June 30, 2015
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Stribild

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Stribild

CLINICAL PHARMACOLOGY

Mechanism Of Action

STRIBILD is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF [see Microbiology].

Pharmacodynamics

Effects on Electrocardiogram

Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known.

The effect of multiple doses of elvitegravir 125 and 250 mg (0.83 and 1.67 times the dose in STRIBILD) (coadministered with 100 mg RTV to boost the blood levels of elvitegravir) on QTc interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 msec. In this study, there was no clinically relevant prolongation of the QTc interval.

The effect of a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) on QTc interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 msec, the threshold for regulatory concern. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400 mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation.

Pharmacokinetics

Absorption and Bioavailability

STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the conversion of tenofovir DF (see Table 7 for additional pharmacokinetic parameters).

Table 7 : Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects

Parameter Mean ± SD [range: min:max] Elvitegravira Cobicistatb Emtricitabineb Tenofovirb
Cmax (microgram per mL) 1.7 ± 0.4 [0.4:3.7] 1.1 ± 0.4 [0.1:2.1] 1.9 ± 0.5 [0.6:3.6] 0.45 ± 0.2 [0.2:1.2]
AUCtau (microgram•hour per mL) 23.0 ± 7.5 [4.4:69.8] 8.3 ± 3.8 [0.5:18.3] 12.7 ± 4.5 [5.2:34.1] 4.4 ± 2.2 [2.1:18.2]
Ctrough (microgram per mL) 0.45 ± 0.26 [0.05:2.34] 0.05 ± 0.13 [0.01:0.92] 0.14 ± 0.25 [0.04:1.94] 0.10 ± 0.08 [0.04:0.58]
SD = Standard Deviation
a From Population Pharmacokinetic analysis, N=419.
b From Intensive Pharmacokinetic analysis, N=61-62, except cobicistat Ctrough N=53.

Effect of Food on Oral Absorption

Relative to fasting conditions, the administration of single dose STRIBILD with a light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.

Relative to fasting conditions, the administration of single dose STRIBILD with a high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.

STRIBILD should be taken with food.

Distribution

Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73.

Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02–200 micrograms per mL.

Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 micrograms per mL.

Metabolism

Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.

Cobicistat: Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Emtricitabine and tenofovir are not significantly metabolized.

Elimination

Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.

Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.

Emtricitabine and tenofovir are primarily excreted in the urine by a combination of glomerular filtration and active tubular secretion.

Special Populations

Patients with Renal Impairment

Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per minute). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Patients with Hepatic Impairment

Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations].

Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.

Hepatitis B and/or Hepatitis C Virus Co-infection

Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.

Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Race

Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.

Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.

Pediatric Patients

Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations].

Geriatric Patients

Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use In Specific Populations].

Assessment of Drug Interactions

[see also CONTRAINDICATIONS and DRUG INTERACTIONS]

The drug-drug interaction studies described in Tables 8 and 9 were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or RTV), or cobicistat administered alone.

As STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided [see WARNINGS AND PRECAUTIONS].

The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 8. The effects of elvitegravir or cobicistat on the exposure of coadministered drugs are shown in Table 9. For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 8 : Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Druga

Coadministered Drug Dose of Coadministered Drug (mg) Elvitegravir Dose (mg) Cobicistat or RTV Booster Dose (mg) N Mean Ratio of Elvitegravir Pharmacokinetic Parameters
(90% CI); No effect = 1.00
Cmax AUC Cmin
Antacids 20 mL single dose given 4 hours before elvitegravir 50 single dose RTV 100 single dose 8 0.95
(0.84,1.07)
0.96
(0.88,1.04)
1.04
(0.93,1.17)
20 mL single dose given 4 hours after elvitegravir 10 0.98
(0.88,1.10)
0.98
(0.91,1.06)
1.00
(0.90,1.11)
20 mL single dose given 2 hours before elvitegravir 11 0.82
(0.74,0.91)
0.85
(0.79,0.91)
0.90
(0.82,0.99)
20 mL single dose given 2 hours after elvitegravir 10 0.79
(0.71,0.88)
0.80
(0.75,0.86)
0.80
(0.73,0.89)
Famotidine 40 once daily given 12 hours after elvitegravir 150 once daily Cobicistat 150 once daily 10 1.02
(0.89,1.17)
1.03
(0.95,1.13)
1.18
(1.05,1.32)
40 once daily given simultaneously with elvitegravir 16 1.00
(0.92,1.10)
1.03
(0.98,1.08)
1.07
(0.98,1.17)
Ketoconazole 200 twice daily 150 once daily RTV 100 once daily 18 1.17
(1.04,1.33)
1.48
(1.36,1.62)
1.67
(1.48,1.88)
Omeprazole 40 once daily given 2 hours before elvitegravir 50 once daily RTV 100 once daily 9 0.93
(0.83,1.04)
0.99
(0.91,1.07)
0.94
(0.85,1.04)
20 once daily given 2 hours before elvitegravir 150 once daily Cobicistat 150 once daily 11 1.16
(1.04,1.30)
1.10
(1.02,1.19)
1.13
(0.96,1.34)
20 once daily given 12 hours after elvitegravir 11 1.03
(0.92,1.15)
1.05
(0.93,1.18)
1.10
(0.92,1.32)
Rifabutin 150 once every other day 150 once daily Cobicistat 150 once daily 12 0.91
(0.84,0.99)
0.79
(0.74,0.85)
0.33
(0.27,0.40)
Rosuvastatin 10 single dose 150 once daily Cobicistat 150 once daily 10 0.94
(0.83,1.07)
1.02
(0.91,1.14)
0.98
(0.83,1.16)
Telaprevir 750 three times daily 150 once daily 150 once daily 16 0.79
(0.74,0.85)
0.84
(0.79,0.89)
1.29
(1.14,1.46)
a All interaction studies conducted in healthy volunteers.

Table 9 : Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir plus Cobicistat, Cobicistat, or STRIBILDa

Coadministered Drug Dose of Coadministered Drug (mg) Elvitegravir Doseb (mg) Cobicistat Booster Dose (mg) N Mean Ratio of Coadministered Drug Pharmacokinetic Parametersc (90% CI); No effect = 1.00
Cmax AUC Cmin
Buprenorphine 16 - 24 once daily 150 once daily 150 once daily 17 1.12
(0.98, 1.27)
1.35
(1.18, 1.55)
1.66
(1.43, 1.93)
Norbuprenorphine 1.24
(1.03, 1.49)
1.42
(1.22, 1.67)
1.57
(1.31, 1.88)
Desipramine 50 single dose N/A 150 once daily 8 1.24
(1.08,1.44)
1.65
(1.36,2.02)
NC
Digoxin 0.5 single dose N/A 150 once daily 22 1.41
(1.29,1.55)
1.08
(1.00, 1.17)
NC
Naloxone 4 - 6 once daily 150 once daily 150 once daily 17 0.72
(0.61, 0.85)
0.72
(0.59, 0.87)
N/A
Norgestimate/ ethinyl estradiol 0.180/0.215/ 0.250 norgestimate once daily 150 once dailyd 150 once dailyd 13 2.08
(2.00,2.17)
2.26
(2.15,2.37)
2.67
(2.43,2.92)
0.025 ethinyl estradiol once daily 0.94
(0.86,1.04)
0.75
(0.69,0.81)
0.56
(0.52,0.61)
R-Methadone 80-120 daily 150 once daily 150 once daily 11 1.01
(0.91, 1.13)
1.07
(0.96, 1.19
1.10
(0.95, 1.28)
S-Methadone 0.96
(0.87, 1.06)
1.00
(0.89, 1.12)
1.02
(0.89, 1.17)
Rifabutin 150 once every other day 150 once daily 150 once daily 12 1.09
(0.98,1.20)e
0.92
(0.83,1.03)e
0.94
(0.85,1.04)e
25-O-desacetyl- rifabutin       12 4.84
(4.09,5.74)e
6.25
(5.08,7.69)e
4.94
(4.04,6.04)e
Rosuvastatin 10 single dose 150 single dose 150 single dose 10 1.89
(1.48,2.42)
1.38
(1.14,1.67)
NC
Telaprevir 750 three times daily 150 once daily 150 once daily 15 1.06
(0.97, 1.16)
1.13
(1.00, 1.29)
1.15
(1.05, 1.25)
a All interaction studies conducted in healthy volunteers.
b N/A = Not Applicable
c NC = Not Calculated
d Study conducted with STRIBILD.
e Comparison based on rifabutin 300 mg once daily.

Microbiology

Mechanism of Action

Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity in Cell Culture

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF: The triple combination of elvitegravir, emtricitabine, and tenofovir was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat.

Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture.

Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir.

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013–0.64 micromolar. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007– 0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 micromolar).

Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 micromolar. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6–5.5 micromolar).

Resistance

In Cell Culture: Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M.

Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

In Clinical Studies

Elvitegravir: Development of substitutions T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H in the HIV-1 integrase protein was primarily associated with resistance to elvitegravir. In addition to these primary elvitegravir resistance-associated substitutions, E92A, F121C/Y, P145S, Q146I/L/R, and N155S were also occasionally observed and were shown to confer reduced susceptibility to elvitegravir. In virus isolates harboring the observed primary elvitegravir resistance-associated substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, V72A/N, I73V, Q95K/R, S119R, E138A/K, G140A/C/S, E157Q, K160N, E170A, S230R, and D232N.

Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in subjects experiencing virologic failure in clinical trials. Genotypic analysis of these isolates identified the M184V/I and K65R amino acid substitutions in the viral RT, respectively.

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF: In clinical trials of HIV-1infected subjects with no antiretroviral treatment history [Studies 102 and 103, see Clinical Studies], by Week 144, the development of one or more primary substitutions associated with resistance to elvitegravir, emtricitabine, and/or tenofovir was observed in viruses from 51% (18/35) of the STRIBILD-treatment failure subjects with evaluable genotypic resistance data who received at least 8 weeks of STRIBILD and had HIV-1 RNA greater than or equal to 400 copies per mL at confirmed virologic failure, the end of each study year, or the time of early study drug discontinuation. The most common substitutions that emerged were M184V/I (N=17) in HIV-1 RT and the primary elvitegravir resistance-associated substitutions, E92Q (N=9), N155H (N=5), Q148R (N=3), T66I (N=2), and T97A (N=1) in integrase; K65R in RT was also detected (N=5). In virus isolates harboring the observed primary elvitegravir resistance substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A, E157Q, and G163R. The virus in all subjects with evaluable data for RT and IN and whose virus developed integrase substitutions associated with elvitegravir resistance (N=14) also developed the M184I/V RT substitutions, and had reduced susceptibility to both elvitegravir and emtricitabine. In phenotypic analyses, HIV-1 isolates expressing M184V/I RT substitutions showed reduced susceptibility to emtricitabine (42-to greater than 152-fold); those expressing the primary elvitegravir resistance-associated integrase substitutions showed reduced susceptibility to elvitegravir (4-to greater than 198-fold); and those expressing the K65R RT substitution showed reduced susceptibility to tenofovir (0.8-to 1.6-fold), compared to wild-type reference HIV-1.

There was an insufficient number of virologic failures with evaluable data (N=1) in clinical trials of virologically-suppressed HIV-1-infected subjects with no history of virologic failure [Studies 115 and 121, see Clinical Studies] to draw conclusions about the development of resistance.

Cross Resistance

STRIBILD-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors.

Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravirresistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into a wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir).

Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabineresistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine.

Tenofovir DF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by tenofovir DF results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to tenofovir DF. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had a reduced response in clinical trials.

Clinical Studies

The efficacy of STRIBILD in HIV-1 Infected patients with no antiretroviral treatment history is based on the analyses of 144-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103 (N=1408, randomized and dosed). The efficacy of STRIBILD in virologically-suppressed HIV-1 infected patients without a history of virologic failure is based on the analyses of 48-week data from two randomized, open-label, controlled studies, Study 115 and Study 121 (N=867, randomized and dosed). Patients in all four studies had estimated creatinine clearance greater than or equal to 70 mL/min at screening.

In HIV-1-Infected Subjects With No Antiretroviral Treatment History

In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily. The mean age was 38 years (range 18-67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm³ (range 3-1348) and 13% had CD4+ cell counts less than 200 cells per mm³. Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg + RTV 100 mg + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) (N=355) once daily. The mean age was 38 years (range 1972), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 1.7-6.6). The mean baseline CD4+ cell count was 370 cells per mm³ (range 5-1132) and 13% had CD4+ cell count less than 200 cells per mm³. Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).

Treatment outcomes of Study 102 and Study 103 through 144 weeks are presented in Table 10.

Table 10 : Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 144a

  Study 102 Study 103
STRIBILD
(N=348)
ATRIPLA
(N=352)
STRIBILD
(N=353)
ATV + RTV + TRUVADA
(N=355)
Virologic Success HIV-1 RNA < 50 copies/mL 80% 75% 78% 75%
  Treatment Difference 4.9% (95% CI = -1.3%, 11.1%) 3.1% (95% CI = -3.2%, 9.4%)
Virologic Failureb 7% 10% 8% 7%
No Virologic Data in Week 144 Window
  Discontinued Study Drug Due to AE or Deathc 6% 8% 6% 8%
  Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 5% 7% 8% 9%
  Missing Data During Window but on Study Drug 1% 0% 1% 1%
a Week 144 window is between Day 967 and 1050 (inclusive).
b. Includes subjects who had ≥ 50 copies/mL in the Week 144 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
c Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
d Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.

In Study 102, the mean increase from baseline in CD4+ cell count at Week 144 was 298 cells per mm³ in the STRIBILD-treated subjects and 272 cells per mm³ in the ATRIPLA treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 144 was 261 cells per mm³ in the STRIBILD-treated subjects and 269 cells per mm³ in the ATV + RTV + TRUVADA-treated subjects.

In Virologically-Suppressed HIV-1-Infected Subjects with No History of Virologic Failure

In Study 115, subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, with no current or past history of resistance to the antiretroviral components of STRIBILD and must have been suppressed (HIV-1 RNA < 50 copies/mL) on a ritonavir-boosted PI in combination with TRUVADA for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to STRIBILD (STRIBILD arm, N=293; randomized and dosed) or stay on their baseline antiretroviral regimen for 48 weeks (PI + RTV + TRUVADA arm, N=140; randomized and dosed). Subjects had a mean age of 41 years (range 21-76), 86% were male, 80% were White, and 15% were Black. The mean baseline CD4+ cell count was 610 cells per mm³ (range 74-1919). At screening subjects were receiving atazanavir (40%), darunavir (40%), lopinavir (17%), fosamprenavir (3%), or saquinavir ( < 1%) as the PI in their regimen.

In Study 121, subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, with no current or past history of resistance to the antiretroviral components of STRIBILD and must have been suppressed (HIV-1 RNA < 50 copies/mL) on a NNRTI in combination with TRUVADA for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to STRIBILD (STRIBILD arm, N = 291; randomized and dosed), or stay on their baseline antiretroviral regimen for 48 weeks (NNRTI +TRUVADA arm, N = 143; randomized and dosed). Subjects had a mean age of 41 years (range 20-72), 93% were male, 78% were White, and 17% were Black. The mean baseline CD4+ cell count was 588 cells per mm³ (range 100-1614). Randomization was stratified by use of efavirenz in the baseline regimen. At screening subjects were receiving efavirenz (78%) (predominantly as ATRIPLA [74%]), nevirapine (17%), rilpivirine (4%) (as COMPLERA [4%]), or etravirine (1%) as the NNRTI in their regimen.

Virologic outcomes of Study 115 and Study 121 are presented in Table 11. Five treated subjects were excluded from the efficacy analysis: in Study 115, three STRIBILD subjects had protocol-prohibited documented resistance and one PI + RTV + TRUVADA subject was not on a protease inhibitor-based regimen at screening; in Study 121, one STRIBILD subject had protocol-prohibited documented resistance.

Table 11 : Virologic Outcomes of Randomized Treatment in Study 115 and Study 121 at Week 48

  Study GS-US-236-0115a Study GS-US-236-0121a
STRIBILD
(N=290)
PI+RTV + TRUVADA
(N=139)
STRIBILD
(N=290)
NNRTI + TRUVADA
(N=143)
Virologic Success HIV-1 RNA < 50 copies/mL 94% 87% 93% 88%
Virologic Failureb 1% 1% 1% 1%
No Virologic Data in Week 48 Window 6% 12% 6% 11%
  Discontinued Study Drug Due to AE or Deathc 2% 1% 2% 1%
  Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 4% 10% 4% 9%
  Missing Data During Window but on Study Drug 0% 0% 0% 1%
a Week 48 window is between Day 295 and 378 (inclusive).
b Includes subjects who had ≥ 50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
c Includes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
d Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, eg., withdrew consent, loss to follow-up, etc.

Last reviewed on RxList: 1/2/2015
This monograph has been modified to include the generic and brand name in many instances.

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