State of the ART: Integrase Inhibitors Clinical Data Juan Berenguer Hospital General Universitario Gregorio Marañón (IiSGM) Madrid, Spain
Disclosures Consulting fees and honoraria Gilead, Janssen, MSD, ViiV Healthcare Grant support Gilead, MSD, ViiV Healthcare
Chemical Structure of INSTIs Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA
ART-naïve patients
RAL or EFV with TDF/FTC in Treatment-Naive Pts Final 5-Year Results From STARTMRK Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013; 63(1):77-85.
ATVr, DRVr, or RAL with FTC/TDF in ART-naïve patients (ACTG A5257) Open label, 1809 participants Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL -20-10 0 10 20 Favors RAL Favors DRV/r ATV/r vs RAL 15% (10%, 20%) DRV/r vs RAL 7.5% (3.2%, 12%) ATV/r vs DRV/r 7.5% (2.3%, 13%) Lennox JL, et al. Ann Intern Med 2014; 161(7):461-471.
RAL 1200 mg QD* or RAL 400 mg BID with TDF/FTC ONCEMRK Study Cahn P, et al. The Lancet HIV 2017; 4(11):e486-e494 * two 600 mg reformulated tablets
Dolutegravir-Based Regimens in Treatment-Naïve Pts HIV RNA <50 Copies/mL (Week 48) SPRING-2 DTG + FTC/TDF or ABC/3TC (n=411) RTG + FTC/TDF or ABC/3TC (n=411) Week 48 HIV RNA <50 Copies/mL (%) 88 85 Favors Comparator Favors Dolutegravir 2.5% SINGLE DTG + ABC/3TC (n=414) EFV/FTC/TDF (n=419) 88 81 7.4% FLAMINGO DTG + FTC/TDF or ABC/3TC (n=242) DRV/r + FTC/TDF or ABC/3TC (n=242) 90 83 7.1% -20-10 0 10 20 Raffi F, et al. Lancet. 2013;381:735-743. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. Clotet B, et al. Lancet. 2014;383:2222-2231. Adjusted Treatment Difference (%) No resistance selected for any dolutegravir-based regimen
EVG/COBI/FTC/TDF vs. EFV/FTC/TDF in Rx-Naïve Pts (GS-102*) Efficacy Endpoint: HIV-1 RNA <50 c/ml (FDA Snapshot) Weeks 48 and 96 Zolopa A, et al. J Acquir Immune Defic Syndr 2013; 63(1):96-100. *Double-blind study
EVG/COBI/FTC/TDF vs. ATV/r + FTC/TDF in Rx-Naïve Pts (GS 103*) Efficacy Endpoint: HIV-1 RNA <50 c/ml (FDA Snapshot) Weeks 48 and 96 Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013; 62(5):483-486. *Double-blind study
E/C/F/TAF vs. E/C/F/TDF in ART-Naïve Pts (104 and 111) Primary Endpoint : Non-inferiority (12% margin) of E/C/F/TAF to Stribild based on HIV-1 RNA <50 copies/ml at Wk 48 FDA Snapshot Secondary Endpoints: Efficacy, safety and tolerability observed through Week 96, Week 144 Sax PE, et al. The Lancet 2015; 385(9987):2606-2615. Wohl D, et al. JAIDS Journal of Acquired Immune Deficiency Syndromes 2016; 72(1):58-64.
E/C/F/TAF vs. E/C/F/TDF in ART-Naïve Pts (104 and 111) Virologic Outcomes at Weeks 48, 96, and 144 1. Wohl D, et al. JAIDS 2016;72(1):58-64 2. Sax P, et al. Lancet 2015;385:2606 15 3. Arribas J, et al. CROI 2017. Seattle, WA. Poster #453 At Week 48 and 96, E/C/F/TAF was non-inferior in efficacy to E/C/F/TDF At Week 144, E/C/F/TAF was superior to E/C/F/TDF in efficacy difference at both <50 copies/ml: 4.2% (95% CI 0.6%, 7.8%; p=0.02) <20 copies/ml: 5.4% (95% CI 1.5%, 9.2%; p=0.01)
E/C/F/TAF vs. E/C/F/TDF in ART-Naïve Pts (104 and 111) Week 144 Safety Summary Arribas J, et al. CROI 2017. Seattle, WA. Poster #453 AEs leading to discontinuations were significantly less on E/C/F/TAF compared to E/C/F/TDF at Week 144
Bictegravir/FTC/TAF vs Dolutegravir-Containing Regimens for Treatment-Naive Pts GS-1489: randomized, double-blind, active-controlled phase III trial [1] Wk 48 ART-naive, HLA-B*5701 negative pts with egfr CG 50 ml/min (N = 629) Bictegravir/FTC/TAF* (n = 314) Dolutegravir/ABC/3TC (n = 315) GS-1490: randomized, double-blind, active-controlled phase III trial [2] Wk 48 ART-naive pts with egfr CG 30 ml/min (N = 645) Bictegravir/FTC/TAF* (n = 320) Dolutegravir + FTC/TAF (n = 325) All pts also received placebo tablets for comparator regimen (eg, pts in GS-1489 who received BIC/FTC/TAF also received DTG/ABC/3TC placebo). *BIC/FTC/TAF 50/200/25 mg PO QD. DTG/ABC/3TC 50/600/300 mg PO QD. DTG + FTC/TAF 50 + 200/25 mg PO QD 1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com
Pts (%) Pts (%) BIC/FTC/TAF vs DTG-Containing Regimens Key Efficacy Findings GS-1489: Wk 48 Virologic Efficacy [1] GS-1490: Wk 48 Virologic Efficacy [2] 100 80 60 40 92 93 BIC/FTC/TAF (n = 314) DTG/ABC/3TC (n = 315) Treatment difference: -0.6% (95% CI: -4.8% to 3.6%) 100 80 60 40 89 93 99 > 99 BIC/FTC/TAF DTG + FTC/TAF 1 PP Treatment difference (1 o ): -3.5% (95% CI: -7.9% to 1.0%) 20 0 HIV-1 RNA < 50 c/ml 1 3 7 4 HIV-1 RNA 50 c/ml No Virologic Data 20 0 HIV-1 RNA < 50 c/ml 4 1 1 < 1 HIV-1 RNA 50 c/ml 6 6 0 0 No Virologic Data No resistance for any regimen components detected for either group No resistance for any regimen components detected for either group 1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com
BIC/FTC/TAF vs DTG-Containing Regimens Outcome Through Wk 48 Key Safety Findings BIC/FTC/TAF (n = 314) GS-1489 [1] GS-1490 [2] DTG/ABC/3TC (n = 315) BIC/FTC/TAF (n = 320) DTG + FTC/TAF (n = 325) Diarrhea, % 13 13 12 12 Headache, % 11 14 13 12 Nausea, % 10 23* 8 9 Insomnia, % 4 6 5 4 Upper respiratory tract infection, % 6 11 5 7 Median egfr CG from BL, ml/min -10.5-10.8-7.3-10.8 Mean BMD from BL, % spine/hip -0.83/-0.78-0.60/-1.02 NR NR D/c for AE, n (%) 0 4 (1) 5 (2) 1 (< 1) *P <.0001; P =.02 No d/c for renal AEs and no proximal tubulopathy for any regimen 1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com
Guidelines: Recommended Regimens for First-line ART DHHS 1 GESIDA 2 EACS 3 IAS-USA 4 INSTI DTG/ABC/3TC DTG + (TAF or TDF)/FTC EVG/COBI/(TAF or TDF)/FTC RAL + (TAF or TDF)/FTC BIC/TAF/FTC DTG/ABC/3TC DTG + TAF/FTC RAL + TAF/FTC DTG/ABC/3TC DTG + (TAF or TDF)/FTC EVG/COBI/(TAF or TDF)/FTC RAL + (TAF or TDF)/FTC DTG/ABC/3TC DTG + TAF/FTC RAL + TAF/FTC EVG/COBI/TAF/FTC NNRTI NONE NONE RPV/TAF/FTC, RPV/TDF/FTC NONE PI NONE DRVc or DRVr + TAF/FTC or TDF/FTC NONE Recommendations may differ according to renal function, HLA-B*5701 status, HBsAg status, osteoporosis status, other comorbidities 1. DHHS ART Guidelines. March 2018. 2. GESIDA January 2018, 3. EACS October 2017, 4 Günthard HF, et al. JAMA. 2016;316:191-210.
Switch
Switching to INSTI-based ART in the setting of virologic suppression Current regimen New regimen Effects (in addition to maintaining viral suppression*) EFV + 2nRTIs bpi + 2nRTIs RAL + 2nRTIs (Switch-ER) RAL + 2nRTIs (Switchmrk) (Spiral) Reference Improves dislipidemia & CNS AEs Nguyen A, AIDS 2011 Improves dislipidemia, *if fully active nrtis Eron JJ, Lancet 2010 Martinez E, AIDS 2010
Switching to INSTI-based ART in the setting of virologic suppression Current regimen New regimen Effects (in addition to maintaining viral suppression*) EFV + 2nRTIs bpi + 2nRTIs bpi + 2nRTIs bpi + 2nRTIs nnrti + 2nRTIs INSTI + 2nRTIs bpi or nnrti or INSTI + 2nRTIs RAL + 2nRTIs (Switch-ER) RAL + 2nRTIs (Switchmrk) (Spiral) DTG + 2nRTIs (Neat 002) DTG/ABC/3TC (Striiving) DTG + RPV (Sword 1&2) Reference Improves dislipidemia & CNS AEs Nguyen A, AIDS 2011 Improves dislipidemia, *if fully active nrtis Eron JJ, Lancet 2010 Martinez E, AIDS 2010 Improves dislipidemia Gatell JM, 9 th IAS 2017 More frequent AEs Improvement treatment satisfaction questionnaires Improvement in renal biomarkers and BMD Trottier B, Antivir Ther 2017 Llibre JM, Lancet 2018 McComsey, AIDS 2018
Switching to INSTI-based ART in the setting of virologic suppression Current regimen New regimen Effects (in addition to maintaining viral suppression*) EFV + 2nRTIs bpi + 2nRTIs bpi + 2nRTIs bpi + 2nRTIs nnrti + 2nRTIs INSTI + 2nRTIs bpi or nnrti or INSTI + 2nRTIs EFV/TDF/FTC; TDF/FTC/COBI/EVG ATVr + TDF/FTC; bpi + 2nRTIs egfr 30-69 ml/min ATVr + TDF/FTC Women RAL + 2nRTIs (Switch-ER) RAL + 2nRTIs (Switchmrk) (Spiral) DTG + 2nRTIs (Neat 002) DTG/ABC/3TC (Striiving) DTG + RPV (Sword 1&2) EVG/C/F/TAF (Study 112) Single arm Reference Improves dislipidemia & CNS AEs Nguyen A, AIDS 2011 Improves dislipidemia, *if fully active nrtis Eron JJ, Lancet 2010 Martinez E, AIDS 2010 Improves dislipidemia Gatell JM, 9 th IAS 2017 More frequent AEs Improvement treatment satisfaction questionnaires Improvement in renal biomarkers and BMD Improvement in BMD & renal biomarkers Trottier B, Antivir Ther 2017 Llibre JM, Lancet 2018 McComsey, AIDS 2018 Pozniak A, JAIDS 2016 Gupta S, IAS 2015 / Post F, CROI 2016 / McDonald C, ASM 2016 / Stein D, ASM 2016 / Podzamczer D, IAS 2017 EVG/C/F/TAF Improvement in BMD & renal biomarkers Hodder S, CROI 2017 GeSIDA Guidelines January 2018 http://gesida-seimc.org/wp-content/uploads/2018/01/gesida_tar_adultos_v3-1.pdf
Study 1878 Switch to B/F/TAF from bdrv or batv + 2 NRTIs Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4
Study 1878 Switch to B/F/TAF from bdrv or batv + 2 NRTIs Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4
Switch to B/F/TAF from bdrv or batv + 2 NRTIs No treatment-emergent resistance detected in BIC/FTC/TAF arm Lipid parameters significantly improved with switch vs baseline ART P =.002 for TG P =.033 for TC:HDL ratio Median egfr decreased with switch vs continued baseline ART, but stabilized after Wk 4, consistent with known benign inhibition of creatinine tubular secretion by BIC Median change at Wk 48: -4.3 ml/min vs +0.2 ml/min (P <.001) Study 1878 Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4
Switching to E/C/E/TAF + DRV in ART-Experienced Pts Phase 3, open-label, randomized study with HIV+, virologically suppressed adults 2 to 3-class drug resistance and at least 2 prior regimen failures Primary endpoint: proportion of participants with HIV-1 RNA < 50 c/ml at week 24 [FDA snapshot algorithm]. Huhn GD, et al. J Acquir Immune Defic Syndr 2017; 74(2): 193-200
Switching to E/C/E/TAF + DRV in ART-Experienced Pts Huhn GD, et al. J Acquir Immune Defic Syndr 2017; 74(2): 193-200
Salvage therapy
Slide 29 of 39 DAWNING Study Dolutegravir in Second Line Open-label randomized noninferiority phase IIIb study Open label, randomized 1:1 DTG + 2 NRTIs LPV/RTV + 2 NRTIs DTG + 2 NRTIs Continuation phase Key eligibility criteria: on first-line 2 NRTIs + NNRTI regimen for 6 months, failing virologically (HIV-1 RNA 400 c/ml on 2 occasions); no primary viral resistance to PIs or INSTIs Stratification: by HIV-1 RNA ( or >100,000 copies/ml), number of fully active NRTIs in the investigator-selected study background regimen (2 or <2) Primary endpoint: proportion with HIV-1 RNA <50 c/ml at Week 48 using the FDA snapshot algorithm (12% noninferiority margin) Randomisation Week 24 interim analysis FDA, US Food and Drug Administration; INSTI, integrase strand transfer inhibitor. Week 48 primary analysis Week 52 From JJ Eron, Jr, MD at San Antonio, Texas, August 21-23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB. Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA
HIV-1 RNA <50 c/ml, % Snapshot Outcomes at Week 24: ITT-E and PP Populations Slide 30 of 39 Virologic outcomes Treatment differences (95% CI) 100 80 60 82 69 86 72 DTG + 2 NRTIs (ITT-E, n=312) LPV/RTV + 2 NRTIs (ITT-E, n=312) DTG + 2 NRTIs (PP, n=282) LPV/RTV DTG 7.3 13,8 20.3 ITT-E 40 LPV/RTV + 2 NRTIs (PP, n=275) 8.1 14,5 PP 21.0 20-12 -10-8 -6-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 0 Virologic success CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol. From JJ Eron, Jr, MD at San Antonio, Texas, August 21-23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA DTG + 2 NRTIs is superior to LPV/RTV + 2 NRTIs with respect to snapshot in the ITT-E (<50 c/ml) at Week 24, P<0.001 Similar result regardless of BL VL, CD4 or # of active NRTI Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.
SAILING (ING111762) Study Design a At Screening and a second consecutive test >400 c/ml within 4 months prior to Screening (if Screening HIV-1 RNA >1000 c/ml, no additional HIV-1 RNA assessment was needed). PBO, placebo; BR, background regimen comprising at least 1 and no more than 2 active agents. Cahn P, et al. Lancet 2013; 382(9893): 700-8. Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
Baseline Characteristics DTG 50 mg QD (n=354) RAL 400 mg BID (n=361) Age, median (y) 42 43 Gender, female 30% 34% Race, white 50% 49% African American/African heritage 41% 44% HIV-1 RNA, median (log 10 c/ml) 4.17 4.21 >50,000 c/ml 30% 29% CD4+ count, median (cells/mm 3 ) 205 193 <200 cells/mm 3 49% 51% HBV/HCV coinfection 14% 18% Duration prior ART, median (y) 6.7 6.0 3 Class resistance 47% 51% DRV/r in background regimen DRV/r use without primary PI mutations 72 (20%) 77 (21%) No DRV/r use or DRV/r use with primary PI mutations 282 (80%) 284 (79%) Cahn P, et al. Lancet 2013; 382(9893): 700-8. Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
Percentage of subjects (%) Primary Endpoint: HIV-1 RNA <50 c/ml at Week 48 80 60 71 64 95% CI for difference Favors RAL Favors DTG 40 20 20 28 9 9 0.7 7.4 14.2 0 Virologic success Virologic nonresponse No W48 data* DTG 50 mg QD (n=354) RAL 400 mg BID (n=361) -20% -12% 0 20% Cahn P, et al. Lancet 2013; 382(9893): 700-8. Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
VIKING-3: Rationale and Study Design Castagna A, et al. J Infect Dis 2014; 210(3): 354-62
Wk 24 population (N=183) total number recruited. Week 48 population (N=114) subjects who had the opportunity to reach Week 48 at time of data cutoff. VIKING-3: Efficacy Snapshot outcome DTG 50 mg BID Wk 24 (N=183) Wk 48 (N=114) Virologic success 126 (69%) 64 (56%) Virologic non-response 50 (27%) 44 (39%) No virologic data 7 (4%) 6 (5%) D/C due to AE or death 5 (3%) 5 (4%) D/C other reasons 2 (1%) 1 (<1%) Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced with Q148 + 2 resistanceassociated mutations. Castagna A, et al. J Infect Dis 2014; 210(3): 354-62 Mean decrease of 1.4 log 10 HIV-1 RNA c/ml after 7 days of functional monotherapy
Women
EVG/COBI/FTC/TDF vs. ATV/r + FTC/TDF in ART- Naïve Women With HIV-1 Infection (WAVES Study) Key eligibility criteria HIV-1 RNA 500 copies/ml / egfr 70 ml/min / No history of ART / Sensitivity to FTC, TDF, and ATV Primary endpoint: proportion of patients with HIV-1 RNA <50 copies/ml at Week 48 (FDA snapshot analysis) Stratification HIV-1 RNA ( 100,000, >100,000 400,000, or >400,000 copies/ml) Race (black or nonblack) Squires K, et al. Lancet HIV 2016; 3: e410-e420 37
Virologic Outcome at Week 48 Mean CD4 cell increase: 196 cells/mm 3 (EVG/COBI/FTC/TDF and ATV+RTV+FTC/TDF) Squires K, et al. Lancet HIV 2016; 3: e410-e420 38
DTG/ABC/3TC vs ATV/r + TDF/FTC in naïve women with HIV-1 infection (ARIA) Orrell C, et al. The Lancet HIV 2017; 4(12): e536-e46.
Initial regimens for ART-naïve pregnant women DHHS 1 GESIDA 2 N-RTI ABC/3TC TDF/FTC or TDF/3TC ABC/3TC TDF/FTC or TDF/3TC INSTI RAL + 2nRTI RAL + 2nRTI NNRTI NONE NONE PI ATV/r + 2nRTI DRV/r + 2nRTI ATV/r + 2nRTI DRV/r + 2nRTI 1. DHHS ART Guidelines. May 2018. 2. GESIDA March 2018.
Additional safety data
Risks of cardiovascular or CNS AEs and IRIS for DTG vs other antiretrovirals: meta-analysis of RCT Hill AM et al. Curr Opin HIV AIDS 2018; 13: 102-111
Risks of cardiac or CNS AEs and IRIS for DTG vs other antiretrovirals: meta-analysis of RCT No significant effect of DTG on the risk of cardiac, IRIS or suicide-related serious adverse events. Higher risk of insomnia for DTG. Other completed RCT should be included in new evaluations of DTG safety. Continued pharmacovigilance, with regular meta-analyses, should be used to monitor safety. Hill AM et al. Curr Opin HIV AIDS 2018; 13: 102-111
http://prais.paho.org/es/who-products-alert-potential-safety-issue-affecting-women-living-with-hiv-using-dolutegravir-at-the-time-of-conception/
Statement on dolutegravir Geneva 18 May 2018 The investigator of an independent NIH funded study has identified a potential safety issue with DTG, and reported it to WHO and ViiV Healthcare. Neural tube defects (NTD) in infants born to women who were taking DTG at the time of conception. The issue has been identified from a preliminary unscheduled analysis of an ongoing observational study in Botswana 4 cases of NTD in 426 women who became pregnant while taking DTG This rate of approximately 0.9% compares to a 0.1% risk of NTD in infants born to women taking other ART medicines at the time of conception. http://prais.paho.org/es/who-products-alert-potential-safety-issue-affecting-women-living-with-hiv-using-dolutegravir-at-the-time-of-conception/
Information on neural tube defects (NTD) The neural tube is the foundation of the spinal cord, brain and the bone and tissues that surround it. Neural tube defects (NTD) occur when the neural tube fails to completely form; this formation takes place between 0 and 28 days after conception. may be related to folate deficiency, other medications or family history. WHO recommends that women take daily supplements of folic acid before conception and during pregnancy to help prevent NTD. http://prais.paho.org/es/who-products-alert-potential-safety-issue-affecting-women-living-with-hiv-using-dolutegravir-at-the-time-of-conception/
DHHS. Recommendations Regarding the Use of DTG in Women with HIV who are Pregnant or of Child-Bearing Potential ART history Clinical Scenario Recommendations/Comments Not on DTG Pregnant < 8 weeks from LMP Do not initiate a DTG-based regimen Pregnant 8 weeks from LMP DTG can be considered as part of an ARV regimen. Desire pregnancy or Not using effective contraception Do not initiate a DTG-based regimen LMP: last menstrual period Do not desire pregnancy and Using effective contraception DTG can be considered as part of an ARV regimen. Pregnancy testing prior to initiation of DTG. Discuss the potential of DTG to the fetus and the effective use of contraception. https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential
DHHS. Recommendations Regarding the Use of DTG in Women with HIV who are Pregnant or of Child-Bearing Potential ART history Clinical Scenario Recommendations/Comments Currently on DTG Pregnant < 8 weeks from LMP Switch DTG to al alternative option Pregnant 8 weeks from LMP DTG can be continued Desire pregnancy or Not using effective contraception Have effective options other than DTG Switch DTG to al alternative option DTG as part of salvage regimen with no alternative options Continue DTG Do not desire pregnancy and Using effective contraception Continue DTG Discuss the potential of DTG to the fetus and the effective use of contraception LMP: last menstrual period https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential
Conclusions