Drugs 2003; 63 (15): 1597-1608

ADIS DRUG PROFILE 0012-6667/03/0015-1597/$33.00/0

© Adis Data Information BV 2003. All rights reserved.

Tenofovir Disoproxil Fumarate

Therese M. Chapman, Jane K. McGavin and Stuart Noble
Adis International Limited, Auckland, New Zealand

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597
1. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598
2. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1599
3. Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1601
4. Potential for Viral Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1602
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606
7. Tenofovir Disoproxil Fumarate: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606

Abstract Features and properties of tenofovir disoproxil fumarate

(Viread®)
▲ Tenofovir disoproxil fumarate (tenofovir DF) is a
prodrug of tenofovir, a nucleotide reverse trans- Indication
criptase inhibitor.
▲ In two large, well designed, placebo-controlled HIV infection
clinical trials, tenofovir DF 300 mg/day resulted in
Mechanism of action
significant reductions in HIV-1 RNA from baseline
compared with placebo at 24 weeks in antire- Antiviral Prodrug of nucleotide reverse
troviral-experienced patients with HIV infection. transcriptase inhibitor
Patients in both treatment groups continued to re-
ceive existing stable antiretroviral therapy. Dosage and administration
▲ In an extension phase of one trial, these reductions Recommended dosage 300mg once daily
in viral load were maintained after 96 weeks of
treatment with tenofovir DF. Route of administration Oral
▲ Preliminary data from a large, 3-year comparative
trial suggest the clinical efficacy of tenofovir DF in Median pharmacokinetic profile of tenofovir (oral tenofovir
disoproxil fumarate 300 mg/day for 28 days in fed patients
combination with baseline antiretroviral therapy is with HIV infection)
similar to that of stavudine in antiretroviral-naive
patients with HIV infection. Peak serum concentration 326 ng/mL
▲ Virological substudies showed that viral suppres-
sion was maintained in patients who developed new Time to peak serum 2.3h
concentration
reverse transcriptase mutations during tenofovir DF
therapy (in combination with existing stable antire- Area under the serum 3020 ng • h/mL
troviral drugs) for up to 48 weeks. Isolates of HIV concentration-time curve
infrequently developed the K65R mutation during
96 weeks of tenofovir DF therapy. Serum terminal elimination 14.4h
half-life
▲ Tenofovir DF is generally well tolerated. The most
commonly observed adverse events seen with te- Adverse events
nofovir DF (in combination with other antiretroviral
drugs) were predominantly of a gastrointestinal na- Most frequent Nausea, diarrhoea, asthenia,
headache, vomiting, flatulence,
ture. abdominal pain and anorexia
1598 Chapman et al.

NH2

N
N
O
N N O CH3
O HO
•
O OH
P O O O CH3
O
CH3 O O O CH3

O CH3
Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (tenofovir DF; In Vitro Activity

Viread®1) is an ester prodrug of the nucleotide re-
verse transcriptase inhibitor tenofovir. Tenofovir, a
nucleotide analogue of adenosine 5′-monophos- Antiviral Activity
phate with activity against HIV reverse trans- ● Tenofovir DF had greater inhibitory activity than
criptase, demonstrates poor oral bioavailability.[1] tenofovir against wild-type virus (HIV-1IIIb) in
Tenofovir DF was synthesised to enhance oral ab- MT-2 T-lymphocytes (concentration required for
sorption[2] and to improve cellular uptake of the 50% inhibition [IC50] 0.003 vs 0.5 μmol/L[6] and
drug.[3] 0.007 vs 0.63 μmol/L).[3] A similar result was seen
This profile focuses on data relevant to the use of for peripheral blood mononuclear cells (PBMC)
tenofovir DF in patients with HIV infection. [IC50 0.005 vs 0.18 μmol/L].[3] This was attributed
to a more rapid intracellular uptake of tenofovir DF
than of tenofovir and a resultant >1000-fold higher
1. Pharmacodynamic Properties intracellular accumulation of the active metabolite
tenofovir diphosphate.[3]
This section provides an overview of the effects ● Tenofovir (1–100 μmol/L) showed strong syner-
of both tenofovir DF and tenofovir since the prodrug gistic inhibition of HIV replication in
is rapidly converted to tenofovir after oral adminis- HIV-1IIIb–infected MT-2 cells in combination with
tration. zidovudine, amprenavir, nevirapine and delavirdine,
and mild-to-moderate synergistic inhibition with
Mechanism of Action didanosine, nelfinavir and adefovir; additive inhibi-
tion was evident in combination with abacavir, lami-
● In vivo, tenofovir DF is hydrolysed to te- vudine, stavudine, zalcitabine, indinavir, ritonavir
nofovir,[4] which is then phosphorylated by cellular and saquinavir.[7,8] No significant antagonistic inter-
kinases to the pharmacologically active metabolite actions were found for any of the antiretroviral
tenofovir diphosphate.[3] Tenofovir diphosphate in- agents with tenofovir.[7,8]
hibits the activity of HIV reverse transcriptase by ● Mycophenolic acid enhanced the activity of te-

competing with the nucleotide deoxyadenosine 5′- nofovir against wild-type, tenofovir-resistant (with
triphosphate for incorporation into viral DNA. Once the K65R mutation) and nucleoside reverse trans-
incorporated into viral DNA, it terminates DNA criptase inhibitor (NRTI)-resistant strains of HIV in
elongation because of lack of a ribose ring.[5] PBMCs.[9]

1 Use of tradename is for product identification purposes only and does not imply endorsement.

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
Tenofovir Disoproxil Fumarate: Adis Drug Profile 1599

Cytotoxicity Where possible, this section focuses on data for the

● Tenofovir DF showed greater cytotoxicity than recommended dosage of tenofovir DF (300 mg/day)
tenofovir in HIV-1IIIb–infected MT-2 cells (50 vs in patients with HIV infection.
250 μmol/L[6] and 22 vs 1250 μmol/L,[3] respective- ● In a pooled analysis of pharmacokinetic data
ly, were required to kill 50% of cells [CC50]). Selec-
from healthy volunteers and patients with HIV in-
tivity (CC50/IC50) ratios for tenofovir and the
fection, there were no significant differences in the
prodrug in MT-2 cells were 500 vs 16 600,[6] and
pharmacokinetic parameters of tenofovir on the ba-
≈2000 vs ≈3000, respectively.[3]
sis of gender, age (19–57 years) or body weight
● High concentrations of tenofovir (up to 2 mmol/
(50–112kg) after administration of tenofovir DF
L) did not significantly inhibit the in vitro growth of
300mg (duration of treatment not reported).[20] No
human renal proximal tubule epithelial cells
published data are available for patients with hepatic
(RPTECs), nor did it significantly affect the ability
impairment, children or the elderly.
of these cells to maintain the integrity of tight junc-
tions in vitro after 10 days of incubation.[10] Con-
versely, cidofovir inhibited the growth of RPTECs Absorption and Distribution
(CC50 of 260 μmol/L) and altered the ability of these
cells to maintain the integrity of the tight junctions ● Transport across Caco-2 intestinal mucosal mo-
of the renal proximal tubule epithelium (concentra- nolayers,[14] uptake into PBMCs[3] and in vivo intes-
tion reducing transepithelial electrical resistance by tinal absorption in rats[15] were markedly greater for
50% [CTER50] 100–120 μmol/L).[10] The effects of tenofovir DF than for tenofovir (27-fold, >1000-fold
adefovir on these cells were mild and dose-depen- and 12-fold, respectively).
dent.[10] Despite this, tenofovir DF has been asso-
● Tenofovir DF showed dose-proportional
ciated with changes to renal function in clinical
trials and postmarketing surveillance (section 5). pharmacokinetics after administration of 75–600
mg/day for 28 days in a randomised, double-blind,
Immunomodulatory Effects
placebo-controlled, dose-escalation study in patients
with HIV infection (n = 49).[19]
● Tenofovir also displays immunomodulatory ef-
fects.[11-13] In in vitro studies using murine or human ● The oral bioavailability of tenofovir after admin-
cell lines, tenofovir stimulated secretion of cyto- istration of tenofovir DF 300 mg/day was 25% and
kines capable of interfering with HIV replication increased to 39% when tenofovir DF was adminis-
(interleukin [IL]-1β, IL-10 and tumour necrosis fac- tered with a standardised high fat meal.[19]
tor-α) and chemokines that inhibit entry of HIV into ● Median steady-state maximum serum tenofovir
cells (regulated upon activation normal T cell ex- concentrations (Cmax) and the area under the serum
pressed and secreted [RANTES] and macrophage tenofovir concentration-time curve (AUC) were 326
inflammatory protein 1α); however, no effect was ng/mL and 3020 ng • h/mL in patients infected with
seen on interferon-γ and IL-2 expression.[11-13] HIV who received tenofovir DF 300 mg/day with
food for 28 days.[19] The median time to Cmax was
2. Pharmacokinetic Properties 2.3 hours.[19]
● Binding of tenofovir to human plasma or serum

Most of the data reported in this section relate to proteins in vitro is <0.7% and <7.2%, over the
the pharmacokinetic profile of tenofovir after ad- tenofovir concentration range 0.01–25 μg/mL.[4,21]
ministration of tenofovir DF monotherapy. The The US prescribing information states that the mean
pharmacokinetic properties of tenofovir DF have steady-state volume of distribution for intravenous
been described in animals,[14,15] healthy volun- tenofovir 1 and 3 mg/kg was 1.3 L/kg and 1.2 L/
teers[16,17] and patients with HIV infection.[18-20] kg.[4]

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
1600 Chapman et al.

Metabolism and Elimination with renal impairment (CLCR <60 mL/min)[4]

whereas in Europe tenofovir DF is contraindicated
● Tenofovir concentrations in serum decline in a in patients with severe renal impairment (CLCR not
biphasic manner.[19] Administration of tenofovir DF reported).[21] However, adjustments to the tenofovir
300 mg/day with food for 28 days to patients with DF dosage interval have been suggested for this
HIV infection resulted in a median serum terminal patient population (section 6).[22]
elimination half-life for tenofovir of 14.4 hours and
clearance rate of 0.51 L/h/kg.[19] In an in vitro study,
the half-life of tenofovir diphosphate in activated Drug Interactions
PBMCs preincubated with tenofovir DF or tenofovir
was 11 hours; however, the half-life of tenofovir ● The potential for a pharmacokinetic interaction
diphosphate in resting PBMC preincubated with between tenofovir DF and drugs metabolised by
tenofovir was 49 hours.[3] cytochrome P450 (CYP450) enzymes is low.[4,21]In
● After administration of intravenous tenofovir 1 vitro studies have shown that tenofovir is not meta-
mg/kg for 7 days to patients with HIV infection, bolised by the CYP450 enzymes, nor does it inhibit
72.4% of the dose was recovered in the urine within drug metabolism by CYP3A4, CYP2D6, CYP2C9
24 hours, suggesting renal elimination is the main or CYP2E1; however, a 6% reduction in CYP1A2
elimination pathway.[18] The US prescribing infor- metabolism was observed.[4,21]
mation reports that within 72 hours of an intrave- ● As tenofovir is eliminated by the kidney, the

nous administration of tenofovir (dosage not report- coadministration of other drugs that reduce renal
ed) approximately 70–80% of the dose is recovered activity or compete for renal elimination may result
in the urine as unchanged drug.[4] The renal clear- in increased serum concentrations of either te-
ance of tenofovir exceeded the calculated creatinine nofovir or the coadministered drug.[4]
clearance of recipients, indicating elimination oc- ● Although various quantitative differences in the

curs via a combination of active tubular secretion pharmacokinetic profiles of tenofovir and coadmin-
and glomerular filtration.[18,19] istered antiretroviral drugs have been documented,
no clinically significant interactions were apparent
Patients with Renal Impairment when tenofovir DF and lamivudine, efavirenz, in-
dinavir or lopinavir/ritonavir were coadministered
● The absorption and clearance of a single oral in two crossover studies in healthy volunteers.[16,17]
dose of tenofovir DF 300mg were not significantly Tenofovir DF 300 mg/day was administered with
different in otherwise healthy patients with mild lamivudine 150mg twice daily or indinavir 800mg
renal impairment (creatinine clearance [CLCR] three times daily for 7 days and with efavirenz 600
50–80 mL/min) from those in healthy volunteers mg/day for 2 weeks (all in the fasted state) and with
(>80 mL/min) [presented in a poster].[22] However, lopinavir/ritonavir 400/100mg twice daily with food
otherwise healthy patients with moderate to severe for 14 days.[16,17]
renal impairment (CLCR <50 mL/min) had greater ● Coadministration of tenofovir DF 300 mg/day
reductions in renal elimination and higher exposure and buffered or enteric-coated didanosine in healthy
to tenofovir (Cmax and AUC) than healthy volun- volunteers did not alter the pharmacokinetic profile
teers (p values not reported).[22] of tenofovir. However, the Cmax and AUC of didan-
● Tenofovir was efficiently removed from the cir- osine were increased relative to didanosine 400mg
culation during standard high-flux haemodialysis alone in the fasted state (increases of 28–64% and
sessions in end-stage renal disease patients (n = 9) 44–60%);[16,23,24] buffered didanosine 400 mg/day
[median extraction coefficient 54%].[22] (250 mg/day if bodyweight <60kg) was adminis-
● In the US it is currently recommended that te- tered 1 hour prior to tenofovir DF (both in the fasted
nofovir DF should not be administered to patients state)[16,23] and enteric-coated didanosine 400mg

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
Tenofovir Disoproxil Fumarate: Adis Drug Profile 1601

was administered either 2 hours before or with te- load endpoint at 24 weeks in both placebo-control-
nofovir DF and a light meal (373 kcal, 20% fat).[24] led trials.[26,27]
● The administration of a reduced dosage of enter-

ic-coated didanosine (250mg) 2 hours before, or Dose-Ranging Trial

with tenofovir DF 300mg (with or without a light In a dose-ranging trial, 186 antiretroviral-experi-
meal) resulted in a Cmax and AUC similar to that of
enced patients (overall mean duration of treatment
enteric-coated didanosine 400mg alone.[25] Al-
4.6 years) were included in the intent-to-treat ana-
though no formal recommendations for modifica-
lysis and received tenofovir DF 75 (n = 53), 150 (n =
tions to the didanosine dosage are available, it is
recommended that caution be exercised when te- 51) or 300mg (n = 54) or placebo (n = 28).[26] The
nofovir DF and didanosine are to be coadministered overall mean baseline CD4+ cell count was 374
and patients receiving this combination be moni- cells/μL and the overall mean baseline HIV-1 RNA
tored closely for didanosine-associated adverse level was 3.7 log10 copies/mL.[26]
events[4,21] and in the US it is recommended that ● Tenofovir DF 75, 150 and 300 mg/day produced
treatment with didanosine should be discontinued in significantly greater reductions from baseline in
patients who develop didanosine-associated adverse plasma HIV-1 RNA (assessed using a time-weight-
events (section 6).[4] ed mean change [DAVG]) than placebo (figure 1).[26]
Significant differences were seen as early as 4
3. Clinical Efficacy weeks (p < 0.01) and remained significant after 24
In the treatment of HIV infection, the antiviral weeks (p < 0.02) [figure 1].[26]
efficacy of tenofovir DF has been compared with TDF 75 mg/day
that of placebo in two clinical trials in antiretroviral- TDF 150 mg/day
experienced patients[26,27] and with that of stavudine TDF 300 mg/day
Average change from baseline DAVG (log10 copies/mL)

0.1 Placebo
in one trial in antiretroviral-naive patients.[28] How-
ever, there are no data on the clinical progression of 0.0
HIV (e.g. AIDS-defining events and mortality).
With the exception of one fully published place- −0.1
bo-controlled trial,[26] the results of these random-
−0.2
ised, double-blind trials have been presented as ab- **
stracts and/or posters. Data are from the intent-to- −0.3 *
treat analysis.[26-28] **
−0.4

Comparisons with Placebo ***

−0.5

In both placebo-controlled trials, patients re- −0.6

***
ceived existing stable antiretroviral therapy (≤4 ***
−0.7
agents for ≥8 weeks prior to study entry) in addition 4 weeks 24 weeks 48 weeks
to tenofovir DF or placebo.[26,27] At 24 weeks, place- Fig. 1. Comparative antiviral efficacy of oral tenofovir disoproxil
bo recipients in both trials were switched to te- fumarate (TDF) 75–300 mg/day and placebo.[26] Change from
nofovir DF 300 mg/day for a further 24 weeks.[26,27] baseline HIV-1 RNA levels in antiretroviral-experienced patients
with HIV infection included in the intent-to-treat analysis (n = 186).
At baseline, 94% of patients in the trials had HIV Patients were randomised to receive double-blind TDF 75, 150 or
isolates with NRTI-associated resistance mutations 300mg or placebo administered once daily in addition to existing
(NAMs).[26,27] antiretroviral therapy for 24 weeks. Patients receiving placebo were
treated with TDF 300 mg/day from week 24. Baseline status: mean
● Tenofovir DF 300 mg/day was significantly CD4+ cell count = 374 cells/μL; mean HIV-1 RNA level = 3.7 log10
more effective than placebo for the primary viral copies/mL. * p < 0.02, ** p < 0.01, *** p < 0.001 vs placebo.

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
1602 Chapman et al.

● The greatest reduction in viral load at 48 weeks ● The efficacy of tenofovir DF 300 mg/day was

was achieved by patients receiving tenofovir DF 300 sustained over 48 weeks (DAVG –0.57; viral load
mg/day (figure 1).[26] However, there was no signif- ≤400 and ≤50 copies/mL 41% and 18%; mean in-
icant difference between the treatment groups for crease in CD4+ cell count 13 cells/μL).[27]
the mean change in CD4+ cell count at any time- ● A subgroup analysis found that tenofovir DF 300

point up to 48 weeks.[26] mg/day resulted in a significant antiretroviral res-

● After 48 weeks of treatment in the above study, ponse (measured by DAVG at 24 weeks) compared
135 patients originally randomised to tenofovir DF with placebo regardless of age (≤40 years or >40
75–300 mg or placebo once daily elected to receive years), gender and race (Caucasian or non-Cauca-
tenofovir DF 300 mg/day in a nonblind extension to sian) or baseline HIV-1 RNA level (<5000 or ≥5000
96 weeks.[29] Viral suppression was maintained in copies/mL) or CD4+ cell count (<200 or ≥200 cells/
94 patients who were originally randomised to re- μL).[31]
ceive tenofovir DF 75–300 mg/day, with a mean
reduction from baseline in HIV-1 RNA of 0.65–0.87 Comparison with Stavudine
log10 copies/mL at 96 weeks.[29]
Interim (96-week) results of a large, 3-year, ran-
domised, double-blind comparative trial of te-
Efficacy Trial
nofovir DF 300 mg/day versus stavudine 40mg
The 300 mg/day regimen of tenofovir DF has twice daily in antiretroviral-naive patients with plas-
also been compared with placebo in a large, multi- ma HIV-1 RNA levels >5000 copies/mL have been
centre study in 550 antiretroviral-experienced (mean reported (available as a poster).[28] In both treatment
duration of antiretroviral therapy 5.4 years) patients. groups, patients received the study drug in combina-
Patients received tenofovir DF 300mg (n = 368) or tion with lamivudine 150mg twice daily and efavi-
placebo (n = 182) once daily for 24 weeks.[27] The renz 600 mg/day.[28]
mean baseline plasma HIV-1 RNA viral load and ● At 96 weeks, tenofovir DF 300 mg/day (n = 299)
CD4+ cell count were 3.36 log10 copies/mL and 427 had similar antiviral efficacy to stavudine 40mg
cells/μL.[27] (30mg if bodyweight <60kg) twice daily (n =
● Tenofovir DF 300 mg/day was significantly 301).[28] Similar proportions of tenofovir DF and
more effective than placebo in reducing viral load at stavudine recipients achieved reductions in HIV-1
24 weeks.[27] The DAVG at 24 weeks, the primary RNA to <400 copies/mL and <50 copies/mL (figure
efficacy endpoint, was reduced to a significantly 2).[28] The mean increase in the CD4+ cell count was
greater extent in patients who received tenofovir DF also similar for the two treatment groups at 96 weeks
300 mg/day than in those receiving placebo (–0.61 (261 vs 266 cells/μL).[28]
vs –0.03 log10 copies/mL; p < 0.0001).[27] In addi-
tion, significantly more tenofovir DF recipients than 4. Potential for Viral Resistance
placebo recipients achieved decreases in HIV-1
RNA levels to ≤400 copies/mL (45% vs 13%) and As with other antiretroviral agents, treatment
≤50 copies/mL (22% vs 1%) at 24 weeks (p < with tenofovir DF may result in the development of
0.0001 for both).[27] viral resistance.
● At 24 weeks, tenofovir DF resulted in a signif-
In Vitro
icant increase from baseline in the mean CD4+ cell
count compared with placebo (12.5 vs –10.8 cells/ ● Eight in vitro passages of HIV-1IIIb in the MT-2

μL; p = 0.0008).[27] Additionally, in patients receiv- cell line in increasing concentrations of unmodified
ing tenofovir DF who achieved HIV-1 RNA levels tenofovir produced viral strains able to grow in the
<50 copies/mL the mean CD4+ cell count increased presence of 2 μmol/L of tenofovir (5-fold above the
by 57 cells/μL.[30] IC50 for wild-type virus).[32] Sequence analysis of 15

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
Tenofovir Disoproxil Fumarate: Adis Drug Profile 1603

100 TDF
mutations displayed susceptibility to tenofovir simi-
STA
90 lar to that of the wild-type strain (1.1-fold decrease
in susceptibility compared with wild-type strain).[32]
Patients with viral suppression (%)

80
● The relatively small reduction in susceptibility to
70
tenofovir (≤2.5-fold compared with wild-type virus)
60
for isolates showing up to 24-fold resistance to
50 zidovudine has been attributed to differential rates
40 of excision of these chain-terminating molecules.[33]
Removal of tenofovir from the reverse transcriptase
30
binding site by wild-type virus and HIV isolates
20 with thymidine analogue-associated mutations
10 (TAMs) by pyrophosphorolysis was 2- to 3-fold less
0
efficient than the removal of zidovudine.[33] ATP-
<400 copies/mL <50 copies/mL dependent removal of tenofovir was less efficient
Fig. 2. Antiviral efficacy of tenofovir disoproxil fumarate (TDF) com- than removal of stavudine and zidovudine by wild-
pared with that of stavudine (STA).[28] Proportion of antiretroviral- type virus (15-fold for both comparisons) and HIV
naive patients with HIV infection (intent-to-treat analysis, n = 600)
receiving TDF or STA with HIV-1 RNA levels <400 copies/mL and
isolates with TAMs (22- and 35-fold).[34]
<50 copies/mL at 96 weeks. In a randomised, double-blind clinical
trial, patients received TDF 300 mg/day or STA 40mg (30mg if
bodyweight <60kg) twice daily in combination with lamivudine In Vivo
150mg twice daily and efavirenz 600 mg/day. Baseline status:
mean CD4+ cell count for patients receiving TDF = 276 cells/μL
and mean CD4+ cell count for patients receiving STA = 283 cells/
μL; mean HIV-1 RNA level = 81 300 copies/mL for each treatment Effect of Baseline Resistance Mutations
group.
The effect of the number and type of TAMs in
HIV isolates at baseline on the viral response to
clones expressing HIV reverse transcriptase genes therapy with tenofovir DF was assessed in a pooled
from the eighth passage showed that the reverse analysis[35] of the genotypic resistance data in pa-
transcriptase mutation K65R was present in 4 of the tients (n = 333) in the two placebo-controlled clin-
15 clones.[32] The recombinant viruses expressing ical trials.[26,27]
the K65R mutation were 3- to 4-fold less susceptible ● After 24 weeks of therapy with tenofovir DF,
to tenofovir than the wild-type strain.[32] significant reductions (p < 0.0001) in viral load were
● Recombinant isolates with mutations associated observed in patients with HIV isolates without
with resistance to other antiretroviral drugs (e.g. TAMs, with 1–2 TAMs and with ≥3 TAMs not
K70E and T69D) had either wild-type or <3-fold including M41L or L210W receiving tenofovir DF
reduced susceptibility susceptibility to tenofovir in compared with those receiving placebo (figure 3).[35]
vitro.[32] Although significant compared with placebo (p <
0.013), responses to tenofovir DF therapy were
● A 1.3-fold increase in susceptibility to tenofovir smaller in patients with HIV isolates with ≥3 TAMs
was seen for HIV strains expressing the lamivudine- including M41L or L210W than in the other sub-
resistance–associated M184V mutation compared groups (figure 3).[35] The greatest response at 24
with wild-type strains in MT-2 cells (no significant weeks was seen in a subgroup of tenofovir DF
difference); however, the increase in susceptibility recipients with isolates with the M184V mutation
for M184V strains was significant compared with and no TAMs (–0.96 log10 copies/mL; p <
wild-type strains in cord-blood mononuclear cells 0.001).[35] Patients with a >4-fold reduction in base-
(4.6-fold increase; p < 0.05).[32] Moreover, HIV line tenofovir DF susceptibility had a reduced res-
strains that contained both the K65R and M184V ponse to tenofovir DF therapy.[35]

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
1604 Chapman et al.

0.2 TDF
● Furthermore, an analysis of 21 patients with viral
Mean change in HIV RNA (log10 copies/mL)

Placebo
0.1
rebound (>0.5 log10 increase in HIV RNA) between
0.0 weeks 48 and 96 found that most patients developed
−0.1 NAMs or mutations associated with resistance to
−0.2 non-nucleoside reverse transcriptase inhibitors or
*
−0.3 protease inhibitors; no phenotypic changes to te-
−0.4
nofovir susceptibility were observed in these pa-
tients.[37]
−0.5
● In a prospective virological genotyping substudy
−0.6
** (n = 274)[38] of the larger placebo-controlled clinical
−0.7 ** **
trial (section 3),[27] the percentage of tenofovir DF-
−0.8
** treated patients that developed TAMs (19%) and
−0.9 NAMs (23%) during the nonblind phase was similar
to that of patients receiving placebo (14% and 24%)
s

10 ut

10 ng
nt

L2 tho

L2 di
W

W
ie

TA

TA

or clu
at

or wi

or tenofovir DF (11% and 16%) in the placebo-

o

2
lp

L in
N

L s
or

41 M
Al

41 s
1

M M
M TA

controlled phase, suggesting baseline antiretroviral

TA
e
or

therapy was associated with the development of

or
m

m
or

these mutations.[38] However, patients that devel-

or
3

oped new mutations maintained HIV-1 RNA sup-

Fig. 3. Antiviral efficacy of tenofovir disoproxil fumarate (TDF)
against HIV isolates with varying type and number of baseline pression at 48 weeks (mean DAVG –0.09 to –0.99
thymidine-associated resistance mutations (TAMs).[35] In a pooled log10 copies/mL).[38]
analysis (n = 333) of prospective virological substudies, baseline
● The K65R mutation occurred in isolates from 3%
genotypes of HIV isolates from antiretroviral-experienced patients
with HIV infection randomised to double-blind TDF 300 mg/day or of patients treated with tenofovir DF.[38] The average
placebo were analysed for the effect of different patterns of TAMs mean DAVG at 48 weeks in these patients was –0.28
on the antiviral efficacy of treatments at 24 weeks (see text for
further details). * p = 0.02, ** p ≤ 0.001 vs placebo. log10 copies/mL (range: 0.86 to –1.15).[38] Low-
level (<2-fold) phenotypic resistance to tenofovir
Emergence of Resistance DF was associated with the K65R mutation in four
evaluable patients; only one evaluable patient with
The emergence of reverse transcriptase muta- the K65R mutation had reduced susceptibility
tions after tenofovir therapy was evaluated in viro- (6.4-fold) to tenofovir DF.[38]
logical substudies[36-39] of the clinical trials reviewed
● Eight patients receiving tenofovir DF in the
in section 3.
above substudy were classified as having viral re-
● After 48 weeks of treatment with tenofovir DF bound (at week 24 they had HIV-1 RNA levels of
300 mg/day in the dose-ranging study, the K65R <50 copies/mL and at 48 weeks had >500 copies/
mutation was detected as a new mutation in isolates mL).[38] Although most of these patients developed
from 2% of patients, while new NAMs were de- genotypic resistance to other agents present in their
tected in isolates from 42% of patients.[36] Isolates baseline antiretroviral therapy, viral rebound was
that developed the K65R mutation had 3- to 4-fold not associated with the development of resistance to
reductions in tenofovir susceptibility compared with tenofovir DF.[38]
wild-type; however, none of the patients showed ● In a genotypic and phenotypic analysis of HIV
evidence of viral load rebound.[36] Similarly, after 96 strains isolated from antiretroviral-naive patients
weeks of treatment, two additional patients (1.5%) with virologic failure during the first 48 weeks of
had virus which developed the K65R mutation; treatment with tenofovir DF or stavudine in combi-
however these patients maintained viral suppression nation with lamivudine and efavirenz (n = 54), the
(–0.39 log 10 copies/mL).[37] most common genotypes were efavirenz-resistant

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
Tenofovir Disoproxil Fumarate: Adis Drug Profile 1605

(4.7%), wild-type (3.6%) or M184V (3.3%).[39] The μL (1% for both treatment groups) in the initial 24
K65R mutation occurred infrequently in both the weeks.[4]
tenofovir DF and stavudine treatment groups (2.3% ● In antiretroviral-naive patients, there was no sig-
and 0.7%); however, it was observed only in combi- nificant difference between tenofovir DF and stavu-
nation with the efavirenz-resistance genotype.[39] dine in the incidence of grade 3 or 4 adverse events
Genotypic or phenotypic tenofovir-associated resis- (23% vs 22%) or laboratory abnormalities (34% vs
tance was detected in 24% of patients with virologi- 39%) after 96 weeks of treatment.[28]
cal failure who received tenofovir DF plus lamivu- ● However, at 96 weeks, significantly (p < 0.001)
dine and efavirenz.[39]
fewer tenofovir DF than stavudine recipients had
adverse events potentially associated with mito-
5. Tolerability
chondrial dysfunction (e.g. peripheral neuropathy,
Data in this section are from the clinical trials of lactic acidosis and lipodystrophy) [4% vs 20%],
tenofovir DF as part of combination therapy (section peripheral neuritis or neuropathy (3% vs 10%) and
3), including two pooled analyses of both placebo- lipodystrophy (1% vs 12%).[28] Furthermore, three
controlled trials in a total of 443 patients receiving patients receiving stavudine experienced lactic aci-
tenofovir DF and 210 patients receiving place- dosis (not reported with tenofovir DF).[28] Addition-
bo.[4,40] ally, the tenofovir DF treatment group had signifi-
● Tenofovir DF is generally well tolerated.[4,40] In a cantly smaller increases in fasting triglycerides, total
pooled analysis the severity and incidence of ad- cholesterol and direct low density lipoprotein levels
verse events were similar for those receiving te- (p < 0.001) and a significantly higher increase in
nofovir DF or placebo over the initial 24 weeks.[40] direct high density lipoprotein (p = 0.032) than the
● In one pooled analysis,[4] the most common treat- stavudine treatment group.[28]
ment-related adverse events during the 24-week pla- ● A retrospective analysis using pooled data from

cebo-controlled period of treatment were of a pre- patients receiving didanosine as part of baseline
dominantly gastrointestinal nature and included: antiretroviral therapy in the two placebo-controlled
nausea (11% in tenofovir DF recipients vs 10% in clinical trials (n = 197) at 24 weeks suggests that the
placebo recipients), diarrhoea (9% vs 8%), asthenia tolerability of didanosine in combination with te-
(8% for both treatment groups), headache (6% vs nofovir DF is similar to that of didanosine with
7%), vomiting (5% vs 2%), flatulence (4% vs 0%), placebo (pancreatitis 1% vs 2%, neuropathy <1% vs
abdominal pain (3% for both treatment groups) and 3%, amylase elevations 41% vs 44%).[41]
anorexia (3% vs 1%). ● Although tenofovir did not show any significant
● Three percent of patients discontinued the study cytotoxicity in isolated human RPTECs in an in
drug due to adverse events in both the tenofovir DF vitro study (section 1), tenofovir has been associated
and placebo treatment groups during the initial 24 with changes in renal function in vivo. Pooled tolera-
weeks of the trials.[40] With a mean treatment period bility data from the placebo-controlled trials in anti-
of 95 weeks, the incidence of therapy discontinua- retroviral-experienced patients showed that eleva-
tion due to adverse events in patients receiving tions in serum creatinine and serum phosphorus
tenofovir DF was 9%.[40] occurred occasionally but were transient in nature
● There was also no significant difference between and resolved without the need for discontinuation of
the tenofovir DF and placebo treatment groups in treatment.[40] Changes in renal function (incidence
the incidence of grade 3 or 4 laboratory abnormali- of hypophosphataemia and elevations in serum cre-
ties such as creatinine kinase >782 U/L (12% vs atinine) in antiretroviral-naive patients were similar
18%), triglycerides >750 mg/dL (8% vs 13%), se- for those receiving tenofovir DF- or stavudine-based
rum amylase >175 U/L (5% vs 7%), serum glucose therapy after 96 weeks.[28] However, rare episodes
>250 mg/dL (2% vs 4%) and neutrophils <650 cells/ of acute renal failure have been observed in patients

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (15)
1606 Chapman et al.

receiving tenofovir DF in combination with other with end-stage renal disease (CLCR <10 mL/min), it
antiretroviral drugs.[42,43] is suggested that tenofovir DF 300mg be adminis-
● Preclinical studies have shown that tenofovir DF tered every 7 days.[22] It is also suggested that pa-
caused bone toxicity in animals at exposures 6–12 tients requiring haemodialysis should receive te-
times those observed in humans.[4] Changes in bone nofovir DF 300mg following the completion of a
mineral density were monitored in 62 patients in the total of 12 hours of haemodialysis.[22]
dose-ranging clinical trial.[26] At week 24, there was Caution and close monitoring of patients is ad-
no significant between-group differences in the vised for the coadministration of tenofovir DF and
change from baseline in bone mineral density; for didanosine,[4,21] and in the US it is recommended
tenofovir DF 75, 150 or 300 mg/day and placebo, that didanosine should be discontinued in patients
median changes were –0.16%, –0.15%, –1.19% and who develop didanosine-associated adverse
–2.00%, respectively. Although there was no evi- events.[4]
dence of any dose-related effect at 24 or 48
weeks,[26] the long-term effect of tenofovir DF on 7. Tenofovir Disoproxil Fumarate:
bone is not known. Current Status
● Tenofovir DF has also been associated with pan-

creatitis, hypophosphataemia, lactic acidosis, dizzi- Tenofovir DF is approved for the treatment of
ness, dyspnoea, rash, renal insufficiency, kidney HIV infection in the US and Europe (see section 6
failure and Fanconi syndrome during postmarketing for specific indication). When combined with stable
surveillance.[4] antiretroviral therapy, tenofovir DF has shown an-
tiviral efficacy in antiretroviral-experienced and -
6. Dosage and Administration naive patients with HIV infection in well controlled
trials and was generally well tolerated. The clinical
In the US, oral tenofovir DF is indicated for the trial in antiretroviral-naive patients is ongoing and
treatment of HIV-1 infection in combination with studies in children with HIV infection are currently
other antiretroviral agents.[4] The original approval underway.
for tenofovir DF in Europe was for use in combina-
tion with other antiretroviral agents for the treatment
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er]. 6th International Congress on Drug Therapy in HIV Infec- Bay, Auckland 10, New Zealand.
tion; 2002 Nov 17-21; Glasgow E-mail: demail@adis.co.nz

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