. 2014 Jun 24;3(2):83–102. doi: 10.1007/s40121-014-0029-7

Table 2.

Important clinical trials for dolutegravir

	Study design and funding	Setting and demographics	Results	Conclusion
Phase 1	Dose-finding [15] R, DB, PC Funding: GSK	S: USA D: single dose: 75% Caucasian; 83% male (n = 10; 8 = drug, 2 = placebo) Multiple dose: 85% Caucasian; 90% male	IC: healthy adults R: single dose study: Cohort 1: received 2 mg, 10 mg, 50 mg; Cohort 2: received 5, 25, 100 mg. Multiple dose study: Cohort 1: 10-mg QD; Cohort 2: 25^a mg QD; Cohort 3: 50-mg QD × 10 days Results: daily dose of 50 mg maintained levels 25-fold higher than the IC₉₀; t _1/2 15 h; minimal to no CYP3A4 activity based on midazolam experiment	Daily dose of 50 mg will achieve therapeutic levels
IMPAACT P1093 I/II OL Cohort 1 [38] Cohort 2 [40] Funding: IMPAACT as funded by NIH, NIAID, NICHD, NIMH and ViiV Healthcare	S: USA D: Cohort 1 (12–18 years old): 22% male, x = 15 years old (IQR 12, 16) n = 23 participants Cohort 2 (>6 and <12 years old): 64% male, 36% African American, x = 9.5 years old, n = 11 participants	IC: meeting the cohort age designation; failing ART regimen (HIV-1 RNA >1,000 c/mL) OL: DTG ~1 mg/kg daily was added to the failing regimen for intensive PK evaluation on days 5–10. Then OBR with at least one fully active drug (30% received FTC/TDF/DRV/r) 1°EP: HIV-1 RNA <400 c/mL or >1 log₁₀ decline at 24 weeks; 2°EP HIV-1 RNA <400 c/mL or >1 log₁₀ decline at 48 weeks Results: Cohort 1: baseline HIV-1 RNA was 4.3 log₁₀ c/mL, and 83% ≥40 kg receiving 50 mg daily dose. At 24 weeks, 83% demonstrated virologic suppression <400 c/mL (70% <50 c/mL at 24 weeks); at 48 weeks this fell to 74% remaining virologically suppressed (61% <50 c/mL) due to incomplete adherence. Cohort 2: baseline HIV-1 RNA was 5.0 log₁₀ c/mL. At 24 weeks, virologic suppression was achieved in 82% (64% <50 c/mL); 48 weeks data not available Pending Cohort 3: 2 to <6 years; Cohort 4: 6 months to <2 years; Cohort 5: >6 weeks to <6 months	Weight band of 1 mg/kg appears a safe and efficacious dose among children and adolescents in this clinical study
Phase 2	PK/PD (2a) R, DB, dose-finding [16] Funding: ViiV Healthcare	S: USA D: 80% Caucasian; 100% males; n = 35 participants	IC: ≥18 years old, HIV-infected, INSTI naïve; not receiving ART R: placebo (n = 7), 2 mg (n = 9), 10 mg (n = 9), and 50 mg (n = 10) for 10 days monotherapy; baseline characteristics were similar across all groups Results: significant reduction in HIV-1 RNA in all treatment groups when compared to placebo (P < 0.001); decrease of HIV RNA 1.51–2.46 log₁₀ copies on monotherapy depending on dose received (day 11)	DTG demonstrated potency, tolerability, and predictable PK/PD relationships
SPRING-1 (2b) R, PB (dose-masked) OL 48 weeks [27] 96 weeks [28] Funding: ViiV Healthcare	S: USA and Europe (Spain, France, Germany, Italy, Russia) D: 80% Caucasian; 86% male; x = 37 years old	IC: ≥18 years, naïve to ART, VL >1,000 c/mL; CD4+ >200 c/μL R (1:1:1:1): DTG 10, 25, 50 mg versus EFV 600 mg with investigator-selected NRTI backbone ABC/3TC or TDF/FTC 1°EP: VL <50 c/mL at week 16 2°EP: VL <50 c/mL at 24 and 48 weeks Results: at 16 weeks, rate of viral decay was robust such that 96, 92, and 90% of 50, 25, 10 mg doses respectively with <50 c/mL compared to 60% for those receiving EFV (1°EP); at 48 weeks results were 91, 88, 90%, versus 82% EFV, respectively (2°EP), DTG sustained efficacy and tolerability through week 96: 88% maintained viral response <50 c/mL for the 50 mg DTG arm versus 72% EFV arm. In the EFV arm, 10% withdrew due to adverse events versus 3% in the DTG arm influencing this difference	DTG demonstrated rapid viral decay as compared to EFV 50 mg daily dose was chosen for phase 3 (maximum tolerated; all doses efficacious) No emerging resistance on DTG
VIKING (2b) dosing study OL [22] Funding: ViiV Healthcare	S: France, Italy, Spain, Canada, US D: 84% Caucasian; 84% male, x = 48 years old	IC: ≥18 years. Treatment experienced with RAL, VL >1,000 c/mL, genotypic INSTI resistance, and ≥1 compound with genotypic/phenotypic resistance in ≥2 classes NRTI, NNRTI, or PI classes R: Cohort 1 (n = 27) daily dosing; Cohort 2 (n = 24) twice daily dosing. DTG was substituted for RAL continuing the failing background regimen to day 10. On day 11, an OBR with at least 1 active drug was substituted 1°EP: HIV RNA ≥0.7 log decrease from baseline or <400 c/mL at day 10. 2°EP: change from baseline HIV-1 RNA after day 11 on OBR, proportion of those suppressed (<400 or <50 c/mL), change in CD4+ cell count Results: 96% in cohort 2 versus 78% in cohort 1 reached 1°EP. At week 24 with an OBR, 75% (cohort 2) versus 41% (cohort 1) had VL <50 c/mL at 24 weeks. A higher IC₅₀ fold change was noted in daily dosing, especially when Q148 + 2 additional mutations were present	In treatment-experienced participants, twice-daily DTG was better than daily dosing Mutation combination Q148 + ≥2 additional mutations was most likely to confer DTG resistance
Phase 3 ART naive	SPRING-2 R, DB NI 48 weeks [29] 96 weeks [30] Funding: ViiV Healthcare	S: Canada, USA, Australia, Europe D: 85% Caucasian; 85% male, x = 36 years old	IC: ≥18 years, naïve to ART, VL >1,000 c/mL; CD4+ >200 c/μL R (1:1): RAL BD compared to DTG QD with investigator-selected NRTI backbone ABC/3TC or TDF/FTC 1°EP: VL <50 c/mL at week 48 2°EP: CD4, severity of AE, lab parameters, evidence of resistance. VF defined as confirmed VL >50 c/mL Results: DTG was NI to RAL at 48 weeks regardless of NRTI background regimen (88% versus 85%) and NI was sustained to 96 weeks (81% versus 76%, respectively). None in DTG had genotypic or phenotypic emerging resistance	DTG is NI to RAL The potential advantage of DTG (QD) versus RAL (BD) could not be assessed due to placebo-dosed randomization No emerging resistance on DTG
SINGLE R, DB, NI → Superiority 48 weeks [32] 96 weeks [33] (OL after 96 weeks) Funding: ViiV Healthcare	S: Canada, USA, Australia, Europe D: black (24%); non-white (32%); males (84%); x = 35 years	IC: ≥18 years, naïve to ART, VL >1,000 c/mL, screening for HLA-B*5701, a contraindication to ABC use R: DTG + ABC/3TC versus FTC/TDF/EFV stratified by VL ≤ or >100,000 c/mL and CD4 ≤ or >200 cells/mL 1°EP: VL <50 c/mL at week 48 Results: DTG demonstrated rapid viral suppression at 28 versus 84 days in the EFV arm (P < 0.0001). 1°EP: 88% DTG + ABC/3TC versus 81% FTC/TDF/EFV meeting NI, and also superiority (P = 0.003, ITT) at 48 weeks and persisted to 96 weeks, 80% versus 72%, respectively (P = 0.006; 95% CI 2.3%, 13.8%). When stratified by VL >100,000 this difference was lost	ABC/3TC/DTG is superior to FTC/TDF/EFV DTG statistically significant more rapid virologic decay compared to EFV No primary emerging resistance on DTG
Flamingo [34] R, OL NI → Superiority Funding: ViiV Healthcare	S: well-resourced countries D: non-white (28%); males 85%; x = 34 years; n = 484	IC: ≥18 years, naïve to ART, VL >1,000 c/mL OL: DTG 50 mg QD versus DRV/r 800 mg/100 mg QD with background either TDF/FTC or ABC/3TC. Stratified by VL ≤ or >100,000 c/mL (25% >100,000 c/mL) 1°EP: VL <50 c/mL at week 48 (NI margin −12%) Results: 48-week snapshot analysis showed 90 versus 83% had VL <50 c/mL. This demonstrated not only NI, but also S (P = 0.025; adjusted difference 7.1%; 95% CI 0.9–13.2). When stratified by those with VL >100,000 DTG superior to DRV/r 93% versus 70%, respectively. Fewer AE with DTG contributed to superiority. DTG had lower LDL values (2% versus 7%, P < 0.001) and less diarrhea (17% versus 29%)	DTG is superior to DRV/r in treatment-naïve participants
Phase 3 ART experienced	SAILING [35] R, DB, NI Funding: ViiV Healthcare	S: 1st to include RLS^b Australia, Canada, Europe D: 68% male; 48% from RLS. 68% subtype B; 14% subtype C; 6% complex subtype. x = 43 years n = 715 participants	IC: ART-experienced, INSTI-naïve; VL >400 c/mL × 2 consecutive or >1,000 c/mL at screening; resistance to ≥2 classes of ARV with 1–2 fully active drugs for OBR stratified by VL ≤ or >50,000 c/mL and DRV/r R: DTG 50 mg QD versus 400 mg RAL BD and investigator-selected OBR. 1°EP: HIV-1 RNA <50 c/mL at week 48. 2°EP: proportion of patients with tx-emergent INSTI resistance Results: 71% in DTG and 64% in RAL met 1°EP. Pre-specified statistical criteria revealed NI of DTG to RAL (adjusted treatment difference greater than −12%) and superiority (P = 0.03 mITT-E analysis; 95% CI >0). Results were stratified by DRV/r use in the presence of primary PI mutations or no DRV/r use versus DRV/r use in the absence of primary mutations and by VL ≤ or >50,000 c/mL. Significantly fewer patients receiving DTG had treatment-emergent INSTI resistance 4/354 (1%) versus 17/361 (5%) RAL arm (P = 0.003). One patient in each arm had baseline pre-existing RAL primary resistance (DTG, Q148H/G140S pathway; RAL, Y143 pathway) and associated elevated fold changes. The genotypic resistance developed in 1% in the DTG arm, though this did not translate to de novo phenotypic resistance	DTG both NI and superior to RAL among ART-experienced but INSTI-naïve participants The benefit of daily dosing could not be assessed given the blinded nature of the trial No phenotypic resistance to DTG occurred, although 1% did have INSTI genotypic substitutions
VIKING-3 Single arm, OL Week 24 [23] Week 48 [36] Funding ViiV Healthcare	S: US, Canada, Europe D: 77% male; 71% white; n = 183 participants	IC: >18 years, VF ≥500 c/mL, documented resistance to RAL and/or EVG + ≥2 other classes with 1 active option remaining for OBR OL: DTG 50-mg BD to evaluate a monotherapy phase of DTG in INSTI-resistant patients for 7 days; OBR from day 8 to 24 weeks 1°EP was changed in baseline HIV-1 RNA at 8 days; proportion achieving <50 c/mL at week 24 Results: on day 8, mean change from baseline RNA was −1.43 log₁₀ c/mL (95% CI −1.52, −1.34). Major resistance mutations included 79% with ≥2 NRTI, 70% with ≥2 PI, 75% had ≥1 NNRTI, 62% with CXCR4 virus detected. Because of this variety, OBR changes on day 8 were diverse. At week 24, 69% achieved <50 c/mL; 56% at week 48. Presence of Q148 plus ≥2 additional mutations were associated with reduction of 0.69 log₁₀ c/mL in day 8 response as compared to those with no Q148 mutation at baseline (P < 0.001)	DTG 50-mg BD was potent as functional monotherapy in highly resistant participants Presence of mutation Q148 plus 2 or more additional mutations reduced effectiveness
VIKING 4 [37] NCT01568892 R, DB, PC OL on day 8 Funding: ViiV Healthcare	Not published	IC: ≥18 years; HIV-1 RNA >1,000 c/mL, ART experienced with INSTI resistance; >2 additional class resistance R: DTG 50 mg BID + OBR versus placebo + OBR; day 8 becomes OL: DTG 50 mg BD + OBR versus placebo + OBR 1°EP: mean change from baseline in HIV RNA at day 8; 2°EP: proportion of patients with HIV RNA <400 c/mL, <50 c/mL Results: not yet published nor presented	Different from VIKING 3 in that includes a randomized placebo

Study design and funding

Setting and demographics

Results

Conclusion

Phase 1

Dose-finding [15]

R, DB, PC

Funding: GSK

S: USA

D: single dose: 75% Caucasian; 83% male (n = 10; 8 = drug, 2 = placebo)

Multiple dose: 85% Caucasian; 90% male

IC: healthy adults

R: single dose study: Cohort 1: received 2 mg, 10 mg, 50 mg; Cohort 2: received 5, 25, 100 mg. Multiple dose study: Cohort 1: 10-mg QD; Cohort 2: 25^a mg QD; Cohort 3: 50-mg QD × 10 days

Results: daily dose of 50 mg maintained levels 25-fold higher than the IC₉₀; t _1/2 15 h; minimal to no CYP3A4 activity based on midazolam experiment

Daily dose of 50 mg will achieve therapeutic levels

IMPAACT P1093

I/II

Cohort 1 [38]

Cohort 2 [40]

Funding: IMPAACT as funded by NIH, NIAID, NICHD, NIMH and ViiV Healthcare

S: USA

D: Cohort 1 (12–18 years old): 22% male, x = 15 years old (IQR 12, 16) n = 23 participants

Cohort 2 (>6 and <12 years old): 64% male, 36% African American, x = 9.5 years old, n = 11 participants

IC: meeting the cohort age designation; failing ART regimen (HIV-1 RNA >1,000 c/mL)

OL: DTG ~1 mg/kg daily was added to the failing regimen for intensive PK evaluation on days 5–10. Then OBR with at least one fully active drug (30% received FTC/TDF/DRV/r)

1°EP: HIV-1 RNA <400 c/mL or >1 log₁₀ decline at 24 weeks; 2°EP HIV-1 RNA <400 c/mL or >1 log₁₀ decline at 48 weeks

Results: Cohort 1: baseline HIV-1 RNA was 4.3 log₁₀ c/mL, and 83% ≥40 kg receiving 50 mg daily dose. At 24 weeks, 83% demonstrated virologic suppression <400 c/mL (70% <50 c/mL at 24 weeks); at 48 weeks this fell to 74% remaining virologically suppressed (61% <50 c/mL) due to incomplete adherence. Cohort 2: baseline HIV-1 RNA was 5.0 log₁₀ c/mL. At 24 weeks, virologic suppression was achieved in 82% (64% <50 c/mL); 48 weeks data not available

Pending Cohort 3: 2 to <6 years; Cohort 4: 6 months to <2 years; Cohort 5: >6 weeks to <6 months

Weight band of 1 mg/kg appears a safe and efficacious dose among children and adolescents in this clinical study

Phase 2

PK/PD (2a)

R, DB, dose-finding [16]

Funding: ViiV Healthcare

S: USA

D: 80% Caucasian; 100% males; n = 35 participants

IC: ≥18 years old, HIV-infected, INSTI naïve; not receiving ART

R: placebo (n = 7), 2 mg (n = 9), 10 mg (n = 9), and 50 mg (n = 10) for 10 days monotherapy; baseline characteristics were similar across all groups

Results: significant reduction in HIV-1 RNA in all treatment groups when compared to placebo (P < 0.001); decrease of HIV RNA 1.51–2.46 log₁₀ copies on monotherapy depending on dose received (day 11)

DTG demonstrated potency, tolerability, and predictable PK/PD relationships

SPRING-1 (2b)

R, PB (dose-masked)

48 weeks [27]

96 weeks [28]

Funding: ViiV Healthcare

S: USA and Europe (Spain, France, Germany, Italy, Russia)

D: 80% Caucasian; 86% male; x = 37 years old

IC: ≥18 years, naïve to ART, VL >1,000 c/mL; CD4+ >200 c/μL

R (1:1:1:1): DTG 10, 25, 50 mg versus EFV 600 mg with investigator-selected NRTI backbone ABC/3TC or TDF/FTC

1°EP: VL <50 c/mL at week 16

2°EP: VL <50 c/mL at 24 and 48 weeks

Results: at 16 weeks, rate of viral decay was robust such that 96, 92, and 90% of 50, 25, 10 mg doses respectively with <50 c/mL compared to 60% for those receiving EFV (1°EP); at 48 weeks results were 91, 88, 90%, versus 82% EFV, respectively (2°EP), DTG sustained efficacy and tolerability through week 96: 88% maintained viral response <50 c/mL for the 50 mg DTG arm versus 72% EFV arm. In the EFV arm, 10% withdrew due to adverse events versus 3% in the DTG arm influencing this difference

DTG demonstrated rapid viral decay as compared to EFV

50 mg daily dose was chosen for phase 3 (maximum tolerated; all doses efficacious)

No emerging resistance on DTG

VIKING (2b) dosing study OL [22]

Funding: ViiV Healthcare

S: France, Italy, Spain, Canada, US

D: 84% Caucasian; 84% male, x = 48 years old

IC: ≥18 years. Treatment experienced with RAL, VL >1,000 c/mL, genotypic INSTI resistance, and ≥1 compound with genotypic/phenotypic resistance in ≥2 classes NRTI, NNRTI, or PI classes

R: Cohort 1 (n = 27) daily dosing; Cohort 2 (n = 24) twice daily dosing. DTG was substituted for RAL continuing the failing background regimen to day 10. On day 11, an OBR with at least 1 active drug was substituted

1°EP: HIV RNA ≥0.7 log decrease from baseline or <400 c/mL at day 10. 2°EP: change from baseline HIV-1 RNA after day 11 on OBR, proportion of those suppressed (<400 or <50 c/mL), change in CD4+ cell count

Results: 96% in cohort 2 versus 78% in cohort 1 reached 1°EP. At week 24 with an OBR, 75% (cohort 2) versus 41% (cohort 1) had VL <50 c/mL at 24 weeks. A higher IC₅₀ fold change was noted in daily dosing, especially when Q148 + 2 additional mutations were present

In treatment-experienced participants, twice-daily DTG was better than daily dosing

Mutation combination Q148 + ≥2 additional mutations was most likely to confer DTG resistance

Phase 3 ART naive

SPRING-2

R, DB

48 weeks [29]

96 weeks [30]

Funding: ViiV Healthcare

S: Canada, USA, Australia, Europe

D: 85% Caucasian; 85% male, x = 36 years old

IC: ≥18 years, naïve to ART, VL >1,000 c/mL; CD4+ >200 c/μL

R (1:1): RAL BD compared to DTG QD with investigator-selected NRTI backbone ABC/3TC or TDF/FTC

1°EP: VL <50 c/mL at week 48

2°EP: CD4, severity of AE, lab parameters, evidence of resistance. VF defined as confirmed VL >50 c/mL

Results: DTG was NI to RAL at 48 weeks regardless of NRTI background regimen (88% versus 85%) and NI was sustained to 96 weeks (81% versus 76%, respectively). None in DTG had genotypic or phenotypic emerging resistance

DTG is NI to RAL

The potential advantage of DTG (QD) versus RAL (BD) could not be assessed due to placebo-dosed randomization

No emerging resistance on DTG

SINGLE

R, DB,

NI → Superiority

48 weeks [32]

96 weeks [33] (OL after 96 weeks)

Funding: ViiV Healthcare

S: Canada, USA, Australia, Europe

D: black (24%); non-white (32%); males (84%); x = 35 years

IC: ≥18 years, naïve to ART, VL >1,000 c/mL, screening for HLA-B*5701, a contraindication to ABC use

R: DTG + ABC/3TC versus FTC/TDF/EFV stratified by VL ≤ or >100,000 c/mL and CD4 ≤ or >200 cells/mL

1°EP: VL <50 c/mL at week 48

Results: DTG demonstrated rapid viral suppression at 28 versus 84 days in the EFV arm (P < 0.0001). 1°EP: 88% DTG + ABC/3TC versus 81% FTC/TDF/EFV meeting NI, and also superiority (P = 0.003, ITT) at 48 weeks and persisted to 96 weeks, 80% versus 72%, respectively (P = 0.006; 95% CI 2.3%, 13.8%). When stratified by VL >100,000 this difference was lost

ABC/3TC/DTG is superior to FTC/TDF/EFV

DTG statistically significant more rapid virologic decay compared to EFV

No primary emerging resistance on DTG

Flamingo [34]

R, OL

NI → Superiority

Funding: ViiV Healthcare

S: well-resourced countries

D: non-white (28%); males 85%; x = 34 years; n = 484

IC: ≥18 years, naïve to ART, VL >1,000 c/mL

OL: DTG 50 mg QD versus DRV/r 800 mg/100 mg QD with background either TDF/FTC or ABC/3TC. Stratified by VL ≤ or >100,000 c/mL

(25% >100,000 c/mL)

1°EP: VL <50 c/mL at week 48 (NI margin −12%)

Results: 48-week snapshot analysis showed 90 versus 83% had VL <50 c/mL. This demonstrated not only NI, but also S (P = 0.025; adjusted difference 7.1%; 95% CI 0.9–13.2). When stratified by those with VL >100,000 DTG superior to DRV/r 93% versus 70%, respectively. Fewer AE with DTG contributed to superiority. DTG had lower LDL values (2% versus 7%, P < 0.001) and less diarrhea (17% versus 29%)

DTG is superior to DRV/r in treatment-naïve participants

Phase 3 ART experienced

SAILING [35]

R, DB, NI

Funding: ViiV Healthcare

S: 1st to include RLS^b

Australia, Canada, Europe

D: 68% male; 48% from RLS. 68% subtype B; 14% subtype C; 6% complex subtype. x = 43 years

n = 715 participants

IC: ART-experienced, INSTI-naïve; VL >400 c/mL × 2 consecutive or >1,000 c/mL at screening; resistance to ≥2 classes of ARV with 1–2 fully active drugs for OBR stratified by VL ≤ or >50,000 c/mL and DRV/r

R: DTG 50 mg QD versus 400 mg RAL BD and investigator-selected OBR. 1°EP: HIV-1 RNA <50 c/mL at week 48. 2°EP: proportion of patients with tx-emergent INSTI resistance

Results: 71% in DTG and 64% in RAL met 1°EP. Pre-specified statistical criteria revealed NI of DTG to RAL (adjusted treatment difference greater than −12%) and superiority (P = 0.03 mITT-E analysis; 95% CI >0). Results were stratified by DRV/r use in the presence of primary PI mutations or no DRV/r use versus DRV/r use in the absence of primary mutations and by VL ≤ or >50,000 c/mL. Significantly fewer patients receiving DTG had treatment-emergent INSTI resistance 4/354 (1%) versus 17/361 (5%) RAL arm (P = 0.003). One patient in each arm had baseline pre-existing RAL primary resistance (DTG, Q148H/G140S pathway; RAL, Y143 pathway) and associated elevated fold changes. The genotypic resistance developed in 1% in the DTG arm, though this did not translate to de novo phenotypic resistance

DTG both NI and superior to RAL among ART-experienced but INSTI-naïve participants

The benefit of daily dosing could not be assessed given the blinded nature of the trial

No phenotypic resistance to DTG occurred, although 1% did have INSTI genotypic substitutions

VIKING-3

Single arm, OL

Week 24 [23]

Week 48 [36]

Funding ViiV Healthcare

S: US, Canada, Europe

D: 77% male; 71% white; n = 183 participants

IC: >18 years, VF ≥500 c/mL, documented resistance to RAL and/or EVG + ≥2 other classes with 1 active option remaining for OBR

OL: DTG 50-mg BD to evaluate a monotherapy phase of DTG in INSTI-resistant patients for 7 days; OBR from day 8 to 24 weeks

1°EP was changed in baseline HIV-1 RNA at 8 days; proportion achieving <50 c/mL at week 24

Results: on day 8, mean change from baseline RNA was −1.43 log₁₀ c/mL (95% CI −1.52, −1.34). Major resistance mutations included 79% with ≥2 NRTI, 70% with ≥2 PI, 75% had ≥1 NNRTI, 62% with CXCR4 virus detected. Because of this variety, OBR changes on day 8 were diverse. At week 24, 69% achieved <50 c/mL; 56% at week 48. Presence of Q148 plus ≥2 additional mutations were associated with reduction of 0.69 log₁₀ c/mL in day 8 response as compared to those with no Q148 mutation at baseline (P < 0.001)

DTG 50-mg BD was potent as functional monotherapy in highly resistant participants

Presence of mutation Q148 plus 2 or more additional mutations reduced effectiveness

VIKING 4 [37]

NCT01568892

R, DB, PC

OL on day 8

Funding: ViiV Healthcare

Not published

IC: ≥18 years; HIV-1 RNA >1,000 c/mL, ART experienced with INSTI resistance; >2 additional class resistance

R: DTG 50 mg BID + OBR versus placebo + OBR; day 8 becomes OL: DTG 50 mg BD + OBR versus placebo + OBR

1°EP: mean change from baseline in HIV RNA at day 8; 2°EP: proportion of patients with HIV RNA <400 c/mL, <50 c/mL

Results: not yet published nor presented

Different from VIKING 3 in that includes a randomized placebo

1°EP primary endpoint, 2°EP secondary endpoint, ABC/3TC abacavir/lamivudine, AE adverse events, ART antiretroviral therapy, BD twice daily dose, c/mL copies/mL, CI confidence interval, D demographics, DB double-blind, DRV/r darunavir/ritonavir, DTG dolutegravir, EFV efavirenz, F funding, FTC emtricitabine, GSK GlaxoSmithKline, IC inclusion criteria, IC ₅₀ half-maximal inhibitory concentration, IC ₉₀ ninety percent inhibitor concentration, INSTI integrase strand transfer inhibitors, IQR interquartile range, ITT intention to treat, LDL low-density lipoprotein, mITT-E modified intent-to-treat-exposed, NI non-inferior, NIAID National Institute of Allergy and Infectious Diseases, NICHD National Institute of Child Health and Human Development, NIH National Institutes of Health, NIMH National Institute of Mental Health, NNRTI non-nucleoside reverse transcriptase inhibitors, NRTI nucleoside reverse transcriptase inhibitors, OBR optimized background regimen, OL open label, PB partially blind, PC placebo-controlled, PD pharmacodynamics, PI protease inhibitor, PK pharmacokinetics, QD daily dose, R randomized, RAL raltegravir, RLS resource-limited setting, S setting, t _1/2 half-life, TDF tenofovir, VF virologic failure, VL viral load, x average age

^aThose receiving 25 mg had a sub-study with midazolam to test CYP3A4 activity

^bLatin America, Taiwan, South Africa and USA