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Mechanism of Action
In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group.
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.
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 6) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. TIVICAY was administered without regard to food in these trials.
Table 6: Dolutegravir Steady-State Pharmacokinetic
Parameter Estimates in HIV-1– Infected Adults
|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)|
|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.
Following oral administration of dolutegravir, peak plasma concentrations were observed 2 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-glycoprotein substrate in vitro. The absolute bioavailability of dolutegravir has not been established.
Effects of Food on Oral Absorption
TIVICAY may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. 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.
Dolutegravir is highly bound ( ≥ 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 11 treatment-na´ve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng/Ml (range: 4 ng/mL to 232 ng/mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established.
Metabolism and Elimination
Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. 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 Ndealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low ( < 1% of the dose).
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.
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).
Hepatic Impairment: Dolutegravir is primarily metabolized and eliminated by the liver. 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. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment.
HBV/HCV Co-infection: 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.
Renal Impairment: Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. In a trial comparing 8 subjects with severe renal impairment (CrCl < 30 mL/min) with 8 matched healthy controls, AUC, Cmax, and C24 of dolutegravir were decreased by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. The cause of this decrease is unknown. 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. No dosage adjustment is necessary for treatment-na´ve or treatment-experienced and INSTI-na´ve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology] with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients requiring dialysis.
Gender: Population analyses using pooled pharmacokinetic data from adult trials indicated gender had no clinically relevant effect on the exposure of dolutegravir.
Race: Population analyses using pooled pharmacokinetic data from adult trials indicated race had no clinically relevant effect on the pharmacokinetics of dolutegravir.
Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.
Pediatric Patients: The pharmacokinetics of dolutegravir in HIV-1–infected children (n = 10) aged 12 to less than 18 years were similar to those observed in HIV-1–infected adults who received dolutegravir 50 mg once daily (Table 7) [see Clinical Studies].
Table 7: Dolutegravir Steady-State Pharmacokinetic
Parameters in Pediatric Subjects
|Age/Weight||Dose of TIVICAYa||Dolutegravir Pharmacokinetic Parameter Estimates Geometric Mean (%CV)|
(n = 10)
(n = 10)
(n = 10)
|12 to < 18 years and > 40 kg a||50 mg once daily||3.49 (38)||46 (43)||0.90 (59)|
|a One subject weighing 37 kg received TIVICAY 35 mg once daily.|
Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. As dolutegravir is not expected to affect the pharmacokinetics of other drugs dependent on hepatic metabolism (Table 8) [see DRUG INTERACTIONS], the primary focus of these drug interaction trials was to evaluate the effect of coadministered drug on dolutegravir (Table 9).
Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 5 [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Table 8: Summary of Effect of Dolutegravir on the
Pharmacokinetics of Coadministered Drugs
|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|
|C max||AUC||Cτ or C24|
|Ethinyl estradiol 0.035 mg||50 mg twice daily||15||0.99
(0.91 to 1.08)
(0.96 to 1.11)
(0.93 to 1.11)
|Methadone 16 to 150 mg||50 mg twice daily||11||1.00
(0. 94 to 1.06)
(0.91 to 1.06)
(0.91 to 1.07)
|Midazolam 3 mg||25 mg once daily||10||-||0.95 (0.79 to 1.15)||-|
|Norgestromin 0.25 mg||50 mg twice daily||15||0.89
(0.82 to 0.97)
(0.91 to 1.04)
(0.85 to 1.03)
|Rilpivirine 25 mg once daily||50 mg once daily||16||1.10
(0.99 to 1.22)
(0.98 to 1.16)
(1.07 to 1.38)
|Tenofovir disoproxil fumarate 300 mg once daily||50 mg once daily||15||1.09
(0.97 to 1.23)
(1.01 to 1.24)
(1.04 to 1.35)
Table 9: Summary of Effect of Coadministered Drugs on
the Pharmacokinetics of Dolutegravir
|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
|Cmax||AUC||Cτ or C24|
|Atazanavir 400 mg once daily||30 mg once daily||12||1.50
(1.40 to 1.59)
(1.80 to 2.03)
(2.52 to 3.11)
|Atazanavir/ritonavir 300/100 mg once daily||30 mg once daily||12||1.34
(1.25 to 1.42)
(1.50 to 1.74)
(1.97 to 2.47)
|Tenofovir 300 mg once daily||50 mg once daily||15||0.97
(0.87 to 1.08)
(0.91 to 1.11)
(0.82 to 1.04)
|Darunavir/ritonavir 600/100 mg twice daily||30 mg once daily||15||0.89
(0.83 to 0.97)
(0.72 to 0.85)
(0.56 to 0.69)
|Efavirenz 600 mg once daily||50 mg once daily||12||0.61
(0.51 to 0.73)
(0.35 to 0.54)
(0.18 to 0.34)
|Etravirine 200 mg twice daily||50 mg once daily||16||0.48
(0.43 to 0.54)
(0.26 to 0.34)
(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)
(0.69 to 0.81)
(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)
(1.02 to 1.20)
(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)
(0.54 to 0.78)
(0.41 to 0.63)
|Lopinavir/ritonavir 400/100 mg twice daily||30 mg once daily||15||1.00
(0.94 to 1.07)
(0.91 to 1.04)
(0.85 to 1.05)
(Maalox®) Simultaneous administration
|50 mg single dose||16||0.28
(0.23 to 0.33)
(0.22 to 0.32)
(0.21 to 0.31)
(Maalox®) 2 hrs after dolutegravir
|50 mg single dose||16||0.82
(0.69 to 0.98)
(0.62 to 0.90)
(0.58 to 0.85)
(One-A-Day®) Simultaneous administration
|50 mg single dose||16||0.65
(0.54 to 0.77)
(0.55 to 0.81)
(0.56 to 0.82)
|Omeprazole 40 mg once daily||50 mg single dose||12||0.92
(0.75 to 1.11)
(0.78 to 1.20)
(0.75 to 1.21)
|Prednisone 60 mg once daily with taper||50 mg once daily||12||1.06
(0.99 to 1.14)
(1.03 to 1.20)
(1.06 to 1.28)
|Rifampina 600 mg once daily||50 mg twice daily||11||0.57
(0.49 to 0.65)
(0.38 to 0.55)
(0.23 to 0.34)
|Rifampinb 600 mg once daily||50 mg twice daily||11||1.18
(1.03 to 1.37)
(1.15 to 1.53)
(1.01 to 1.48)
|Rifabutin 300 mg once daily||50 mg once daily||9||1.16
(0.98 to 1.37)
(0.82 to 1.10)
(0.57 to 0.87)
|Rilpivirine 25 mg once daily||50 mg once daily||16||1.13
(1.06 to 1.21)
(1.05 to 1.19)
(1.15 to 1.30)
|Tipranavir/ritonavir 500/200 mg twice daily||50 mg once daily||14||0.54
(0.50 to 0.57)
(0.38 to 0.44)
(0.21 to 0.27)
|Telaprevir 750 mg every 8 hours||50 mg once daily||15||1.18
(1.11 to 1.26)
(1.19 to 1.31)
(1.29 to 1.51)
|Boceprevir 800 mg every 8 hours||50 mg once daily||13||1.05
(0.96 to 1.15)
(0.95 to 1.20)
(0.91 to 1.28)
| a Comparison is rifampin taken with
dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.
b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.
Mechanism of Action
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (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 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 nucleoside reverse transcriptase inhibitors (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 with the antiviral, ribavirin.
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-Na´ve Subjects: No subjects in the dolutegravir 50-mg once-daily treatment arms of treatment-na´ve trials SPRING-2 and SINGLE had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 6 with HIV-1 RNA > 400 copies/mL at failure or last visit through Week 48 and having resistance data). One additional subject in SINGLE with 275 copies/mL HIV-1 RNA had a treatment-emergent INSTI-resistance substitution (E157Q/P) detected at Week 24, but no corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was isolated in the dolutegravir arm in either the SPRING-2 or SINGLE trials.
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects: In SAILING, viruses from 5 of 15 subjects in the dolutegravir arm with post-baseline resistance data had evidence of treatment-emergent integrase substitutions (1 subject each with L74I/M, Q95Q/L, or V151V/I, and 2 subjects with R263K). However, none of these subjects' isolates had detectable phenotypic decreases in susceptibility to either dolutegravir or raltegravir. In the comparator raltegravir arm, 9 of 32 subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92E/Q, Q95Q/R, T97A, G140A/S, Y143C/R, Q148H/R, V151I, N155H, E157E/Q, and G163G/R) and raltegravir phenotypic resistance.
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.
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, Y143C/H/R, Q148H/K/R 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 using a subset of subjects who had reached Week 24, as well as those who discontinued or rebounded before Week 24 (n = 124) (Table 10). The response rate at Week 24 for subjects with only historic evidence of INSTIresistance at baseline was 75% (33/44). The response rate at Week 24 to dolutegravir-containing regimens was 36% (13/36) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions. Diminished virologic responses (25% [7/28]) were observed when ≥ 3 of the following INSTI-resistance substitutions were present at baseline: L74I/M, E138A/D/K/T, G140A/S, Y143H/R, Q148H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
Table 10: Response by Baseline Integrase Genotype in
Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in
|Baseline Genotype||Response at Week 24 ( < 50 copies/mL) Subset
N = 124
|Overall Response||64% (79/124)|
|N155H without a Q148 substitution||80% (16/20)|
|Y143C/H/R without a Q148 substitution||56% (10/18)|
|Q148H/R + G140A/S without additional INSTI-resistance substitutions||56% (10/18)|
|Q148H/R + ≥ 2 INSTI-resistance substitutionsa,b||18% (3/17)|
|a INSTI-resistance substitutions include
L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
b The most common pathway with Q148H/R + ≥ 2 INSTI-resistance substitutions had Q148+G140+E138 substitutions (n = 12).
Response by Baseline Phenotype
Response rates by baseline phenotype were analyzed using a subset of subjects who had reached Week 24, as well as those who discontinued or rebounded before Week 24 (n = 120) (See Table 11). 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 INSTIresistant patients.
Table 11: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 24 ( < 50 copies/mL) Subset
N = 120
|Overall Response||63% (75/120)|
|< 3-fold change||72% (63/87)|
|3- < 10-fold change||42% (10/24)|
|≥ 10-fold change||22% (2/9)|
Integrase Strand Transfer Inhibitor Treatment-Emergent Resistance
There were 40 subjects on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNA > 400 copies/mL at Week 24, the failure timepoint, or the last timepoint on trial who were included in the Week 24 resistance analysis set. In the Week 24 resistance analysis set, 45% (18/40) of the subjects 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 E138K or A, G140S or A, or Q148H or R or K; substitutions at Q148 were detected in subjects with changes documented at or prior to enrollment in the trial. Substitutions L74M, E92Q, Y143H or C, S147G, V151A, M154I, and N155H each emerged in 1 or 2 subjects' isolates. At failure, the median dolutegravir fold-change from reference was 23-fold (range: 0.92 to 209) for isolates with emergent INSTI-resistance substitutions (n = 18).
Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 30% (12/40) of the subjects in the Week 24 resistance analysis set.
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 INSTIresistance substitutions T66K, I151L, and S153Y conferred a > 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 > 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 NRTIresistant, and 2 PI-resistant HIV-1 mutant clones compared with the wild-type strain.
The efficacy of TIVICAY is based on analyses of data from 2 trials, SPRING-2 (ING113086) and SINGLE (ING114467), in treatment-na´ve, HIV-1-infected subjects (n = 1,641); one trial, SAILING (ING111762), in treatment-experienced, INSTI-na´ve HIV-1-infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV-1-infected subjects (n = 183). The use of TIVICAY in pediatric patients aged 12 years and older is based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multi-center, open-label trial in subjects (n = 23) without INSTI resistance.
The efficacy of TIVICAY in HIV-1-infected treatmentna´ve adults is based on the analyses of 48-week data from 2 randomized, international, multicenter, double-blind, active-controlled trials, SPRING-2 and SINGLE.
In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixeddose dual NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% nonwhite, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA > 100,000 copies/mL, 48% had CD4+ cell count < 350 cells/mm³, and 39% received EPZICOM; these characteristics were similar between treatment groups.
In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus coinfection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA > 100,000 copies/mL, and 53% had CD4+ cell count < 350 cells/mm³; these characteristics were similar between treatment groups.
Week 48 outcomes for SPRING-2 and SINGLE are provided in Table 12. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
Table 12: Virologic Outcomes of Randomized Treatment
in SPRING-2 and SINGLE at Week 48 (Snapshot Algorithm)
|TIVICAY 50 mg Once Daily + 2NRTIs
(N = 403)
|Raltegravir 400 mg Twice Daily + 2NRTIs
(N = 405)
|TIVICAY 50 mg +EPZICOM Once Daily
(N = 414)
|ATRIPLA Once Daily
(N = 419)
|HIV-1 RNA < 50 copies/mL||88%||86%||88%||81%|
|Treatment differencea||2.6% (95% C]||: -1.9%, 7.2%)||7.4% (95% CI: 2.5%, 12.3%)|
|No virologic data at Week 48 window||7%||7%||7%||13%|
|Discontinued study/study drug due to adverse event or deathc||2%||1%||2%||10%|
|Discontinued study/study drug for other reasonsd||5%||6%||5%||3%|
|Missing data during window but on study||0||0||0||<1%|
|Proportion (%) of Subjects With HIV-1 RNA < 50 copies/mL at Week 48 by Baseline Category|
|Plasma viral load (copies/mL)|
|a Adjusted for pre-specified stratification
b Includes subjects who changed BR to new class or changed BR not permitted per protocol or due to lack of efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack or loss of efficacy, and subjects who were HIV-1 RNA ≥ 50 copies/mL in the Week 48 window.
c Includes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the Week 48 window if this resulted in no virologic data on treatment during the Week 48 window.
d Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.
SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline for both groups was +230 cells/mm³ at 48 weeks.
SINGLE: Treatment differences were maintained across baseline characteristics including HIV-1 RNA, CD4+ cell count, age, gender, and race.
The adjusted mean changes in CD4+ cell counts from baseline were 267 cells/mm³ in the group receiving TIVICAY + EPZICOM and 208 cells/mm³ for the ATRIPLA group at 48 weeks. The adjusted difference between treatment arms and 95% CI was 58.9 cells/mm³ (33.4 cells/mm³, 84.4 cells/mm³) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, baseline CD4+ cell count, and multiplicity).
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects
In the international, multicenter, double-blind trial (SAILING), 719 HIV-1- infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 49% non-white, 16% had hepatitis B and/or C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA > 100,000 copies/mL, and 72% had CD4+ cell count < 350 cells/mm³; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 24 outcomes for SAILING are shown in Table 13.
Table 13: Virologic Outcomes of Randomized Treatment
in SAILING at 24 Weeks (Snapshot Algorithm)
|TIVICAY 50 mg Once Daily + BRa
(N = 354)
|Raltegravir 400 mg Twice Daily + BRa
(N = 361)
|HIV-1 RNA < 50 copies/mL||79%||70%|
|Adjustedb treatment difference||9.7% (95% CI: 3.4%, 15.9%)|
|No virologic data at Week 24 window||6%||6%|
|Discontinued study/study drug due to adverse event or death||2%||2%|
|Discontinued study/study drug for other reasonsc||3%||3%|
|Missing data during window but on study||< 1%||< 1%|
|Proportion (%) With HIV-1 RNA < 50 copies/mL at Week 24 by Baseline Category|
|Plasma viral load (copies/mL)|
|≤ 50,000 copies/mL||83%||77%|
|> 50,000 copies/mL||70%||53%|
|No darunavir use or use of darunavir with primary PI substitutions||79%||67%|
|Use of darunavir without primary PI substitutions||80%||81%|
|a BR = Background regimen. Background regimen
was restricted to ≤ 2 antiretroviral treatments with at least 1 fully
b Adjusted for pre-specified stratification factors.
c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.
Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.
The mean changes in CD4+ cell counts from baseline were 114 cells/mm³ in the group receiving TIVICAY and 106 cells/mm³ in the raltegravir group.
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects
VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy with continued treatment of TIVICAY 50 mg twice daily.
In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days, then received TIVICAY with optimized background therapy from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or C virus co-infection. Median baseline CD4+ cell count was 140 cells/mm³, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had ≥ 2 NRTI, 75% ≥ 1 NNRTI, and 71% ≥ 2 PI major substitutions; 62% had non-R5 virus.
Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10). Response at Week 24 was affected by baseline INSTI substitutions [see Microbiology].
After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 24 virologic outcomes for VIKING-3 are shown in Table 14.
Table 14: Virologic Outcomes of Treatment of VIKING-3
at 24 Weeks (Snapshot Algorithm)
|TIVICAY 50 mg Twice Daily + Optimized Background Therapy
(N = 114)
|HIV-1 RNA < 50 copies/mL||63%|
|No virologic data at Week 24|
|Discontinued study/study drug due to adverse event or death||4%|
|Proportion (%) With HIV-1 RNA <50 copies/mL at Week 24 by Baseline Category|
Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had a reduced response at Week 24 in a stepwise fashion [see Microbiology].
The median change in CD4+ cell count from baseline was 65 cells/mm³ at Week 24.
IMPAACT P1093 is a Phase ½, 48-week, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of TIVICAY in combination treatment regimens in HIV-1-infected infants, children, and adolescents.
The initial dose-finding stage included intensive pharmacokinetic evaluation in 10 INSTI-na´ve subjects (aged 12 to 18 years). Dose selection was based upon achieving similar dolutegravir plasma exposure and trough concentration as seen in adults. After dose selection, an additional 13 subjects were enrolled for evaluation of long-term safety, tolerability, and efficacy.
These 23 subjects had a mean age of 14 years (range: 12 to 17), were 78% female and 52% black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4+ cell count was 466 cells/mm³ (range: 11 to 1,025), and median CD4+% was 22% (range: 1% to 39%). Overall, 17% had baseline plasma HIV-1 RNA > 50,000 copies/mL and 39% had a CDC HIV clinical classification of category C. Most subjects had previously used at least 1 NNRTI (52%) or 1 PI (78%).
At 24 weeks, 70% of subjects treated with TIVICAY once daily (35 mg: n = 4, 50 mg: n = 19) plus optimized background therapy achieved a viral load < 50 copies/mL. The median CD4+ cell count (percent) increase from baseline to Week 24 was 63 cells/mm³ (5%).
Last reviewed on RxList: 8/26/2013
This monograph has been modified to include the generic and brand name in many instances.
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