state of the art: integrase inhibitors clinical...

State of the ART:

Integrase Inhibitors Clinical Data

Juan BerenguerHospital 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 Mg2+ 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 PtsFinal 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)

-20 0-10 10 20

15% (10%, 20%)

7.5% (3.2%, 12%)

7.5% (2.3%, 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors RAL

Favors DRV/r

Lennox JL, et al. Ann Intern Med 2014; 161(7):461-471.

RAL 1200 mg QD* or RAL 400 mg BID with TDF/FTCONCEMRK Study

Cahn P, et al. The Lancet HIV 2017; 4(11):e486-e494* two 600 mg reformulated tablets

Dolutegravir-Based Regimens in Treatment-Naïve PtsHIV RNA <50 Copies/mL (Week 48)

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.

No resistance selected for any dolutegravir-based regimen

-20 -10 0 10 20

DTG + FTC/TDF or ABC/3TC (n=411)

RTG + FTC/TDF or ABC/3TC (n=411)

SPRING-2

Adjusted Treatment Difference (%)

2.5%

Week 48HIV RNA <50

Copies/mL (%)

88

85

Favors Comparator Favors Dolutegravir

DTG + ABC/3TC (n=414)

EFV/FTC/TDF (n=419)

SINGLE7.4%88

81

DTG + FTC/TDF or ABC/3TC (n=242)

DRV/r + FTC/TDF or ABC/3TC (n=242)

FLAMINGO7.1%90

83

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

• 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)

1. Wohl D, et al. JAIDS 2016;72(1):58-642. Sax P, et al. Lancet 2015;385:2606–153. Arribas J, et al. CROI 2017. Seattle, WA. Poster #453

E/C/F/TAF vs. E/C/F/TDF in ART-Naïve Pts (104 and 111)Week 144 Safety Summary

AEs leading to discontinuations were significantly less on E/C/F/TAF compared to E/C/F/TDF at Week 144Arribas J, et al. CROI 2017. Seattle, WA. Poster #453

Bictegravir/FTC/TAF vs Dolutegravir-Containing Regimens for Treatment-Naive Pts

• GS-1489: randomized, double-blind, active-controlled phase III trial[1]

Slide credit: clinicaloptions.com1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082.

Bictegravir/FTC/TAF*

(n = 314)

Dolutegravir/ABC/3TC†

(n = 315)

ART-naive, HLA-B*5701–negative

pts with eGFRCG ≥ 50 mL/min

(N = 629)

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

Wk 48

▪ GS-1490: randomized, double-blind, active-controlled phase III trial[2]

Bictegravir/FTC/TAF*

(n = 320)

Dolutegravir + FTC/TAF‡

(n = 325)

ART-naive pts with

eGFRCG ≥ 30 mL/min

(N = 645)

Wk 48

http://www.clinicaloptions.com/

BIC/FTC/TAF vs DTG-Containing RegimensKey Efficacy Findings

No resistance for any regimen components detected for either group

Slide credit: clinicaloptions.com

No resistance for any regimen components detected for either group

GS-1489: Wk 48 Virologic Efficacy[1] GS-1490: Wk 48 Virologic Efficacy[2]

Pts

(%

)

Pts

(%

)

100

80

60

40

20

0HIV-1 RNA

< 50 c/mL

HIV-1 RNA

≥ 50 c/mL

No Virologic

Data

BIC/FTC/TAF (n = 314)

DTG/ABC/3TC (n = 315)

92 93

1 3 7 4

100

80

60

40

20

0HIV-1 RNA

< 50 c/mL

HIV-1 RNA

≥ 50 c/mL

No Virologic

Data

BIC/FTC/TAF

DTG + FTC/TAF

89 93

4 16

0

99 > 99

1 < 16

0

PP1°

Treatment difference: -0.6%

(95% CI: -4.8% to 3.6%)Treatment difference (1o): -3.5%

(95% CI: -7.9% to 1.0%)

1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082.


BIC/FTC/TAF vs DTG-Containing RegimensKey Safety Findings

• No d/c for renal AEs and no proximal tubulopathy for any regimen

Slide credit: clinicaloptions.com

Outcome Through Wk 48

GS-1489[1] GS-1490[2]

BIC/FTC/TAF(n = 314)

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 eGFRCG ∆ 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

1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082.


Guidelines: Recommended Regimens for First-line ART

Recommendations may differ according to renal function, HLA-B*5701 status, HBsAg status, osteoporosis status, other comorbidities

DHHS1 GESIDA2 EACS3 IAS-USA4

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

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*)

Reference

EFV + 2nRTIsRAL + 2nRTIs(Switch-ER)

Improves dislipidemia & CNS AEs Nguyen A, AIDS 2011

bPI + 2nRTIsRAL + 2nRTIs(Switchmrk)(Spiral)

Improves dislipidemia, *if fully active nRTIsEron JJ, Lancet 2010Martinez E, AIDS 2010



Reference





bPI + 2nRTIsDTG + 2nRTIs(Neat 002)

Improves dislipidemia Gatell JM, 9th IAS 2017

bPI + 2nRTIsnnRTI + 2nRTIsINSTI + 2nRTIs

DTG/ABC/3TC(Striiving)

More frequent AEs Improvement treatment satisfaction questionnaires

Trottier B, Antivir Ther 2017

bPI or nnRTI or INSTI + 2nRTIsDTG + RPV(Sword 1&2)

Improvement in renal biomarkers and BMDLlibre JM, Lancet 2018McComsey, AIDS 2018



Reference





bPI + 2nRTIsDTG + 2nRTIs(Neat 002)

Improves dislipidemia Gatell JM, 9th IAS 2017

bPI + 2nRTIsnnRTI + 2nRTIsINSTI + 2nRTIs

DTG/ABC/3TC(Striiving)

More frequent AEs Improvement treatment satisfaction questionnaires

Trottier B, Antivir Ther 2017

bPI or nnRTI or INSTI + 2nRTIsDTG + RPV(Sword 1&2)

Improvement in renal biomarkers and BMDLlibre JM, Lancet 2018McComsey, AIDS 2018

EFV/TDF/FTC; TDF/FTC/COBI/EVGATVr + TDF/FTC; bPI + 2nRTIseGFR 30-69 mL/min

EVG/C/F/TAF(Study 112)Single arm

Improvement in BMD & renal biomarkersPozniak A, JAIDS 2016Gupta S, IAS 2015 / Post F, CROI 2016 / McDonald C, ASM 2016 / Stein D, ASM 2016 / Podzamczer D, IAS 2017

ATVr + TDF/FTCWomen

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

Switch to B/F/TAF from bDRV or bATV + 2 NRTIsStudy 1878

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

Huhn GD, et al. J Acquir Immune Defic Syndr 2017; 74(2): 193-200

• 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].

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

Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA

Slide 29 of 39

From JJ Eron, Jr, MD at San Antonio, Texas, August 21-23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS−USA.

• 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)

DAWNING Study – Dolutegravir in Second Line

Week 48primaryanalysis

Randomisation

FDA, US Food and Drug Administration; INSTI, integrase strand transfer inhibitor.

Open-label randomized noninferiority phase IIIb study

DTG + 2 NRTIsOpen label,

randomized

1:1LPV/RTV + 2 NRTIs

DTG + 2 NRTIs

Continuation phase

Week 24interim analysis

Week 52

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA

Slide 30 of 39

From JJ Eron, Jr, MD at San Antonio, Texas, August 21-23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS−USA.

• 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

Snapshot Outcomes at Week 24: ITT-E and PP Populations

CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol.

82

69

86

72

0

20

40

60

80

100

Virologicsuccess

HIV

-1 R

NA

<50

c/m

L, %

DTG + 2 NRTIs (ITT-E, n=312)

LPV/RTV + 2 NRTIs (ITT-E,n=312)

DTG + 2 NRTIs (PP, n=282)

LPV/RTV + 2 NRTIs (PP,n=275)

Virologic outcomes Treatment differences (95% CI)

LPV/RTV DTG

13,8

14,5

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24

ITT-E

PP

7.3 20.3

21.08.1

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

Similar result regardless of BL VL, CD4 or # of active NRTI

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

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.


DTG 50 mg QD(n=354)

RAL 400 mg BID(n=361)

Age, median (y) 42 43Gender, female 30% 34%Race, white 50% 49%

African American/African heritage 41% 44%HIV-1 RNA, median (log10 c/mL) 4.17 4.21

>50,000 c/mL 30% 29%CD4+ count, median (cells/mm3) 205 193

<200 cells/mm3 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 regimenDRV/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%)

Baseline Characteristics



Primary Endpoint: HIV-1 RNA <50 c/mL at Week 48

71

20

9

64

28

9

0

20

40

60

80

Virologic success Virologic non-response

No W48 data*

Pe

rce

nta

ge o

f su

bje

cts

(%)

DTG 50 mg QD (n=354) RAL 400 mg BID (n=361)

95% CI for differenceFavors

RALFavors

DTG

-20% 0 20%

7.40.7 14.2

-12%


VIKING-3: Rationale and Study Design

Castagna A, et al. J Infect Dis 2014; 210(3): 354-62

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%)

• 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

Mean decrease of 1.4 log10 HIV-1 RNA c/mL after 7 days of functional monotherapy

• Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response.

• Response was most reduced with Q148 + ≥ 2 resistance-associated mutations.

Castagna A, et al. J Infect Dis 2014; 210(3): 354-62

EVG/COBI/FTC/TDF vs. ATV/r + FTC/TDF in ART-Naïve Women With HIV-1 Infection (WAVES Study)

37

• 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

Virologic Outcome at Week 48

• Mean CD4 cell increase: 196 cells/mm3 (EVG/COBI/FTC/TDF and ATV+RTV+FTC/TDF)

38Squires K, et al. Lancet HIV 2016; 3: e410-e420

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

DHHS1 GESIDA2

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.


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.


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 orNot using effective contraception

• Do not initiate a DTG-based regimen

Do not desire pregnancy andUsing 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

LMP: last menstrual period

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 orNot using effective contraception

Have effective options other than DTG• Switch DTG to al alternative optionDTG as part of salvage regimen with no alternative options• Continue DTG

Do not desire pregnancy andUsing effective contraception

• Continue 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

LMP: last menstrual period

Conclusions

state of the art: integrase inhibitors clinical...

Documents