI p<0.001 Brown T et al. CROI 2014; Abst. 779LB Landovitz R et al. CROI 2014; Boston, MA. Abst. 85

22 Otros análisis ITT, off-art=failure (SNAPSHOT) Any toxicity discontinuation Treatment Group ATV/r 95 (16%) RAL DRV/r 8 (1%) 32 (5%) Gastrointestinal toxicity Nausea Gastrointestinal, specify toxicity(ies) Diarrhea Vomiting Abdominal distention Abdominal cramps/pain Hyperbilirubinemia Jaundice Bilirubin, total, increased Hyperpigmentation ATV/r 70% 73% 63% 62% Other hepatic toxicity Increased LFTs Cholecystitis Elevated LFT's with + HCV dx RAL 84% 83% 80% 76% DRV/r 77% 77% 73% 71%

23 NRTI-Sparing Options Regimen Strengths Weaknesses LPV/RTV + EFV (A5142)[1] LPV/RTV monotherapy [2-5] DRV/RTV monotherapy [6,7] LPV/RTV + 3TC [8] Good efficacy Large study Simplicity Tolerability Simplicity Tolerability Decrease toxicity Efficacy Poor tolerability Lipid elevation Concerns regarding efficacy Mixed results for efficacy No data with preferred PI/RTVs DRV/RTV + RAL [9,10] Good tolerability Twice daily Concerns regarding efficacy in naives ATV BID + RAL [11] No booster Poor tolerability Poor efficacy DRV/RTV + MVC (R5-only pts) [12] INSTI sparing Concerns regarding efficacy Study recently stopped 1. Riddler SA, et al. N Engl J Med. 2008;358: Delfraissy JF, et al. AIDS. 2008;22: Cameron DW, et al. J Infect Dis. 2008;198: Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40: Nunes EP, et al. HIV Clin Trials. 2009;10: Arribas J, et al. AIDS. 2010;24: Katlama C, et al. AIDS. 2010;24: Cahn P, et al. EACS Abstract LBPS7/6. 9. Raffi F, et al. CROI Abstract 84LB. 10. Taiwo B, et al. AIDS. 2011;25: Kozal MJ, et al. HIV Clin Trials. 2012;13:

24 Patients (%) LPV/r-3TC non inferior to triple ART at W48 Δ 4.6 (95% CI: -2.2 to 11.8; 100 P =.171) n = Virologic Success* Virologic Nonresponse Dual ART (n = 214) Triple ART (n = 202) D/C Due to AE or Death D/C for Other Reasons *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm CD4+ cell count increase +227 with dual ART vs +217 with triple ART Grade 2-3 adverse events more frequent in triple-art arm (88 vs 65 events) Hyperlipidemia more common in dual-art arm (23 vs 16 pts) Lab abnormalities similar VF in 22 pts, of whom 2 had resistance (M184V) Both on dual ART Cahn P, et al. EACS Abstract LBPS7/6.

25 Protocol-Defined Virologic Failure and Emergent Resistance Mutations PDVF: 2 measurements of HIV-1 RNA at least 1 week apart >400 copies/ml at week 24 > 50 copies/ml at week 48 Emergent resistance mutations: DT: 2 out of 5 both M184V TT: 0 out of 8 *p=0.72 Cahn P, et al. EACS Abstract LBPS7/6.

26 NEAT-001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC in tx naive pts Randomized, open-label phase III study Stratified by country of origin and participation in virology/immunology substudy Wk 96 ART-naive pts with HIV-1 RNA > 1000 c/ml CD4+ cell count 500 cells/mm 3 (N = 805) Primary endpoint DRV/RTV 800/100 mg QD + RAL 400 mg BID (n = 401) DRV/RTV 800/100mg QD + TDF/FTC 300/200 mg QD (n = 404) Virologic: change of treatment before Wk 32 because of insufficient response or HIV-1 RNA 50 c/ml at Wk 32 or beyond Clinical: death, any new AIDS-defining event, any new non-aids event Raffi F, et al. CROI Abstract 84LB.

27 NEAT: RAL + DRV/r non inferior to TDF/FTC + DRV/r at W 96 Overall, regimens noninferior by % reaching composite primary endpoint of 6 virologic and clinical endpoints at Wk 96 RAL: 17.4%; TDF/FTC: 13.7% Inferior response in pts with BL CD4 < 200 and a trend toward more primary endpoints in pts with BL VL 100K. Similar numbers of pts with PDVF (RAL: n = 66; TDF/FTC: n = 52) No pts with resistance in TDF/FTC arm vs 5 with integrase mutations and 1 with K65R in RAL arm Overall N = 805 BL HIV-1 RNA Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL - TDF/FTC < 100,000 c/ml 100,000 c/ml BL CD4+ cell count n = 530 n = 275 < 200/mm 3 n = /mm 3 n = RAL TDF/FTC Raffi F, et al. CROI Abstract 84LB (P =.09) Significantly greater mean increases in fasting lipids in RAL arm (P =.02)

28 71% 64%

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30 83% 81%

31 Percentage suppressed VL suppression at 96 weeks 100% 91% 93% 90% 80% 83% 70% 60% 50% 40% 30% 20% 10% 0% PI/NRTI PI/RAL PImono 88% 87% 86% 86% 67% 74% 73% 74% 73% 61% 44% 44% <10000 c/ml <1000 c/ml <400 c/ml <50 c/ml PI/NRTI PI/RAL PImono+ Paton N, et al. 7th IAS Conference. Kuala Lumpur, Abstract WeLBB02.

32 El futuro

33 - Tasa de AE - < Eficacia global - FDA Categoría D - Tasa de TDR

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35 Tenofovir Alafenamide (TAF, GS-7340): Study 292: W24 Efficacy Fracaso virológico 1% vs 2% sin resistencia Ramanathan et al. CROI 2013; Atlanta, GA. Abst Gulick R, et al. CROI 2013; Atlanta, GA. Abstract 122.

36 Patients (%) TAF/FTC/EVG/COBI Non inferior to QUAD at W pts Noninferiority at W 24 primary endpoint analysis 89.7% vs 87.5 % with HIV-1 RNA < 50 c/ml, respectively 6 pts (3 per arm) eligible for resistance analysis at W48 No pts with virological failure or resistance in TAF arm 1 pt with NRTI and INSTI resistance in TDF arm (M184V, E92Q) Δ 1.0% (95% CI: to +10.0; P =.84) n = Virologic Success* 6.3 W48 TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI Virologic Nonresponse No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. 1. Zolopa A, et al. CROI Abstract 99LB. 2. Sax P, et al. ICAAC Abstract H-1464d.

37 Treatment-emergent AE, % Nausea Diarrhea Fatigue Headache TAF (n = 112) TDF (n = 58) Grade 3/4 creatine phosphokinase, % 5 3 Median change in egfr ml/min (P =.04) Median change in lipids, mg/dl Total cholesterol LDL-C HDL-C Triglycerides Change in BMD, % Spine Hip (P <.001) +4 (P =.001) +2 (P =.007) (P =.002) -2.0 (P <.001) Gulick R, et al. CROI 2013; Atlanta, GA. Abstract 122. Zolopa A, et al. CROI Abst. 99LB.

38 Median (Q1, Q3) Change in BMD Median (Q1, Q0) Change in BMD Change in egfr and BMD With TAF vs TDF at W48 Patients on TAF had smaller decrease in egfr 2 TAF/FTC/EVG/COBI (n = 112) TDF/DTC/EVG/COBI (n = 58) -5.5 vs ml/min with TDF (P =.041) -2 P <.001 No renal discontinuations and no tubulopathy in either arm Less change in renal tubular proteins with TAF Spine Smaller change in both spine and hip BMD (by DXA) over 48 wks with TAF vs TDF Sax P, et al. ICAAC Abstract H-1464d Hip Wks P <.001

39 HIV-1 RNA < 50 c/ml by Snapshot Algorithm (%) LATTE: GSK in Naive Pts: Efficacy at 24-Wk Induction GSK (744), DTG analogue with long half-life, oral or injectable Randomized, dose-ranging phase IIb study of oral formulation Primary endpoint: HIV-1 RNA < 50 c/ml at Wk % 88% 87% 85% mg (n = 60) mg (n = 60) mg (n = 61) EFV 600 mg (n = 62) 30-mg dose chosen for studies in ART-naive pts 0 BL Wks Margolis D, et al. EACS Abstract PS7/1

40 H-672 Meta-Analysis of Safety Data from 8 Clinical Studies with GSK , an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension Y. Lou, E. Gould, S. Chen, D. Wilfret, W. Spreen, S. Piscitelli, D. Margolis; Inhibidor de Integrasa en tabletas (t½~40 hrs) o inyectable IM o SC (t ½~30-40 días). 245 sujetos en estudios de Fase 1 y 2a Cefalea (22%) y nausea (5%). Reacciones en sitio de inyección (7 23%) Laboratorio Grado 3 = 2 (CK, BIL) y Grado 4 = 2 (CK, osteomielitis) no relacionados QT no afectado: - 2,9 mseg