"On January 7, 2010, FDA approved an updated Atripla label including new efficacy, safety and resistance data in treatment experienced patients from a trial (Study 073: A Phase IV, Open-Label, Randomized, Multicenter Study Evaluating Efficacy "...
For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information.
Mechanism Of Action
TRUVADA is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate.
One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).
The pharmacokinetic properties of emtricitabine are summarized in Table 6. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate
The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 6. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.
Table 6 : Single Dose Pharmacokinetic Parameters for
Emtricitabine and Tenofovirin Adultsa
|Fasted Oral Bioavailabilityb (%)||92 (83.1–106.4)||25 (NC–45.0)|
|Plasma Terminal Elimination Half-Lifeb (hr)||10 (7.4–18.0)||17 (12.0–25.7)|
|Cmax c (μg/mL)||1.8 ± 0.72d||0.30 ± 0.09|
|AUCc (μg•hr/mL)||10.0 ± 3.12d||2.29 ± 0.69|
|CL/Fc (mL/min)||302 ± 94||1043 ± 115|
|CLrenal c (mL/min)||213 ± 89||243 ± 33|
|a NC = Not calculated
b Median (range)
c Mean (± SD)
d Data presented as steady state values
Effects of Food on Oral Absorption
TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.
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.
Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.
TRUVADA should not be administered to HIV-1 infected pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb).
Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.
Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).
Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See WARNINGS AND PRECAUTIONS]. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in HIV-infected adult patients with estimated creatinine clearance 30–49 mL/min. No data are available to make dose recommendations in pediatric patients with renal impairment. TRUVADA should not be used in patients with estimated creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See DOSAGE AND ADMINISTRATION].
TRUVADA for a PrEP indication should not be used in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [See DOSAGE AND ADMINISTRATION].
Patients with Hepatic Impairment
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. The pharmacokinetics of TRUVADA or 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.
Assessment of Drug Interactions
The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.
In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 7 and 8). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and efavirenz, methadone, nelfinavir, oral contraceptives, or ribavirin in trials conducted in healthy volunteers (see Tables 9 and 10).
Table 7 Drug Interactions: Changes in Pharmacokinetic
Parameters forEmtricitabine in the Presence of the Coadministered Druga
|Coadministered Drug||Dose of Coadministered Drug (mg)||Emtricitabine Dose (mg)||N||% Change of Emtricitabine Pharmacokinetic Parametersb (90% CI)|
|Tenofovir DF||300 once daily × 7 days||200 once daily × 7 days||17||⇔||⇔||↑ 20
(↑12 to ↑ 29)
|Zidovudine||300 twice daily × 7 days||200 once daily × 7 days||27||⇔||⇔||⇔|
|Indinavir||800 × 1||200 × 1||12||⇔||⇔||NA|
|Famciclovir||500 × 1||200 × 1||12||⇔||⇔||NA|
|Stavudine||40 × 1||200 × 1||6||⇔||⇔||NA|
|a All interaction trials conducted in healthy
b. ↑ = Increase; ↓ = Decrease; ⇔ = No Effect; NA = Not Applicable
Table 8 : Drug Interactions:
Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence
|Coadministered Drug||Dose of Coadministered Drug (mg)||Emtricitabine Dose (mg)||N||% Change of Coadministered Drug Pharmacokinetic Parametersb (90% CI)|
|Tenofovir DF||300 once daily × 7 days||200 once daily × 7 days||17||⇔||⇔||⇔|
|Zidovudine||300 twice daily × 7 days||200 once daily × 7 days||27||↑ 17
(↑ 0 to ↑38)
(↑5 to ↑20)
|Indinavir||800 × 1||200 × 1||12||⇔||⇔||NA|
|Famciclovir||500 × 1||200 × 1||12||⇔||⇔||NA|
|Stavudine||40 × 1||200 × 1||6||⇔||⇔||NA|
|a All interaction trials conducted in healthy
b ↑ = Increase; ↓ = Decrease; ⇔ = No Effect; NA = Not Applicable
Table 9: Drug Interactions: Changes in
Pharmacokinetic Parameters for Tenofovira in the Presence of the
|Coadministered Drug||Dose of Coadministered Drug (mg)||N||% Change of Tenofovir Pharmacokinetic Parametersb (90% CI)|
|Atazanavirc||400 once daily × 14 days||33||↑14
(↑ 8 to ↑ 20)
(↑21 to ↑28)
(↑15 to ↑30)
|Atazanavir/ Ritonavirc||300/100 once daily||12||↑34
(↑20 to ↑51)
(↑30 to ↑ 45)
|Darunavir/ Ritonavird||300/100 twice daily||12||↑24
(↑8 to ↑42)
(↑10 to ↑35)
(↑19 to ↑57)
|Didanosinee||250 or 400 once daily × 7 days||14||⇔||⇔||⇔|
|Emtricitabine||200 once daily × 7 days||17||⇔||⇔||⇔|
|Entecavir||1 mg once daily x 10 days||28||⇔||⇔||⇔|
|Indinavir||800 three times daily × 7 days||13||↑14
(↓ 3 to ↑33)
|Lamivudine||150 twice daily × 7 days||15||⇔||⇔||⇔|
|Lopinavir/ Ritonavir||400/100 twice daily × 14 days||24||⇔||↑32
(↑25 to ↑38)
(↑ 37 to ↑66)
|Saquinavir/ Ritonavir||1000/100 twice daily × 14 days||35||⇔||⇔||↑23
(↑ 16 to ↑ 30)
|Tacrolimus||0.05 mg/kg twice daily x 7 days||21||↑13
(↑1 to ↑27)
|Tipranavir/ Ritonavirf||500/100 twice daily||22||↓23
(↓32 to ↓ 13)
(↓ 9 to ↑5)
(↓ 2 to ↑17)
|750/200 twice daily
(↓46 to ↓29)
(↓ 6 to ↑10)
(↑1 to ↑27)
|a Subjects received VIREAD 300 mg once daily
b Increase = ↑; Decrease = ↓; No Effect = ⇔; NC = Not Calculated
c Reyataz Prescribing Information
d Prezista Prescribing Information
e Subjects received didanosine buffered tablets.
f. Aptivus Prescribing Information
Table 10 : Drug Interactions: Changes in
Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir
|Coadministered Drug||Dose of Coadministered Drug (mg)||N||% Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI)|
(↓ 1 to ↑ 26)
|Atazanavirb||400 once daily × 14 days||34||↓21
(↓27 to ↓14)
(↓30 to ↓19)
(↓48 to ↓ 32)
|Atazanavirb||Atazanavir/Ritonavir 300/100 once daily × 42 days||10||↓28
(↓50 to ↑5)
(↓42 to ↓3)
(↓46 to ↑10)
|Darunavird||Darunavir/Ritonavir 300/100 mg once daily||12||↑ 16
(↓6 to ↑42)
(↓5 to ↑54)
(↓10 to ↑69)
|Didanosinee||250 once, simultaneously with tenofovir DF and a light mealf||33||↓20g
(↓32 to ↓7)
|Emtricitabine||200 once daily × 7 days||17||⇔||⇔||↑20
(↑12 to ↑29)
|Indinavir||800 three times daily × 7 days||12||↓11
(↓30 to ↑12)
|Entecavir||1 mg once daily x 10 days||28||⇔||↑13
(↑11 to ↑15)
|Lamivudine||150 twice daily × 7 days||15||↓24
(↓34 to ↓12)
|Lopinavir Ritonavir||Lopinavir/Ritonavir 400/100 twice daily × 14 days||24||⇔||⇔||⇔|
|Saquinavir Ritonavir||Saquinavir/Ritonavir 1000/100 twice daily × 14 days||32||↑22
(↑6 to ↑41)
|↑29h (↑12 to ↑48)||↑ 47h
(↑ 23 to ↑76)
(↑3 to ↑46)
|Tacrolimus||0.05 mg/kg twice daily x 7 days||21||⇔||⇔||⇔|
|Tipranaviri||Tipranavir/Ritonavir 500/100 twice daily||22||↓17
(↓ 26 to ↓6)
(↓25 to ↓9)
(↓ 30 to ↓10)
|Tipranavir/Ritonavir 750/200 twice daily
(↓16 to ↓ 4)
(↓15 to ↓3)
(↓22 to 0)
|a Increase = ↑; Decrease = ↓; No
Effect = ⇔; NA =
b Reyataz Prescribing Information
c In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
d Prezista Prescribing Information.
e Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules.
f 373 kcal, 8.2 g fat
g Compared with didanosine
(enteric-coated) 400 mg administered alone under fasting conditions.
h Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
i Aptivus Prescribing Information.
Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir disoproxil fumarate with didanosine enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. See DRUG INTERACTIONS regarding use of didanosine with VIREAD.
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 reverse transcriptase (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.
Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate 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 and Tenofovir Disoproxil Fumarate: In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
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 (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. 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).
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. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. 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 to 5.5 μM).
Prophylactic Activity in a Nonhuman Primate Model of HIV Transmission
Emtricitabine and Tenofovir Disoproxil Fumarate: The prophylactic activity of the combination of daily oral emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral FTC and TDF remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.
Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical trial of treatment-naive subjects [Study 934, see Clinical Studies], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2–4 fold reduction in susceptibility to tenofovir.
In treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed greater than 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.
iPrEx Trial: In a clinical study of HIV-1 seronegative subjects [iPrEx Trial, see Clinical Studies], no amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 48 subjects in the TRUVADA group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with resistance to emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the TRUVADA group and 1 of 8 in the placebo group). One of the two subjects in the TRUVADA group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment.
Partners PrEP Trial: In a clinical study of HIV-1 seronegative subjects [Partners PrEP Trial, see Clinical Studies], no variants expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 12 subjects in the TRUVADA group, 15 subjects in the VIREAD group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the TRUVADA group, 5 in the VIREAD group, and 6 in the placebo group). One of the three subjects in the TRUVADA group who was infected with wild type virus at enrollment selected an M184V expressing virus by week 12. Two of the five subjects in the VIREAD group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment developed a K65R substitution by week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrollment, 4 subjects (2 in the VIREAD group, 1 in the TRUVADA group, and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with tenofovir or emtricitabine and may have been present in the infecting virus.
Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, 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 K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
Tenofovir Disoproxil Fumarate: HIV-1 isolates from subjects (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.
Animal Toxicology And/Or Pharmacology
Tenofovir and tenofovir disoproxil fumarate 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.
Clinical Study 934 supports the use of TRUVADA tablets for the treatment of HIV-1 infection. Additional data in support of the use of TRUVADA are derived from clinical Study 903, in which lamivudine and tenofovir disoproxil fumarate (tenofovir DF) were used in combination in treatment-naive adults, and clinical Study 303 in which emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these trials, please consult the prescribing information for tenofovir DF and emtricitabine. The iPrEx study and Partners PrEP study support the use of TRUVADA to help reduce the risk of acquiring HIV-1.
Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm³ (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count ( < or ≥ 200 cells/mm³); 41% had CD4+ cell counts < 200 cells/mm³ and 51% of subjects had baseline viral loads > 100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 11.
Table 11 : Outcomes of
Randomized Treatment at Week 48 and 144 (Study 934)
|Outcomes||At Week 48||At Week 144|
|FTC + TDF + EFV
|AZT/3TC + EFV
|FTC + TDF + EFV
|AZT/3TC + EFV
|Change in antiretroviral regimen||1%||1%||1%||1%|
|Discontinued due to adverse event||4%||9%||5%||12%|
|Discontinued for other reasonsd||10%||14%||20%||22%|
|a Subjects who were responders at Week 48 or
Week 96 (HIV-1 RNA < 400 copies/mL) but did not consent to continue trial
after Week 48 or Week 96 were excluded from analysis.
b Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Weeks 48 and 144.
c Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Weeks 48 and 144.
d Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.
Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA < 400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA < 400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm³ in the emtricitabine + tenofovir DF group and 158 cells/mm³ in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm³ at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
The iPrEx trial was a randomized double-blind placebo-controlled multinational study evaluating TRUVADA in 2499 HIV-seronegative men or transgender women who have sex with men and with evidence of high risk behavior for HIV-1 infection. Evidence of high risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.
All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received TRUVADA and 1248 received placebo. The mean age of subjects was 27 years, 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.
Subjects were followed for 4237 person-years. The primary outcome measure for the study was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the TRUVADA group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18% to 60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34% to 72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the TRUVADA and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence.
Partners PrEP Trial
The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3 arm trial conducted in 4758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586), in preventing HIV-1 acquisition by the uninfected partner.
All subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61-64% across study drug groups), and had a mean age of 33-34 years.
Following 7827 person-years of follow up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to TRUVADA and placebo, respectively. Two of the 13 seroconversions in the TRUVADA arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for TRUVADA relative to placebo was 75% (95% CI: 55% to 87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence.
Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.
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