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Mechanism Of Action
COMPLERA is a fixed-dose combination of the antiretroviral drugs emtricitabine, rilpivirine and tenofovir disoproxil fumarate [See Microbiology].
Effects on Electrocardiogram
The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).
When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of rilpivirine [See WARNINGS AND PRECAUTIONS].
COMPLERA: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), rilpivirine, emtricitabine and tenofovir exposures were bioequivalent when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).
Single-dose administration of COMPLERA tablet to healthy subjects under fasted conditions provided approximately 25% higher exposure of rilpivirine compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of emtricitabine and tenofovir were comparable (N=15).
Emtricitabine: Following oral administration, emtricitabine is absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of EMTRIVA to 20 HIV-1-infected subjects, the mean steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 μg per mL and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr per mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg per mL. The mean absolute bioavailability of EMTRIVA capsules was 93%. Less than 4% of emtricitabine binds to human plasma proteins in vitro over the range of 0.02 to 200 μg per mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine, approximately 14% in the feces and 13% is recovered as metabolites in the urine. The metabolites of emtricitabine include 3'-sulfoxide diastereomers (approximately 9% of the dose) and the glucuronic acid conjugate (approximately 4% of the dose). Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with creatinine clearance > 80 mL per minute of 213 ± 89 mL per minute (mean ± SD). The plasma emtricitabine half-life is approximately 10 hours.
Rilpivirine: The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-na´ve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1-infected subjects than in healthy subjects. After oral administration, the Cmax of rilpivirine is achieved within 4–5 hours. The absolute bioavailability of rilpivirine is unknown.
Table 5 : Population Pharmacokinetic Estimates of
Rilpivirine 25 mg Once Daily in Antiretroviral Treatment-Na´ve HIV-1-infected
Subjects (Pooled Data from Phase 3 Trials through Week 96)
|Parameter||Rilpivirine 25 mg once daily N=679|
|Mean ± Standard Deviation||2235 ± 851|
|Median (Range)||2096 (198 - 7307)|
|Mean ± Standard Deviation||79 ± 35|
|Median (Range)||73 (2 - 288)|
Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism by the cytochrome CYP3A system. The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (less than 1% of dose) were detected in urine.
Tenofovir Disoproxil Fumarate: Following oral administration of a single 300 mg dose of VIREAD to HIV-1-infected subjects in the fasted state, Cmax was achieved in one hour. Cmax and AUC values were 0.30 ± 0.09 μg per mL and 2.29 ± 0.69 μg•hr per mL, respectively. The oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro over the range of 0.01 to 25 μg per mL. Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with creatinine clearance > 80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Effects of Food on Oral Absorption
The food effect trial for COMPLERA evaluated two types of meals. The trial defined a meal with 390 kcal containing 12 g fat as a light meal, and a meal with 540 kcal containing 21 g fat as a standard meal. Relative to fasting conditions, the administration of COMPLERA to healthy adult subjects with both types of meals resulted in increased exposures of rilpivirine and tenofovir. The Cmax and AUC of rilpivirine increased 34% and 9% with a light meal, while increasing 26% and 16% with a standard meal, respectively. The Cmax and AUC of tenofovir increased 12% and 28% with a light meal, while increasing 32% and 38% with a standard meal, respectively. Emtricitabine exposures were not affected by food.
The effects on rilpivirine, emtricitabine and tenofovir exposure when COMPLERA is administered with a high fat meal were not evaluated.
COMPLERA should be taken with food.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.
Rilpivirine: Population pharmacokinetic analysis of rilpivirine in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to rilpivirine.
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.
No clinically relevant pharmacokinetic differences have been observed between men and women for emtricitabine, rilpivirine, and tenofovir DF.
Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in adolescent subjects (12 to less than 18 years of age). The pharmacokinetics of rilpivirine in pediatric subjects have not been established.
Pharmacokinetics of emtricitabine, rilpivirine and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [See Use In Specific Populations].
Patients with Renal Impairment
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax, and AUC of emtricitabine and tenofovir were increased [See WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Rilpivirine: Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction [See Use In Specific Populations].
Patients with Hepatic Impairment
Emtricitabine: The pharmacokinetics of emtricitabine have 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.
Rilpivirine: Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment [See Use In Specific Populations].
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV-infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.
Hepatitis B and/or Hepatitis C Virus Coinfection
Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in hepatitis B and/or C virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to rilpivirine.
Assessment of Drug Interactions
COMPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, COMPLERA should not be administered with other HIV antiretroviral medications. Information regarding potential drug-drug interactions with other HIV antiretroviral medications is not provided. Please refer to the Edurant, VIREAD and EMTRIVA prescribing information as needed.
The drug interaction studies described were conducted with emtricitabine, rilpivirine, or tenofovir DF as individual agents; no drug interaction studies have been conducted using COMPLERA.
Emtricitabine and Tenofovir Disoproxil Fumarate: In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug [See DRUG INTERACTIONS].
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
Drug interaction studies were performed for emtricitabine and the following medications: tenofovir DF and famciclovir. Tenofovir increased the Cmin of emtricitabine by 20% (90% confidence interval [CI]: [↓12 to ↓29]) and had no effect on emtricitabine Cmax and AUC. Emtricitabine had no effect on the Cmax, AUC and Cmin of tenofovir. Coadministration of emtricitabine and famciclovir had no effect on the Cmax or AUC of either medication.
Drug interaction studies were performed for tenofovir DF and the following medications: entecavir, methadone, oral contraceptives (ethinyl estradiol/norgestimate), ribavirin, and tacrolimus. Tacrolimus increased the Cmax of tenofovir by 13% (90% CI: [↓1 to ↓27]) and had no effect on the tenofovir AUC and Cmin. Tenofovir had no effect on the Cmax, AUC and Cmin of tacrolimus.
The Cmax, AUC and Cmin of tenofovir were not affected in the presence of entecavir. Tenofovir increased the AUC of entecavir by 13% (90% CI: [↓11 to ↓15]) and had no effect on the entecavir Cmax and Cmin.
Tenofovir had no effect on the Cmax, AUC and Cmin of methadone or ethinyl estradiol/norgestimate or the Cmax and AUC of ribavirin.
Rilpivirine: Rilpivirine is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.
Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
The effects of coadministration of other drugs on the AUC, Cmax and Cmin values of rilpivirine are summarized in Table 6. The effect of coadministration of rilpivirine on the AUC, Cmax and Cmin values of other drugs are summarized in Table 7. For information regarding clinical recommendations, see DRUG INTERACTIONS.
Table 6 : Drug Interactions: Changes in
Pharmacokinetic Parameters for Rilpivirine in the Presence of the
|Coadministered Drug||Dose of Coadministered Drug (mg)||Dose of Rilpivirine||Na||Mean % Change of Rilpivirine Pharmacokinetic Parametersb
|Acetaminophen||500 mg single dose||150 mg once dailyc||16||↑ 9
(↑ 1 to ↑ 18)
(↑ 10 to ↑ 22)
(↑ 16 to ↑ 38)
|Atorvastatin||40 mg once daily||150 mg once dailyc||16||↓9
(↓21 to ↑ 6)
(↓19 to ↓1)
(↓16 to ↓4)
|Chlorzoxazone||500 mg single dose taken 2 hours after rilpivirine||150 mg once dailyc||16||↑ 17
(↑ 8 to ↑ 27)
(↑ 16 to ↑ 35)
(↑ 9 to ↑ 28)
|Ethinyl estradiol/ Norethindrone||0.035 mg once daily/1 mg once daily||25 mg once daily||16||↔d||↔d||↔d|
|40 mg single dose taken 12 hours before rilpivirine||150 mg single dosec||24||↓1
(↓16 to ↑ 16)
(↓22 to ↑ 7)
|Famotidine||40 mg single dose taken 2 hours before rilpivirine||150 mg single dosec||23||↓85
(↓88 to ↓81)
(↓80 to ↓72)
|40 mg single dose taken 4 hours after rilpivirine||150 mg single dosec||24||↑ 21
(↑ 6 to ↑ 39)
(↑ 1 to ↑ 27)
|Ketoconazole||400 mg once daily||150 mg once dailyc||15||↑ 30
(↑ 13 to ↑ 48)
(↑ 31 to ↑ 70)
(↑ 57 to ↑ 97)
|Methadone||60 -100 mg once daily individualized dose||25 mg once daily||12||↔d||↔d||↔d|
|Omeprazole||20 mg once daily||150 mg once dailyc||16||↓40
(↓52 to ↓27)
(↓49 to ↓29)
(↓42 to ↓22)
|Rifabutin||300 mg once daily||25 mg once daily||18||↓31
(↓38 to ↓24)
(↓48 to ↓35)
(↓54 to ↓41)
|300 mg once daily||50 mg once daily||18||↑ 43
(↑ 30 to ↑ 56)e
(↑ 6 to ↑ 26)e
(↓15 to↑ 1)e
|Rifampin||600 mg once daily||150 mg once dailyc||16||↓69
(↓73 to ↓64)
(↓82 to ↓77)
(↓90 to ↓87)
|Sildenafil||50 mg single dose||75 mg once daily||16||↓8
(↓15 to ↓1)
(↓8 to ↑ 5)
(↓2 to ↑ 9)
|Telaprevir||750 mg every 8 hours||25 mg once daily||16||↑ 49
(↑ 20 to ↑ 84)
(↑ 44 to ↑ 120)
(↑ 55 to ↑ 141)
|Tenofovir Disoproxil Fumarate||300 mg once daily||150 mg once dailyc||16||↓4
(↓19 to ↑13)
(↓13 to ↑18)
(↓17 to ↑16)
|NA = not available
a N=maximum number of subjects for Cmax, AUC, or Cmin
b Increase = ↓; Decrease = ↓; No Effect = ↔;
c The Interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug.
d Comparison based on historic controls.
e Reference arm for comparison was 25 mg q.d. rilpivirine administered alone.
Table 7 : Drug Interactions: Changes in
Pharmacokinetic Parameters for Coadministered Drugs in the Presence of
|Coadministered Drug||Dose of Coadministered Drug (mg)||Dose of Rilpivirine||Na||Mean % Change of Coadministered Drug Pharmacokinetic Parametersb
|Acetaminophen||500 mg single dose||150 mg once dailyc||16||↓3
(↓14 to ↑ 10)
(↓14 to ↓3)
|Atorvastatin||40 mg once daily||150 mg once dailyc||16||↑ 35
(↑ 8 to ↑ 68)
(↓3 to ↑ 12)
(↓31 to ↑ 3)
|2-hydroxy- atorvastatin||16||↑ 58
(↑ 33 to ↑ 87)
(↑ 29 to ↑ 50)
(↑ 10 to ↑ 58)
|4-hydroxy- atorvastatin||16||↑ 28
(↑ 15 to ↑ 43)
(↑ 13 to ↑ 33)
|Chlorzoxazone||500 mg single dose taken 2 hours after rilpivirine||150 mg once dailyc||16||↓2
(↓15 to ↑ 13)
(↓5 to ↑ 13)
|Digoxin||0.5 mg single dose||25 mg once daily||22||↑ 6
(↓3 to ↑ 17)
(↓7 to ↑ 4)d
|Ethinyl estradiol||0.035 mg once daily||25 mg once daily||17||↑ 17
(↑ 6 to ↑ 30)
(↑ 10 to ↑ 19)
(↑ 3 to ↑ 16)
|Norethindrone||1 mg once daily||17||↓6
(↓17 to ↑ 6)
(↓16 to ↓6)
(↓10 to ↑ 8)
|Ketoconazole||400 mg once daily||150 mg once dailyc||14||↓15
(↓20 to ↓10)
(↓30 to ↓18)
(↓75 to ↓54)
|R(-) methadone||60-100 mg once daily individualized dose||25 mg once daily||13||↓14
(↓22 to ↓5)
(↓26 to ↓5)
(↓33 to ↓9)
(↓22 to ↓3)
(↓26 to ↓4)
(↓33 to ↓8)
|Metformin||850 mg single dose||25 mg once daily||20||↑ 2
(↓5 to ↑ 10)
(↓10 to ↑ 6)e
|Omeprazole||20 mg once daily||150 mg once dailyc||15||↓14
(↓32 to ↑ 9)
(↓24 to ↓3)
|Rifampin||600 mg once daily||150 mg once dailyc||16||↑ 2
(↓7 to ↑ 12)
(↓8 to ↑ 7)
(↓13 to ↑ 15)
(↓23 to ↑ 7)
|Sildenafil||50 mg single dose||75 mg once dailyc||16||↓7
(↓20 to ↑ 8)
(↓13 to ↑ 8)
(↓20 to ↑ 2)
(↓15 to ↓1)d
|Telaprevir||750 mg every 8 hours||25 mg once daily||13||↓3
(↓21 to ↑ 21)
(↓24 to ↑ 18)
(↓33 to ↑ 18)
|Tenofovir Disoproxil Fumarate||300 mg once daily||150 mg once dailyc||16||↑19
(↑6 to ↑34)
(↑16 to ↑31)
(↑10 to ↑38)
|NA = not available
a N=maximum number of subjects for Cmax, AUC, or Cmin
b Increase = ↓; Decrease = ↓; No Effect = ↔;
c The Interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily).
d AUC (0-last)
e N (maximum number of subjects with data) for AUC(0-∞)=15
Mechanism of Action
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 polymerase α, β, ε, and mitochondrial DNA polymerase γ.
Rilpivirine: Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Tenofovir Disoproxil Fumarate: 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.
Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate: The triple combination of emtricitabine, rilpivirine, and tenofovir was not antagonistic in cell culture.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 μM. 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 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine, and rilpivirine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.
Rilpivirine: Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM. Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510 to 10830 nM). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM. The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc or the integrase strand transfer inhibitor raltegravir.
Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in 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 μM. 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 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM–5.5 μM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.
In Cell Culture
Emtricitabine and Tenofovir Disoproxil Fumarate: 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 addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.
Rilpivirine: Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.
In HIV-1-Infected Subjects With No Antiretroviral Treatment History
In the Week 96 pooled resistance analysis for subjects receiving rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF in the Phase 3 clinical trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the rilpivirine plus emtricitabine/tenofovir DF arm compared to the efavirenz plus emtricitabine/tenofovir DF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the rilpivirine plus emtricitabine/tenofovir DF arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 42% (18/43) of the resistance analysis subjects in the efavirenz plus emtricitabine/tenofovir DF arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to emtricitabine or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the rilpivirine arm compared to 26% (11/43) in the efavirenz arm.
Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6-621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the rilpivirine resistance analysis subjects than in efavirenz resistance analysis subjects (See Table 8).
NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of ≤ 100,000 copies/mL compared to viruses from subjects with baseline viral loads of > 100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts ≥ 200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts < 200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.
Table 8 : Proportion of Frequently Emerging Reverse
Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Subjectsa
Who Received Rilpivirine or Efavirenz in Combination with
Emtricitabine/Tenofovir DF from Pooled Phase 3 TMC278-C209 and TMC278-C215
Trials in the Week 96 Analysis
|C209 and C215
|Rilpivirine + FTC/TDF
|Efavirenz + FTC/TDF
|Subjects who Qualified for Resistance Analysis||14% (77/550)||8% (43/546)|
|Subjects with Evaluable PostBaseline Resistance Data||70||31|
|Emergent NNRTI Substitutionsb|
|Any||63% (44/70)||55% (17/31)|
|K101E/P/T/Q||19% (13/70)||10% (3/31)|
|K103N||1% (1/70)||39% (12/31)|
|V179I/D||6% (4/70)||10% (3/31)|
|Y181C/I/S||13% (9/70)||3% (1/31)|
|Emergent NRTI Substitutionsd|
|Any||63% (44/70)||32% (10/31)|
|M184I/V||59% (41/70)||26% (8/31)|
|K65R/N||11% (8/70)||6% (2/31)|
|A62V, D67N/G, K70E, Y115F, or K219E/Re||20% (14/70)||3% (1/31)|
|a Subjects who qualified for resistance
b V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230
c This combination of NRTI and NNRTI substitutions is a subset of those with the E138K.
d A62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R
e These substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in rilpivirine resistance analysis subjects.
In Virologically-Suppressed HIV-1-Infected Subjects
Study 106: Through Week 48, four subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and one subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All four of the subjects who had resistance emergence on COMPLERA had evidence of emtricitabine resistance and three of the subjects had evidence of rilpivirine resistance.
Rilpivirine, Emtricitabine, and Tenofovir Disoproxil Fumarate:
In Cell Culture
No significant cross-resistance has been demonstrated between rilpivirine-resistant HIV-1 variants and emtricitabine or tenofovir, or between emtricitabine- or tenofovir-resistant variants and rilpivirine.
Site-Directed NNRTI Mutant Virus
Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9-fold for clinical isolates and 6-fold for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.
In HIV-1-Infected Subjects With No Antiretroviral Treatment History
Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.
Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In a pooled 96-Week analysis for subjects receiving rilpivirine in combination with emtricitabine/tenofovir DF in the Phase 3 clinical trials TMC278-C209 and TMC278-C215, 43 of the 70 (61%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine ( ≥ 2.5-fold). Of these, 84% (n=36/43) were resistant to efavirenz ( ≥ 3.3 fold change), 88% (n=38/43) were resistant to etravirine ( ≥ 3.2 fold change) and 60% (n=26/43) were resistant to nevirapine ( ≥ 6 fold change). In the efavirenz arm, 3 of the 15 (20%) efavirenz resistance analysis subjects had viruses with resistance to etravirine and rilpivirine, and 93% (14/15) had resistance to nevirapine. Virus from subjects experiencing virologic failure on rilpivirine in combination with emtricitabine/tenofovir DF developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the substitutions associated with NNRTI resistance K103N or rilpivirine-associated substitutions were susceptible to emtricitabine.
Tenofovir Disoproxil Fumarate: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. 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 substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or rilpivirine-associated substitutions were susceptible to tenofovir.
Animal Toxicology And/Or Pharmacology
Tenofovir Disoproxil Fumarate: Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
In HIV-1-Infected Subjects With No Antiretroviral Treatment History
The efficacy of COMPLERA is based on the analyses of 48- and 96-week data from two randomized, double-blind, controlled studies (Study C209 (ECHO) and TRUVADA subset of Study C215 (THRIVE)) in treatment-na´ve, HIV-1-infected subjects (N=1368). The studies are identical in design with the exception of the background regimen (BR). Subjects were randomized in a 1:1 ratio to receive either rilpivirine 25 mg (N=686) once daily or efavirenz 600 mg (N=682) once daily in addition to a BR. In Study C209 (N=690), the BR was emtricitabine/tenofovir DF. In Study C215 (N=678), the BR consisted of 2 NRTIs: emtricitabine/tenofovir DF (60%, N=406) or lamivudine/zidovudine (30%, N=204) or abacavir plus lamivudine (10%, N=68).
For subjects who received emtricitabine/tenofovir DF (N=1096) in C209 and C215, the mean age was 37 years (range 18-78), 78% were male, 62% were White, 24% were Black, and 11% were Asian. The mean baseline CD4+ cell count was 265 cells/mm3 (range 1–888) and 31% had CD4+ cell counts < 200 cells/mm3. The median baseline plasma HIV-1 RNA was 5 log10 copies/mL (range 2–7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had baseline viral loads ≤ 100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL and 11% of subjects had baseline viral load > 500,000 copies/mL.
Treatment outcomes through 96 weeks for the subset of subjects receiving emtricitabine/tenofovir DF in studies C209 and C215 (Table 9) are generally consistent with treatment outcomes for all participating subjects (presented in the prescribing information for Edurant). The incidence of virologic failure was higher in the rilpivirine arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
Table 9 : Virologic Outcome of Randomized Treatment of
Studies C209 and C215 (Pooled Data for Subjects Receiving Rilpivirine or
Efavirenz in Combination with Emtricitabine/Tenofovir DF) at Week 96a
|Rilpivirine + FTC/TDF
|Efavirenz + FTC/TDF
|HIV-1 RNA < 50 copies/mLb||77%||77%|
|HIV-1 RNA ≥ 50 copies/mLc||14%||8%|
|No virologic data at Week 96 window|
|Discontinued study due to adverse event or deathd||4%||9%|
|Discontinued study for other reasonse and the last available HIV-1 RNA < 50 copies/mL (or missing)||4%||6%|
|Missing data during window but on study||< 1%||< 1%|
|HIV-1 RNA < 50 copies/mL by Baseline HIV-1 RNA (copies/mL)|
|HIV-1 RNA ≥ 50 copies/mLc by Baseline HIV-1 RNA (copies/mL)|
|HIV-1 RNA < 50 copies/mL by Baseline CD4+ Cell Count (cells/mm )|
|HIV-1 RNA ≥ 50 copies/mLc by Baseline CD4+ Cell Count (cells/mm )|
|a Analyses were based on the last observed
viral load data within the Week 96 window (Week 90-103).
b Predicted difference (95% CI) of response rate is 0.5% (-4.5% to 5.5%) at Week 96.
c Includes subjects who had ≥ 50 copies/mL in the Week 96 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 load value of ≥ 50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol.
d Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.
e 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.
Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm3 for rilpivirine plus emtricitabine/tenofovir DF-treated subjects and 223 cells/mm3 for efavirenz plus emtricitabine/tenofovir DF-treated subjects.
In Virologically-Suppressed HIV-1-Infected subjects
The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination with two NRTIs to COMPLERA was evaluated in Study 106, a randomized, open-label study in virologically-suppressed HIV-1-infected adults. Subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of COMPLERA, and must have been suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to COMPLERA at baseline (COMPLERA arm, N = 317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, N = 159) and then switch to COMPLERA for an additional 24 weeks (N =152). Subjects had a mean age of 42 years (range 19-73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean baseline CD4+ cell count was 584 cells/mm3 (range 42–1484). Randomization was stratified by use of tenofovir DF and/or lopinavir/ritonavir in the baseline regimen.
Treatment outcomes are presented in Table 10.
Table 10 : Virologic Outcomes of Randomized Treatment
in Study GS-US-264-0106
|COMPLERA Week 48a
N = 317
|Stayed on Baseline Regimen (SBR) Week 24b
N = 159
|HIV-1 RNA < 50 copies/mLc||89% (283/317)||90% (143/159)|
|HIV-1 RNA ≥ 50 copies/mLd||3% (8/317)||5% (8/159)|
|No Virologic Data at Week 24 Window|
|Discontinued Study Drug Due to AE or Deathe||2% (7/317)||0%|
|Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLf||5% (16/317)||3% (5/159)|
|Missing Data During Window but on Study Drug||1% (3/317)||2% (3/159)|
|a Week 48 window is between Day 295 and 378
b For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to COMPLERA, the Week 24 window is between Day 127 and first dose day on COMPLERA.
c Predicted difference (95% CI) of response rate for switching to COMPLERA at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is -0.7% (-6.4% to 5.1%).
d Includes subjects who had HIV-1 RNA ≥ 50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had a viral load value of ≥ 50 copies/mL.
e 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.
f 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.
Last reviewed on RxList: 5/19/2015
This monograph has been modified to include the generic and brand name in many instances.
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