state of the art: integrase inhibitors (clinical overview)

State of the ART: Integrase Inhibitors (clinical overview)

Mauro Schechter, MD PhDPrincipal Investigator, Projeto Praça Onze

Professor, Infectious DiseasesUniversidade Federal do Rio de Janeiro

Rio de Janeiro, Brasil

Global HIV Clinical Forum 2018Amsterdam

July 21, 2018

Honoraria for ad boards and lectures: Abbvie, Gilead, GSK/ViiV,

Janssen, Merck,

Disclosures

“There is no now. There are only immediate

memories of an extremely recente past”

(Anonymous and numerous)

Disclosures

BENCHMRK: Viral Suppression (NC=F)

and CD4 Cell Count (OF)

BENCHMRK = Blocking Integrase in Treatment Experienced Patients with a Novel Compound against HIV, Merck; F = failure; NC = noncompleter; OBT = optimized background therapy; OF = observed failure; OLRAL = open-label raltegravir; PBO = placebo; RAL = raltegravir.1. Eron JJ et al. Lancet Infect Dis. 2013;13(7):587-96. 2. Steigbigel RT et al. N Engl J Med. 2008;359(4):339-54.

100

Pa

tie

nts

With

HIV

RN

A

<5

0 c

op

ies/m

L, %

Weeks

80

0

20

024 9648

40

60

156 192 240

Double-Blind Open-Label OLRAL

33%

62%

26%

57%

22%

51%

16%

45%

16%

42%

Raltegravir group

Placebo group

100

Pa

tie

nts

With

HIV

RN

A

<4

00

co

pie

s/m

L, %

Weeks

80

0

20

024 9648

40

60

156 192 240


37%

72%

28%

62%

23%

54%

18%

49%

17%

45%41%

78%

250

Ch

an

ge

fro

m B

ase

line

CD

4 C

ell

Co

un

t, c

ells

/mm

3

Weeks

200

0

50

0

24 9648

100

150

156 192 240


45

109

49

125

68

164

56

165

61

183

BIC

RAL EVG

Metal-Chelating Core: Oxygen atoms chelate a pair of Mg2+ ions and bind the integrase catalytic active site

1. Lazerwith SE, et al. ASM 2016. Poster #414. 2. Gallant J, et al. ASM 2016. Poster #415. 3. Tsiang M, et al. ASM 2016. Poster #416. 4.Tsiang M, et al., AAC 2016;60:7086.

Metal-Chelating Core Halogenated Phenyl Ring Side Chain

DTG

Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3’ base of viral DNA

Integrase Inhibitors

GUIDELINES

Nukes Non-nukes Instis PIs

TDF ou

TAF/

FTC/3TC

ABC/

3TC

AZT/

3TCEFV NVP RPV DTG EVG RAL BIC ATV DRV LPV

IAS-USA (2016)6

DHHS (2018)7

EACS (2017)8

WHO (2016)9

*

Brazil (2017)4

Preferential

Alternative

Not recommended, only special situationss

Not available *400 mg

4. BRASIL. Ministério da Saúde. Protocolo Clínico e Diretrizes Terapêuticas para Manejo da Infecção pelo HIV em Adultos. 2017. Disponível em: <http://www.aids.gov.br/system/tdf/pub/2013/64484/pcdt_adulto_270917.pdf?file=1&type=node&id=64484&force=1> . Acesso em: 24 abr. 2018.; 6. GÜNTHARD, HF. JAMA; 316(2):191-210, 2016.; 7. DHHS. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2018. Disponível em: <https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf>. Acesso em: 24 abr 2018.; 8. EACS. Guidelines. Version 9.0. Disponível em: <http://www.eacsociety.org/files/guidelines_9.0-english.pdf>. Acesso em: 24 abr. 2018.; 9. WHO. Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. 2016. Disponível em: <http://apps.who.int/iris/bitstream/handle/10665/208825/9789241549684_eng.pdf?sequence=1> . Acesso em: 24 abr. 2018.;

First Line Therapy (May, 2018)

BIC

RAL EVG




DTG



• Study overview

– International, multicenter, double-blind, double-dummy, randomized (1:1), active-controlled,

noninferiority, phase 3 study

• Endpoints

– The primary endpoint was noninferiority with respect to the percentage of patients with HIV-1

RNA <50 copies/mL at Week 48, with a secondary time point at 96 weeks

– A prespecified exploratory analysis examined results at Weeks 156, 192, and 240

STARTMRK: RAL vs EFV Plus TDF/FTC in Treatment-Naive Adult HIV-1 Patients—Study Design

BID = twice daily; EFV = efavirenz; FTC = emtricitabine; QHS = every night; RAL = raltegravir; TDF = tenofovir.1. Rockstroh JK et al. J Acquir Immune Defic Syndr. 2013;63(1):77–85.

RAL 400 mg BID + TDF/FTC

(n=281)

EFV 600 mgQHS + TDF/FTC

(n=282)

1:1

Screening baseline HIV-1 RNA: >50,000 copies/mL vs ≤50,000 copies/mL Viral hepatitis coinfection status: positive for hepatitis B, hepatitis C, or both vs negative for both

Eligibility criteria:• ≥18 years old

•Treatment naïve

• HIV-1 infected• Viral load >5000

copies/mL• Without genotypic

resistance to EFV, TDF, or FTC

• Patients with stable, chronic hepatitis could be enrolled if serum aminotransferase was ≤5-fold the ULN range

71 Patients (25.2%)

Discontinued6 – Lack of efficacy

14 – Adverse events

210 Patients (74.5%) Completed

Entire 5-Year Study

281 Patients Treated With

RAL-Based Regimen

184 Patients (64.8%) Completed

Entire 5-Year Study

98 Patients (34.5%)

Discontinued10 – Lack of efficacy

28 – Adverse events

282 Patients Treated With

EFV-Based Regimen

563 Enrolled Patients

Randomized 1:1 to RAL/EFV Arms

STARTMRK: Viral Suppression and CD4 Cell Counts at Week 240

BID = twice daily; EFV = efavirenz; F = failure; FTC = emtricitabine; NC = noncompleter; OF = observed failure; QHS = every bedtime; RAL = raltegravir; TDF = tenofovir.1. Lennox JL et al. Lancet. 2009;374(9692):796-806. 2. Lennox JL et al. J Acquir Immune Defic Syndr. 2010;55(1):39-48. 3. Rockstroh JK et al. Clin Infect Dis. 2011;53(8):807-16. 4. DeJesus E et al. HIC ClinTrials. 2012;13(4):228-32. 5. Rockstroh JK et al. J Acquir Immune Defic Syndr. 2013;63(1):77-85.

Viral Suppression (NC=F Analysis)

80

Pa

tien

ts w

ith

HIV

RN

A

Leve

ls <

50

co

pie

s/m

L, %

Weeks

60

40

0 48 144 216

100

20

024 72 19296 120 168 240

Number of Contributing Patients

RAL 400 mg BID

EFV 600 mg QHS

281 280 280 277279 281 281281 279277 281

282 281 281 282282 282 282282 281 282 279

12

278

282

82

86

79

81

61%

71%

67

76

69

75

Exploratory

analysis

Secondary

endpoint

Primary

endpoint

• Difference (95% Cl) = 9.5 (1.7,17.3)

• P<0.001

• Superiority concluded

300

Change fro

m B

aselin

e

CD

4 C

ell

Count, c

ells

/mm

3

Weeks

250

200

0 48 144 216

350

150

100

50

0

24 72 19296 120 168 240

400

12

RALEFV

189

163

240

225

374

312

361

301295

331

• Study overview: Phase 3, prospective, randomized, open label trial• Hypothesis: FTC/TDF QD with ATV/r QD, RAL BID, or DRV/r QD will be

equivalent in terms of virologic efficacy and tolerability over 96 weeks• Co-primary End Points

– Virologic Failure: time to HIV-1 RNA >1,000 c/mL at or after Week 16 to before Week 24, or >200 c/mL at or after Week 24

– Tolerability Failure: time to DTC of randomized component for toxicity • Secondary Endpoint: the earlier occurrence of either virologic failure or

tolerability failure• Substudies:

– Mean change from baseline in fasting lipid profile over time– Percentage bone mineral density change at total hip,

lumbar spine, and total body

ACTG 5257: Ritonavir-Boosted DRV or ATV versus RAL:

Study Design

ART = antiretroviral; ATV/r = atazanavir/ritonavir; BID = twice daily; DRV/r = darunavir/ritonavir ; DTC – discontinuation; FTC = emtricitabine; QD = once daily; RAL = raltegravir; TDF = tenofovir disoproxil fumarate.1. Lennox JL et al. Ann Intern Med. 2014;161(7):461-71. 2. Ofotokun I et al. Clin Infect Dis. 2015;60(12):1842-51. 3. Brown TT et al. J Infect Dis. 2015;212(8):1241-9.

ATV/r 300/100 mg QD + FTC/TDF 200/300 mg QD

(n=605)

RAL 400 mg BID + FTC/TDF 200/300 mg QD

(n=603)

1:1:1

Stratified by screening baseline HIV-1 RNA: ≥100,000 copies/mL vs <100,000 copies/mL with balancing by institution. Stratified by metabolic substudy participation and Framingham 10-yr risk of MI or coronary death (<6% vs ≥6%)

Eligibility criteria:• ≥18 years old• ART naïve• HIV-1 infected• Plasma HIV-1 RNA

>1000 copies/mL DRV/r 800/100 mg QD + FTC/TDF 200/300 mg QD

(n=601)

1814 patients randomized 1:1:1 to

ATV/r:RAL:DRV/r 5 patients excluded 1 acute illness, 1 prior ART, and 3 prior ART

and resistance

1809 patients included in all analyses

605 patients ATV/r5 never started ART

603 patients RAL4 never started ART

601 patients DRV/r4 never started ART

89 patients (14.7%)

discontinued10 death29 lost to follow up

28 unable to travel to clinic

22 nonadherentor other

72 patients (11.9%)

discontinued6 death

23 lost to follow up

35 unable to travel to clinic8 nonadherent

or other

101 patients (16.8%)

discontinued13 death34 lost to follow up

30 unable to travel to clinic

24 nonadherentor other

556 patients (91.9%) completed

96 weeks


96 weeks


96 weeks

ACTG 5257

Primary endpoint analyses at Week 96

Lennox JL et al. Ann Intern Med 2014;161:461–471. .

▪ Significantly greater incidence of

treatment failure with ATV/r vs

RAL or DRV/r

– in part due to a high proportion of

patients with hyperbilirubinemia

Tolerability failure

▪ RAL superior to

either boosted PI

▪ DRV/r superior to

ATV/r

Composite endpoint

Difference in 96-week cumulative incidence (97.5% CI)

0–10 10 20

ATV/r vs RAL3.4% (–0.7 to 7.4)

DRV/r vs RAL5.6% (1.3 to 9.9)

ATV/r vs DRV/r–2.2% (–6.7 to 2.3)

0–10 10 20

ATV/r vs RAL15% (10to 20)

Favours RAL

ATV/r vs DRV/r7.5% (2.3 to 13.0)

Favours DRV/r

DRV/r vs RAL7.5% (3.2 to 12.0)

Favours RAL

0–10 10 20

DRV/r vs RAL3.6% (1.4 to 5.8)

ATV/r vs RAL13% (9.4 to 16.0)

Favours RAL

ATV/r vs DRV/r9.2% (5.5 to 13.0)

Favours DRV/r

VF

▪ Regimens equivalent

in time to VF

▪ Design

▪ Objective– Non inferiority of RAL QD: % HIV RNA < 40 c/mL by ITT, NC=F

(lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power)

RAL 1200 mg ** QD + RAL 400 mg BID placebo

TDF/FTC fdc QD

RAL 400 mg BID + RAL 1200 mg ** QD placebo

TDF/FTC fdc QD

> 18 years

ARV-naïveHIV RNA > 1000 c/mL

*Randomisation was stratified by baseline HIV RNA (< or > 100 000 c/mL) and viral hepatitis co-infection status** Reformulated RAL 600 mg tablet

ONCEMRK Study: raltegravir 1200 mg QD

vs 400 mg BID, with TDF/FTC

Randomisation*2 : 1

Double-blind

N = 266

N = 531

W96W48

Cahn P. AIDS 2016, Durban, Abs. FRAB0103LB

ONCEMRK Study: raltegravir 1200 mg QD

vs 400 mg BID, with TDF/FTC

53.5

78.283.5

87.4 88.7 88.9

51.9

76.382.1

86.5 87.2 88.3

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Week

Difference QD vs BID = 0.5% (- 4.2 ; 5.2)

Patients with baseline HIV RNA > 100 000 c/mL: % HIV RNA < 40 c/mL

(observed failure):

QD = 86.7% vs BID = 83.8% ; difference = 2.9% (- 6.5 ; 14.1)

%

Cahn P. AIDS 2016, Durban, Abs. FRAB0103LB

▪ CD4/mm3 increase at W48 (observed failure): QD = + 232 vs BID = + 234 ; ∆ -2 (- 31 ; 27)

HIV RNA < 40 c/mL (NC = F ; snapshot), % (95% CI)

RAL 1200 mg QD + TDF/FTC

RAL 400 mg BID + TDF/FTC

ONCEMRK: Adverse Events by Race/Ethnicity

• ‡ Determined by the investigator to be related to study drug.• § Study medication withdrawn.• AE = adverse event; BID = twice daily; DR = drug-related; QD = once daily; RAL = raltegravir.• 1. Cahn P et al. Oral presentation at HIV Glasgow 2016. Glasgow, UK. Abstract # 3514101.

% Subjects With

White Black

RAL 1200 mg

QD (N=301)

RAL 400 mg

BID (N=172)

RAL 1200 mg

QD (N=98)

RAL 400 mg

BID (N=36)Any adverse event (AE) 82.7 86.0 90.8 94.4Drug-related‡ (DR) AE 25.9 22.7 27.6 36.1Serious AE 5.0 9.9 11.2 8.3Serious & DR AE 0.3 0.6 0.0 2.8Discontinued§ owing toAE 0.3 1.2 1.0 5.6

% Subjects With

Asian Hispanic/Latino

RAL 1200 mg

QD (N=83)

RAL 400 mg

BID (N=40)

RAL 1200 mg

QD (N=126)

RAL 400 mg

BID (N=52)Any adverse event (AE) 69.9 85.0 88.1 84.6Drug-related‡ (DR) AE 15.7 25.0 30.2 19.2Serious AE 4.8 12.5 1.6 7.7Serious & DR AE 0.0 0.0 0.0 0.0Discontinued§ owing toAE 0.0 2.5 1.6 1.9

BIC

RAL EVG




DTG



The QUAD Pill: Study Design

Treatment- naive

Any CD4 count

Quad QD

EFV/FTC/TDF QHS

Placebo

EFV/FTC/TDF QHS

Quad Placebo QD

n=350

n=350

Week 48 Week 192

• Elvitegravir 150 mg

• Cobicistat 150 mg

• Emtricitabine 200 mg

• Tenofovir disoproxil fumarate 300 mg

88%84%

7% 6% 5%9%

84% 82%

7% 8% 9% 11%

0

20

40

60

80

100

W48 W96 W48 W96 W48 W96

Virologic Success Virologic Failure No data at W48 (or 96)

Per

cen

tag

e o

f su

bje

cts

(%)

QUAD (STBD) EFV/FTC/TDF (ATR)

Quad Vs Efavirenz: 48 and 96 weeks results

Median Change from Baseline in Serum Creatinine

BL 2 4 8 12 16 24 32 40 48

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

-0.05

-0.10

Ch

ange

fro

m B

L in

Ser

um

Cre

atin

ine

(mg

/dL)

(IQ

R)

Week

Two Phase 3, International, randomized, double-blind,

active-controlled studies comparing TDF vs TAF

19

Primary Endpoint HIV-1 RNA <50 copies/mL* at Week 48 by FDA Snapshot analysis (12% Non-inferiority margin of E/C/F/TAF to E/C/F/TDF)†

Secondary EndpointsEfficacy, safety** and tolerability observed through Week 96, Week 144

ClinicalTrials.gov Identifier: NCT01780506 and NCT01797445

Treatment Naïve PatientsStudy 102 and 103

Secondary Endpoints

Tx-Naïve Adults

HIV-1 RNA ≥ 1000 c/mL

eGFR ≥ 50 mL/min

Primary Endpoint

Week 48 Week 96

Stratification by • HIV-1 RNA ≤ />100,000 c/mL• CD4 cell count• Geographic region

1:1

Week 144

E/C/F/TAF QD

E/C/F/TAF Placebo QD

E/C/F/TDF Placebo QD

E/C/F/TDF QD (STB)

N =866

N =867

*Taqman 2.0 assay†Combined efficacy analysis was pre-specified. **SCr, proteinuria, hip and spine BMD were pre-specified week 48 safety endpoints.Study 104 (North America, EU, Asia) and Study 111 (North America, EU, Latin America)

E/C/F/TAF: elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mgSTB: Stribild; elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir DF 300 mg

1. Wohl D, et al. JAIDS 2016 3. Ward, D., HIV and Aging 2016, Poster #33.2. Sax P, et al. Lancet 2015 4. Arribas J, et al. CROI 2017. Seattle, WA. Poster #453

% (n/n) of Participants Difference (95% CI)

E/C/F/TDFn=867

E/C/F/TAFn=866

Age

<50 yrs80

(602/753)83

(647/777)

≥50 yrs*81

(92/114)92

(82/89)

Sex

Male82

(603/740)84

(616/733)

Female*72

(91/127)85

(113/133)

Race

Black71

(152/213)75

(168/223)

Nonblack*83

(542/654)87

(561/643)

Region

US*80

(423/532)84

(447/532)

Non-US81

(271/335)84

(282/334)

Treatment Difference in Virologic Outcomes at Week 144

by Pre-specified Subgroups

20

-1 8 -1 2 -6 0 6 1 2 1 8 2 4-2 4

E/C/F/TAFE/C/F/TDF

* Statistically significant.

Arribas J, et al. CROI 2017. Seattle, WA. Poster #453

Me

dia

n (

IQR

) %

Ch

an

ge

Fro

m B

L

21

* p-values calculated using 2-sided Wilcoxon rank-sum test to compare treatment groupsBL, baseline; β2M, β2 microglobulin; IQR, interquartile range; RBP, retinol binding protein; UPCR, urine protein:Cr ratio.

E/C/F/TDFE/C/F/TAF

23 3454

-32 -32 -26

-100

-50

0

50

100

150

200

250

300

350

0 48 96 144Week

β2M:Cr

BL, µg/g100.6103.1

848 803 722

848 789 681

761

737

5174

111

10 14 35

-100

-50

0

50

100

150

200

250

300

350

0 48 96 144

Week

RBP:Cr

BL, µg/g63.967.1

855 812 769 728

855 800 746 687

20 16 25

-4 -9 -11

-100

-50

0

50

100

150

0 48 96 144

Week

866 819 768 740

866 801 751 699

UPCR

BL, mg/g43.943.8

n=

n=

p <0.001* for all

Renal Parameters through Week 144

Arribas J, et al. CROI 2017. Seattle, WA. Poster #453

• At Week 144, median decrease from baseline in eGFRCG was significantly smaller with E/C/F/TAF vs E/C/F/TDF (-1.6 vs -7.7 mL/min; p<0.001)

• Through Week 144, significantly greater losses in spine and hip BMD in TDF group

• No D/C due to bone AEs in TAF arm vs 6 in TDF arm

• Initiated meds during the study to increase BMD: 16% TAF vs. 21% TDF; p=0.018

Spine

Week

Hip

-0,45-0,76 -0,90 -0,93

-1,56

-3,00-3,57 -3,53

-6

-4

-2

0

2

0 24 48 96 144

E/C/F/TAF: (n=)

E/C/F/TDF: (n=)

795

790

845

850

797

816

744

745

702

686

791

784

836

848

789

815

735

742

690

683

Me

dia

n C

ha

ng

e (

Q1

,Q3

)

E/C/F/TAF E/C/F/TDF

‡

P <0.001

for all

Week

Arribas J, et al. JAIDS 2017. E-pub. DOI: 10.1097/QAI.0000000000001350

P <0.001

for all

*p-value calculated using analysis of variance model including treatment as a fixed effect.

-1,22 -1,20 -0,97 -0,89

-2,72 -2,76 -2,82 -2,87

-6

-4

-2

0

2

0 24 48 96 144

Median Change in Spine and Hip BMD

through Week 144

BIC

RAL EVG




DTG



Spring-2: A double-dummy, multicentre study comparing Dolutegravir to Raltegravir in Treatment Naïve Patients

Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/mL at Week 48 (FDA Snapshot), with a -10% non-inferiority margin

DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs*

(n=411)

RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs*

(n=411)

• Treatment-naïve, HIV-1-infected adults

• HIV-1 RNA ≥1000 c/mL• Stratified by NRTI and

viral load

DTG (50 mg QD) + 2 NRTIs

Screening period Randomised phase Open-label phase

Randomisation (Day 1) Analysis Week 48 Analysis Week 96 Screening Visit (Day -14)

*Investigator’s selection ABC/3TC or TDF/FTCFDA, Food and Drug Administration

TreatmentNumber of responders/

total assessed, n (%)Difference in

proportion (95% CI) (DTG - RAL)Adjusted difference in

proportion (95% CI) (DTG - RAL)

DTG 50 mg QD 332/411 (81) 4.4% (–1.2%, 10.0%) 4.5% (–1.1%, 10.0%)

RAL 400 mg BID 314/411 (76)

Error bars indicate 95% CI Adaptado a partir das referências 3, 4, 6

DTG and RAL were associated with similar increases in CD4+ cell count from baseline over time.

Spring-2: A double-dummy, multicentre study comparing Dolutegravir to Raltegravir in Treatment Naïve Patients

AEs, n (%)DTG 50 mg QD

(n=411)RAL 400 mg BID

(n=411)

WEEK 48

Any event 339 (82) 340 (83)

Nausea 59 (14) 53 (13)

Headache 51 (12) 48 (12)

Nasopharyngitis 46 (11) 48 (12)

Diarrhoea 47 (11) 47 (11)

WEEK 96

Any event 349 (85) 349 (85)

Nausea 60 (15) 56 (14)Nasopharyngitis 55 (13) 58 (14)Diarrhoea 57 (14) 55 (13)Headache 56 (14) 55 (13)

SPRING-2: Adverse Events

Discontinuations due to AEs were 2% for DTG vs 2% for RAL at Week 96

Change in serum CR, Mean (+/- SD)2,3

25

20

15

10

5

0

-5Mea

n ch

ange

from

bas

elin

e

of C

R (μm

ol/L

)

2 4 8 12 16 24 32 40 48

Week

+12.3*

+4.7*

Baseline (µmol/L): DTG: 74.7 versus RAL: 75.2

Adaptado a partir das referências 3, 4, 5, 7, 8

*Mean change in serum CR (mg/dL): DTG, +0.14mg/dL, RAL, +0.05 mg/dL; based on conversion rate 0.011mg/dL = 1 µmol/LCR, creatinine

0.3

0

0.2

0.1

mg/dL

SPRING-2: Effect of Dolutegravir on Creatinine Serum Levels

A small initial increase in creatinine was observed with DTG, due to the blockade of creatininesecretion. There was no further increase in mean serum CR from Week 48 to Week 96 (Week 0 to

96: DTG +14.6 mmol/L; RAL +8.2 mmol/L)5

Creatinine clearance byCockcroft-Gault, mean (SD)

DTG 50 mg QD + NRTIs*

RAL 400 mg BID + NRTIs*

n mL/min n mL/min

Baseline 411 125 (25.8) 411 127.8 (31.2)

Week 24 389 -17.5 (13.4) 384 -6.4 (13.8)

Week 48 369 -16.5 (14.2) 353 -5.4 (13.9)

These changes are not considered to be clinically

relevant as the glomerular filtration rate is unchanged

Unexpectedly High Rate of Intolerance for Dolutegravir in Real Life Setting

• Guido van den Berk, Josephine Oryszczyn, Willem Blok, Narda van der Meche, Rosa Regez, Daoud Ait Moha, Kees Brinkman

• dept internal medicin OLVG, Amsterdam, The Netherlands

abstract

948

background

methods

conclusion

results

- Integrase inhibitors (INSTI)are now preferred antiretrovirals in first line cART.

- Dolutegravir (DTG) is possibly considered as one of the most efficacious, convenient and tolerated INSTI, with hardly any chance for drug-drug interactions.

- Since we encountered many patients who stopped DTG because of intolerance, we analyzed the experience with DGV in our whole patient population since licensing in the Netherlands (aug 2014)

- OLVG cohort: ±3000 patients, (97,4% on cART)

- retrospective analysis of all patients who started DTG, either as initial therapy or after switching from other antiretrovirals for any reason.

- Baseline characteristics at the moment of DTG start were recorded.

- We calculated the proportion of patients who stopped DTG, analyzed the reason for interruption and evaluated potential risk factors.

- Chi-squared test and Z-score to check for significant differences between groups and proportions.

In a real life setting a substantial proportion of patients unexpectedly interrupted DTG treatment for reasons of intolerance, in particular sleeping, gastrointestinal and psychiatric problems.

This was much higher than reported in clinical trials.

DTG treatment was stopped in 62/387 (16,0%) patients. There were no virological failures. Main reason for DGV interruption was intolerance in 56/62 (90,3%) patients: 19/56 (31,3%) sleeping problems, 18/56 (29,5%) gastrointestinal problems, 12/56 (19,7%) psychiatric problems, 8/56(12,9%) headache, 9/56 (14,6%) fatigue and 6/55 (10,9%). Some patients reported more than one toxicity.

Psychiatric reason to stop (n=12) varied from anxiety, depression and agitation to psychosis (n=2)

results

total (N=387) naives(N=65) non-naives (N=322)

median age (IQR) 48 46 (22) 48 (13) ns

female 44 11,4% 8 12,3% 36 11,2% ns

dutch origin 136 35,1% 28 43,1% 108 33,5% ns

median CD4/mm3 (IQR) 650 530 (395) 655 (345) ns

median DTG days (IQR) 220 196 (147) 221 (148) ns

DTG separate.. 156 15 141

DTG in STR.. 231 50 181

DTG stopped 62 16,0% 13 20,0% 49 15,2% ns

median DTG days (IQR) 78 81 (71) 75 (99) ns

female 5 11,4% 3 37,5% 2 5,6% p=0.01

DTG separate 24 15,4% 1 6,7% 23 16,3% ns

DTG in STR 38 16,6% 12 24,0% 26 14,4% ns

reason for interruption

other than toxicity* 6 9,7% 1 7,7% 5 10,2%

toxicity 56 90,3% 12 92,3% 44 89,8% ns

sleeping.. 19 31,3% 5 38,5% 14 28,6% ns

gastro-intestinal.. 18 29,5% 4 30,8% 14 28,6% ns

neuro-psychiatric.. 12 19,7% 3 23,1% 9 18,4% ns

paresthesia.. 6 9,7% 0 0,0% 6 12,2% ns

headache.. 8 12,9% 0 0,0% 8 16,3% ns

fatigue.. 9 14,6% 1 7,7% 8 16,3% ns

allergy.. 1 1,7% 1 7,7% 0 0,0% ns

other.. 5 8,2% 1 7,7% 4 8,2% ns*LTFU, HBV protection, insurance, induction, patient request, interaction

BIC

RAL EVG




DTG



1. White K, et al., European Workshop HIV & Hep 2016. Rome, Italy. Poster O-01. 2. Tsiang M, et al., AAC 2016;60:7086-7097.

92%89%

04%2% 4%6% 2%

0

10

20

30

40

50

60

70

80

90

100

EVG RAL

% o

f Is

ola

tes b

y F

C C

ate

go

rie

s

17%

17%

17%

49%

DTG

2%13%

15%

70%

BIC

Mean fold changes: BIC 2.8 (ref) ; DTG 5.8, p=0.042; RAL >100, p<0.001; EVG >106, p<0.001

Each of 47 patient-derived clinical isolates (from Monogram Biosciences) had ≥ 1 primary and/or other INSTI mutations with phenotypic resistance to INSTIs and comprised all available INSTI resistant variants in the Monogram library).

Stratification of 47 HIV-1 Clinical Isolates Based on Fold Change in Resistance

< 2.5 ≥ 102.5 to < 5 5 to < 10

EC50 Fold Change (FC) vs Reference Wild Type

EC50=effective concentration of half maximal response; FC=fold change; IN=Integrase; T1/2=half-life.

Phenotypic Analysis of Clinical Isolates

ART-naive Adults▪ HIV-1 RNA ≥ 500 c/mL ▪ eGFRCG ≥ 30 mL/min

n=320

n=325

1:1

Week 0

DTG + FTC/TAF Placebo QD

B/F/TAF QD

B/F/TAF Placebo QDDTG + FTC/TAF QD

48 14496

Study 14903,4 *

B/F/TAF Vs DTG in Treatment-Naïve

ART-naive Adults▪ HIV-1 RNA ≥ 500 c/mL ▪ eGFRCG ≥ 50 mL/min▪ HLA B*5701 negative

n=314

n=315

1:1

Week 0

ABC/3TC/DTG Placebo QD

B/F/TAF QD

B/F/TAF Placebo QDABC/3TC/DTG QD

48 14496

Study 14891,2 *

Ran

do

miz

edD

ou

ble

-Blin

dR

and

om

ized

Do

ub

le-B

lind

Gallant J, et al. IAS 2017. Paris, France. Oral #MOAB0105LB; Gallant J, et al. Lancet 2017;390:2063-72; Sax P, et al. IAS 2017. Paris, France. Poster Discussion #TUPDB0201LB; Sax P, et al. Lancet 2017;390:2073-82;

White K, et al . CROI 2018. Boston, MA. Poster 532; Gallant J, et al. Lancet 2017;390:2063-72;. Sax P, et al. Lancet 2017;390:2073-82.

32

B/F/TAF displayed rapid viral suppression (M=E)1

and non-inferior efficacy2,3* vs. DTG-based regimens at Week 48

Par

tici

pan

ts(%

)

* Based on Snapshot analysis

Virologic Efficacy:

HIV-1 RNA <50 copies/mL, Missing=Excluded AnalysisPooled ART-naïve Studies 1489 and 1490

Drug-Related Adverse Events (AEs) through Week 48

Study 14891

All grade

(≥ 2% in either arm)

B/F/TAF

n=314

DTG/ABC/3TC

n=315

Any Drug-related AEs 26%* 40%

Diarrhea 6% 4%

Nausea 5%† 17%

Headache 5% 5%

Fatigue 3% 3%

Abnormal dreams 3% 3%

Dizziness 2% 3%

Insomnia 2% 3%

Study 18442

All grade (≥ 1% in either arm)

B/F/TAFn=282

DTG/ABC/3TCn=281

Any Drug-related AEs 8%** 16%

Headache 3% 3%

Abnormal dreams <1% 2%

Diarrhea <1% 1%

Fatigue <1% 1%

Flatulence 0% 2%

Nausea 0% 2%

Insomnia 0% 1%

B/F/TAF was well tolerated with significantly fewer drug-related AEsthan DTG/ABC/3TC in ART-naïve and suppressed patients,

largely due to GI and CNS AEs

Difference between treatment arms: * p<0.0013, † p<0.0001, and ** p=0.01

White K, et al . CROI 2018. Boston, MA. Poster 532; Gallant J, et al. Lancet 2017;390:2063-72;. Sax P, et al. Lancet 2017;390:2073-82.

RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR

Clinical dose 400 mg BID* OR 1200

mg QD

150 mg QD with cobi and

FTDF or FTAF

50 mg QD

50 mg BID (INI-resistant)

50 mg QD with FTAF

Metabolism UGT1A1 CYP3A (major), UGT1A1/3

(minor)

UGT1A1 (major), CYP3A

(minor)

UGT1A1 and CYP3A

(equal)

DDI Potential Least Highest Slightly greater

than RAL

Slightly greater

than DTG

1. Tivicay SmPC updated October 2015. 2. Min S, et al. Antimicrob Agents Chemother 2010;54:254–8. 3. Min S, et al. AIDS 2011;25:1737–45

4. Isentress SmPC July 2015; 5. Stribild SmPC updated June 2015); 6. Ramanathan S, et al. Clin Pharmacokinet 2011;50:229–44.

Integrase Inhibitors: Clinical

Pharmacology Profile

Legend primarily applies to drug therapy

www.hiv-druginteractions.org

Selected DDI for Boosted Regimens

(PI/r; PI/c; EVG/c)

Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Drug class Comment

Corticosteroids Risk of Cushing syndrome. Avoid PI/r, PI/c, EVG/c. Risk not just oral but inhaled, eye

drops, injection, topical. Triamcinolone, budesonide, fluticasone, mometasone contra-

indicated.

Antidepressants Avoid tricyclics - can cause anticholinergic effects, sedation, orthostatic hypotension.

Benzodiazepines Caution - increased sensitivity in elderly with risk of cognitive impairment, falls etc. AEs

increased by inhibition of CYP metabolism. Use lowest dose for short duration. Midazolam,

triazolam contraindicated.

Chemotherapy drugs Many chemotherapy drugs metabolised by CYP. Increased risk of chemo related

toxicities.

Anticoagulants;

Vit K antagonists

Monitor INR and adjust dose accordingly. Dose adjustment may be required if

switching from ritonavir to cobicistat.

Direct acting

anticoagulant (DOAC)

Significant effect expected (limited data). Effect not routinely measured. Recommended -

avoid with boosted regimens

Calcium channel blockers Increased exposure and potential hypotensive effect. Start with lowest dose and titrate

based on response

Statins Increased exposure of some statins. Simva-, lovastatin contraindicated. Pitavastatin can

be used. Others – start with low dose and titrate.

Integrase Inhibitors and Cation Containing

Medications: Recommendations

Coadministered

Drug

Raltegravir Dolutegravir Elvitegravir/c Bictegravir

Mg/Al containing

antacid

Not

recommended

(NR) bd & qd

Separate well (6h

before/2h after

Separate by

least 4h

Take BIC under

fasting 2h before

Calcium

supplements

No dose

adjustment (bd)

NR - qd

Separate well (6h

before/2h after

Not stated BIC and

supplement can

be taken with

food

Multivitamins Not stated Separate well (6h

before/2h after

Separate by

least 4h

Not stated

Iron supplements Not stated Separate well (6h

before/2h after

Not stated BIC and

supplement can

be taken with

food

Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Bictarvy PI 02/18

Selected DDI for Integrase Inhibitors

(RAL; DTG; EVG/c; BIC)

Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Drug Class Comment

Antacids

Calcium, Mineral

supplements

Integrase inhibitors form complex with divalent cations in the g.i.tract which limits

absorption. Potential risk of treatment failure.

Metformin DTG increases metformin exposure (inhibits OCT2 in kidney).

EVG/c probably increases metformin exposure.

RAL has no effect.

BIC increases metformin exposure - but less than DTG.

Note: No DDIs with most other antidiabetic drugs.

Rifampicin DTG – Rifampicin decreases DTG exposure.

RAL – Rifampicin decreases RAL exposure

EVG/c – Rifampicin decreases EVG exposure

BIC – Rifampicin decreases BIC exposure

Rifabutin DTG and RAL – no clinically significant change in exposure

EVG/c – Rifabutin decreases EVG exposure

BIC – Rifabutin decreases BIC exposure

REFLATE Trial

(Missing = Failure, Study drug discontinuation = Failure)

INSPIRING: Phase IIb, randomized, multicenter, open-label, non-

comparative, active-control parallel-group study

• ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; HR, isoniazid, rifampin; HRZE, isoniazid, rifampin, pyrazinamide, ethambutol; NRTI, nucleoside reverse transcriptase inhibitor; RIF, rifampin; TB, tuberculosis.aDuration of continuation phase of TB treatment according to local guidelines (continuation phase up to 7 months in some countries).ClinTrials.gov NCT02178592

HR (4 months)a

Day 1 52 weeks

End of randomized phase24 weeks

DTG (50 mg QD) + 2 NRTIs

Interim analysis: % <50 c/mL

(Snapshot) Primary endpoint at Week 48: % <50 c/mL

(Snapshot)

DTG (50 mg BID) + 2 NRTIs (n = 69)

EFV (600 mg QD) + 2 NRTIs (n = 44)

TB therapy

HIV/TB coinfected

ART-naive adults

Inclusion criteria

• HIV-1 RNA ≥1000 copies/mL and CD4+ ≥50 cells/mm3

• Pulmonary, pleural, or lymph node tuberculosis with RIF-sensitive MTB confirmed by culture or GeneXpert

• RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date

DTG:EFV 3:2 randomization stratified by

• Screening plasma HIV-1 RNA 100,000 or >100,000

copies/mL

• Screening CD4+ 100 cells/mm3 or >100 cells/mm3

DTG dose switch2 weeks post-completion of TB treatment

Screening

−28 to −14 days

HRZE (2 months)

1. DOOLEY, KE. et al. INSPIRING: Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. In: CROI, 2018. Disponível em: <http://www.natap.org/2018/CROI/croi_07.htm>. Acesso em: 28 mar. 2018.

Adapted from reference 1

Virologic and Immunologic Results in the

ITT-E Population Through Week 24

-20

0

20

40

60

80

100

-4 0 4 8 12 16 20 24 28

Per

cen

tage

, %

Week

Proportion of Participants With HIV-1 RNA <50 copies/mL, % (95% CI)

DTG (n=69)

EFV (n=44)

81 (72, 90)

89 (79, 98)

Modified FDA snapshot analysis (ITT-E) Pre-dose concentration: DTG 50 mg BID with RIF

Time n DTG Conc (ng/mL)Geomean (90%CI) %CV

Wk 8 41 852 (208-2340) 118

Wk 24 22 942 (19-3380) 276

Pre-dose concentration: DTG 50 mg QD without RIF (post-TB treatment phase)

Time n DTG Conc (ng/mL)Geomean (90%CI) %CV

Wk 36 16 1143 (80-4370) 151

Wk 48 12 591 (19-3310) 359

INSPIRING Pharmacokinetic Data

INSPIRING DTG Ctau when administered twice daily with

RIF were similar to DTG 50 mg once daily without RIF and

to previously reported data for DTG 50 mg once daily in

Phase 2/3 HIV trials.

• Median change from Baseline CD4+ cell count (Q1, Q3) at Week 24: DTG, 146 cells/mm3 (71,

214); EFV 93 cells/mm3 (47, 178)



Participants With TB and Non–TB-Associated IRIS

n (%)DTG

(n=69)EFV

(n=44)

Participants with events sent to adjudication committee for TB-associated IRISMet criteria for TB-associated IRISPossibly met criteria for TB-associated IRIS

9 (13)4a (6)

0

12 (27)4b (9)

0

Participants with events sent to adjudication committee for non–TB-associated IRISMet criteria for non-TB-associated IRISPossibly met criteria for non-TB-associated IRIS

2 (3)1c (1)1d (1)

3 (7)00

No participant in either arm permanently discontinued treatment due to IRIS

a1 x Grade 1, 2 x Grade 2 and 1 x Grade 3.b3 x Grade 2 and 1 x Grade 4.cGrade 2 (IRIS and strongyloidiasis; also experienced TB-associated IRIS).dGrade 1 (Herpes zoster).



REALITY: RAL Intensification in First-line ART

• Randomized, open-label phase III trial in Uganda, Kenya, Zimbabwe, and Malawi

– Primary endpoint: 24-wk mortality; endpoints assessed via “blinded” adjudication

Gibb DM, et al. CROI 2018. Abstract O23.

▪ Baseline characteristics well balanced between arms

ART-naive adults,

adolescents, and children

with HIV infection;

≥ 5 yrs with CD4+ count

< 100 cells/mm3

(N = 1805)

Follow-up to Wk 48

RAL intensified:

2 NRTI + NNRTI +

additional RAL

(n = 902)

Standard ART:

2 NRTI + NNRTI

(n = 903)

Standard ART:

2 NRTI + NNRTI

Wk 12 Wk 24

RAL Intensification of First-line ART:

HIV-1 RNA and All-Cause Mortality

• 24-wk mortality rate

– RAL intensified: 10.9%

– Standard ART: 10.2%

– HR: 1.10 (95% CI: 0.82-1.46; P = .53)

• 48-wk mortality rate– RAL intensified: 12.4%

– Standard ART: 13.0%

– HR: 0.98 (95% CI: 0.76-1.28; P = .91)

Gibb DM, et al. CROI 2018. Abstract O23. Reproduced with permission.

RAL Intensified

Standard ART

Overall P < .0001

Wks Since Randomization (ART Initiation)

HIV

-1 R

NA

< 5

0 c

/mL,

% (

95%

CI)

P value: < .0001 < .0001 .36 .47

100

80

60

40

20

0

0 4 12 24 48

80.7%76.7%

71.9%

41.0%

13.4%

51.7%

74.7%79.2%

HIV-1 RNA < 50 copies/mL at Wk 48 (ITT)

RAL Intensification of First-line ART: IRIS-

Compatible Events and Prophylaxis Outcomes

• No impact of additional RAL on

IRIS-compatible eventsGibb DM, et al. CROI 2018. Abstract O23. Slide credit: clinicaloptions.com

IRIS-Compatible

Events,* n (%)

RAL

Intensified

Standard

ART

All fatal events

▪ TB-IRIS

▪ Cryptococcal-IRIS

▪ Other of known

etiology

▪ Unknown etiology

36 (4.0)

20 (2.2)

8 (0.9)

5 (0.6)

3 (0.3)

31 (3.4)

21 (2.3)

5 (0.6)

4 (0.4)

1 (0.1)

All fatal/nonfatal events

▪ TB-IRIS

▪ Cryptococcal-IRIS

▪ Other of known

etiology

▪ Unknown etiology

89 (9.9)

53 (5.9)

15 (1.7)

17 (1.9)

4 (0.4)

86 (9.5)

54 (6.0)

16 (1.8)

14 (1.6)

2 (0.2)

*P > .05 for all comparisons.

Independent Predictor of

Fatal/Nonfatal IRIS Events

sHR

(95% CI)

P

Value

RAL intensified vs standard ART1.08

(0.80-1.45).63

Enhanced vs standard

prophylaxis

0.60

(0.44-0.82).001

CD4+ count (per 10 cells/mm3

higher)

0.87

(0.82-0.93)< .001

Age at last birthday (per yr older) .03

▪ ≤ 29 yrs 1.07

(1.02-1.22).008

▪ ≥ 30 yrs 0.99

(0.97-1.01).44

Current TB disease at ART

initiation

1.62

(1.11-2.37).01

http://www.clinicaloptions.com/

Differences in the DDI Profile of TDF & TAF

TDF TAF Potential Mechanism

Rifabutin NR Induction of P-gp

Rifampicin NR* Induction of P-gp

Rifapentine NR Induction of P-gp

Carbamazepine CA Induction of P-gp

Oxcarbazepine CA Induction of P-gp

Phenobarbitone CA Induction of P-gp

Phenytoin CA Induction of P-gp

St John’s Wort NR Induction of P-gp

Data from: www.hiv-druginteractions.org ; Descovy SmPC Oct 017; Custodio JM, EACS 2017.

NR = Not Recommended

CA = Consider Alternative

*TAF BD + RIF data presented at EACS 2017

http://www.hiv-druginteractions.org/

• INSTIs are widely recommended as the preferred third drug in first line therapy

• All INSTIs are generally well tolerated*

• Occasional reports of insomnia, depression, and suicidal ideation, primarily in

patients with a history of psychiatric illnesses

• Treatment-emergent mutations that confer resistance are very uncommon in

patients receiving INSTIs as part of a three-drug regimen for initial therapy

• In addition to differences in resistance profile, INSTIs differ considerably in

potential drug-drug interactions that can have important clinical implications

• Drug-drug interactions, safety profile, and cost may affect the choice of the

backbone and of INSTI

*Except for DTG in some European cohorts, with up to 16% discontinuation rates due to AEs

Conclusions

• David Back

• Mark Boyd

• Kees Brinkman

• Carlos Brites

• Ricardo Diaz

• Valdez Madruga

• Anton Pozniak

• Jonathan Shapiro

Acknowledgements

OBRIGADO !!!!

state of the art: integrase inhibitors (clinical overview)

Documents