Dolutegravir-Lamivudine (Dovato

Dolutegravir-Lamivudine (Dovato)

Prepared by:

Brian R. Wood, MDDavid H. Spach, MD

Last Updated: December 22, 2019


Photograph courtesy of ViiV

INSTI NRTI

50 mg 300 mg

Dose: 1 tablet once daily with or without food

Dovato[doe VAH toe]

Dolutegravir-Lamivudine


• Class

- Dolutegravir: integrase strand transfer inhibitor (INSTI)

- Lamivudine: nucleoside reverse transcriptase inhibitor (NNRTI)

• Indication

- Initial therapy for adults with no antiretroviral treatment history and

with no known or suspected substitutions associated with resistance to

dolutegravir or lamivudine

• Dose

- Fixed dose tablet: Dolutegravir 50 mg and Lamivudine 300 mg

- 1 tablet once daily with or without food

• Adverse Events

- Headache, diarrhea, nausea, insomnia, and fatigue

- Possible neural tube defects with dolutegravir

• Initial 2-Drug Therapy

- GEMINI 1 and 2: DTG + 3TC versus DTG + 2 NRTI’s

- PADDLE: Dolutegravir-lamivudine single arm

- ACTG 5353: Dolutegravir-lamivudine single arm

• Maintenance 2-Drug Therapy

- LAMIDOL: Dolutegravir-lamivudine single arm

- ASPIRE: Dolutegravir-lamivudine vs. continued 3-drug ART

- TANGO*: DTG + 3TC vs. TAF-based 3-drug ART

*Results unpublished


Summary of Key Studies


INITIAL THERAPY

DTG + 3TC versus DTG + TDF-FTC as Initial ART

GEMINI 1 and GEMINI 2: Week 48 Data


GEMINI 1 and 2: Background

Source: Cahn P, et al. Lancet. 2019;393:143-55.

Study Design: GEMINI 1 and 2

• Background:

- Two identical, double-blind, multinational,

noninferiority, randomized controlled trials

that compared initial antiretroviral therapy

(ART) of dolutegravir plus lamivudine (DTG +

3TC) versus dolutegravir plus tenofovir-DF-

emtricitabine (DTG + TDF-FTC)

• Enrollment Criteria:

- Treatment-naïve adults

- HIV RNA 1,000-500,000 copies/mL

- No NRTI, INSTI, or major PI mutations

- No chronic HBV

- No need for HCV therapy

- Not pregnant or breastfeeding

DTG + 3TC

(Dual ART)n = 716

DTG + TDF-FTC

(Triple ART)n = 717

Primary endpoint: % with HIV RNA

<50 copies/mL at 48 weeks by ITT


GEMINI 1 and 2: Baseline Characteristics


• Source: Cahn P et al. Lancet. 2019;393(10167):143-155GEMINI 1 and 2 Baseline Characteristics

CharacteristicDTG + 3TC

(n = 716)

DTG + TDF-FTC(n = 717)

Age, years, median (IQR) 32 (26-40) 33 (26-42)

Female, n (%) 113 (16) 98 (14)

White, n (%) 480 (67) 497 (69)

Black or African American, n (%) 99 (14) 76 (11)

CD4 cell count, mean (SD) 462 (219.2) 461.3 (213.1)

CD4 count ≤200 cells/mm3, n (%) 63 (9) 55 (8)

HIV RNA (log10 copies/mL) 4.42 (0.66) 4.45 (0.65)

≤100,000 copies/mL, n (%) 576 (80) 564(79)

>100,000 copies/mL, n (%) 140 (20) 153 (21)


GEMINI 1 and 2: Results

Week 48 Virologic Response (Intention-to-Treat Analysis)

91 909393 93 94

0

20

40

60

80

100

Pooled Data GEMINI-1 GEMINI-2

HIV

RN

A <

50 c

op

ies

/mL

(%

)

Dolutegravir + Lamivudine Dolutegravir + Tenofovir DF-Emtricitabine

Source: Cahn P, et al. Lancet. 2019;393:143-55

669/717 320/356 332/358 335/360 337/359655/716


GEMINI 1 and 2: Results by Baseline HIV RNA Level


91 91 9293 9490

0

20

40

60

80

100

Pooled Data ≤100,000 >100,000

HIV

RN

A <

50 c

op

ies

/mL

(%

)



669/717 526/576 531/564 129/140 138/153655/716

Baseline HIV RNA copies/mL


GEMINI 1 and 2: Results by Baseline CD4 Cell Count


91 93

79

93 93 93

0

20

40

60

80

100

Pooled Data >200 ≤200

HIV

RN

A <

50 c

op

ies

/mL

(%

)



669/717 605/653 618/662 50/63 51/55655/716

Baseline CD4 Count (cells/mm3)



Week 48 Changes in Renal Function


10.4

-12.1

-0.1

6.3

13.5

-15.5

0

4.1

-20

-15

-10

-5

0

5

10

15

20

Creatinineμmol/L

GFR by creatinine(mL/min/1.73 m2)

Cystatin C(mg/L)

GFR by cystatin CCKD-EPI (mL/min per

1.73 m2)

Ad

juste

d M

ed

ian

Ch

an

ge f

rom

Baseli

ne




Week 48 Changes in Markers of Renal Proximal Tubulopathy


0.870.93 0.92

1.031.11

1.31

0.0

0.5

1.0

1.5

2.0

Protein to creatinine (g/moL) Retinol-binding protein creatinine (μg/mmoL)

β-2 microglobulin creatinine (μg/mmoL)

Rati

o o

f W

eek 4

8 t

o B

aselin

e




Week 48 Changes in Serum Bone Biomarkers


1.220.60 0.40 0.14

4.07

6.17

13.10

0.330.0

2.5

5.0

7.5

10.0

12.5

15.0

Bone-specific alkalinephosphatase

Osteocalcin Procollagen 1 N-terminal propeptide

Type 1 collagen C-telopeptide

Ad

juste

d M

ean

Ch

an

ge f

rom

B

aselin

e (

μg

/L)



GEMINI 1 & 2: Conclusion


Interpretation: “The non-inferior efficacy and similar tolerability profile of

dolutegravir plus lamivudine to a guideline-recommended three-drug

regimen at 48 weeks in ART-naive adults supports its use as initial

therapy for patients with HIV-1 infection.”


GEMINI 1 and GEMINI 2: Week 96 Data


GEMINI 1 and 2: Results by Baseline HIV RNA Level


86 87 8490 90

86

0

20

40

60

80

100

Pooled Data ≤100,000 >100,000

HIV

RN

A <

50 c

op

ies

/mL

(%

)


Source: Cahn P, et al. J Acquir Immune Defic Syndrome. 2019 Dec 10. Epub ahead of print

499/576 510/564 117/140 132/153

Baseline HIV RNA copies/mL

642/717616/716


GEMINI 1 and 2: Results by Baseline CD4 Cell Count


86 88

68

90 90 87

0

20

40

60

80

100

Pooled Data >200 ≤200

HIV

RN

A <

50 c

op

ies

/mL

(%

)



642/717 573/653 594/662 43/63 48/55616/716

Baseline CD4 Count (cells/mm3)



Week 96 Changes in Renal Function


12.3

-14.6

10.7

15.4

-18.2

8.8

-25

-20

-15

-10

-5

0

5

10

15

20

25

Creatinine(μmol/L)

GFR from creatinine, CKD-EPI(mL/min/1.73 m2)

GFR from cystatin CCKD-EPI (mL/min per 1.73 m2)

Ad

juste

d M

ed

ian

Ch

an

ge f

rom

Baseli

ne




Week 96 Changes in Serum Bone Biomarkers


0.29 0.27

11.00

0.10

2.364.21

23.70

0.240

5

10

15

20

25

30

Bone-specific alkalinephosphatase

Osteocalcin Procollagen 1 N-terminal propeptide

Type 1 collagen C-telopeptide

Ad

juste

d M

ean

Ch

an

ge f

rom

B

aselin

e (

μg

/L)



GEMINI 1 and 2: Week 96 Conclusion


Conclusion: “Consistent with 48-week data, dolutegravir + lamivudine

demonstrated long-term, non-inferior efficacy vs dolutegravir + tenofovir

disoproxil fumarate/emtricitabine without increased risk of treatment

emergent resistance, supporting its use in treatment-naive HIV-1–

infected individuals.”

Dolutegravir + Lamivudine as Initial Dual Therapy

PADDLE

Dolutegravir plus Lamivudine as Initial Dual Therapy

PADDLE: Design

Source: Cahn P, et al. J Int AIDS Soc. 2017;20:1-7.

Study Design: PADDLE

• Background: Pilot, phase 4, single-arm,

open-label trial conducted in Argentina to

evaluate the efficacy and tolerance of once

daily dolutegravir plus lamivudine as initial

dual therapy

• Inclusion Criteria (n = 20)

- Age ≥18 years

- Antiretroviral therapy naive

- Nadir CD4 count >200 cells/mm3

- HIV RNA >5,000 and ≤100,000 copies/mL

- Wild-type baseline genotype

- No HBV co-infection

• Regimen (Once daily)

- Dolutegravir 50 mg + Lamivudine 300 mg

Dolutegravir

+ Lamivudine(n = 10)

*Cohort 1 *Cohort 2

Cohort 2 patients enrolled following confirmation

that 8/10 patients had >1 log decrease in HIV

RNA at week 8

Dolutegravir


4 patients enrolled with HIV RNA >100,000 copies/mL


PADDLE: Baseline Characteristics


Demographic and

Baseline CharacteristicsDolutegravir + Lamivudine

(n = 20)

Age (years), median 34 years

Male 19 (95%)

Mode of Transmission

MSM

Heterosexual

15 (75%)

5 (25%)

HIV RNA (copies/mL), median 24,128

CD4 count (cells/mm3), median 507


PADDLE: Results

Week 48 Virologic Response (by FDA Snapshot Analysis)


90

0

20

40

60

80

100

HIV

RN

A <

50 c

op

ies

/mL

(%

)

*Other 2 participants:

- 1 committed suicide during study

- 1 developed virologic failure with HIV RNA = 99 copies/mL at week 36 and 246 copies/mL at week 39;

patient had HIV RNA <50 copies/mL at week 48 (baseline HIV RNA = 106,320 copies/mL)

18/20*


PADDLE: Conclusion


Conclusion: “This novel dual regimen of dolutegravir and lamivudine

warrants further clinical research and consideration as a potential

therapeutic option for ARV-therapy-naive patients.”

DTG + 3TC for Initial ART

ACTG 5353

Dolutegravir plus Lamivudine for Initial ART

ACTG 5353: Background

Source: Nyaku AN, et al. J Antimicrob Chemother. 2019;74:1376-80.

Study Design: ACTG 5353

• Background:

- Phase II, single-arm, pilot study to

assess virologic efficacy of

dolutegravir plus lamivudine as initial

2-drug antiretroviral therapy


- Antiretroviral-naïve adults

- HIV RNA ≥1,000 copies/mL and

<500,000 copies/mL

- No evidence of NRTI, integrase, or

major PI resistance mutations

- No chronic HBV infection

Dolutegravir + Lamivudine(n = 120)

24 weeks

n = 83 with HIV RNA ≤100,000 copies/mL

n = 37 with HIV RNA >100,000 copies/mL


ACTG 5353: Baseline Characteristics


ACTG 5353: Baseline Characteristics

CharacteristicOverall Study Population

(n =120)

Age, years, median (IQR) 30 (24-41)

Male, % 87

Black or African American, % 40

Latino, % 27

CD4 count, cells/mm3, median (IQR) 387 (288-596)

HIV RNA, log10 copies/mL, median (IQR) 4.61 (3.94-5.05)


ACTG 5353: Results



85 88

78

0

20

40

60

80

100

All ≤100,000 copies/mL >100,000 copies/mL

HIV

RN

A <

50 c

op

ies

/mL

(%

)

Baseline HIV RNA

1 participant with virologic failure by week 24 had M184V and R263R/K detected

No virologic failure with resistance occurred between week 24 and week 48


ACTG 5353: Results


ACTG 5353 Virologic Results

ResultTotal

(n=120)

Baseline HIV

RNA ≤100,000

(n=83)

Baseline HIV

RNA >100,000

(n=37)

Virologic success,

HIV RNA <50 copies/mL, n (%)102 (85) 73 (88) 29 (78)

Virologic non-success, n (%) 6 (5) 3 (4) 3 (8)

HIV RNA >50 copies/mL 2 1 1

Stopped for lack of efficacy

while HIV RNA >50 copies/mL1 0 1

Stopped for other reasons, HIV

RNA >50 copies/mL 3 2 1

No data in window, n (%) 12 (10) 7 (8) 5 (14)

On study but missing data in

window3 0 3

Stopped for other reasons

(LTFU, pregnancy)9 7 2


ACTG 5353: Conclusion


Conclusion: “These results add to the evidence that

dolutegravir plus lamivudine is a safe and effective option for

initial ART in individuals with HIV-1 RNA <500,000

copies/mL.”


SWITCH STUDIES

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ART

TANGO


TANGO: Background

Source: van Wyk J, et al. Clin Infect Dis. 2020. Jan 6. [Epub ahead of print]

Study Design: TANGO

• Background:

- Ongoing, phase 3, randomized, open

label, multicenter, non-inferiority trial

comparing switching to 2-drug DTG-3TC

versus remaining on 3- or 4-drug TAF-

based regimen


- Age ≥18 years

- HIV RNA <50 copies/mL for >6 months

- Taking 3- or 4-drug TAF-based ART

- TDF to TAF switch allowed if ≥3 months

before screening

- No HBV or need for HCV treatment

- No prior virologic failure

- No prior NRTI or INSTI resistance

Switch Regimen


(2 Active Drugs)n = 369

Maintain Regimen

TAF-Based Regimen

(3 Active Drugs)n = 372

Primary endpoint: virologic response

at 48 weeks by FDA snapshot


TANGO: Baseline Characteristics


• Source: Cahn P et al. Lancet. 2019;393(10167):143-155CharacteristicDTG/3TC(n = 369)

TAF-Based ART(n = 372)

Age, years, median (range) 40 (20-74) 39 (18-73)

Female, n (%) 25 (7) 33 (9)

White, n (%) 297 (81) 289 (78)

African American/African, n (%) 50 (14) 58 (16)

CD4 cell count <500, n (%) 98 (27) 74 (20)

CD4 cell count ≥500, n (%) 271 (73) 298 (80)

Months on ART, median (range) 33.8 (7.1-201.2) 35.1 (7.0-160.8)

Baseline third agent class

INSTI 289 (78) 296 (80)

NNRTI 51 (14) 48 (13)

PI 29 (8) 28 (8)


TANGO: Results



93 93

0

20

40

60

80

100

HIV

RN

A <

50 c

op

ies

/mL

(%

)

Dolutegravir-Lamivudine TAF-Based ART

• Confirmed withdrawal for virologic failure: 0 in DTG/3TC arm, 1 in TAF-based ART arm

• No new resistance mutations occurred

• 4 with baseline M184V/I in DTG/3TC arm (by proviral genotype) suppressed at week 48


TANGO: Results

Week 48 Changes in Renal Function (Plasma/Serum Markers)


6.7

-7.7

0.12.2

-3.0-1.6

-15

-10

-5

0

5

10

15

Creatinine* GFR by creatinine* GFR by cystatin C

Ad

jus

ted

mea

n c

han

ge

fro

m

ba

se

lin

e


*Statistically significant difference


TANGO: Results

Week 48 Changes in Markers of Proximal Tubulopathy (Urine Tests)


-2.9

6.3

-2.7

1.6

6.7

-7.8-10.0

-7.5

-5.0

-2.5

0.0

2.5

5.0

7.5

10.0

Protein toCreatinine (g/mol)

Retinol-binding protein toCreatinine (ug/mmol)

Beta-2 microglobulin tocreatinine (mg/mmol)

Ch

an

ge f

rom

baselin

e,

%



TANGO: Conclusions


Conclusion: “The 2-drug regimen dolutegravir-lamivudine was non-

inferior in maintaining virologic suppression vs a tenofovir alafenamide-

based regimen at Week 48, with no virologic failure or emergent

resistance reported in the dolutegravir-lamivudinegroup, supporting its

use as a simplification strategy for virologically suppressed people living

with HIV-1.”

Dolutegravir + Lamivudine as Maintenance Dual Therapy

LAMIDOL

Dolutegravir plus Lamivudine as Maintenance Dual Therapy

LAMIDOL: Design

Source: Joly V, et al. J Antimicrob Chemother. 2019;74:739-45.

Study Design: LAMIDOL

• Background: Non-comparative, open-label,

single-arm, multicenter trial to evaluate the

efficacy and tolerance of once daily

dolutegravir plus lamivudine as

maintenance dual therapy

• Inclusion Criteria:

- Age ≥18 years

- Nadir CD4 count >200 cells/mm3

- HIV RNA <50 copies/mL for ≥2 years

- Wild-type baseline genotype

- First-line 3-drug ART:

2 NRTI’s + NNRTI, boosted PI, or INSTI

- Prior modifications for intolerance or

simplification allowed

- No HBV co-infection

• Regimen (Once daily)

- Dolutegravir 50 mg + Lamivudine 300 mg

Dolutegravir


*Phase 1: third agent switched to dolutegravir

*Phase 1 **Phase 2

8 weeks

**Phase 2: 2NRTIs switched to lamivudine

Dolutegravir

+ 2 NRTI’s(n = 110)

40 weeks


LAMIDOL: Baseline Characteristics


Participants who Entered Phase 2Dolutegravir-Lamivudine

n = 104

Age (median) 45 years

Male 89 (85.6%)

MSM 73 (70.2%)

Duration since HIV diagnosis (median) 6.3 years

Time on current ART (median) 4.0 years

Nadir CD4 count (median) 399 cells/mm3

Current CD4 count (median) 743 cells/mm3

Baseline NNRTI 58 (55.8%)

Baseline PI 24 (23.1%)

Baseline INSTI 22 (21.2%)


LAMIDOL: Results

Week 48 Virologic Response (by FDA Snapshot Analysis)


97

0

20

40

60

80

100

HIV

RN

A <

50 c

op

ies

/mL

(%

)

*Other 3 participants:

- 1 with low-level viremia (resuppressed with 3-drug antiretroviral therapy),

- 1 treatment modification decided by investigator, and

- 1 lost to follow-up

101/104*


LAMIDOL: Conclusion


Conclusion: “Dolutegravir plus lamivudine is a promising maintenance

therapy in HIV-1-infected patients with controlled virological

suppression.”

DTG + 3TC Maintenance ART vs. Continued 3-Drug ART

ASPIRE

DTG + 3TC Maintenance ART vs Continued 3-Drug ART

ASPIRE: Background

Source: Taiwo B, et al. Clin Infect Dis. 2018;66:1794-7.

Study Design: ASPIRE

• Background:

- Open-label, multicenter, pilot randomized

trial that enrolled persons with suppressed

HIV RNA levels and compared switch to 2-

drug regimen versus continuing standard 3-

drug antiretroviral therapy

• Inclusion Criteria:

- Adults living with HIV

- HIV RNA <50 copies/mL ≥2x over 48 weeks

- Screening HIV RNA <20 copies/mL

- Taking any 3-drug ART regimen

- No history of virologic failure

- No known NRTI or INSTI mutations

- No chronic HBV

- CrCl ≥50 mL/min

Dolutegravir + Lamivudine(n = 44)

Continue 3-drug ART(n = 45)


ASPIRE: Baseline Characteristics


ASPIRE: Baseline Characteristics

CharacteristicOverall Study Population

(n = 89)

Age, years, median (IQR) 47 (38-54)

Male, % 88

White, % 60

Black or African American, % 38

Hispanic ethnicity, % 15

CD4 count, cells/mm3, median (IQR) 680 (498-927)

Time on ART, years, median (IQR) 5.7 (3.7-7.5)

Pre-randomization INSTI, % 37

Pre-randomization PI, % 33

Pre-randomization NNRTI, % 30

93 9191 89

0

20

40

60

80

100

24 weeks 48 weeks

HIV

RN

A <

50 c

op

ies

/mL

(%

)

Dolutegravir + Lamivudine 3-Drug Antiretroviral Therapy


ASPIRE: Results

Week 24 & 48 Virologic Responses (Intention-to-Treat Analysis)


One virologic failure occurred in the dolutegravir + lamivudine arm; no resistance mutations detected

41/44 41/45 40/44 40/45


ASPIRE: Conclusion


Conclusion: “In this randomized pilot clinical trial, dolutegravir plus lamivudine

was noninferior to continuation of standard 3-drug maintenance antiretroviral

therapy. There was no emergence of drug resistance in the participant who

experienced virologic failure while receiving dolutegravir plus lamivudine.”

Acknowledgment

The National HIV Curriculum is an AIDS Education and Training Center

(AETC) Program supported by the Health Resources and Services

Administration (HRSA) of the U.S. Department of Health and Human

Services (HHS) as part of an award totaling $800,000 with 0% financed

with non-governmental sources. This project is led by the University of

Washington’s Infectious Diseases Education and Assessment (IDEA)

Program.

The content in this presentation are those of the author(s) and do not necessarily represent

the official views of, nor an endorsement, by HRSA, HHS, or the U.S. Government.

Documents

Dolutegravir-Lamivudine (Dovato