DURABLE EFFICACY OF DOLUTEGRAVIR (DTG) PLUS … · 2019. 7. 25. · 10th IAS Conference on HIV...

10th IAS Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico

DURABLE EFFICACY OF DOLUTEGRAVIR (DTG) PLUS LAMIVUDINE (3TC) IN ANTIRETROVIRAL TREATMENT–NAIVE ADULTS WITH HIV-1 INFECTION: 96-WEEK RESULTS FROM THE GEMINI STUDIES

1Fundación Huesped, Buenos Aires, Argentina; 2Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; 3Hospital La Paz, Madrid, Spain; 4Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Rome, Italy; 5Bliss Healthcare Services, Orlando, FL, USA; 6Royal Sussex County Hospital, Brighton, UK; 7Brighton & Sussex Medical School, Brighton, UK; 8National Taiwan University Hospital, Taipei, Taiwan; 9Rheinische Friedrich-Wilhelms Universität, Bonn, Germany; 10Hôpital Saint Antoine, Paris, France; 11ViiV Healthcare, Brentford, UK; 12ViiV Healthcare, Research Triangle Park, NC, USA; 13GlaxoSmithKline, Stockley Park, UK

P Cahn,1 J Sierra Madero,2 J Arribas,3 A Antinori,4 R Ortiz,5 A Clarke,6,7 C-C Hung,8J Rockstroh,9 P-M Girard,10 J Sievers,11 C Man,12 R Urbaityte,13 M Underwood,12

A Tenorio,12 K Pappa,12 B Wynne,12 M Gartland,12 M Aboud,11 J van Wyk,11 KY Smith12


• The requirement for lifelong ART for HIV-1 infection has highlighted interest in 2-drug regimens (2DRs) to minimize cumulative drug exposure1

• In the primary analysis of the GEMINI-1 and GEMINI-2 studies at Week 48, DTG + 3TC was non-inferior to DTG + TDF/FTC in the treatment of HIV-1–infected treatment-naive adults2

• These results led to the approval of DTG/3TCa as a once-daily, single-tablet 2DR by the US Food and Drug Administration and the European Medicines Agency

• We present data from the prespecified Week 96 secondary endpoint analyses of GEMINI-1 and GEMINI-2 evaluating durability after 2 years of therapy with DTG + 3TC

2

INTRODUCTION

Cahn et al. IAS 2019; Mexico City, Mexico. Slides WEAB0404LB.

aDOVATO.

1. Kelly et al. Drugs. 2016;76:523-531. 2. Cahn et al. Lancet. 2019;393:143-155.

10th IAS Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico 3

a−10% non-inferiority margin for individual studies.


GEMINI-1 AND GEMINI-2 PHASE III STUDY DESIGN

Identically designed, randomized, double-blind, parallel-group, multicenter, non-inferiority studies

DTG + 3TC (N=716)

Day 1

Screening (28 days)

DTG + TDF/FTC (N=717)

DTG + 3TC

Week48

Double-blind phase

Open-labelphase

Continuation phase

Week144

Week 24

Week96

• ART-naive adults

1:1

Primary endpoint at Week 48: participants withHIV-1 RNA <50 c/mL (ITT-E Snapshot)a

CountriesArgentina Australia BelgiumCanada France GermanyItaly Republic of Korea Mexico Netherlands Peru PolandPortugal Romania Russian Federation South Africa Spain Switzerland Taiwan United Kingdom United States

Eligibility criteria• VL 1000-500,000 c/mL at screening• ≤10 days of prior ART• No major RT or PI resistance mutation• No HBV infection or need for HCV therapy

Baseline stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL) and CD4+ cell count (≤200 vs >200 cells/mm3).


a2% of participants in each group had baseline HIV-1 RNA >500,000 c/mL and were included in the ITT-E analysis.Cahn et al. Lancet. 2019;393:143-155.


DEMOGRAPHIC AND BASELINE CHARACTERISTICS FOR THE POOLED GEMINI-1 AND GEMINI-2 POPULATION

CharacteristicDTG + 3TC

(N=716)DTG + TDF/FTC

(N=717)Age, median (range), y

≥50 y, n (%)32 (18-72)

65 (9)33 (18-70)

80 (11)Female, n (%) 113 (16) 98 (14)Race, n (%)

African American/African heritageAsianWhiteOther

97 (14)71 (10)

480 (67)68 (9)

76 (11)72 (10)

497 (69)72 (10)

Ethnicity, n (%)Hispanic or LatinoNot Hispanic or Latino

215 (30)501 (70)

232 (32)485 (68)

HIV-1 RNA, median (range), log10 c/mL≤100,000>100,000a

4.43 (1.59-6.27)576 (80)140 (20)

4.46 (2.11-6.37)564 (79)153 (21)

CD4+ cell count, median (range), cells/mm3

>200≤200

427.0 (19-1399)653 (91)63 (9)

438.0 (19-1497)662 (92)

55 (8)


70.2

84.4

93.4 93.389.4 89.5

72.0

87.0

93.2 91.587.2 86.0

0

20

40

60

80

100H

IV-1

RN

A <

50

c/m

L, %

(9

5%

CI)

Study visit

5

aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL),CD4+ cell count (≤200 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). The upper limit of the 95% CI for the pooled analysis was 0.0007%. bIn GEMINI-1, HIV-1 RNA <50 c/mL (95% CI) was achieved in 300/356 participants (84.3% [80.5-88.1]) in the DTG + 3TC group and 320/358 (89.4% [86.2-92.6]) in the DTG + TDF/FTC group (adjusted treatment difference [95% CI], −4.9% [−9.8, 0.03]). In GEMINI-2, the corresponding values were 316/360 (87.8% [84.4-91.2]) and 322/359 (89.7% [86.5-92.8]), respectively (adjusted treatment difference [95% CI], −1.8% [−6.4, 2.7]).


DTG + 3TC IS NON-INFERIOR TO DTG + TDF/FTC IN SNAPSHOT HIV-1 RNA <50 C/ML AT WEEK 96

Snapshot

Treatment Responders, n (%)Adjusted difference, %

(95% CI)a

DTG + 3TC 616/716 (86.0) −3.4 (−6.7, 0.0)

DTG + TDF/FTC 642/717 (89.5)Snapshot

Non-inferiority criteria were met for GEMINI-1, GEMINI-2, and the pooled analysisb

0 4 8 12 16 24 36 48 60 72 84 96


70.2

84.4

93.4 93.389.4 89.5

72.0

87.0

93.2 91.587.2 86.0

0

20

40

60

80

100H

IV-1

RN

A <

50

c/m

L, %

(9

5%

CI)

Study visit

6

aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL), CD4+ cell count (≤200 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). The upper limit of the 95% CI for the pooled analysis was 0.0007%. TRDF (unadjusted difference) was a pre-planned analysis at Week 96.bIn GEMINI-1, HIV-1 RNA <50 c/mL (95% CI) was achieved in 300/356 participants (84.3% [80.5-88.1]) in the DTG + 3TC group and 320/358 (89.4% [86.2-92.6]) in the DTG + TDF/FTC group (adjusted treatment difference [95% CI], −4.9% [−9.8, 0.03]). In GEMINI-2, the corresponding values were 316/360 (87.8% [84.4-91.2]) and 322/359 (89.7% [86.5-92.8]), respectively (adjusted treatment difference [95% CI], −1.8% [−6.4, 2.7]).


DTG + 3TC IS NON-INFERIOR TO DTG + TDF/FTC IN SNAPSHOT HIV-1 RNA <50 C/ML AT WEEK 96

Snapshot

Treatment Responders, n (%)Adjusted difference, %

(95% CI)a

DTG + 3TC 616/716 (86.0) −3.4 (−6.7, 0.0)

DTG + TDF/FTC 642/717 (89.5)

DTG + 3TC 692/716 (96.6) 0.2 (−1.8, 2.2)

DTG + TDF/FTC 691/717 (96.4)

Snapshot

TRDF

• Non-inferiority criteria were met for GEMINI-1, GEMINI-2, and the pooled analysis• Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal, withdrawal due to lack of

efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria

0 4 8 12 16 24 36 48 60 72 84 96


aOne participant met the criteria for CVW at Week 12 but was not reported at the Week 48 analysis because of a laboratory reporting error identified after the Week 48 analysis.


NO TREATMENT-EMERGENT RESISTANCE WAS OBSERVED AMONG PARTICIPANTS WHO MET CONFIRMED VIROLOGIC WITHDRAWAL CRITERIA

GEMINI-1 GEMINI-2 Pooled

Variable, n (%)DTG + 3TC

(N=356)

DTG + TDF/FTC(N=358)

DTG + 3TC(N=360)

DTG + TDF/FTC

(N=359)DTG + 3TC

(N=716)

DTG + TDF/FTC

(N=717)

Week 48 CVW 4 (1.1) 2 (0.6) 2 (0.6) 2 (0.6) 6 (0.8) 4 (0.6)

Week 96 CVW 5 (1.4) 4 (1.1)a 6 (1.7) 3 (0.8) 11 (1.5) 7 (1.0)a

Treatment-emergent resistance

0 0 0 0 0 0


aIn participants with no virologic data at Week 96, none had last HIV-1 RNA value >50 c/mL except for 1 participant in the DTG +TDF/FTC group. bOther reasons for discontinuation at Week 96 included protocol deviation, lost to follow-up, physician decision, withdrawal by participant, and lack of efficacy (in 1 participant in the DTG + TDF/FTC group). Cahn et al. Lancet. 2019;393:143-155.


PROPORTION OF PARTICIPANTS WITH SNAPSHOT HIV-1 RNA ≥50 C/ML SIMILAR FROM WEEK 48 TO WEEK 96 IN BOTH GROUPS

Virologic outcomes Summary of no virologic data at SnapshotWeek 48 Week 96

Snapshot outcome, n (%)

DTG + 3TC(N=716)

DTG + TDF/FTC

(N=717)DTG + 3TC

(N=716)

DTG + TDF/FTC

(N=717)

HIV-1 RNA <50 c/mL 655 (91.5) 669 (93.3) 616 (86.0) 642 (89.5)

HIV-1 RNA ≥50 c/mL 20 (2.8) 13 (1.8) 22 (3.1) 14 (2.0)

No virologic dataa 41 (5.7) 35 (4.9) 78 (10.9) 61 (8.5)

Discontinuation (AE or death)

10 (1) 13 (2) 22 (3) 21 (3)

Discontinuation (other reasons)b

29 (4) 22 (3) 56 (8) 38 (5)

On study but missing data in window

2 (<1) 0 0 2 (<1)

91

3 6

93

2 5

86

311

90

29

0

20

40

60

80

100

HIV-1 RNA <50 c/mL HIV-1 RNA ≥50 c/mL No virologicdata

Pro

po

rtio

n o

f p

atie

nts

, %

Week 48 DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

Week 96 DTG + 3TC (N=716) DTG + TDF/FTC (N=717)


TRDF, treatment-related discontinuation equals failure. aTRDF was a pre-planned analysis at Week 96.


PROPORTION OF PARTICIPANTS WITH HIV-1 RNA <50 C/ML BY BASELINE VIRAL LOAD AND CD4+ CELL COUNT AT WEEK 96: SNAPSHOT AND TRDF ANALYSIS

87 8890 9097 9797 96

84

68

86 8794 9495 96

0

20

40

60

80

100

>100,000≤100,000

Baseline HIV-1

RNA, c/mL

>200 ≤200

Baseline CD4+

cell count, cells/mm3

HIV

-1 R

NA

<5

0 c

/mL

or

with

ou

t T

RD

F, %

560/

576

499/

576

510/

564

117/

140

132/

153

132/

140

146/

153

573/

653

594/

662

633/

653

43/

63

48/

55

59/

63

53/

55

545/

564

638/

662 n/N

Snapshot

DTG + 3TC

DTG + TDF/FTC

TRDFa

DTG + 3TC

DTG + TDF/FTC

• At Week 96, there were 3 confirmed virologic withdrawals in the DTG + 3TC group and 2 in the DTG + TDF/FTC group in the CD4 < 200 stratum


aRelative risk (95% CI) for the DTG + 3TC vs DTG + TDF/FTC group was 0.78 (0.64, 0.95). b3 deaths (acute myocardial infarction, n=1; Burkitt’s lymphoma, n=1; coronary artery disease, n=1), 1 in GEMINI-1 and 2 in GEMINI-2; all were in the DTG + 3TC group and were considered unrelated to the study drug regimen.


OVERALL AE PROFILES WERE SIMILAR; HOWEVER, THERE WAS A LOWER RISK OF DRUG-RELATED AEs IN THE DTG + 3TC GROUP AT WEEK 96

n (%)DTG + 3TC

(N=716)DTG + TDF/FTC

(N=717)Any AE 591 (83) 609 (85)

AEs occurring in ≥10% of participants in either groupNasopharyngitisDiarrheaHeadache

71 (10)89 (12)79 (11)

114 (16)93 (13)87 (12)

Drug-related AEsa

Any Grade 2-5 drug-related AEs Grade 2-5 drug-related AEs occurring in ≥1% of participants

Headache

140 (20)50 (7)

8 (1)

179 (25)57 (8)

8 (1)AEs leading to withdrawal from the study

AEs of interest leading to withdrawal from the studyNeuropsychiatricRenal-relatedOsteoporosis

24 (3)

10 (1)2 (<1)

0

23 (3)

5 (1)7 (1)2 (<1)

Any serious AEb 64 (9) 67 (9)

• Increased weight was reported as an AE in 13 (1.8%) participants treated with DTG + 3TC and in 10 (1.4%) treated with DTG + TDF/FTC• Overall mean change from baseline was 3.1 kg in the DTG + 3TC group and 2.1 kg in the DTG +TDF/FTC group


aEstimated mean change from baseline in each group was calculated from a repeated measures model adjusting for study, treatment, visit, baseline plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, presence of diabetes mellitus, presence of hypertension, baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction. No assumptions were made about the correlations between participant readings of biomarkers (the correlation matrix for within-participant errors was unstructured). bEstimated from geometric means ratio for baseline and Week 96. Based on the same model as plasma/serum markers except adjusting for loge-transformed baseline biomarker (continuous).


CHANGE IN RENAL BIOMARKERS AT WEEK 96 FAVORS DTG + 3TC

DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

12.3

-14.6

10.7

15.4

-18.2

8.8

-20

-16

-12

-8

-4

0

4

8

12

16

Ad

juste

d m

ea

n c

ha

nge

fr

om

ba

se

line

a

-12.2

16.2

-18.7

3.2

50.8

35.0

-30

-20

-10

0

10

20

30

40

50

60

Ch

an

ge

fro

m b

ase

line

, %

b

Plasma/Serum markers Urine markers*P<0.001

**P<0.005

GFR fromcystatin C, CKD-EPI (mL/min/1.73 m2)

GFR fromcreatinine, CKD-EPI

(mL/min/1.73 m2)

Creatinine(µmol/L)

Protein/Creatinine

(g/mol)

Retinol-bindingprotein/

Creatinine(µg/mmol)

Beta-2microglobulin/

Creatinine(mg/mmol)

*

*

**

*

*

*


aEstimated mean change from baseline in each group was calculated from a repeated measures model adjusting for study, treatment, visit, baseline plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, BMI, smoking status, current vitamin D use, baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction. No assumptions were made about the correlations between participant readings of biomarkers (the correlation matrix for within-participant errors was unstructured).


CHANGE IN BONE BIOMARKERS AT WEEK 96 FAVORS DTG + 3TC


0.29 0.27

11.0

0.10

2.364.21

23.7

0.240

5

10

15

20

25

Serum bone-specific alkalinephosphatase

Serumosteocalcin

Serum procollagen 1N-terminal propeptide

Serum type 1 collagenC-telopeptide

Ad

juste

d m

ea

n c

ha

ng

e fro

m

ba

se

line

, µ

g/L

a

*P<0.001

**

*

*


aAdjusted mean change from baseline to Week 96 based on mixed-effect repeat measures model. Absolute values based on summaries. Changes at Week 96 represented by dashed lines. Direction of change from baseline indicated by arrows above bars.


CHANGE IN SERUM LIPIDS AT WEEK 96 FAVORS THE DTG + TDF/FTC GROUP

0

1

2

3

4

5

6

Me

an

va

lue

Total cholesterol(mmol/L)

LDL cholesterol (mmol/L)

HDL cholesterol (mmol/L)

Triglycerides(mmol/L)

0.08a

**

**

**

**

*

Total cholesterol/HDL cholesterol

ratio

**P<0.001

*P<0.05

0.36a

0.19a

0.14a

0.12a

0.16a 0.40a

0.11a

0.16a

0.12a



Durability

• DTG + 3TC maintained non-inferior efficacy over 96 weeks vs DTG + TDF/FTC in ART-naive adults

Barrier to Resistance

• Low rates of confirmed virologic withdrawal through Week 96, and no resistance development in either arm

Safety

• Overall safety and tolerability were comparable between groups

• Lower risk of drug-related AEs with DTG + 3TC

• Change in renal and bone biomarkers significantly favors DTG + 3TC

• Improvements in TC:HDL ratio in both arms

These results confirm DTG + 3TC is a compelling treatment option for PLWH

Viral Load Rebound Including ‘Blips’ Through 48 Weeks are presented in poster MOPEB231

14

CONCLUSIONS



We thank the study participants; their families and caregivers; investigators and site staff who participated in the study; and the ViiV Healthcare, GlaxoSmithKline, Pharmaceutical Product Development, and Parexel study team members

15

ACKNOWLEDGMENTS


ArgentinaCahnCassettiDavidFiguerasFigueroaLossoLopardoLupoPorteiro SánchezAustraliaBloch CooperFinlaysonKelleherKohLewisMcMahonMooreRothShieldsBelgiumDe Wit

Belgium (cont)FlorenceGoffardDemeesterLacorVandercam VandekerckhoveCanadaAngel BarilConwayde PokomandySzaboWalmsleyFrance BouchaudChidiacDelobelGirardGoujard KatlamaMolinaPialouxPhilibert

Germany Bogner Esser KrznaricLehmannRockstrohSpinnerStellbrink StephanStoehrItalyAntinoriBarchiCaramelloCastelliCattelanD’Arminio MontforteDi BiargoDi PerriGoriGulminettiLazzarinMaggioloMenzaghi

Italy (cont)MigliorinoMussiniPencoPuotiQuirinoRizzardiniSighinolfiViale MexicoAmaya TapiaAndrade VillanuevaGranados ReyesSierra-MaderoPerez RiosSantoscoy GomezNetherlandsDen Hollander RijndersPeruHidalgoHercillaIllescas

PolandOlczakPortugalCorreia PachecoMansinhoSaraiva da CunhaSarmento e CastroSerrãoTeófiloRomaniaArbuneJianuOpreaPreotescuPrisacariuRussiaBelonosova BorodkinaChernovaGankinaKizhloKulaginKurinaNagimova

Russia (cont)PokrovskyRiamovaVoronin YakovlevSouth AfricaKaplanSouth KoreaLeeKim S-WKim S-IKim WJSpain Antela LopezArribas LopezCasado OsorioCastabo CarracedoDe Los Santos GilEstrada PerezFalco FerrerForceGalinda PuertoGarcia DeltoroGatell

Spain (cont)Goenaga SanchezGonzalez CordonKnobelLopez Bernaldo de QuirosLosa GarciaMasiaMontero-AlsonsoOcampo HermidaPasquau LiapoPortilla SogorbPulidoRivero RomanSantos FernandezTorres PereaTroya VicianaSwitzerlandCalmyHauserFehr

TaiwanChengHuangHungKoLinLuTsengWangWongWuYangUSAArduinoBensonBerheBredeekBrinsonCampbellCrofootCunninghamDeJesusDretlerEron

USA (cont)FichtenbaumFlammGoldsteinGuptaHaginsHoffman-TerryJayaweeraKinderKleinMcDonaldMillsNahassOrtizOsiyemiOvertonParksPrelutskyRamgopalSchraderShaSimonSimsSkiest

USA (cont)SlimTashimaThedingerUnited KingdomClarkeGazzardFox JohnsonKeggKhooMazhudeOrkinSchembriUstianowski

DURABLE EFFICACY OF DOLUTEGRAVIR (DTG) PLUS … · 2019. 7. 25. · 10th IAS Conference on HIV...

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