Drug Profile
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CONTENTS
Current status
Introduction to
the compound
Chemical properties
Emerging treatment
guidelines
Expert commentary
Five-year view
Key issues
References
Affiliations
†
Author for correspondence
Hospital La Paz, Unidad de HIV,
Paseo de La Castellana, 261,
28046 Madrid, Spain
Tel.: +34 917 277 099
Fax: +34 917 290 033
rmmunoz2004@yahoo.es
KEYWORDS:
coformulation, emtricitabine,
HAART, NRTI, once-daily
dosing, tenofovir
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reprints@future-drugs.com
Tenofovir disoproxil
fumarate–emtricitabine
coformulation for once-daily dual
NRTI backbone
Rosa María Muñoz de Benito† and Jose Ramón Arribas López
Truvada® is the coformulation of tenofovir disoproxil fumarate (TDF; 300 mg) and
emtricitabine (FTC; 200 mg) in a single tablet, providing the nucleotide backbone for
once-daily dosing, as a component of highly active antiretroviral therapy (HAART). TDF
(the bioavailable prodrug of tenofovir) is hydrolyzed to tenofovir intracellularly and
phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir is a nucleotide
analog of deoxyadenosine monophosphate, with activity against HIV-1, -2 and hepatitis B
virus. FTC, the fluorinated derivative of lamivudine, is an analog of deoxycitidine, active
against HIV-1, -2 and hepatitis B virus. Their long half-lives in plasma and in peripheral
blood mononuclear cells allow once-daily dosing. Both are eliminated renally. Resistance
mutation K65R is selected for by tenofovir and confers a two- to fourfold reduced
susceptibility to this drug. The incidence of K65R is low (3%) and has not been observed in
clinical trials with the concomitant use of tenofovir and FTC. FTC selects for M184V mutation
less frequently than lamivudine. Tenofovir drug interactions include increased exposure to
didanosine and inferior immmune recovery that preclude their concomitant use. Boosted
protease inhibitors increase exposure to tenofovir without dose adjustment required. FTC
has no significant drug interactions. They are not metabolized by cytochrome P450, which
confers little potential for interactions with drugs metabolized by these enzymes. As
tenofovir and FTC are renally eliminated, drugs eliminated by tubular secretion must be
avoided. Both antiretrovirals, as individual agents and in coadministration have evidenced
antiviral potency in clinical trials. Pivotal study 934 evidenced superior efficacy of the
combination TDF/FTC/efavirenz (EFV) versus zidovudine/FTC/EFV. The toxicity profile of
tenofovir and FTC has been extensively studied. Lipid profile is more favorable with
tenofovir than thymidine analog. Tenofovir requires surveillance of glomerular filtration rate
and dosing interval adjustment when creatinine clearance is less than 50 ml/min and
avoidance less than 30 ml/min. Fat loss is less likely with tenofovir than with thymidine
analog. Clinical trials have assessed the performance of the coformulation of TDF
and FTC.
Expert Rev. Anti Infect. Ther. 4(4), 523–535 (2006)
The purpose of antiretroviral treatment reverse-transcriptase inhibitors (NRTIs) plus
(ART) is the long-term suppression of viral either a non-nucleoside reverse-transcriptase
replication. Virological control prevents inhibitor (NNRTI) or a protease inhibitor (PI).
disease progression, prolongs survival and Selection of the appropriate antiretroviral
improves quality of life. Currently, highly regimen must be guided not only by the
active antiretroviral therapy (HAART) as intrinsic potency of its components, but also
recommended by international guidelines, by those properties that render it more suitable
consists of a regimen including two nucleoside for the individual patient, therefore, favoring
10.1586/14787210.4.4.523 © 2006 Future Drugs Ltd ISSN 1478-7210 523
Muñoz de Benito & Arribas López
compliance. Recently, the first two dual-NRTIs coformulated
as one pill once daily (Truvada®, manufactured by Gilead
Sciences) and Kivexa™/Epzicom™ (manufactured by Glaxo-
SmithKline) have been launched, raising the interest of both
patients and healthcare providers. This article offers an over-
view on Truvada, the fixed-dose combination of tenofovir diso-
proxil fumarate (TDF) and emtricitabine (FTC). So far, the
backbone combination of TDF and FTC has been assessed in
two clinical trials (GS 934 and ABT 418), on which the
authors shall focus. Besides, this article will review those studies
where each individual antiretroviral has been used.
Current status
Viral response to ARTs has improved with available combina-
tions as demonstrated in a recent analysis where the proportion
of naive patients achieving HIV RNA less than 50 copies/ml at
48 weeks was 57%, compared with a proportion of 45%
observed in 2001 [1]. A diversity of characteristics such as drug
interactions, adverse events, pill burden and complexity of the
regimen (dosing frequency and food restrictions) may have
critical influence on the outcome of antiretroviral therapy. The
availability of drugs that involve a low pill burden and once-
daily dosing is an important aspect to improve the effectiveness
of HAART.
Nucleoside/nucleotide analogs for once-daily dosage
presently available are lamivudine (3TC), FTC, abacavir
(ABC), didanosine (ddI) and TDF. Appropriate dual-NRTI
combinations for once-daily dosing are 3TC plus ddI, FTC
plus ddI, tenofovir plus 3TC, tenofovir plus FTC, ABC plus
3TC or ABC plus FTC. On the other hand, combinations that
are not recommended, after unfavorable outcomes reported in
naive patients, are 3TC plus ABC plus tenofovir [2], and 3TC
plus tenofovir plus ddI in triple NRTI regimens [3].
ABC/3TC (Kivexa or Epzicom) is currently the only alterna-
tive to Truvada as coformulation of two NRTIs for once-daily
dosing in single-pill combination.
Introduction to the compound
TDF and FTC have been coformulated to provide a single
tablet dual-NRTI backbone for once-daily dosing [4]. Truvada
is the oral coformulation of TDF (300 mg) and FTC (200 mg),
approved for once-daily administration in association with
other antiretroviral agents.
Study FTC-114 was a 21-day, randomized, three-way
cross-over study to evaluate the steady-state pharmaco-
kinetics of FTC (200 mg capsules administered once daily for
7 days) and tenofovir (administered as TDF tablets 300 mg
once daily for 7 days) when administered alone and together
in healthy volunteers. FTC had no effect on the pharmaco-
kinetics of tenofovir. TDF also had no clinically significant
effect on the pharmacokinetics of FTC. Although the mini-
mum concentration (Cmin) of FTC increased by approxi-
mately 20% with TDF coadministration, area under the
curves (AUCs) and maximum concentration (Cmax) were not
affected [5].
524
Study GS-US-104-0172 was a Phase I 28-day, randomized,
four-way crossover, pharmacokinetic study in healthy volun-
teers. The study was designed to evaluate the bioequivalence of
the TDF/FTC tablet compared with TDF and FTC adminis-
tered concurrently, and the effect of food (high-fat meal and
light meal) on pharmacokinetics.
The ratios for both the rate and extent (Cmax and AUC) of
tenofovir bioavailability after its administration as TDF or as
the combination tablet demonstrated bioequivalence of teno-
fovir between the two treatments. Similarly, bioequivalence
was demonstrated between the FTC capsule and the
TDF/FTC tablet. There are no data from clinical trials spe-
cific to the administration of coformulated tenofovir/FTC in
combination therapy.
Chemical properties
Pharmacodynamic profile
Tenofovir is an acyclic nucleotide (monophosphate nucleo-
side) analog of deoxyadenosine monophosphate with a molec-
ular weight of 287.2. Its prodrug, TDF, is orally absorbed and
hydrolyzed to tenofovir, which is phosphorylated intra-
cellularly to tenofovir diphosphate (PMPApp). The active
metabolite competes with natural nucleoside deoxyadenosine
5´-triphosphate for incorporation by HIV reverse
transcriptase (RT), and causes viral transcription chain termi-
nation. Tenofovir has in vitro activity against HIV-1 and -2
retroviruses and hepadnavirus.
FTC is a synthetic analog of the pyrimidine nucleoside
2´-deoxycytidine with a molecular weight of 247.25. This
fluorinated derivative of 3TC is more readily incorporated by
HIV RT into viral DNA, which has been postulated to justify
its higher in vitro potency [6]. Once inside the cell it is phos-
phorylated to the active metabolite FTC 5´-triphosphate
(FTCTP), which inhibits HIV-1 and -2 RT and DNA
polymerase of hepatitis B virus (HBV).
FTC and tenofovir undergo phosphorylation to their active
metabolites. FTC and tenofovir have long half-lives in plasma
(10 and 17 h, respectively) and in peripheral blood mono-
nuclear cells (PBMCs) (39 and 60 h) [7,8]. Their prolonged
intracellular life is a relevant issue, as viral activity and toxicity
are most accurately predicted by intracellular concentration
Incubation of both drugs results in higher phosphorylation
rate and active metabolite concentration for each individual
component [9]. Increased phosphorylation of the combination
correlates with synergistic activity against HIV in vitro, both
wild-type and K65R mutant, and a higher activity of tenofovir
against M184 mutant in the presence of FTC [10].
The coformulation of FTC and tenofovir has demonstrated
bioequivalence to each drug in individual formulation [4].
Antiviral activity
TDF concentration required for 50% inhibition (IC50) of HIV
was 0.005 µmol/l in PBMCs. Intracellular uptake of TDF is
more rapid and reaches a higher intracellular concentration
than tenofovir [11].
Expert Rev. Anti Infect. Ther. 4(4), (2006)

FTC IC50 for clinical isolates of HIV is
0.002–0.008 µmol/l [12]. Its potency is four- to tenfold that of
3TC in vitro and in vivo as monotherapy [6]. However, this
higher in vitro potency has not translated into superior efficacy in
combination therapy in clinical trials.
Cytotoxic effects
Merely a weak interaction exists between PMPApp and human
DNA polymerase, and in an in vitro model tenofovir does not
appear to inhibit mitochondrial synthesis to the same extent as
other NRTIs [13]. Mitochondrial DNA is not affected in
HepG2 cells after incubation with FTC [14].
Resistance mutations
K65R
HIV-1 isolates with reduced susceptibility to tenofovir have
been selected in vitro. These viruses expressed K65R sub-
stitution in RT and demonstrated a two- to fourfold reduc-
tion in susceptibility to tenofovir. Cross-resistance exists with
ABC, zalcitabine and ddI, which also select for K65R. On the
other hand, a negative impact on viral replication capacity has
been observed after its emergence in vitro and in clinical
isolates [15,16].
The emergence of K65R after tenofovir therapy has been
assessed in several clinical trials. Experienced patients in studies
902 and 907 developed K65R in 3% of cases after intensifica-
tion with tenofovir [17–20]. There is one study in naive patients
with tenofovir (903) in which, at week 144, K65R was observed
in 2.6% of individuals (in 17% of the patients who experienced
virological failure); of note, it was always associated with
efavirenz (EFV) resistance [21]. By contrast, the combination of
tenofovir plus FTC has not been followed by the emergence of
this mutation in any case, as assessed in two studies in naive
patients at week 48 (GS 934) [22] and at week 96 (418) [23].
Available data support the notion of an initial progressive
increase in prevalence of K65R over time, with a stabilization
in the past 2 years as evidenced in different retrospective
studies [24–27].
A divergent impact on K65R incidence has been observed in
two particular backgrounds. On the one hand, a high
emergence of K65R has been reported (50–92%) among
patients failing on a triple-nucleoside regimen, including teno-
fovir (TDF/3TC/ABC or TDF/3TC/ddI) probably as a result
of concomitant use of two drugs selecting for this mutation
[28–30]. Alternatively, antiretroviral regimens, including thymi-
dine analogs are associated with reduced emergence of K65R;
indeed an inverse correlation has been observed between the
number of thymidine analog-associated mutations (TAMs) and
the emergence of K65R [24]. Nevertheless, in the presence of
three or more TAMs, including either M41L or L210W,
response to tenofovir is reduced [21].
K65R is frequently associated with M184V. Both mutations
confer increased susceptibility to zidovudine (AZT). Maximal
response to tenofovir was observed in patients harboring, at
baseline, M184V mutation in the absence of TAMs.
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Tenofovir disoproxil fumarate–emtricitabine
Furthermore, susceptibility to tenofovir was enhanced in strains
with M184V in addition to K65R, when compared with strains
with K65R isolated [15].
M184V
Resistance to FTC is associated with the development of
M184V mutation in the RT. FTC and 3TC select for
M184V/I, which confers cross-resistance between them.
M184V emerges more frequently after failure in 3TC-treated
patients (59%) than it does with FTC (17%) [30]. It can be
speculated that it is related to the higher antiviral in vitro
potency and extended half-life of FTC. If this is confirmed in
further studies, it might be viewed as a relevant issue owing to
the growing prevalence of this mutation in recent years,
representing 80% of NRTI mutations in 2004 [27].
An overview of genotypic findings after virological failure in
studies FTC-301A, FTC-302 and MKC-40 evidenced a low
incidence of M184V mutation (4%) [31]. Resistance analyses in
clinical trials where the combination of tenofovir and FTC
have been studied also revealed a low incidence of this muta-
tion. In study GS 934, 1% of patients treated for 48 weeks with
tenofovir/FTC/EFV versus 3% in the AZT/3TC/EFV arm
developed M184V [22]. In study 418, up to 96 weeks of treat-
ment with tenofovir/FTC/lopinavir, four out of 190 patients
developed resistance to FTC [23].
Emergence of this mutation was much higher in regimens
consisting of triple nucleosides among which M184V
developed in 98–100% of virological failures [28–30].
In summary, K65R prevalence is low and has reached a
plateau after an initial upward trend. Recent data suggest that
using tenofovir along with FTC and either EFV or lopina-
vir/ritonavir (tenofovir/FTC/EFV or tenofovir/FTC/lopina-
vir/ritonavir) decreases the risk of development of K65R. The
emergence of M184V (the most prevalent NRTI mutation)
may be less likely with FTC than 3TC.
Pharmacokinetic profile
Tenofovir
TDF has an oral bioavailability of 25% after an overnight fast,
which increases to 39% after a high-fat meal. Cmax is reached
2.3 h after its administration with a meal [32]. Administration
with food (high fat or light meal) increases tenofovir’s AUC (35
and 34%) as well as Cmax (16 and 13.5%, respectively).
Tenofovir has a long half-life in plasma (17 h), yet inferior to
tenofovir diphosphate intracellular half-life in peripheral blood
mononuclear cells (PBMCs) (>60 h) [7]. When the ICARE trial
studied the distribution of PMPApp in patients with HIV
RNA less than 20 copies/ml, its presence was demonstrated in
PBMC (309/1 × 106 cells), while it was undetectable in lymph
node mononuclear cells (LNMCs), posing the question of
suboptimal penetration in lymph nodes [33].
Pharmacokinetics of tenofovir are not altered by hepatic
impairment. Tenofovir is not a substrate for cytochrome p450
(CYP) 3A4 enzymes nor does it inhibit CYP enzymes, which
confers this agent to a limited potential to interact with drugs
525
Muñoz de Benito & Arribas López
metabolized by this pathway. Tenofovir is renally excreted
unchanged by a combination of glomerular filtration and active
tubular secretion.
Emtricitabine
Oral administration of FTC is followed by rapid absorption,
with a mean bioavailability of 93% [8]. Cmax is reached 1–3 h
after oral administration. Cmax and AUC are unrelated to
food intake.
FTC does not undergo metabolism by CYP enzymes nor
does it interfere with CYP-mediated metabolism of other
drugs. Renal elimination (86%) of FTC occurs by glomerular
filtration and active tubular secretion. A small proportion
(13%) is eliminated in the feces [8].
FTC’s half-life in plasma is 10 h, while intracellular FTC
triphosphate half-life is 39 h in PBMCs [34], supporting
once-daily dosing.
A pharmacokinetic study has established the formulation
bioequivalence of tenofovir/FTC fixed-dose combination tablet
relative to coadministration of tenofovir tablets and FTC
capsules in individual dosage form [4].
Tenofovir and FTC share a symmetric pharmacokinetic
profile owing to their extended half-life and similar elimina-
tion interval. They have synergistic antiviral activity, and the
coadministration of both drugs in healthy volunteers
demonstrated a lack of pharmacokinetic interactions [5].
Interactions
Several unpredicted drug interactions have been observed with
tenofovir. Administration of tenofovir with ddI resulted in an
increased plasma concentration of the latter, presumably by
inhibition of purine nucleoside phosphorylase (PNP) enzyme
involved in the catabolism of ddI [35]. ddI’s AUC raised by
44–60%, and Cmin increased by 48–64%, making the risk of
adverse events related to ddI exposure (peripheral neuropathy
and pancreatitis) more likely [36]. This interaction prompted a
recommendation to adjust the dosage of ddI [37] when their
coadministration was not yet precluded.
Interactions also exist with PIs. Such is the case with lopina-
vir/ritonavir that increases the AUC of tenofovir by 30% and
eventually the risk of kidney toxicity, although this has not
been proved thus far. Atazanavir’s AUC, Cmax and Cmin are
reduced 25, 21 and 40%, respectively in coadministration with
tenofovir [7]. The addition of ritonavir reduces the negative
impact of tenofovir on the Cmin (to 23%), but the AUC is
unmodified, yet boosted ATV concentration plus TDF is
higher than unboosted ATV concentration without TDF. On
the other hand, ATV/ritonavir increases tenofovir AUC 30%.
Systemic tenofovir exposure increased by 22% after
coadministration with TMC-114/ritonavir [38], and 32% with
the IP in development brecanavir/ritonavir [39], with no dose
adjustment required in any of them. The higher exposure to
tenofovir in concurrence with boosted PIs, might eventually
increase the risk of adverse events, but this is yet to be assessed
and no specific recommendation has been made.
526
Tenofovir is transported by human organic anion transporter
(OAT)-1 and then exported from the renal tubule cell by a
multidrug resistance-associated protein (MRP)2 efflux pump.
Concurrent administration of drugs that compete for active
tubular uptake or secretion and nephrotoxic agents, such as
amphotericin B, aminoglycosides, vancomycin, foscarnet and
pentamidine should be avoided [7]. FTC is free of interaction
with other drugs. It is not metabolized by CYP enzymes and is
cleared renally mostly unchanged.
As tenofovir and FTC do not undergo metabolism by CYP
enzymes, there is little potential to interfere with coadministered
drugs metabolized by this pathway. Their renal elimination
makes it advisable to avoid coadministration with drugs elimi-
nated by active tubular secretion (e.g., cidofovir and ganciclovir)
for the risk of increased concentrations of them.
Therapeutic efficacy
Both tenofovir and FTC in individual formulation have
demonstrated antiviral efficacy in multiple-drug regimens.
Tenofovir
Three clinical trials have established tenofovir efficacy in a
combination antiretroviral regimen, both in experienced (studies
902 [17] and 907 [18]) and naive patients (study 903 [40]).
The data from study 903 after 144 weeks (HIV RNA
< 50 copies/ml in 68% patients), support the efficacy and dura-
bility of tenofovir in association with 3TC and EFV in naive
patients. The combination of tenofovir with PIs lopina-
vir/ritonavir and atazanavir/ritonavir in experienced patients
has shown efficacy and tolerability in a clinical trial, BMS-045,
after 48 weeks of follow-up [41].
Several studies have raised concerns about the efficacy of
combination tenofovir/ddI. Early virological failure has been
observed after initial treatment with TDF plus ddI plus EFV in
patients with viral load greater than 100,000 copies and CD4
cell count less than 250 cell/mm3 [42–44].
Of note, a recent study pointed to a different virological
outcome when the third component is a PI instead of a
NNRTI [45]. A negative impact on immunological recovery has
been observed in patients suppressed on a stable antiretroviral
regimen who switched to tenofovir, ddI and EFV with a signif-
icant median decline in CD4 cell count (-25 cells/µl) after
48 weeks [46], a finding consistent with another study that
reported a mean decrease in CD4 count (95 cells/µl) following
coadministration of tenofovir and ddI [47]. This decline in CD4
count was confirmed in suppressed patients, irrespective of a
PI- or NNRTI-containing regimen [48]. The rationale for this is
that potent inhibitors of PNP can inhibit T-cell division
causing a decline in CD4 count [49]. Recently, a ddI dose-
related lymphocyte toxicity has been proposed, after the
observation of unaffected immune recovery following adjusting
ddI to less than 4.1 mg/kg [50].
Unexpected virological outcome and detrimental immuno-
logical effects make it advisable to avoid concurrent use of teno-
fovir and ddI, while awaiting guidelines to address this issue.
Expert Rev. Anti Infect. Ther. 4(4), (2006)

The European Agency for the Evaluation of Medicinal
Products (EMEA) issued a recommendation in March 2005 [51]
against coadministration of tenofovir and ddI, especially in
naive patients with high viral loads an low CD4 counts. The
recently issued (October, 6th 2005) Department of Health and
Human Services (DHHS) guidelines recommend that NNRTI
plus tenofovir and ddI should not be used as an initial regimen
in antiretroviral-naive patients owing to reports of early viro-
logical failure and rapid emergence of resistance mutations to
NNRTI, tenofovir and ddI [101].
A high rate of virological failure (33–95%) has also been
found with triple nucleoside combinations that included
tenofovir (TDF plus 3TC plus ABC, or TDF plus 3TC plus
ddI) [28–30].
Emtricitabine
The efficacy of FTC has been assessed in naive and experienced
patients [52,101]. Studies FTC-301, FTC-302 and FTC-303
demonstrated long-term viral efficacy of FTC in combination
therapy [52,101]. A large trial comparing FTC with stavudine
(d4T) in combination with ddI and EFV, evidenced superiority
of FTC-based therapy in terms of virological suppression (HIV
RNA < 50 copies/ml at 60 weeks 76 vs 54%), durability and
immunological response (CD4 cell count change from baseline
156 vs 119 in an intention-to-treat [ITT] analysis) [52].
FTC is equally effective as 3TC as evidenced in studies
FTC-302 and -303 [53]. The FTC-302 trial compared FTC
with 3TC in combination with d4T and a NNRTI evidencing
HIV RNA less than 50 after 48 weeks in 60% of patients with
FTC and 64% of those with 3TC, while confirmed virological
failures with genotypic modification was 9.6% in both
arms [53]. In study 303, FTC was confirmed to be comparable
with 3TC in terms of efficacy, safety and resistance pattern.
Tenofovir plus emtricitabine
It has been shown that the combination of
TDF plus FTC has synergistic activity
in vitro against wild-type HIV and K65R,
and M184V mutants [10].
Responder (%)
The therapeutic efficacy of the combina-
tion tenofovir and FTC has been studied
as part of a regimen with either an NNRTI
or a PI showing high rates of virological
control. The only clinical trials that have
assessed the coadministration of tenofovir
and FTC in an individual formulation as
part of a combination regimen are studies
934 and 418.
Study 418 was designed to assess the
safety and efficacy of a once-daily regimen Exclude NNRTI; -R(n = 487); FTC + TDF: 84%; CBV: 73%; p = 0.002 (4.3%; 18.6%)
with lopinavir/ritonavir 800/200 mg,
tenofovir 300 mg and FTC 200 mg in 190 Figure 1. Study 934. Proportion of patients with HIV RNA less than 400 copies/ml.
antiretroviral-naive patients randomized 3:2 CBV: Combivir; FTC: Emtricitabine; NNRTI: Non-nucleoside reverse-transcriptase inhibitor;
TDF: Tenofovir disoproxil fumarate.
to lopinavir/ritonavir 800/200 mg once
Reproduced with permission from Gilead Sciences, Inc. © 2006.
daily or 400/100 mg twice daily [23].
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Tenofovir disoproxil fumarate–emtricitabine
Results after 96 weeks of follow-up evidenced HIV RNA less
than 50 copies in 53% of patients in the lopinavir/ritonavir once
daily arm and 57% in the lopinavir/ritonavir twice daily arm.
A pivotal study for the combination of TDF plus FTC is
study GS01-934, a noninferiority trial where 509 naive
patients were randomized 1:1 to receive a combination regi-
men with TDF plus FTC plus EFV versus AZT plus 3TC plus
EFV. The primary end point was the percentage of patients
with serum HIV RNA less than less than 400 copies/ml at
week 48. After 48 weeks of treatment, in an ITT analysis,
responders (HIV RNA < 400 copies) were 84% in the
TDF/FTC group versus 73% in the AZT/3TC group
(FIGURE 1), and the proportion of patients with HIV RNA less
than 50 copies was 80% in the TDF plus FTC versus 70% in
the control group (FIGURE 2). The difference in efficacy in ITT
analysis was due to withdrawal of study medications in a
higher proportion of patients on AZT/3TC/EFV, after adverse
events (mainly anemia) occurred. An increase in CD4 count of
190 cells was observed in TDF/FTC group versus 158 cells in
the control arm (FIGURE 3) [54].
Hepatitis B virus
There is a growing interest in therapies for HBV in coinfected
patients. The prevalence of chronic hepatitis B in HIV patients
is 5–15%, and its natural history is negatively influenced by
HIV itself. Tenofovir has demonstrated efficacy to attain HBV
DNA undetectability and hepatitis B e antigen seroconversion
both against wild-type and 3TC-resistant HBV with mutation
tyrosine–methionine–aspartate–aspartate (YMDD) [55]. In a
clinical trial comparing tenofovir and adefovir in coinfected
patients, tenofovir was found to decrease HBV DNA more
efficiently than adefovir [56].
FTC selectively inhibits HBV DNA polymerase. FTC has
more potent activity against HBV than 3TC, elicits resistance
less frequently [57] and improves liver histology.
100
p = 0.005
80 FTC + TDF 81%*
CBV 70%*
60
40
20
*95% CI: (3.4%, 18.1%)
0
BL 8 16 24 32 40 48
Weeks
527
Muñoz de Benito & Arribas López

inferior increase in triglycerides, total

100 cholesterol and low-density lipoprotein
p = 0.034 (LDL) cholesterol, along with higher
80 FTC + TDF 77%* elevation in high-density lipoprotein
Responder (%)

CBV 68%* (HDL) cholesterol in the group with

60 tenofovir [40].
Furthermore, switching from d4T to
40 tenofovir modified the lipid profile with an
observed 24-week decrease from baseline
20 triglycerides level of -62 mg/dl [60]. Follow-
*95% CI: 0.9%, 16.2% up through 48 weeks confirmed a further
0 decrease in serum triglycerides (-72 mg/dl)
BL 8 16 24 32 40 48 beyond that observed at week 24; total
Weeks cholesterol (-38) and LDL cholesterol (-16)
also decreased significantly after this period
Exclude NNRTI; -R(n = 487); FTC + TDF: 80%; CBV: 70%; p = 0.021 (1.6%; 16.6%)
of observation [61]. Interestingly, an impact
on cardiovascular risk factors has been
Figure 2. Study 934. Proportion of patients with HIV RNA less than 50 copies/ml.
CBV: Combivir; FTC: Emtricitabine; NNRTI: Non-nucleoside reverse-transcriptase inhibitor;
observed after switching d4T to TDF
TDF: Tenofovir disoproxil fumarate. owing to lipoatrophy, with an estimated
Reproduced with permission from Gilead Sciences. Inc © 2006. cardiovascular risk (Framingham equation)
significantly reduced from baseline (7.2) to
The dual antiviral activity of tenofovir and FTC for HIV and week 48 (6.6) [62]. In RAVE study, switching a thymidine analog
HBV opens new perspectives in the treatment of coinfected to tenofovir resulted in a favorable metabolic outcome in total
patients. The combination of tenofovir with FTC may increase cholesterol, LDL cholesterol and triglycerides after 48 weeks [63].
virological outcome and decreases the emergence resistance [58].
Fat distribution
Safety & tolerability Abnormal fat distribution has been associated with antiretro-
Tenofovir virals, especially with thymidine analogs [64]. Trial 934 assessed
Gastrointestinal disorders (diarrhea, nausea, vomiting and flatu- lipoatrophy after 48 weeks of follow-up in a subgroup of
lence) were most commonly reported as adverse events in clinical patients with an unfavorable result in the arm using a thymi-
trials with tenofovir-containing therapy [9,18,40]. Grade 3–4 events dine analog. At that time point, total limb fat in the TDF/FTC
occurred in 13% patients versus 14% in the placebo group [17,18], arm was 8.9 versus 6.8 kg in the in comparator arm with
and discontinuation owing to adverse events after 113 months AZT/3TC [59].
follow-up was 13% [9]. Laboratory abnormalities Grade 3–4 more Study 903 demonstrated a reduced incidence of lipoatrophy
frequently reported were elevated creatinine kinase, amilase and after 144 weeks of follow-up in patients receiving tenofovir
hypertriglyceridemia, nevertheless, their occurrence did not differ compared with the group receiving d4T (3 vs 19%) [40].
significantly from placebo group [18].
225
Lipid profile
Mean change (cells/mm3)

Metabolic abnormalities, such as dyslipi- 190 FTC + TDF

175
demia, have been described after the use of 158 CBV
HAART, justifying the assessment of its
125
incidence with different antiretrovirals.
A favorable lipid profile has been observed
in patients receiving TDF/FTC in study 75
p = 0.002
934. Serum lipid abnormalities were less at week 48
frequently found with this combination 0
BL 8 16 24 32 40 48
than in the arm receiving AZT/3TC, with
Weeks
mean change in fasting cholesterol 21 versus
FTC + TDF + EFV 238 234 223 218 209 199
35 mg/dl (p < 0.001) and a mean change in
CBV + EFV 222 216 199 188 175 164
triglycerides 3 versus 31 mg/dl (not reaching
statistical significance) [59].
Lipid parameters have been extensively Figure 3. Study 934. CD4 change.
studied in patients receiving tenofovir. A CBV: Combivir; EFV: Efavirenz; FTC: Emtricitabine; TDF: Tenofovir disoproxil fumarate.
Reproduced with permission from Gilead Sciences. Inc © 2006.
comparison with d4T demonstrated

528 Expert Rev. Anti Infect. Ther. 4(4), (2006)


A comparison between tenofovir and d4T has demonstrated
a progressive limb fat gain in patients on tenofovir after
96 weeks (7.9 kg) and 144 weeks (8.6 kg); whereas patients on
d4T experienced a decrease from 5.0 to 4.5 kg in the same
period [65]. Further substitution of tenofovir for d4T was
accompanied by a gain in limb fat from 4.60 to 5.02 kg after
48 weeks of follow-up [61]. In thymidine analog recipients with
moderate-to-severe lipoatrophy, switching to tenofovir allowed
restoration of limb fat and subcutaneous adipose tissue after
48 weeks [63].
Tenofovir does not interfere with mitochondrial DNA
synthesis, which confers this drug to a low potential to develop
adverse events related to mitochondrial toxicity, such as myo-
pathy, cardiopathy, polyneuropathy, pancreatitis, lipoatrophy
and lactic acidosis. In study 903, neuropathy and lactic acidosis
were less frequently observed with tenofovir than with d4T [39].
Bone density
Tenofovir reduces phosphate absorption, posing an eventual
risk to loss of mineral density. Bone effects were observed in
animals receiving high doses of tenofovir and changes in
biomarkers associated with increased bone metabolism have
been reported. In study 903, a decline in bone mineral density
was observed in tenofovir- and d4T-treated patients, but the
magnitude of decrease in lumbar spine was higher in the group
with tenofovir. Spine density decrease appeared between weeks
24 and 48 [66], with minimal progression in osteopenia after a
long follow-up (-3.3% at week 48, -1.6% at week 144 and
-1.0% at week 192) and no occurrence of spontaneous frac-
tures [67]. The clinical significance of these changes is
unknown, since a high prevalence of baseline osteopenia has
been reported and HIV infection itself [66,68], and antiretro-
virals have also been linked to bone demineralization. A longi-
tudinal study has demonstrated that HAART independently
predicts a decrease in bone mineral content (-1.6% per year in
extremitiy). PI-based regimens predict bone mineral loss in
extremitiy (-1.9%), while AZT predicts a decrease in bone
mineral content (-2.6%) [69].
Renal toxicity
Renal dysfunction is the dose-limiting toxicity of acyclic nucleo-
tide compounds (cidofovir, adefovir) at high doses [70]. Renal
toxicity of tenofovir has been assessed in clinical trials (902, 903,
907, 934 and 418) and in cohort studies with differing results.
Renal safety of a regimen with TDF/FTC/EFV was followed
after 48 weeks in study 934 in which no toxicity Grade (1–4) in
serum creatinine level occurred. The median change in glomer-
ular filtration rate (GFR) estimated by Cockroft–Gault (CG)
equation was -1 ml/min in the TDF/FTC/EFV group and
6 ml/min in the AZT/FTC/EFV arm, while by modification of
diet in renal diseases (MDRD) method it was
-1 ml/min/1.73 m2 in both groups [54].
After coadministration of FTC/tenofovir/lopinavir for
96 weeks in a study (418) involving 195 naive patients, creati-
nine was less than or equal to 1.5 mg/dl in 98% of the patients.
www.future-drugs.com
Tenofovir disoproxil fumarate–emtricitabine
In two subjects, serum creatinine increased by more than
3 mg/dl; one of them had baseline creatinine clearance (ClCr)
less than 40 ml/h, the other developed tubulointerstitial
nephropathy requiring hemodialysis temporarly [23].
The discontinuation of tenofovir owing to renal impairment
was less than 1% in three large studies (902, 903 and 907).
Among naive patients from study 903 [40], renal parameters
were compared in 299 subjects receiving tenofovir and 301 in
the d4T arm for a period of 144 weeks [71]. Creatinine toxicity
Grade 1 (≥ 0.5 mg/dl above baseline) occurred in 4% of
patients with TDF and 2% in the control group with d4T;
Grade 2 (2.1–3 mg/dl) in less than 1% with TDF and 0% with
d4T, while no Grade 3 (3.1–6mg/dl) was detected in the TDF
group and less than 1% in the d4T arm as reproduced
in TABLE 1.
Abnormal creatinine results were observed before week 48
and resolved without discontinuation of the drug. There was
no significant difference between both groups in mean ClCr
and serum creatinine values.
The incidence of hypophosphatemia (7%) was equal over
144 months of treatment with TDF and d4T (TABLE 2).
Grade 1, 2 and 3 proteinuria, glucosuria and hematuria did
not differ between groups and no case of Fanconi syndrome
was observed.
In the Recover study, 0.67 per 100 patient-years discontin-
ued tenofovir for renal impairment; risk factors were identified
in all of them [72]. In cohort studies, renal impairment has been
rarely observed. In tenofovir expanded access progam, 0.3% of
patients had Grade 3–4 creatinine level and 0.6% Grade 3–4
hypophosphatemia [73]. Serum creatinine alteration, in the
absence of risk factors, was observed in 0.01% of subjects in a
large cohort of 1058 patients with normal baseline renal func-
tion [74]. The reported median increase of creatinine was
0.11 mg/ml after a follow-up of 227 patient-years [75]; similar
to the findings of a retrospective study where median increase
in creatinine values was 0.1 mg/ml after 3 months, with no
further modification beyond this time point [76]. An observa-
tional cohort found no difference in renal toxicity after
48 months between the comparator arm (AZT/3TC/EFV;
n = 313) and the arm with TDF/3TC/EFV (n = 163); mean
GFR -9.9 versus -9% [77].
A decrease in renal function was disclosed in an observational
cohort comparing TDF with alternative NRTIs for 322 days
with a relative decline of 4% in ClCr in the TDF group [78].
Table 1. Renal toxicity grades.
Creatinine TDF (%) d4T (%)
Grade 1 (≥ 0.5 mg/dl) 4 2
Grade 2 (2.1–3 mg/dl) <1 0
Grade 3 (3.1–6 mg/dl) 0 <1
d4T: Stavudine; TDF: Tenofovir disoproxil fumarate.
Adapted from [71].
529
Muñoz de Benito & Arribas López
Table 2. Hypophosphatemia toxicity grades.
Phosphorus TDF (%) d4T (%)
Grade 1 (2–2.2 mg/dl) 4 4
Grade 2 (1.5–1.9 mg/dl) 3 2
Grade 3 (1.0–1.4 mg/dl) <1 <1
Adapted from [71].
d4T: Stavudine; TDF: Tenofovir disoproxil fumarate.
Another cohort study reported a mean difference in ClCr of
6.8 ml/min comparing 290 patients on TDF-containing
HAART with 618 patients on non-TDF HAART [79].
In summary, renal safety was demonstrated in clinical trials, but
there are cases of renal impairment reported when TDF was
implemented in ‘real life’. Although some cases were unrelated to
risk factors, most of the patients had underlying conditions or
concomitant use of nerphrotoxic agents. Furthermore, an associa-
tion has been observed with advanced HIV disease [78]. Clinical
significance of these data is uncertain. Currently, a safety study
(GS-235) is being carried in order to clarify the impact of
tenofovir in different grades of renal impairment.
It is advisable to determine ClCr, especially in patients with
HIV-associated nephropathy, diabetes or hypertension and to
adjust the dose of tenofovir appropriately. Clearance should be
reassessed if serum creatinine raises (even within normal values)
or during intercurrent conditions that might impair renal func-
tion. In patients with ClCr of 30–49 ml/min, dosing interval
adjustment every 48 h and close monitoring are advised. In
case clearance is less than 30 ml/min, administration should be
avoided [9].
Proximal tubule dysfunction has been described in patients
receiving TDF [70], mostly in association with nephrotoxic
agents or previously impaired renal function. There is no
established clear indication to monitor phosphorus level.
Tenofovir has been studied in the context of hepatic impair-
ment with no alteration in its exposure, proving unnecessary
any dosage adjustment.
Patients with chronic hepatitis B who have been treated
with tenofovir should be carefully monitored whenever
discontinuation of these drugs for a possible ‘flare’ of
acute hepatitis.
Emtricitabine
Most frequently reported adverse events in clinical trials with
FTC in combination therapy were headache, diarrhea, nausea
and rash [8]. FTC has been associated with skin discoloration.
Skin hyperpigmentation has also been associated with other
antiretrovirals, mainly AZT. Overall incidence of skin discolora-
tion reported is less than 1.7% [8]. In Phase III clinical trials, the
incidence of hyperpigmentation was significantly higher when
compared with d4T: (3 versus less than 1% [52]) and (3TC 6 ver-
sus 1% [53]). The severity is generally Grade 1 (80%) not requir-
ing discontinuation in any case, location predominates on palms
530
and soles, appears in the first weeks to months of treatment and
affects black individuals (8%), less frequently Asians (4%), His-
panics (3%) and Caucasians (1%) [80]. Lesions do not progress
despite continuing administration for more than 6 months [81].
Although no results on FTC in liver disease are available, its
renal elimination and minimal hepatic metabolism (< 13%)
raise no restriction issue in that clinical setting. As mentioned
above for tenofovir, FTC discontinuation in patients with
chronic hepatitis B can result in liver function alteration.
Tenofovir and FTC are classified Pregnancy category B.
Emerging treatment guidelines
Recommendations of recent guidelines include tenofovir and
FTC among preferred antiretrovirals in nucleoside backbone
for the initial treatment in naive patients.
Guidelines issued by the DHHS makes a selection of two
NRTIs as part of combination therapy that includes AZT or
tenofovir with either 3TC or FTC [101]. These guidelines cate-
gorize AZT with either 3TC or FTC as a preferred NRTI
backbone to be administered with EFV or lopinavir/ritonavir.
The combination of FTC, TDF and EFV is listed as one of the
preferred NNRTI-based treatments for use in naive treatment,
and as alternative when associated with nevirapine or
lopinavir/ritonavir.
Expert commentary
Consistent data from clinical trials on FTC and tenofovir
coadministered in individual formulation have demonstrated to
be effective and safe when studied in multiple-drug regimens,
therefore supporting the potential for this new coformulation.
The accomplishment of transforming HIV infection into a
chronic illness led patients to demand antiretrovirals that,
besides potency, have other characteristics that facilitate their
treatment. On the other hand, prolonged survival and improve-
ment in quality of life raised concern about long-term toxicities
related to HAART.
NRTIs are associated with metabolic alterations. Lipoatrophy
has been related particularly with thymidine analogs, and
abnormalities in lipid profile are not infrequent in patients
treated with d4T. This has prompted the search for regimens
that minimize these adverse events.
Adherence
Efficacy of ART correlates to the degree of adherence. Lapses in
dosing may lead to loss of full viral suppression and eventually
to resistance. A large pill burden, frequent dosage, dietary
requirements or poor tolerability may compromise adherence,
and therefore, the potency of a regimen. Simplified dosing is
deemed essential among strategies to improve adherence.
Patient preferences point to a reduced number of pills, once-
daily dosing, lack of food restrictions and forgiveness, support-
ing the present trend toward once-daily regimens [82]. An asso-
ciation has been evidenced between satisfaction, adherence and
effectiveness of once- versus twice-daily regimens [83]. Further-
more, patient satisfaction is enhanced with symmetric dosing
Expert Rev. Anti Infect. Ther. 4(4), (2006)

such that patients on a pure once-daily schedule demonstrated
more satisfaction than those with both twice- and once-daily
components in the same regimen [84].
Tenofovir and FTC have been coadministered in individual
formulation as part of once-daily combination therapy (with
EFV in study 934 and with lopinavir/ritonavir in study
418 [23,54]) demonstrating effective antiviral activity and a
favorable safety profile.
Long half-lives extends the exposure to a particular drug.
Both TDF and FTC are dosed once daily owing to the long
plasma half-life and long intracellular half-life of their active
metabolites [34,36].
Pharmacokinetic properties and interaction with other anti-
retrovirals are important considerations to build a combination
ART. Symmetryc drugs, that is, those with similar half-life and
elimination time can be administered at equivalent intervals [85].
Tenofovir and FTC share similar half-life and elimination inter-
val, the symmetry of their pharmacokinetic profile is a relevant
characteristic for the combination of these drugs both in terms of
patient preference and safety in case of therapeutic interruptions.
Currently, there are two NRTI coformulations available for
once-daily dosing: Truvada and Kivexa/Epzicom. Both share
similar antiviral potency, but differ in their safety profile. The
use of any of them allows to avoid the toxicities associated to
thymidine analogs (hyperlipidemia and lipoatrophy), but adds
concerns about ABC hypersensitivity reaction with Kivexa/Epzi-
com, and renal function surveillance in the case of Truvada.
Patients must receive information about the risk and symptoms
of ABC hypersensitivity reaction. In patients with renal dys-
function, the election will favor the use of Kivexa/Epzicom,
while patients coinfected with HBV would benefit from the
administration of Truvada owing to the antiviral effectiveness of
both tenofovir and FTC against HBV.
It would be of interest to clarify in clinical trials the renal
safety of tenofovir and related risk factors such as immuno-
logical status, concomitant use of PI or NNRTI in the regimen
as well as other factors (hypertension, anemia) that might
explain the conflicting results reported on this issue so far.
Five-year view
In the foreseeable future, once-daily dosing is bound to become a
new paradigm in ART. Simplification of therapeutic schedules is
already in progress and will proceed in the coming years.
Coformulation is expected to be the base for the strategy to
reduce the pill burden. The search of new drugs for once daily
or the adaptation of twice-daily drugs for once-daily dosing
(lopinavir/ritonavir) and modification in absorption to prolong
half-life is the present trend in pharmaceutical companies.
There are ongoing clinical trials to assess the efficacy and toler-
ability of a once-daily schedule with the administration of
Truvada and the PI TMC-114.
The aim to administer all components of HAART with the low-
est number of pills and once-daily dosing is intended to minimize
lapses in treatment, and therefore, to overcome the emergence of
resistance, hence improving the outcome of a regimen.
www.future-drugs.com
Tenofovir disoproxil fumarate–emtricitabine
Backbone selection will favor pharmacokinatically symmetric
drugs with extended plasma and intracellular half-lives. Along
with intrinsic potency, a good tolerance profile with minimal
potential for drug interactions or interference by food will,
obviously, influence the choice.
A fixed-dose formulation containing tenofovir, FTC and
efvirenz is expected to be launched since the formulation of the
fixed-dose combination has demonstrated bioequivalence to
the individual products dosed separately. There are clinical
trials under development to test TMC 114 in once-daily dosage
in association with tenofovir/FTC.
The joint venture of the manufactures of Truvada (Gilead
Sciences) and Sustiva® (Bristol-Myers Squibb) has recently
submitted a New Drug Application to the US FDA in April
2006. This will represent the first coformulation of the
complete components of HAART in one single pill for once-
daily administration, therefore, achieving a long-term expected
scope by both patients and healthcare providers. This will pave
the way to future company agreements.
At present new classes of antiretrovirals are being assessed in
clinical trials. Entry inhibitors, among them CCR5 coreceptor
antagonists maraviroc (Pfizer) and vicriviroc (Schering-Plough)
are in Phase III studies, and preliminary results are expected in
the following months. Integrase inhibitors, that prevent
integration of viral DNA into host genome are about to be
tested in clinical trials.
New drugs from ‘old’ classes are soon to be available in
practice, these include tipranavir (Aptivus®, Boehringer), the
first nonpeptidic PI which is already in the clinic, and
TMC-114 (Tibotec), another PI under expanded access after
good results from clinical trials. In the next 5 years, new drugs
an new classes of drugs will make a wider scenario possible for
the best choice in the individual patient.
Key issues
• Adherence is a determinant for a regimen success.
Implementation of convenient schedules favors adherence
to treatment.
• Once-daily dosing, low pill burden, nonstaged schedules and
well tolerated drugs, all together enhance adherence.
• The coformulation of tenofovir and emtricitabine joints two
nucleoside reverse-transcriptase inhibitors (NRTIs) with a
good pharmacological profile: long half-life allowing once-
daily dosing, effective antiretroviral activity (plus additional
activity against hepatitis B virus), lack of interference with
drugs metabolized by cytochrome P450 3A4 pathway, absent
interference with mitochondrial DNA, favorable toxicity
profile (with two issues that deserve surveillance: mineral
bone density and renal function).
• The above considerations make this dual NRTI backbone a
good option in terms of both efficacy, convenience
and safety.
531
Muñoz de Benito & Arribas López
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Website
101 Department of Health and Human
Services: guidelines for the use of
antiretroviral agents in HIV-1-infected
adults and adolescents. October 6, 2005
http://aidsinfo.nih.gov
www.future-drugs.com
Tenofovir disoproxil fumarate–emtricitabine
Affiliations • Jose Ramón Arribas López, MD, PhD
Associate Professor, Universidad Autónoma de
• Rosa María Muñoz de Benito, MD, PhD
Madrid, Facultad de Medicina, Unidad de HIV,
Hospital La Paz, Unidad de HIV, Paseo de La
Castellana, 261, 28046 Madrid, Spain Hospital La Paz, Paseo de La Castellana, 261,
28046 Madrid, Spain
Tel.: +34 917 277 099
Tel.: +34 917 277 099
Fax: +34 917 290 033
rmmunoz2004@yahoo.es Fax: +34 917 290 033
josearribas@telefonica.net
535