12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

12.2 Pharmacodynamics

Effects on Electrocardiogram

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

12.3 Pharmacokinetics

The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 9) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials.

Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults
a Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2. b Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3.
Parameter	50 mg Once Daily Geometric Meana (%CV)	50 mg Twice Daily Geometric Meanb (%CV)
AUC(0-24) (mcg∙h/mL)	53.6 (27)	75.1 (35)
Cmax (mcg/mL)	3.67 (20)	4.15 (29)
Cmin (mcg/mL)	1.11 (46)	2.12 (47)

TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the 2 dosage forms are not substitutable on a milligram-per-milligram basis [see Dosage and Administration (2.3)].

Absorption

Following oral administration of dolutegravir, peak plasma concentrations were observed 1 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5.

Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.

Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following a 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.

Distribution

Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.

Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng/mL (range: 3.74 ng/mL to 18.3 ng/mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.

Elimination

Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses.

Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A.

Polymorphisms in Drug‑Metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41).

Excretion: After a single oral dose of [14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).

Specific Populations

Pediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10 [see Clinical Studies (14.3)].

Mean dolutegravir AUC0-24h and C24h in HIV-1–infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean Cmax is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations (8.4)].

Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEYa Trials)
a Data from 2 weight-band-based pharmacokinetic substudies in the ODYSSEY trial. b The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets.
Weight Band	Doseb of TIVICAY or TIVICAY PD	n	Pharmacokinetic Parameter Geometric Mean (%CV)
Weight Band	Doseb of TIVICAY or TIVICAY PD	n	Cmax (mcg/mL)	AUC0-24h (mcg∙h/mL)	C24h (ng/mL)
3 kg to <6 kg	TIVICAY PD 5 mg once daily	8	3.80 (34)	49.37 (49)	962 (98)
6 kg to <10 kg	TIVICAY PD 15 mg once daily	17	5.27 (50)	57.17 (76)	706 (177)
10 kg to <14 kg	TIVICAY PD 20 mg once daily	13	5.99 (33)	68.75 (48)	977 (100)
14 kg to <20 kg	TIVICAY PD 25 mg once daily	19	5.97 (42)	58.97 (44)	725 (75)
20 kg to <25 kg	TIVICAY PD 30 mg once daily	9	7.16 (26)	71.53 (26)	759 (73)
≥20 kg	TIVICAY 50 mg once daily	49	4.92 (40)	54.98 (43)	778 (62)

Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.

Patients with Hepatic Impairment: In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

Patients with Renal Impairment: In a trial evaluating the pharmacokinetics of a single 50-mg tablet of dolutegravir comparing 8 subjects with severe renal impairment (CrCl less than 30 mL/min) with 8 matched healthy controls, AUC, Cmax, and C24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection.

Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir.

Drug Interaction Studies

Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12.

Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 8 [see Dosage and Administration (2.2), Drug Interactions (7.3)].

Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs
a The number of subjects represents the maximum number of subjects that were evaluated.
Coadministered Drug(s) and Dose(s)	Dose of TIVICAY	n	Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of TIVICAY	n	Cmax	AUC	Cτ or C24
Elbasvir 50 mg once daily	50 mg single dose	12	0.97 (0.89, 1.05)	0.98 (0.93, 1.04)	0.98 (0.93, 1.03)
Ethinyl estradiol 0.035 mg	50 mg twice daily	15	0.99 (0.91 to 1.08)	1.03 (0.96 to 1.11)	1.02 (0.93 to 1.11)
Grazoprevir 200 mg once daily	50 mg single dose	12	0.64 (0.44, 0.93)	0.81 (0.67, 0.97)	0.86 (0.79, 0.93)
Metformin 500 mg twice daily	50 mg once daily	15a	1.66 (1.53 to 1.81)	1.79 (1.65 to 1.93)	_
Metformin 500 mg twice daily	50 mg twice daily	15a	2.11 (1.91 to 2.33)	2.45 (2.25 to 2.66)	_
Methadone 16 to 150 mg	50 mg twice daily	11	1.00 (0.94 to 1.06)	0.98 (0.91 to 1.06)	0.99 (0.91 to 1.07)
Midazolam 3 mg	25 mg once daily	10	_	0.95 (0.79 to 1.15)	_
Norelgestromin 0.25 mg	50 mg twice daily	15	0.89 (0.82 to 0.97)	0.98 (0.91 to 1.04)	0.93 (0.85 to 1.03)
Rilpivirine 25 mg once daily	50 mg once daily	16	1.10 (0.99 to 1.22)	1.06 (0.98 to 1.16)	1.21 (1.07 to 1.38)
Sofosbuvir 400 mg once daily Metabolite (GS-331007)	50 mg once daily	24	0.88 (0.80, 0.98)	0.92 (0.85, 0.99)	NA
Sofosbuvir 400 mg once daily Metabolite (GS-331007)	50 mg once daily	24	1.01 (0.93, 1.10)	0.99 (0.97, 1.01)	0.99 (0.97, 1.01)
Tenofovir disoproxil fumarate 300 mg once daily	50 mg once daily	15	1.09 (0.97 to 1.23)	1.12 (1.01 to 1.24)	1.19 (1.04 to 1.35)
Velpatasvir 100 mg once daily	50 mg once daily	24	0.94 (0.86, 1.02)	0.91 (0.84, 0.98)	0.88 (0.82, 0.94)

Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
a The number of subjects represents the maximum number of subjects that were evaluated. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. c Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.
Coadministered Drug(s) and Dose(s)	Dose of TIVICAY	n	Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of TIVICAY	n	Cmax	AUC	Cτ or C24
Atazanavir 400 mg once daily	30 mg once daily	12	1.50 (1.40 to 1.59)	1.91 (1.80 to 2.03)	2.80 (2.52 to 3.11)
Atazanavir/ritonavir 300/100 mg once daily	30 mg once daily	12	1.34 (1.25 to 1.42)	1.62 (1.50 to 1.74)	2.21 (1.97 to 2.47)
Darunavir/ritonavir 600/100 mg twice daily	30 mg once daily	15	0.89 (0.83 to 0.97)	0.78 (0.72 to 0.85)	0.62 (0.56 to 0.69)
Efavirenz 600 mg once daily	50 mg once daily	12	0.61 (0.51 to 0.73)	0.43 (0.35 to 0.54)	0.25 (0.18 to 0.34)
Elbasvir/grazoprevir 50/200 mg once daily	50 mg single dose	12	1.22 (1.05, 1.40)	1.16 (1.00, 1.34)	1.14 (0.95, 1.36)
Etravirine 200 mg twice daily	50 mg once daily	16	0.48 (0.43 to 0.54)	0.29 (0.26 to 0.34)	0.12 (0.09 to 0.16)
Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily	50 mg once daily	9	0.88 (0.78 to 1.00)	0.75 (0.69 to 0.81)	0.63 (0.52 to 0.76)
Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily	50 mg once daily	8	1.07 (1.02 to 1.13)	1.11 (1.02 to 1.20)	1.28 (1.13 to 1.45)
Fosamprenavir/ritonavir 700 mg/100 mg twice daily	50 mg once daily	12	0.76 (0.63 to 0.92)	0.65 (0.54 to 0.78)	0.51 (0.41 to 0.63)
Lopinavir/ritonavir 400/100 mg twice daily	30 mg once daily	15	1.00 (0.94 to 1.07)	0.97 (0.91 to 1.04)	0.94 (0.85 to 1.05)
Rilpivirine 25 mg once daily	50 mg once daily	16	1.13 (1.06 to 1.21)	1.12 (1.05 to 1.19)	1.22 (1.15 to 1.30)
Tenofovir 300 mg once daily	50 mg once daily	15	0.97 (0.87 to 1.08)	1.01 (0.91 to 1.11)	0.92 (0.82 to 1.04)
Tipranavir/ritonavir 500/200 mg twice daily	50 mg once daily	14	0.54 (0.50 to 0.57)	0.41 (0.38 to 0.44)	0.24 (0.21 to 0.27)
Antacid (MAALOX) simultaneous administration	50 mg single dose	16	0.28 (0.23 to 0.33)	0.26 (0.22 to 0.32)	0.26 (0.21 to 0.31)
Antacid (MAALOX) 2 h after dolutegravir	50 mg single dose	16	0.82 (0.69 to 0.98)	0.74 (0.62 to 0.90)	0.70 (0.58 to 0.85)
Calcium carbonate 1,200 mg simultaneous administration (fasted)	50 mg single dose	12	0.63 (0.50 to 0.81)	0.61 (0.47 to 0.80)	0.61 (0.47 to 0.80)
Calcium carbonate 1,200 mg simultaneous administration (fed)	50 mg single dose	11	1.07 (0.83 to 1.38)	1.09 (0.84 to 1.43)	1.08 (0.81 to 1.42)
Calcium carbonate 1,200 mg 2 h after dolutegravir	50 mg single dose	11	1.00 (0.78 to 1.29)	0.94 (0.72 to 1.23)	0.90 (0.68 to 1.19)
Carbamazepine 300 mg twice daily	50 mg once daily	16a	0.67 (0.61 to 0.73)	0.51 (0.48 to 0.55)	0.27 (0.24 to 0.31)
Ferrous fumarate 324 mg simultaneous administration (fasted)	50 mg single dose	11	0.43 (0.35 to 0.52)	0.46 (0.38 to 0.56)	0.44 (0.36 to 0.54)
Ferrous fumarate 324 mg simultaneous administration (fed)	50 mg single dose	11	1.03 (0.84 to 1.26)	0.98 (0.81 to 1.20)	1.00 (0.81 to 1.23)
Ferrous fumarate 324 mg 2 h after dolutegravir	50 mg single dose	10	0.99 (0.81 to 1.21)	0.95 (0.77 to 1.15)	0.92 (0.74 to 1.13)
Multivitamin (One-A-Day) simultaneous administration	50 mg single dose	16	0.65 (0.54 to 0.77)	0.67 (0.55 to 0.81)	0.68 (0.56 to 0.82)
Omeprazole 40 mg once daily	50 mg single dose	12	0.92 (0.75 to 1.11)	0.97 (0.78 to 1.20)	0.95 (0.75 to 1.21)
Prednisone 60 mg once daily with taper	50 mg once daily	12	1.06 (0.99 to 1.14)	1.11 (1.03 to 1.20)	1.17 (1.06 to 1.28)
Rifampinb 600 mg once daily	50 mg twice daily	11	0.57 (0.49 to 0.65)	0.46 (0.38 to 0.55)	0.28 (0.23 to 0.34)
Rifampinc 600 mg once daily	50 mg twice daily	11	1.18 (1.03 to 1.37)	1.33 (1.15 to 1.53)	1.22 (1.01 to 1.48)
Rifabutin 300 mg once daily	50 mg once daily	9	1.16 (0.98 to 1.37)	0.95 (0.82 to 1.10)	0.70 (0.57 to 0.87)

12.4 Microbiology

Mechanism of Action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Antiviral Activity in Cell Culture

Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against 3 HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.

Antiviral Activity in Combination with Other Antiviral Agents

The antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the NRTIs, abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir, or inhibited by the antiviral, ribavirin.

Resistance

Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H.

Treatment-Naïve Subjects: No subject who received dolutegravir 50-mg once-daily in the treatment-naïve trials SPRING-2 (96 weeks) and SINGLE (144 weeks) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 12 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies/mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was observed in the dolutegravir arm in either the SPRING-2 or SINGLE trials. No treatment-emergent primary resistance substitutions were observed in either treatment group in the FLAMINGO trial through Week 96.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In the dolutegravir arm of the SAILING trial for treatment-experienced and INSTI-naïve subjects (n = 354), treatment-emergent integrase substitutions were observed in 6 of 28 (21%) subjects who had virologic failure and resistance data. In 5 of the 6 subjects’ isolates emergent INSTI substitutions included L74L/M/I, Q95Q/L, V151V/I (n = 1 each), and R263K (n = 2). The change in dolutegravir phenotypic susceptibility for these 5 subject isolates was less than 2-fold. One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with a corresponding 148-fold reduction in dolutegravir susceptibility at failure. In the comparator raltegravir arm, 21 of 49 (43%) subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92Q, T97A, E138Q, G140S/A, Y143R/C, Q148H/R, V151I, N155H, E157Q, and G163K/R) and raltegravir phenotypic resistance.

Virologically Suppressed Subjects: SWORD-1 and SWORD-2 are identical trials in virologically suppressed subjects receiving 2 NRTIs plus either an INSTI, an NNRTI, or a PI, that switched to dolutegravir plus rilpivirine (n = 513) or remained on their current antiviral regimen (n = 511). In the pooled SWORD-1 and SWORD-2 trials, 12 subjects (7 in SWORD-1 and 5 in SWORD-2) had confirmed virologic failure (HIV-1 RNA greater than 200 copies/mL) while receiving dolutegravir plus rilpivirine at any time through Week 148. Ten of the confirmed virologic failures had post-baseline resistance data, with 6 isolates showing evidence of rilpivirine resistance, and 2 with evidence of dolutegravir resistance substitutions. Six isolates showed genotypic and/or phenotypic resistance to rilpivirine with emergent NNRTI-resistance substitutions E138E/A (rilpivirine 1.6-fold change), M230M/L (rilpivirine 2-fold change), L100L/I, K101Q, and E138A (rilpivirine 4.1-fold change), K101K/E (rilpivirine 1.2-fold change), K101K/E, M230M/L (rilpivirine 2-fold change), and L100L/V/M, M230M/L (rilpivirine 31-fold change). In addition, 1 virologic failure subject had NNRTI‑resistance substitutions K103N and V179I at Week 88 with rilpivirine phenotypic fold change of 5.2 but had no baseline sample.

One virologic failure isolate had emergent INSTI‑resistance substitution V151V/I present post-baseline with baseline INSTI‑resistance substitutions N155N/H and G163G/R (by exploratory HIV proviral DNA archive sequencing); no integrase phenotypic data were available for this isolate at virologic failure. One other subject had the dolutegravir resistance substitution G193E at baseline and virologic failure, but no detectable phenotypic resistance (fold change = 1.02) at Week 24.

No resistance-associated substitutions were observed for the 2 subjects meeting confirmed virologic failure in the comparative current antiretroviral regimen arms at Week 48.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: VIKING-3 examined the efficacy of dolutegravir 50 mg twice daily plus optimized background therapy in subjects with prior or current virologic failure on an INSTI- (elvitegravir or raltegravir) containing regimen. Use of TIVICAY in INSTI-experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Response by Baseline Genotype

Of the 183 subjects with baseline data, 30% harbored virus with a substitution at Q148, and 33% had no primary INSTI-resistance substitutions (T66A/I/K, E92Q/V, Y143R/C/H, Q148H/R/K, and N155H) at baseline, but had historical genotypic evidence of INSTI-resistance substitutions, phenotypic evidence of elvitegravir or raltegravir resistance, or genotypic evidence of INSTI-resistance substitutions at screening.

Response rates by baseline genotype were analyzed in an “as-treated” analysis at Week 48 (n = 175) (Table 13). The response rate at Week 48 to dolutegravir-containing regimens was 47% (24 of 51) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions (Table 13). In addition, a diminished virologic response of 40% (6 of 15) was observed when the substitution E157Q or K was present at baseline with other INSTI-resistance substitutions but without a Q148H or R substitution.

Table 13. Response by Baseline Integrase Genotype in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3
INSTI = integrase strand transfer inhibitor.
a Includes INSTI-resistance substitutions Y143R/C/H and N155H. b INSTI-resistance substitutions included T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Two additional subjects had baseline genotypes of Q148Q/R plus L74L/I/M (virologic failure) and Q148R plus E138K (responder). c The most common pathway with Q148H/R + greater than or equal to 2 INSTI-resistance substitutions had Q148+G140+E138 substitutions (n = 16).
Baseline Genotype	Week 48 (<50 copies/mL) n = 175
Overall Response	66% (116/175)
No Q148 substitutiona	74% (92/124)
Q148H/R + G140S/A/C without additional INSTI-resistance substitutionb	61% (17/28)
Q148H/R + ≥2 INSTI-resistance substitutionsb,c	29% (6/21)

Response by Baseline Phenotype

Response rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n = 163) (Table 14). These baseline phenotypic groups are based on subjects enrolled in VIKING-3 and are not meant to represent definitive clinical susceptibility cut points for dolutegravir. The data are provided to guide clinicians on the likelihood of virologic success based on pretreatment susceptibility to dolutegravir in INSTI-resistant patients.

Table 14. Response by Baseline Dolutegravir Phenotype (Fold-Change from Reference) in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3
Baseline Dolutegravir Phenotype (Fold-Change from Reference)	Response at Week 48 (<50 copies/mL) Subset n = 163
Overall Response	64% (104/163)
<3-fold change	72% (83/116)
3- <10-fold change	53% (18/34)
≥10-fold change	23% (3/13)

Integrase Strand Transfer Inhibitor Treatment-Emergent Resistance

There were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNA greater than 400 copies/mL at the failure timepoint, Week 48 or beyond, or the last timepoint on trial. Thirty-nine subjects with virologic failure had resistance data that were used in the Week 48 analysis. In the Week 48 resistance analysis 85% (33 of 39) of the subjects with virologic failure had treatment-emergent INSTI-resistance substitutions in their isolates. The most common treatment-emergent INSTI-resistance substitution was T97A. Other frequently emergent INSTI-resistance substitutions included L74M, I or V, E138K or A, G140S, Q148H, R or K, M154I, or N155H. Substitutions E92Q, Y143R or C/H, S147G, V151A, and E157E/Q each emerged in 1 to 3 subjects’ isolates. At failure, the median dolutegravir fold-change from reference was 61-fold (range: 0.75 to 209) for isolates with emergent INSTI-resistance substitutions (n = 33).

Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 49% (19 of 39) of subjects in the Week 48 resistance analysis.

In VIKING-4 (ING116529), 30 subjects with current virological failure on an INSTI-containing regimen and genotypic evidence of INSTI-resistance substitutions at screening were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days and then all subjects received open-label dolutegravir plus optimized background regimen from Day 8. Virologic responses at Week 48 by baseline genotypic and phenotypic INSTI-resistance categories and the INSTI resistance-associated substitutions that emerged on dolutegravir treatment in VIKING-4 were consistent with those seen in VIKING-3.

Cross-Resistance

Site-Directed Integrase Strand Transfer Inhibitor-Resistant Mutant HIV-1 and HIV-2 Strains: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions) and 6 INSTI-resistant site-directed mutant HIV-2 viruses. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.

Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent antiviral activity against 2 NNRTI-resistant, 3 NRTI-resistant, and 2 PI-resistant HIV-1 mutant clones compared with the wild-type strain.