"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
Mechanism of Action
Tenofovir disoproxil fumarate is an antiviral drug [See Microbiology].
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg•hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption
Administration of VIREAD 300 mg tablets following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.
Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Gender: Tenofovir pharmacokinetics are similar in male and female subjects.
Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 11). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of VIREAD 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
Table 11 : Mean (± SD)
Tenofovir Pharmacokinetic Parameters by Age Groups for HIV–1–infected Pediatric
|Dose and Formulation||300 mg Tablet||8 mg/kg Oral Powder|
|12 to < 18 Year (N=8)||2 to < 12 Years (N=23)|
|Cmax (μg/mL)||0.38 ± 0.13||0.24 ± 0.13|
|AUCtau (μg•hr/mL)||3.39 ± 1.22||2.59 ± 1.06|
Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of VIREAD 300 mg tablet were comparable to exposures achieved in HIV-1-infected adults and adolescents receiving once-daily doses of 300 mg.
Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment [See WARNINGS AND PRECAUTIONS]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (Table 12). It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis [See DOSAGE AND ADMINISTRATION].
Table 12 : Pharmacokinetic
Parameters (Mean ± SD) of Tenofovira
in Subjects with Varying Degrees of Renal Function
|Baseline Creatinine Clearance (mL/min)|| > 80
|Cmax (μg/mL)||0.34 ± 0.03||0.33 ± 0.06||0.37 ± 0.16||0.60 ± 0.19|
|AUC0-∞ (μg•hr/mL)||2.18 ± 0.26||3.06 ± 0.93||6.01 ± 2.50||15.98 ± 7.22|
|CL/F (mL/min)||1043.7 ± 115.4||807.7 ± 279.2||444.4 ± 209.8||177.0 ± 97.1|
|CLrenal (mL/min)||243.5 ± 33.3||168.6 ± 27.5||100.6 ± 27.5||43.0 ± 31.2|
|a 300 mg, single dose of VIREAD|
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single 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. No change in VIREAD dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other medicinal products is low.
VIREAD has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 13 and 14 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug. Coadministration of VIREAD with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of VIREAD with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.
No clinically significant drug interactions have been observed between VIREAD and efavirenz, methadone, nelfinavir, oral contraceptives, or ribavirin.
Table 13 : 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)
(↑21 to ↑36)
|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 14 : Drug Interactions: Changes in
Pharmacokinetic Parameters forCoadministered Drug in the Presence of VIREAD
|Coadministered Drug||Dose of Coadministered Drug (mg)||N||% Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI)|
|Abacavir||300 once||8||↑ 12
(↓ 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)
|↓25c (↓42 to ↓3)||↓23c
(↓ 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 VIREAD and a light mealf||33||↓20g (↓32 to ↓ 7)||⇔ g||NA|
|Emtricitabine||200 once daily × 7 days||17||⇔||⇔||↑20
(↑12 to ↑29)
|Entecavir||1 mg once daily x 10 days||28||⇔||↑13
(↑ 11 to ↑15)
|Indinavir||800 three times daily × 7 days||12||↓ 11
(↓ 30 to ↑12)
|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)
(↑ 12 to ↑48)
(↑ 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 = Not Applicable
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
Mechanism of Action
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, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase 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.
Activity against HIV
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 (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies, tenofovir was not antagonistic 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). 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 μM to 2.2 μM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold reduction in susceptibility to tenofovir.
In Study 903 of treatment-naïve subjects (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See Clinical Studies], genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to VIREAD were not identified in this trial.
In Study 934 of treatment-naïve subjects (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz) [See Clinical Studies], genotypic analysis 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 showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the VIREAD + EMTRIVA 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.
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Studies 902 and 907 conducted in treatment-experienced subjects (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT) [See Clinical Studies], 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.
The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. VIREAD-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to VIREAD was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Studies 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 15 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.
Table 15 : HIV-1 RNA Response at Week 24 by Baseline
VIREAD Susceptibility (IntentTo-Treat)a
|Baseline VIREAD Susceptibilityb||Change in HIV-1 RNAc (N)|
|< 1||-0.74 (35)|
|> 1 and ≤ 3||-0.56 (49)|
|> 3 and ≤ 4||-0.3 (7)|
|> 4||-0.12 (9)|
|a Tenofovir susceptibility was determined by
recombinant phenotypic Antivirogram assay (Virco).
b Fold change in susceptibility from wild-type.
c Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL.
Activity against HBV
The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 μM, with CC50 (50% cytotoxicity concentration) values greater than 100 μM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.
Cumulative VIREAD genotypic resistance has been evaluated annually for up to 240 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL at the end of each study year (or at discontinuation of VIREAD monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on VIREAD monotherapy (15% versus 4%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 16); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD (genotypic and phenotypic analyses).
Table 16 : Amino Acid
Substitutions in Viremic Subjects across HBV Trials of VIREAD
|Compensated Liver Disease||Decompensated Liver Disease
|Viremic at Last Time Point on VIREAD||35/417 (8%)||34/247 (14%)||9/136 (7%)||7/39 (18%)|
|Treatment-Emergent Amino Acid Substitutionse||19f/33 (58%)||10g/27 (37%)||6h/8 (75%)||3/5 (60%)|
|a Nucleotide-naïve subjects from Studies 0102
(N=246) and 0103 (N=171) receiving up to 240 weeks of treatment with VIREAD.
b HEPSERA-experienced subjects from Studies 0102/0103 (N=195) and 0106 (N=52) receiving up to 192 weeks of treatment with VIREAD after switching to VIREAD from HEPSERA. Study 0106, a randomized, double-blind, 168-week Phase 2 trial, has been completed.
c Lamivudine-resistant subjects from Study 0121 (N=136) receiving up to 96 weeks of treatment with VIREAD after switching to VIREAD from lamivudine.
d Subjects with decompensated liver disease from Study 0108 (N=39) receiving up to 48 weeks of treatment with VIREAD.
e Denominator includes those subjects who were viremic at last time point on VIREAD monotherapy and had evaluable paired genotypic data.
f Of the 19 subjects with treatment-emergent amino acid substitutions during Studies 0102 and 0103, 5 subjects had substitutions at conserved sites and 14 ubjects had substitutions only at polymorphic sites, and 8 subjects had only transient substitutions that were not detected at the last time point on VIREAD.
g Of the 10 HEPSERA-experienced subjects with treatment-emergent amino acid substitutions, 2 subjects had substitutions at conserved sites and 8 had substitutions only at polymorphic sites.
h Of the 6 lamivudine-resistant subjects with treatment-emergent substitutions during Study 0121, 3 subjects had substitutions at conserved sites and 3 had substitutions only at polymorphic sites.
Cross-resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.
In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7-to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6-to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9-to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9-to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating VIREAD therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 240 weeks of VIREAD treatment, 11 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir-and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
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 Efficacy in Adults with HIV-1 Infection
Treatment-Naïve Adult Patients
Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm³ (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads > 100,000 copies/mL and 39% had CD4+ cell counts < 200 cells/mm³ . Treatment outcomes through 48 and 144 weeks are presented in Table 17.
Table 17 : Outcomes of
Randomized Treatment at Week 48 and 144 (Study 903)
|Outcomes||At Week 48||At Week 144|
|Added an antiretroviral agent||1%||1%||2%||1%|
|Death||< 1%||1%||< 1%||2%|
|Discontinued due to adverse event||6%||6%||8%||13%|
|Discontinued for other reasonsc||8%||7%||14%||15%|
|a Subjects achieved and maintained confirmed
HIV-1 RNA < 400 copies/mL through Week 48 and 144.
b Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48 and 144.
c Includes lost to follow-up, subject's withdrawal, noncompliance, protocol violation and other reasons.
Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration ( > or ≤ 100,000 copies/mL) and CD4+ cell count ( < or ≥ 200 cells/mm³). Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm³ for the VIREAD arm and 283 cells/mm³ for the stavudine arm.
Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the stavudine group experienced a new CDC Class C event.
Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD 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 18.
Table 18 : Outcomes of Randomized Treatment at Week 48
and 144 (Study 934)
|Outcomes||At Week 48||At Week 144|
|FTC +VIREAD +EFV
|FTC +VIREAD +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 the 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 + VIREAD 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 + VIREAD 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 EMTRIVA + VIREAD 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 + VIREAD group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Treatment-Experienced Adult Patients
Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label VIREAD for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm³ (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
The percent of subjects with HIV-1 RNA < 400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.
Table 19 : Outcomes of
Randomized Treatment (Study 907)
|Outcomes||0–24 weeks||0–48 weeks||24–48 weeks|
|Placebo Crossover to VIREAD
|HIV-1 RNA < 400 copies/mLa||40%||11%||28%||30%|
|Discontinued due to adverse event||3%||3%||5%||5%|
|Discontinued for other reasonsc||3%||3%||5%||1%|
|a Subjects with HIV-1 RNA < 400 copies/mL
and no prior study drug discontinuation at Week 24 and 48 respectively.
b Subjects with HIV-1 RNA ≥ 400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.
c. Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.
At 24 weeks of therapy, there was a higher proportion of subjects in the VIREAD arm compared to the placebo arm with HIV-1 RNA < 50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm³ for the VIREAD group and -5 cells/mm³ for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm³ for the VIREAD group.
Through Week 24, one subject in the VIREAD group and no subjects in the placebo arm experienced a new CDC Class C event.
Clinical Efficacy in Adults with Chronic Hepatitis B
HBeAg-Negative Chronic Hepatitis B
Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg-(anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.
HBeAg-Positive Chronic Hepatitis B
Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and < 5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.
The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.
The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA < 400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).
Table 20 : Histological,
Virological, Biochemical, and Serological Response atWeek 48
|0102 (HBeAg-)||0103 (HBeAg+)|
|Histology Histological Responsea||72%||69%||74%||68%|
|HBV DNA < 400 copies/mL ( < 69 IU/mL)||93%||63%||76%||13%|
|ALT Normalized ALTb||76%||77%||68%||54%|
|Serology HBeAg Loss/ Seroconversion||NAc||NAc||20%/19%||16%/16%|
|HBsAg Loss/ Seroconversion||0/0||0/0||3%/1%||0/0|
|a Knodell necroinflammatory score improvement
of at least 2 points without worsening in Knodell fibrosis.
b The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline.
c NA = Not Applicable
Treatment Beyond 48 Weeks
In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.
In Study 0102, 304 of 375 subjects (81%) continued in the study through Week 240. Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 82% had HBV DNA < 400 copies/mL, and 69% had ALT normalization at Week 240. Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 88% had HBV DNA < 400 copies/mL and 76% had ALT normalization through Week 240. No subject in either treatment group experienced HBsAg loss/seroconversion through Week 240.
In Study 0103, 185 of 266 subjects (69%) continued in the study through Week 240. Among subjects randomized to VIREAD, 63% had HBV DNA < 400 copies/mL, 44% had ALT normalization, and 34% had HBeAg loss (26% seroconversion to anti-HBe antibody) through Week 240. Among subjects randomized to HEPSERA followed by up to 192 weeks of open-label treatment with VIREAD, 64% had HBV DNA < 400 copies/mL, 54% had ALT normalization, and 34% had HBeAg loss (29% seroconversion to anti-HBe antibody) through Week 240. At Week 240, HBsAg loss was 9% in both treatment groups, and seroconversion to anti-HBs was 7% for the subjects initially randomized to VIREAD and 9% for subjects initially randomized to HEPSERA.
Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.
Patients with Lamivudine-Resistant Chronic Hepatitis B
Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/-rtL180M). One hundred forty-one adult subjects were randomized to the VIREAD treatment arm. The mean age of subjects randomized to VIREAD was 47 years (range 18-73), 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAgnegative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA < 400 copies/mL, and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL at Week 96 was similar between the VIREAD monotherapy and the comparator arms.
Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
Patients with Chronic Hepatitis B and Decompensated Liver Disease
VIREAD was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of VIREAD compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).
Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm. At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAgpositive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL [See ADVERSE REACTIONS].
At 48 weeks, 31/44 (70%) and 12/26 (46%) Viread-treated subjects achieved an HBV DNA < 400 copies/mL, and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.
Last reviewed on RxList: 11/11/2013
This monograph has been modified to include the generic and brand name in many instances.
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