Pharmacology & Pharmacy, 2013, 4, 651-662
Published Online December 2013 (http://www.scirp.org/journal/pp)
http://dx.doi.org/10.4236/pp.2013.49092
Open Access PP
651
Tenofovir Renal Toxicity: Evaluation of Cohorts and
Clinical Studies—Part One
Adikwu Elias*, Ogbuehi Ijeoma, Nkereuwem Jonathan Edikpo, Deo Oputiri, Oru-Bo Precious Geoffrey
Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Choba, Rivers State, Nigeria.
Received September 11th, 2013; revised October 24th, 2013; accepted November 8th, 2013
Copyright © 2013 Adikwu Elias et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Tenofovir is one of the most commonly used antiretrovirals in adolescents and adults because of its potency and favor-
able pharmacokinetic and relative safety toxicological profile. It has been combined successfully with antiretroviral
drugs from classes such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleoside reverse
transcriptase inhibitors to achieve virologic suppression in a high percentage of recipients. Despite its therapeutic suc-
cess, quite a number of cohorts and clinical studies have associated tenofovir with the development of renal toxicity
with few studies on the opposing end. This stimulated us to review reported cohorts and clinical studies on tenofovir
renal toxicity. In this study it was observed that literature reported incidence of tenofovir renal toxicity falls within the
range of 0.7% - 17%. Available studies gave different appellations to tenofovir renaltoxicity, which include fanconis
syndrome, proximal tubule dysfunction, acute renal failure, chronic renal failure, chronic kidney disease and nephro-
genic diabetes insipidus. Markers of renal toxicity (tubulopathy) which include glycosuria, hyperaminoaciduria, pro-
teinuria, hyperphosphaturia, hyperuricosuria, retinol-binding protein, beta2-microglobulinuria, decreased creatinine
clearance and decreased glomerular filtration rate were also reported. In some studies renal biopsy demonstrated cyto-
plasmic vacuolization, apical localization of nuclei and reduction of the brush border on proximal tubule epithelial cells.
This study observed that tenofovir renal toxicity could be reversible on discontinuation of tenofovir therapy despite
contrary views by some studies. Regardless of tenofovir reported renal toxicity, it is well tolerated with a relative safety
profile but it is advised that renal profile of patients should be evaluated before and routinely during tenofovir therapy.
Keywords: Tenofovir; Pharmacology; Renal; Toxicity; Cohorts
1. Introduction
The human immunodeficiency virus (HIV-1) is a retro-
virus of the lentivirus genus that primarily infects cells of
the host immune system. Once an individual is infected,
HIV-1 replication takes place in several steps. In the first
step, the virion attaches itself and fuses with the host cell
membrane using co-receptors and releases two single-
stranded RNA molecules and three different viral en-
zymes into the host cell cytoplasm. The introduced viral
RNA is transcribed by viral reverse transcriptase enzyme
into DNA and the viral DNA is transported into the nu-
cleus. The viral DNA is processed and incorporated by
the viral integrase enzyme into the host genome. The
integrated viral DNA (aprovirus) is transcribed and
translated by the host system to produce viral proteins
and single-stranded RNA for new virions. After assem-
blage, the new virions bud off and mature using the viral
protease, completing the HIV-1 lifecycle [1].
One of the key principles of antiretroviral therapy is
the inhibition of the above mentioned HIV replication
stages. These have led to the combination of at least three
antiviral drugs, preferably from at least two different
classes as the standard practice and are known as highly
active antiretroviral therapy (HAART) which is currently
the therapy of choice for HIV infected patients [2]. Dif-
ferent types of antiretroviral combination therapies are
available and use of a particular therapy depends on the
tolerability, the cost, and the therapeutic objectives [3].
However, despite remarkable viral replication suppres-
sion, immune response restoration and decreased mortal-
ity, long-term HAART appears to be associated with the
development of some toxicological effects like cardio-
toxicity, hepatotoxicity and nephrotoxicity [4,5]. These
*Corresponding author.

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 652
have impaired therapeutic success via poor adherence,
loss of serum HIV suppression, development of drug-
resistant HIV strains, and increased probability of illness
progression [6]. Among these HAART associated toxi-
cological effects is renal toxicity which was reported to
be pronounced in tenofovir (TDF) containing antiretro-
viral regimen [7].
Tenofovir is one of the most commonly used antiret-
rovirals (ARVs) in adolescents and adults because of its
potency and a favorable pharmacokinetic (PK) profile
that allows it to be dosed once daily [8,9]. Tenofovir has
been found to be effective in many combination regi-
mens for the treatment of HIV infection, both in previ-
ously untreated and in treated individuals. It has been
combined successfully with antiretroviral drugs from
classes like protease inhibitors. Non-nucleoside reverse
transcriptase inhibitors and nucleoside reverse transcrip-
tase inhibitors to achieve virologic suppression in a high
percentage of recipients, but researches have associated
tenofovir with renal toxicity and decreased mineral bone
density [10]. Due to increased reports on tenofovir in-
duced renal toxicity and its place in the management of
HIV, this work which is the first part (Part 1) of two parts
investigated reported cohorts and clinical studies on the
renal profile of tenofovir.
2. Pharmadynamics and Pharmacokinetics
of Tenofovir
Tenofovir was approved by the US Food and Drug Ad-
ministration (FDA) on October, 29, 2001 as a once-daily
300 mg tablet for individuals aged 18 years and above
for the treatment of HIV-1 infection in combination with
other ARVs [11]. It is a 9-R-2-phosphonomethoxypropyl
adenine (PMPA) that belonging to the acyclic nucleoside
phosphonate family [12]. It is an ester prodrug and is
orally administered. Due to the presence of a phospho-
nate group, tenofovir is negatively charged at neutral pH,
which limits its oral bioavailability [13]. When adminis-
tered, it is first hydrolyzed by carboxylesterase and
phosphodiesterase during its first passage through the
liver to producedtenofovir [14,15]. Tenofovir is later
phosphorylated in the cell by adenylate kinase to produce
tenofovir monophosphate (TFV-MP). TF-MP undergoes
conversion by nucleotide diphosphate kinase to produce
tenofovir diphosphate (TFV-DP). TFV-DP has antiviral
property and it competes with the naturally nucleotide
counterpart deoxyadenosine 5’-triphosphate to inhibit
viral reverse transcriptase. The incorporation of TFV-DP
into the viral DNA chain terminates DNA elongation and
stops further DNA synthesis [16].
Tenofovir has a relatively long half-life of 12 - 18
hours [17]. The oral bioavailability in fasted patients is
approximately 25%. Administration of food (high fat
meal) increases the oral bioavailability, with an increase
in the AUC of approximately 40%. The binding of teno-
fovir to human plasma or serum proteins is less than
7.2%. The volume of distribution at steady-state is 1.3 ±
0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous ad-
ministration of tenofovir 1.0 mg/kg and 3.0 mg/kg re-
spectively [18]. Tenofovir is not metabolized by liver
enzymes but is extensively and rapidly eliminated as
unchanged drug in the urine TDF is eliminated by a
combination of glomerular filtration and active tubular
secretion. There may be competition with other com-
pounds that are also excreted through the kidney [19].
TDF associated toxicities include a decline in mineral
density of bone, renal increase in parathyroid hormone
(PTH) secretion, phosphaturia and hypophosphataemia
while fatal lactic acidosis has been reported when TDF
was added to a regimen containing didanosine due to
TDF induced increase indidanosine concentration [20].
The use of TDF is associated with proximal tubular
dysfunction with or without decreased renal function.
Renal impairments, including cases of acute renal failure
and Fanconi’s syndrome, have been reported with the use
of TDF in clinical practice [21]. The pharmacokinetics of
tenofovir are altered in patients with renal impairment
and patients with creatinine clearance <50 mL/min or
with end-stage renal disease (ESRD) requiring dialysis. It
is recommended that the dosing interval for tenofovir be
modified in patients with creatinine clearance <50 mL/
min or in patients with ESRD who require dialysis [22].
Renal tubular dysfunction and tubular toxicity have been
associated with increased TDF plasma concentration.
TDF-associated elevations of PTH have been found in-
dependent of vitamin D deficiency and have also been
linked to vitamin D deficiency in studies of adults with
HIV [23,24].
Tenofovir is recommended as one of the preferred nu-
cleotide reverse transcriptase inhibitors (NRTIs) for
first-line ART in adults. It is available as a co-formula-
tion with other ARVs to make dual or triple fixed-dose
combinations. Tenofovir exhibited synergistic and addi-
tive activity when combined with certain antiretrovirals
and demonstrates no antagonistic interactions in their
presence. Strong synergism has been seen with zi-
dovudine and nevirapine. Additive inhibition has been
reported when co-administered with abacavir, lami-
vudine and emteicitabine [25,26]. There are reports of
HIV-1 isolates with reduced susceptibility to tenofovir in
vitro. These viruses expressed a K65R mutation in re-
verse transcriptase and showed a 3 - 4 fold reduction in
susceptibility to tenofovir [27].
3. HIV Associated Renal Disease
Renal functions abnormalities are present in a large per-
centage of patients with HIV infection especially those
with very high viral load and comobidities. HIV-associ-
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 653
ated renal disease has become a relatively frequent cause
of end-stage renal disease (ESRD) requiring dialysis and
seems to be associated with progression to AIDS and
death. Kidney disease associated with HIV is a signifi-
cant challenge to patients and clinicians by increasing the
risk for AIDS-defining illness, hospitalization, and death
[28,29]. Due to morbidity and mortality as a result of
HIV associated renal disease, in this section we critically
examine reported cases of renal disease attributed to HIV.
One of the first cases of kidney disease associated with
HIV as reported in 1984 by Rao et al. [30] was charac-
terized by nephrotic syndrome with focal and segmental
glomerulosclerosis in nine cases of acquired immunode-
ficiency syndrome (AIDS). Naicker and colleagues in
their work also attested to the fact that the association
between HIV and renal disease was first reported in 1984
in New York City and Miami. These groups showed that
HIV-positive individuals have proteinuria and progres-
sion to end-stage renal disease which occurs within 8 -
16 weeks; death rate approached 100% within 6 months
of diagnosis [31].
Subsequently, various glomerular and renal syndromes
were described in histology or autopsy studies [32]. Dif-
ferent types of renal diseases associated with HIV have
been reported this include classic Human immunodefi-
ciency virus associated nephropathy (HIVAN), HIV-
associated thrombotic microangiopathy, and immune-
mediated glomerulonephritis which were discussed in the
second part of this work. A survey conducted during the
period 1995 through 1999 showed an increasing preva-
lence of HIV associated renal disease from 6.3% to 9.1%
in HIV patients [33]. Another report revealed that preva-
lence of chronic kidney disease in HIV patients may be
between 5% to 15% depending on the series. However,
some studies revealed that the prevalence of renal histo-
logical involvement ranged from 1% - 15% depending on
the different autopsy series [34,35].
Similar increase in prevalence was also reported by
Deti and colleagues who showed that incidence rate of
chronic renal failure were 1.27 cases per 100 person-
years. This tends to rise with time: 1.9% at one year,
3.3% at two years, 4% at three years, and 4.4% at four
years [36]. Rates of ARF in HIV outpatients were re-
ported at 2.9% in 1995 and 6.0% in 2003 in a study of
25,114 patients which shows an increase in trend [37].
Data from the US Renal Database System (USRDS)
showed that every year, approximately 800 - 900 new
cases of end-stage renal disease (ESRD) attributed to
HIVAN are recorded in the US and nearly 90% are re-
ported in African-Americans [38]. Szczech in her study
also reported CKD correlated with proteinuria and ele-
vated creatinine level in 7% to 32% of HIV-seropositive
patients and were associated with an increased rate of
death in a study of 2038 female HIV-infected patients
[39]. Another study that showed the prevalence of HIV
infection in renal disease is the report from the Veterans
Affairs Medical System. This report showed that the
overall incidence of end-stage renal disease was 3.9
cases/1000 person-years among HIV-infected veterans.
In this report a higher incidence of end-stage renal dis-
ease was observed among HIV-infected African-Ameri-
cans which may suggests genetic predisposition in HIV
associated renal disease [40].
A similar incidence of higher end-stage renal disease
in blacks was also reported in a single-center study from
Johns Hopkins, with an 18-fold higher risk for progres-
sion to ESRD among HIV infected African-Americans
compared with HIV-infected Caucasians [41]. Haile-
mariam et al. (2001) [42] reported series of 239 autopsies
performed on patients with AIDS in Switzerland from
1981 to 1989 (before the introduction of HAART). Vari-
ous renal abnormalities were reported among the 228
white patients. However, the only case of HIVAN in this
series was detected in one of six African patients in-
cluded in the study. The prevalence of higher HIV asso-
ciated kidney disease in black population is supported by
a study which employed varying criteria for diagnosis of
kidney disease. This study reported a variable prevalence
of these diseases in patients with HIV in sub-Saharan
Africa: 6% in South Africa, 38% in Nigeria, 26% in Côte
d'Ivoire, 28% in Tanzania, 25% in Kenya, 20% - 48.5%
in Uganda and 33.5% in Zambia. Results from these
studies also suggested that a broader spectrum of histo-
pathological lesions in HIV-associated kidney disease
exists in African populations than previously thought
[43].
A study conducted on an urban US HIV population
found evidence of CKD in 24% of the patients. Forty
patients which represents (10%) had CKD stage 1, 19
patients which represents (4%) had stage 2, 29 patients
(7%) stage 3, four patients (1%) stage 4, and eight pa-
tients (2%) stage 5 [44].
Another study carried out in Baltimore, Maryland
supported the involvement of HIV in renal disease. In
their work they measured CKD incidence, GFR slope,
and progression to ESRD in 3332 African American and
927 white HIV-infected subjects. A total of 284 subjects
developed CKD, 35% of whom subsequently developed
ESRD [45]. In a cross-sectional study of another urban
HIV-infected population in New York City, 22% of Af-
rican-American patients (versus 11.4% of whites) had
either CKD or ESRD; 4.1% of the studied population
including Caucasians and Hispanics had ESRD [46].
Rollins et al., 2006 [47] reported that HIV-associated
nephropathy is caused by focal sclerosing glomerulopa-
thy with is characterized by proteinuria, renal failure, and
rapid progression to ESRD. It is said to have a genetic
predisposition because it is very common in Africans
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 654
infected with HIV. It occurs late in the course of HIV-1
infection and includes a CD4 cell count 200 cells/mm3
and a high viral burden. But with the advent of HAART
in the treatment of HIV, the incidence of HIV associated
renal disease must have decreased due to decline in mor-
bidity and mortality rate.
4. Tenofovir Renal Toxicity
Tenofovir is one of the widely prescribed antiretroviral
drugs and is an essential part of all the regimen (HAART)
use in the treatment of HIV-1 adults. TDF has achieved
very wide acceptability because it is easy to be adminis-
tered, efficacious, and relatively favorable toxicological
profile. These qualities have increase the choice and use
of TDF as one of the widely prescribed antiretroviral
drugs for the treatment of HIV-1. Despite its therapeutic
success some reports have associated TDF with devel-
opment of renal toxicity which include proximal tubular
dysfunction, Fanconi syndrome, acute kidney injury,
acute renal failure and chronic renal failure. Reports of
renal toxicity attributed to TDF have been published as
case reports, cohorts and clinical studies. This section
analyzed “with all degree of clarity” these reported co-
horts and clinical studies taking into cognizance, the in-
cidence, reversibility of tenofovir renal toxicity and dis-
crepancy in reports.
4.1. Epidemiology
The incidence of a disease could be fundamentally cor-
related with its morbidity and mortality rate hence the
incidence of tenofovir associated renal toxicity can’t be
overemphasized. Studies have reported different inci-
dence. This portion evaluated reported incidence of ten-
ofovir associated renal toxicity. We will start by looking
at a retrospective review of the Food and Drug Admini-
stration Adverse Events Reporting System from 2001
through 2006 which registered 164 subjects who had
Fanconi’s syndrome. Report showed that 83% of subject
with Fanconi syndrome received tenofovir with protease
inhibitors [48]. Evaluation of 754 HIV infected subject
treated with tenofovir by SCOLTA reported 2.5% inci-
dence of creatinine elevations over 1.5-fold the upper
limit of normal in a mean followup of 19.5 months [49,50].
Similar observation was reported when a total of 172
patients receiving tenofovir disoproxil fumarate (TDF)
for a median of 16 months were evaluated. Seven (4%)
patients developed grade 1 increases in serum creatinine
(SCr). Fifteen (8.7%) patients had an increase in SCr of
greater than 1.5 times baseline values. Four (2.3%) pa-
tients discontinued TDF due to increase in SCr and/or
abnormal urinalysis. Of 62 patients with urinalysis,
twenty-eight which represents (16%) and 11 which
represents (6%) of the patients developed grade 1 and
grade 2 hypophosphataemia respectively [51].
Some studies have identified rising incidence of hy-
pophosphatemia in patients treated with tenofovir a
prevalence of 9.8% among tenofovir-treated patients,
6.7% among non tenofovir, HAART-treated patients and
2.6% among treatment-naive, HIV-infected individuals
were reported. This observed hypophosphatamia which is
a biomaker of renal toxicity may be associated with some
comorbidities [52,53]. An outstanding incidence was
reported by retrospective cohort analysis of HIV-infected
adults who received tenofovir at the Themba Lethu in
South Africa. Of 890 patients initiated on tenofovir, 573
(64.4%) had normal renal function had mild renal dys-
function and 46 (5.2%) had moderate renal dysfunction.
2.4% experienced nephrotoxicity, 7.8% died and 9.7%
were lost during 48-months of follow-up. Incidence of
tenofovir associated renal toxicity can be seen from an
evaluation of 10,343 tenofovir-treated patients [54].
Another study showed 8.4% of patients attained a
greater than 1.5-fold increase in SCr within 6 months of
starting tenofovir therapy [55]. One of the studies that
could have correlated incidence of tenofovir renal toxic-
ity, risk and exposure was the evaluation of association
of cumulative and ever exposure to tenofovir on kidney
outcomes in 10,841 HIV-infected patients. After multi-
variable adjustment, each year of exposure to tenofovir
was associated with 34% increased risk of proteinuria
11% increased risk of rapid decline and 33% increased
risk of CKD [56]. In a cohort Of 4183 HIV-positive pa-
tients, 1058 patients were exposed to tenofovir DF, Only
84 (8%) patients experienced a creatinine value >120
μmol/L [57]. Some incidence as reported by some au-
thors include 0.7% by Cooper et al., (2010) [58] 1.65%
by Padilla et al., ( 2005) [59] 0.78% and 2% by Gupta et
al., (2012) [60].
4.2. Cohorts and Clinical Studies
Tenofovir has been associated with development of renal
toxicity in humans and animals. Quite a number of co-
horts, case reports and clinical studies have reported dif-
ferent forms of tenofovir associated renal toxicity. In this
section, we critically looked at various cohorts andclini-
cal studies to evaluate the profile of tenofovir on the re-
nal system. Verhelst et al. (2002) [61] was the first to
describe a patient who was treated with tenofovir and
developed reversible Fanconi syndrome, nephrogenic
diabetes insipidus, and acute renal failure. Renal biopsy
demonstrated cytoplasmic vacuolization, apical localiza-
tion of nuclei, and reduction of the brush border on
proximal tubule epithelial cells. Subsequently more re-
ports on tenofovir associated renal toxicity were rolled
out from various studies. One of these reports is a retro-
spective cohort analysis of 1647 patients enrolled in the
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 655
Kaiser Permanente Health Maintenance Organization
during 2002 to 2005. In this study tenofovir exposure
was found to be significantly associated with a decline in
GFR and proximal tubular dysfunction [62].
Another cohort that showed the nephrotoxic effect of
tenofovir was performed by Milinkovic and colleagues.
They evaluated 1293 patients and reported that 103 pa-
tients stopped tenofovir therapy in which 29 discontinued
due to renal toxicity [63]. In the ANRS CO3 Aquitaine
Cohort, 2613 HIV-infected patients were followed-up
between 2004 and 2008 to estimate the incidence of
chronic renal failure and related risk factors. The inci-
dence rate of chronic renal failure was much higher (12.7
cases for 1000 person-years) which is said to be associ-
ated with factors like immunodeficiency and tenofovir
exposure [64]. The above reports are in agreement with
the work of Wood ward and friends who evaluated the
renal profile of 5687 patients in a clinical centre provid-
ing HIV care services. They identified 22 patients with
TDF associated renal toxicity of which 21 were males
and one female [65]. Also a similar Swiss HIV Cohort
Study found a consistent evidence for a significant re-
duction in GFR associated with tenofovir use [66].
The incidence of CKD was also investigated in the
Euro-SIDA Cohort Study, which included 6843 HIV-
infected persons that were followed-up from 2004 on-
wards. Progression to chronic nephropathy was observed
in 225 patients among 21,482 person-years which repre-
sents an incidence of 1.05/100 person-years. After ad-
justment for traditional risk factors, exposure to tenofovir
was significantly associated with a higher incidence of
CKD [67]. This is consistent with a study that evaluated
281 HIV infected patients receiving TDF followed up for
4 - 6 weeks, 3, 6, 9 and 12 months, result showed asso-
ciation between TDF and renal toxicity [68]. It is out-
standing to know that in a retrospective cohort study
conducted by Manosuthi et al. one hundred and thirty
patients were evaluated. Report showed that the overall
incidence of renal failure was 0.26 per 100 persons/
month [69]. Also a cross-sectional study involving 845
HIV-infected outpatients showed a prevalence of chronic
renal failure higher than that of the general population,
and significant predictors of lower GFR in multivariate
analyses were found to be associated with the use of ten-
ofovir or stavudine [70].
Cao and others investigated the impact of tenofovir
containing regiment in 75 HIV-positive patients. Their
results showed that tenofovir containing regimen resulted
in greater renal function decline over 48 weeks [71]. This
may agree with an observational cohort of renal evalua-
tion of patients on TDF performed by Patel and core-
searchers. In this cohort, 1271 patients were evaluated,
83 developed renal dysfunction of which 79 had im-
paired serum creatinine and 5 had faconis syndrome.
Renal dysfunction was higher in tenofovir and PI con-
taining regimen [72]. Soler-Palacin and co researchers in
their study also showed the capability of tenofovir to
induced renal toxicity. The evaluated 40 patients on TDF
for a median duration of 77 months and reported signifi-
cant association between TDF and renal tubular dysfunc-
tion in HIV infected children [73].
In a cross-sectional study of 99 HIV-infected patients
who used tenofovir had increased urine retinol-binding
protein/creatinine ratio and protein/creatinine ratio,
showing a subclinical renal tubulopathy [74]. This can be
correlated with a cross-sectional study of plasma and
24-hour urine markers of tubulopathy (glycosuria, hy-
peraminoaciduria, hyperphosphaturia, hyperuricosuria,
and beta2-microglobulinuria) in 284 HIV-positive pa-
tients who demonstrated a significant relationship be-
tween exposure to tenofovir and tubular dysfunction in
the absence of impaired glomerular function [75]. Simi-
lar findings were reported in the ASSERT study, a mul-
ticenter, randomized, open-label trial comparing the
safety profiles of tenofovir/emtricitabine and abacavir/
lamivudine in association with efavirenz in 385 HIV-
infected subjects. After a 48-week follow-up, no differ-
ence in eGFR was observed between the arms, but mark-
ers of tubular damage (urinary excretion of retinol-bind-
ing protein and beta2-microglobulin) increased signifi-
cantly in the tenofovir/emtricitabine group [76].
Compel et al., also added their voices to affirm the re-
nal toxicity of tenofovir by evaluating 843 patients on
TDF containing ART. They discovered that 26 patients
developed chronic kidney disease. Those who developed
CKD were older and 85% of participants had other risk
factor for progression [77]. Decrease in renal function via
was also reported in a study involving 40 patients starting
a TDF-containing regimen and 388 patients starting
regimen not containing TDF, and followed during 42
months. Between baseline and 12 months, the eGFR de-
creased significantly in patients receiving TDF (−10.40
ml/min), After 12 months, patients receiving TDF ex-
perienced a higher rate of transition from mild renal im-
pairment (60 - 90 ml/min/1.73 m2) to moderate renal im-
pairment (30 - 60 ml/min/1.73 m2) when compared with
patients not receiving TDF [78].
Cohorts studies performed in African countries are
consistent with reports from other countries on renal tox-
icity associated with tenofovir and this can be correlated
with report of higher incidence of tenofovir nephrotoxic-
ity in blacks [79]. In a cohort that took place in Zambia
involving 10485 patients on ART in which 6900 were on
TDF containing regimens available result showed that
exposure to TDF was associated with a mean decrease of
−14.7 ml/min in crcl from baseline of 6 months [80].
Another study of 324 ARVnaıve patients found a greater
incidence of proximal tubular dysfunction and greater
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 656
decline in eGFR over 24 months in tenofovir-treated pa-
tients [81].
In a cohort analysis of 512 patients on tenofovir con-
taining antiretroviral regimen for 26 months it was ob-
served that TDF induced AKI developed in 25 patients.
On stopping TDF 15 patients had complete recovery of
renal function, 5 had partial recovery while 5 patients
died [82]. This is in agreement with a study involving
324 patients in which 201 TDF exposed patients were
compared with 123 tenofovir un-exposed subjects. Re-
sults showed that tenofovir exposed patients had a sig-
nificant greater decline in glomerular filtration rate and a
significant higher incidence of proximal tubular dysfunc-
tion through 24 months [83]. Similarly, both current and
past tenofovir use were associated with increased risk of
proximal renal tubular dysfunction in a cross-sectional
study of 399 HIV infected persons [84].
A single-centre cohort study of 503 Japanese patients
administered either tenofovir or abacavir base ART was
performed by Nishijima et al. and incidence of renal
function was defined as more than 25% fall in estimated
glomerular filtration rate from the base line. Result
showed that incidence of renal dysfunction in tenofovir
arm was higher than the abacavir arm per 100 persons-
year [85]. This report is consistent with an evaluation of
226 patients on TDF containing regimen in which 18
patients had a decline in renal function [86]. This can be
correlated with a European multicenter cohort study in-
volving 78 HBV infected patients exposed to TDF for 76
weeks and reported significant renal damage [87]. Johns
Hopkins cohort data showed significant reductions in
creatinine clearance at 180 days, 270 days, and 360 days
over a 360-day follow-up in 344 patients receiving teno-
fovir compared with 314 patients who received nRTIs
other than tenofovir [88].
4.3. Is It Reversible?
Still on tenofovir associated renal toxicity, there are dis-
crepancies in reports on the reversibility of tenofovir
renal toxicity. Some studies have reported the reversibil-
ity of tenofovir associated renal toxicity. These studies
include a research that evaluated the association between
tenofovir use and renal abnormality in HIV-1-infected
children on antiretroviral therapy; the biochemistry re-
sults for 456 ART-exposed children were evaluated. Re-
sults showed that twenty out of 456 (4.4%) had hypo-
phosphataemia, and one had eGFR less than 60 ml/min
per 1.73 m2. The hypophosphataemia incidence rate was
4.3/100 person-years in the TDF group versus 0.9/100
person-years in those not exposed to TDF. They con-
cluded that hypophosphataemia was uncommon (4%),
but was associated with prolonged TDF use, and was
generally reversible following TDF withdrawal [89].
Another study in which patients received tenofovir
therapy for a mean of 19.6 months show that nine pa-
tients presented with acute kidney injury, and four had
mild renal insufficiency with subnephrotic proteinuria,.
11 of 13 patients who discontinued tenofovir showed
significant recovery of renal function including four who
required transient hemodialysis [90]. The progress of
renal damage after discontinuation of tenofovir (TDF) in
patients who started therapy with normal renal parame-
ters was also assessed by Bonjoch and colleagues. They
evaluated 183 patients who were exposed to TDF for 39
(22 - 63) months. After 22 (13 - 49.5) months of TDF
discontinuation, renal parameters returned to normal
values in 59% of patients [91]. Kelly and colleagues also
reported that proteinuria was reversible in 11 of 12 pa-
tients who discontinued tenofovir because of proteinuria
without altering other medications [92].
Other cases of reversible tubular dysfunction, includ-
ing Fanconi syndrome, nephrogenic diabetes insipidus,
and/or ARF, have also been reported, with onset usually
within 5 to 12 months after starting therapy and recovery
usually occurring within a few months after tenofovir
discontinuation [93,94]. Another study that supports the
reversibility of tenofovir nephrotoxicity is a cohort of
1286 HIV patients treated with tenofovir containing
regimens and followed up for 48 weeks results showed
an incidence of 0.39 per 100/year which was reversed on
cessation of therapy [95].
Some studies gave contrary views on the reversibility
of tenofovir renal toxicity. One of these studies was per-
formed by McKelvey who evaluated the renal function of
24 HIV positive patients treated with tenofovir for
greater than 3 months and reported that the use of TDF is
associated with impairment of renal function. This im-
pairment was not fully reversible in the majority of pa-
tients following cessation of TDF [96]. This is consistent
with a study by Wever and colleagues which evaluated
the reversibility of TDF-related nephrotoxicity in 24
HIV-infected male outpatients who ceased TDF due to
renal impairment and observed that TDF-related renal
toxicity was not always fully reversible [97]. Zimmer-
man and co researchers in their work reported that teno-
fovir-associated ARF manifests as acute tubular necrosis
that may not resolve with tenofovir withdrawal [98].
Comparatively more studies gave credence to the re-
versibility of tenofovir associated nephrotoxicity.
4.4. Discrepancy in Reports
Despite reported cases of tenofovir associated renal tox-
icity some few studies have attested to the safety of ten-
ofovir on the renal system. One of the studies that
showed the safety profile of tenofovir on the renal system
is a long time follow up of 542 tenofovir exposed pa-
tients in which no significant renal impairment was ob-
served [99]. Another report is a 3-year study that com-
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 657
pared 602 therapy-naive patients with a backbone of
lamivudine and efavirenz treatment with either tenofovir
or stavudine, no difference in the incidence of renal dys-
function was found [100]. In a HIV Outpatient Study
(HOPS), use of tenofovir-containing HAART was asso-
ciated with modest decreases in GFR during the first year
of therapy, but clinically significant renal toxicity was
very uncommon [101] and decline in GFR in subjects
with preexisting renal dysfunction was also very limited
[102]. Similar observation was reported in an analysis
involving a total of 514 patients receiving tenofovir
which report showed that TDF containing ART was as-
sociated with less renal impairment than ART without
tenofovir [103].
Clinical trials and post-marketing data reported excel-
lent safety profile of tenofoviron HIV + subjects includ-
ing the absence of significant renal injury. This finding is
supported by an in vitro experimental study [104]. A
long-term analysis of renal safety in patients receiving
TDF compared with d4T for 144 weeks; mean serum
creatinine did not change in the TDF group compared
with a 0.1 mg/dl decrease from baseline in the d4T group.
No patient experienced grade 4 (1.0 mg/dl) hypophos-
phatemia and no patient developed Fanconi’s syndrome
or proximal renal tubular dysfunction [105]. Gallant, et
al., 2009 [106] evaluated 432 antiretroviral-naive pa-
tients who initiated either tenofovir or any alternative
NRTI. Patients taking both tenofovir and NRTI experi-
enced an initial decline in GFR during the first six
months of therapy, but renal function stabilized between
six and 24 months. A comparative randomized study of
ABC/3TC versus TDF/FTC in 333 persons found no
statistically significant differences in eGFR over 48
weeks [107].
Furthermore, tenofovir did not appear to be associated
with worsening kidney function in the multicenter, ob-
servational FRAM study, despite widespread use at the
follow-up visit [108]. A 1-year prospective study of 424
HIV-infected persons also reported no association be-
tween tenofovir use and tubular damage [109]. This is
consistent with an investigation on the safety and effi-
cacy of once daily doses of tenofovir administered in
combination with other antiretroviral therapy in treat-
ment-experienced HIV-1-infected patients. One-hundred
and eighty-nine subjects were exposed to various doses
of TDF for 48-weeks; no significant changes in renal
function were observed [110].
Observation from a STACCATO trial where Thai pa-
tients were treated with tenofovir containing antiretrovi-
ral drug showed lack of renal toxicity [111]. Vigano and
co researcher evaluated the renal safety of tenofovir in
HIV-infected children treated with tenofovir for 96
weeks. They reported no evidence of renal toxicity in
tenofovir treated HIV infected children [112]. In a cohort
of 933 HIV patients treated with tenofovir containing
antiretroviral regimen, followed through for 6 and 12
months showed that TDF associated renal toxicity is rare
[113]. Another cohort of 53 HIV patients exposed to
TDF containing antiretroviral regimens for 48 weeks
performed by Gerard and co-researchers reported that
TDF related severe nephrotoxicity is an uncommon event
[114]. The safety and efficacy of TDF compared with
placebo in 235 patients was evaluated in addition to other
observations TDF had a similar safety profile with pla-
cebo [115]. On the other hand, large observational stud-
ies and clinical trials have shown no evidence of glome-
rular or tubular damage when tenofovir is employed as a
component of an initial antiretroviral regimen [116,117].
5. Conclusion
Cohorts and clinical studies have attested to the fact that
tenofovir may have renal toxicity which could be re-
versible on discontinuation of therapy. The incidence of
tenofovir renal toxicity may be low due to reports and
with respect to therapeutic success achieved with the
clinical use of tenofovir in combination with other anti-
retroviral agents. Due to reports, it is recommended that
patients’ renal status should be evaluated before and in
the course of tenofovir therapy.
REFERENCES
[1] L. R. Smith, R. de Boer, S. Brul, Y. Budovskaya and H.
Van der Spek, “Premature and Accelerated Aging: HIVor
HAART?” Frontiersin Genetics|Genetics of Aging, Vol. 3,
No. 328, 2013. pp. 1-10.
[2] M. Dybul, A. S. Fauci, J. G. Bartlett, J. E. Kaplan and A.
K. Pau, “Guidelines for Using Antiretroviral Agents
among HIV-Infected Adults and Adolescents,” Annals of
Internal Medicine. Vol. 137, No. 5, 2002, PP, 381–433.
[3] J. L. Ngondi, J. Oben, D. M. Forkah, L. H. Etame and D.
M. Banya, “The Effect of Different Combination Thera-
pies on Oxidative Stress Markers in HIV Infected Patients
in Cameroon,” AIDS Research and Therapy, Vol. 3, No.
19, 2006, pp. 1-7.
[4] A. Elias and N. Brambaifa, “Concentration-Effect, Inci-
dence and Mechanism of Nevirapine Hepatotoxicity,”
American. Journal of Pharmacology and Toxicology, Vol.
8, No. 1, 2013, pp. 20-30.
http://dx.doi.org/10.3844/ajptsp.2013.20.30
[5] A. Elias, D. Oputiri, O. P. Geoffrey and D. A. Enimeya,
“Nevirapine Hepatotoxicity Implication of Risk Factors,”
American Journal of Pharmacology and Toxicology, Vol.
8, No. 2, 2013, pp. 51-63.
http://dx.doi.org/10.3844/ajptsp.2013.51.63
[6] A. Mandas, E. L. Iorio, M. G. Congiu, C. Balestrieri, A.
Mereu, et al., “Oxidative Imbalance in HIV-1 Infected
Patients Treated with Antiretroviral Therapy,” Journal of
Biomedicine and Biotechnology, 2009, Article ID: 749575.
http://dx.doi.org/10.1155/2009/749575
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 658
[7] S. Mouss, F. Berger and G. Schmutz, “Antiretroviral
Therapy with Tenofovir Is Associated with Mild Renal
Dysfunction,” AIDS, Vol. 19, No. 1, 2005, pp. 93-99.
http://dx.doi.org/10.1097/00002030-200501030-00012
[8] K. A. Lyseng-Williamson, N. A. Reynolds and G. L.
Plosker, “Tenofovir Disoproxil Fumarate: A Review of
Its Use in the Management of HIV Infection,” Drugs, Vol.
65, No. 3, 2005. pp. 413-432.
http://dx.doi.org/10.2165/00003495-200565030-00006
[9] T. M. Chapman, J. K. McGavin and S. Noble, “Tenofovir
Disoproxil Fumarate,” Drugs, Vol. 63, No. 15, 2003, pp.
1597-1608.
http://dx.doi.org/10.2165/00003495-200363150-00006
[10] J. M. Lucey, P. Hsu and J. B. Ziegler, “Tenofovir Related
Fanconis Syndrome and Osteomalacia in a Teenager with
HIV,” British Medical Journal Case Report, 2013
[11] WHO, “Antiretroviral Therapy for HIV Infection in Ado-
lescents and Adults: Recommendations for a Public Health
Approach,” World Health Organization, Geneva, 2010.
http://whqlibdoc.who.int/publications/2010/97892415997
64_
[12] R. V. Srinivas and A. Fridland, “Antiviral Activities of
9-R-2-Phosphonomethoxypropyl Adenine (PMPA) and
Bis(isopropyloxymethylcarbonyl) PMPA against Various
Drug-Resistant Human Immunodeficiency Virus Strains,”
Antimicrobial Agents Chemotherapy, Vol. 42, No. 6,
1998, pp. 1484-1487.
[13] B. L. Robbins, R. V. Srinivas, C. Kim, N. Bischofberger
and A. Fridland, “Anti-Human Immunodeficiency virus
Activity and Cellular Metabolism of a Potential Prodrug
of the Acyclic Nucleoside Phosphonate 9-R-(2-Phos-
phonomethoxypropyl)adenine (PMPA), Is (isopropyloxy-
methylcarbonyl) PMPA,” Antimicrobial Agents Chemo-
therapy, Vol. 42, 1998, pp. 612-617.
[14] B. P. Kearney, J. F. Flaherty and J. Shah, “Tenofovir
Disoproxil Fumarate: Clinical Pharmacology and Phar-
macokinetics,” Clinical Pharmacokinetics, Vol. 43, No. 9,
2004, pp. 595-612.
http://dx.doi.org/10.2165/00003088-200443090-00003
[15] J. P. Shaw, C. M. Sueoko, R. Oliyai, W. A. Lee, et al.,
“Metabolism and Pharmacokinetics of Novel Oral Prodrugs
of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA)
in Dogs,” Pharmarmacological Research, Vol. 14, No.
12, 1997, pp. 1824-1829.
http://dx.doi.org/10.1023/A:1012108719462
[16] A. M. James, I. Ofotokun, A. Sheth, P. Edward, A. costa,
R. Jennifer and R. King, “Tenofovir: Once-Daily Dosage
in the Management of HIV Infection,” Clinical Medicine
Insights: Therapeutics, Vol. 4, 2012, pp. 201-216.
[17] P. Barditch-Crovo, S. G. Deeks, A. Collier, S. Safrin, et
al., “Phase i/ii Trial of the Pharmacokinetics, Safety, and
Antiretroviral Activity of Tenofovir Disoproxil Fumarate
in Human Immunodeficiency Virus Infected Adults,” An-
timicrobial Agents Chemotherapy, Vol. 45, No. 10, 2001,
pp. 2733-2739.
http://dx.doi.org/10.1128/AAC.45.10.2733-2739.2001
[18] HIV/AIDS Treatment Guidelines/AIDSinfo.
aidsinfo.nih.gov/guidelines
[19] H. J. Stellbrink, C. Orkin, J. R. Arribas, J. Compston and
J. Gerstoftetal, “Comparison of Changes in Bone Density
and Turnover with Abacavir-Lamivudine versus Teno-
fovir-Emtricitabine in HIV-Infected Adults: 48-Week
Results from the ASSERT Study,” Clinical Infectious
Diseases, Vol. 51, No. 8, 2010, pp. 963-972.
http://dx.doi.org/10.1086/656417
[20] M. D. Murphy, M. O’Hearn and M. S. Chou, “Fatal Lac-
tic Acidosis and Acute Renal Failure after Addition of
Tenofovir to an Antiretroviral Regimen Containing Di-
danosine,” Clinical Infectious Diseases, Vol. 36, No. 8,
pp. 1082-1085. http://dx.doi.org/10.1086/368313
[21] G. Mathew and S. J. Knaus, “Acquired Fanconi’s Syn-
drome Associated with Tenofovir Therapy,” Journal of
Green Internal Medicine, Vol. 21, No. 11, 2006, pp. 3-5.
http://dx.doi.org/10.1111/j.1525-1497.2006.00518.x
[22] Gilead, “Product Monograph Tenofovir Disoproxil Fu-
marate Tablets 300 mg,” CA2012, Gilead Sciences, Inc.,
Foster City, 2012.
[23] M. M. Rosenvinge, K. Gedela, A. J. Copas, A. Wikinson,
et al., “Tenofovir-Linked Hyperparathyroidism Is Inde-
pendently Associated with the Presence of Vitamin D De-
ficiency,” Journal of Acquired Immune Deficiency Syn-
dromes, Vol. 54, No. 5, 2010, pp. 496-499.
http://dx.doi.org/10.1097/QAI.0b013e3181caebaa
[24] K. E. Childs, S. L. Fisherman, C. Constable, J. A. Gutierrez,
et al., “Short Communication: Inadequate Vitamin D Ex-
acerbates Parathyroid Hormone Elevations in Tenofovir
Users,” AIDS Research and Human Retroviruses, Vol. 26,
No. 8, 2010, pp. 855-859.
http://dx.doi.org/10.1089/aid.2009.0308
[25] B. Kearney, J. Flaherty and J. Sayre, “A Multiple-Dose
Randomized, Crossover Drug Interaction Study between
Tenofovir DF and Lamivudine or Didanosine,” The 1st
IAS Conference on HIV Pathogenesis and Treatment,
Buenos Aires, 8-11 July 2001.
[26] A. S. Mulato and J. M. Cherrington, “Anti-HIV Activity
of Adefovir (PMEA) and PMPA in Combination with
Antiretroviral Compounds: In Vitro Analyses,” Antiviral
Research, Vol. 36, No. 2, 1997, pp. 91-97.
http://dx.doi.org/10.1016/S0166-3542(97)00043-0
[27] D. Miller, “K65R TAMs and Tenofovir,” AIDS Review,
Vol. 6, No. 1, 2002, pp. 22-23.
[28] L. Gardner, R. Klein, L. A. Szczech, et al., “HIV Epide-
miology Research Study Group Rates and Risk Factors
For Condition-Specific Hospitalizations in HIV-Infected
and Uninfected Women,” Journal of Acquired Immune
Deficiency Syndrome, Vol. 34, No. 3, 2003, pp. 320-330.
http://dx.doi.org/10.1097/00126334-200311010-00011
[29] L. A. Szczech, D. R. Hoover, J. G. Feldman, et al., “As-
sociation between Renal Disease and Outcomes among
HIV-Infected Women Receiving or Not Receiving Anti-
retroviral Therapy,” Clinical Infectious Disease, Vol. 39,
No. 8, 2004, pp. 1199-1206.
http://dx.doi.org/10.1086/424013
[30] T. K. S. Rao, E. A. Friedman and D. Nicastri, “The Types
of Renal Disease in the Acquired Immunodeficiency Syn-
drome,” New England Journal of Medicine, Vol. 316, No.
2, 1987, pp. 1062-1068.
http://dx.doi.org/10.1056/NEJM198704233161705
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 659
[31] S. Naicker, T. M. Han and J. Fabian, “HIV/AIDS—
Dominant Player in Chronic Kidney Disease,” Ethnicity
& Disease, Vol. 16, No. 2, 2006, pp. 56-60.
[32] R. J. Glassock, A. H. Cohen, G. Danovitch and K. P. Parsa,
“Human Immunodeficiency Virus and the Kidney,” An-
nals of Internal Medicine, Vol. 112, No. 6, 1990, pp. 35-
49. http://dx.doi.org/10.7326/0003-4819-112-1-35
[33] R. M. Selik, R. H. Byers and M. S. Dworkin, “Trends in
Diseases Reported on US Death Certificates that Men-
tioned HIV Infection, 1987-1999,” Journal of Acquired
Immune Deficiency Syndrome, Vol. 29, No. 4, 2002, pp.
378-387.
[34] V. Shahinian, S. Rajaraman, M. Borucki, J. Grady, M.
Hollander and T. Ahuja, “Prevalence of HIV-Associated
Nephropathy in Autopsies of HIV-Infected Patients,”
American Journal of Kidney Disease, Vol. 35, No. 5,
2000, pp. 884-888.
http://dx.doi.org/10.1016/S0272-6386(00)70259-9
[35] L. A. Szczech, S. J. Gange, C. Van der Horst, et al., “Pre-
dictors of Proteinuria and Renal Failure among Women
with HIV Infection,” Kidney International, Vol. 61, No. 1,
2002, pp. 195-202.
http://dx.doi.org/10.1046/j.1523-1755.2002.00094.x
[36] E. Deti, R. Thiebaut, F. Bonnet, et al., “Prevalence and
Factors Associated with Renal Impairment in HIV-In-
fected Patients, ANRS C03 Aquitaine Cohort, France,”
HIV Medicine, Vol. 11, No. 5, 2010, pp. 308-317.
http://dx.doi.org/10.1111/j.1468-1293.2009.00780.x
[37] N. Franceschini, S. Napravnik, J. Eron, L. A. Szczech and
W. F. Finn, “Incidence and Etiology of Acute Renal Fail-
ure among Ambulatory HIV Infected Patients,” Kid- ney
International, Vol. 67, 2005, pp. 1526-1531.
http://dx.doi.org/10.1111/j.1523-1755.2005.00232.x
[38] US Renal Data System (USRDS), “USRDS 2001 Annual
Data Report,” Bethesda MD, The National Institutes of
Health, National Institute of Diabetes and Digestive and
Kidney Diseases, 2001.
[39] L. A. Szczech, S. K. Gupta, R. Habash, A. Guasch, R.
Kalayjian, et al., “The Clinical Epidemiology and Course
of the Spectrum of Renal Diseases Associated with HIV
infection,” Kidney International, Vol. 66, No. 3, 2004, pp.
1145-1152.
http://dx.doi.org/10.1111/j.1523-1755.2004.00865.x
[40] A. I. Choi, R. A. Rodriguez, P. Bacchetti, et al., “Racial
Differences in End-Stage Renal Disease Rates in HIV In-
fection versus Diabetes,” Journal of American Society of
Nephrology, Vol. 18, No. 11, 2007. pp. 2968-2974.
[41] G. Lucas, B. Lau, M. Atta, D. Fine, J. Keruly and R.
Moore, “Chronic Kidney Disease Incidence and Progres-
sion to End-Stage Renal Disease, in HIV-Infected Indi-
viduals: A Tale of Two Races,” Journal of Infectious Dis-
ease, Vol. 197, No. 11, 2008, pp. 1548-1557.
http://dx.doi.org/10.1086/587994
[42] S. Hailemariam, M. Walder, H. R. Burger, G. Cathomas,
et al., “Renal Pathology and Premortem Clinical Presen-
tation of Caucasian Patients with AIDS: An Autopsy Stu-
dy from the Era Prior to Antiretroviral Therapy,” Swiss
Medical Weekly, Vol. 131, No. 27-28, 2001, pp. 412-417.
[43] J. Fabian and S. Naicker, “HIV and Kidney Disease in
Sub-Saharan Africa,” Nature Reviews Nephrology, Vol. 5,
2009, pp. 591-598.
http://dx.doi.org/10.1038/nrneph.2009.141
[44] S. Fernando, F. Finkelstein, B. Moore and S. Weissman,
“Prevalence of Chronic Kidney Disease in an Urban HIV
Infected Population,” American Journal of Medical Sci-
ence, Vol. 335, No. 2, 2008, pp. 89-94.
http://dx.doi.org/10.1097/MAJ.0b013e31812e6b34
[45] G. M. Lucas, J. A. Eustace, S. Sozio, E. K. Mentari, K. A.
Appiah and R. D. Moore, “Highly Active Antiretroviral
Therapy and the Incidence of HIV-1-Associated Neph-
ropathy: A 12-Year Cohort Study,” AIDS, Vol. 18, No. 3,
2004, pp. 541-546.
http://dx.doi.org/10.1097/00002030-200402200-00022
[46] C. M. Wyatt, J. A. Winston, C. D. Malvestutto, et al.,
“Chronic Kidney Disease in HIV Infection: An Urban
Epidemic,” AIDS, Vol. 21, No. 5, 2007, pp. 2101-2103.
http://dx.doi.org/10.1097/QAD.0b013e3282ef1bb4
[47] J. Roling, H. Schmid, M. Fischereder, R. Draenert and F.
D. Goebel, “HIV-Associated Renal Diseases and Highly
Active Antiretroviral Therapy—Induced Nephropathy,” Cli-
nical Infectious Diseases, Vol. 42, No. 10, 2006, pp.
1488-1495. http://dx.doi.org/10.1086/503566
[48] S. K. Gupta, “Tenofovir-Associated Fanconi Syndrome:
Review of the FDA Adverse Event Reporting System,”
AIDS Patient Care and STDs, Vol. 22, No. 2, 2008, pp.
99-103. http://dx.doi.org/10.1089/apc.2007.0052
[49] F. Zoulim, S. Radenne and C. Ducerf, “Management of
Patients with Decompensated Hepatitis B Virus Associa-
tion Cirrhosis,” Liver Transplantation, Vol. 14, No. 2,
2008, pp. 1-7. http://dx.doi.org/10.1002/lt.21615
[50] P. Bonfanti, G. V. De Socio, S. Carradori, et al., “Teno-
fovir Renal Safety in HIV-Infected Patients: Results from
the SCOLTA Project,” Biomedicine and Pharmacother-
apy,” Vol. 62, No. 1, 2008, pp. 6-11.
http://dx.doi.org/10.1016/j.biopha.2007.04.008
[51] T. Antoniou, J. Raboud, S. Chirhin, D. Yoong. V. Go-
van, et al., “Incidence of and Risk Factors for Teno-
fovir-Induced Nephrotoxicity: A Retrospective Cohort
Study,” HIV Medicine, Vol. 6, No. 4, 2005, pp. 284-290.
http://dx.doi.org/10.1111/j.1468-1293.2005.00308.x
[52] S. Pujari, A. Dravid, N. Gupta, K. Joshix and V. Bele,
“Effectiveness and Safety of Generic Fixed Dose Combi-
nation of Tenofovir/Emtricitabine/Efavirenz in HIV-1 In-
fected Patients in Western India,” Journal of Interna-
tional Aids Society, Vol. 10, No. 196, 2008, pp. 2-6.
[53] B. R. Buchacz, K. Young, K. Baker, et al., “Renal Func-
tion in Patients Receiving Tenofovir with Ritonavir/Lo-
pinavir or Ritonavir/Atazanavir in the HIV Outpatient
Study (HOPS) Cohort,” Journal of Acquired Immune De-
ficiency Syndromes, Vol. 43, No. 5, 2006, pp. 626-628.
http://dx.doi.org/10.1097/01.qai.0000242461.35768.45
[54] A. Brennan, D. Evans, M. Maskew, S. Naicker and P. Ive,
“Relationship between Renal Dysfunction, Nephrotoxic-
ity and Death among HIV Adults on Tenofovir,” AIDS,
Vol. 25, No. 13, 2011, pp. 1603-1609.
[55] M. Harris, B. Yip, N. Zalunardo, et al., “Increases in
Creatinine during Therapy with Tenofovir,” 2nd IAS Con-
ference on HIV Pathogenesis and Treatment, Paris, 2003,
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 660
Abstract 55.
[56] R. Scherzera, M. Estrellab, Y. Lia, S. G. Deeksc, C.
Grunfelda and M. G. Shlipaka, “Association of Tenofovir
Exposure with Kidney Disease Risk in HIV Infection,”
AIDS, Vol. 26, No. 7, 2012, pp. 1-9.
[57] R. Jones, J. Stebbing, M. Nelson, et al., “Renal Dysfunc-
tion with Tenofovir Disoproxil Fumarate-Containing
Highly Active Antiretroviral Therapy Regimens Is Not
Observed More Frequently: A Cohort and Case-Control
Study,” Journal of Acquired Immune Deficiency Syn-
drome, Vol. 37, No. 4, 2004, pp. 1489-1495.
http://dx.doi.org/10.1097/01.qai.0000138983.45235.02
[58] R. D. Cooper, N. Wiebe, N. Smith, P. Keiser, S. Naicker
and M. Tonelli, “Systematic Review and Meta-Analysis:
Renal Safety of Tenofovir Disoproxil Fumarate in HIV-
Infected Patients,” Clinical Infectious Diseases, Vol. 51,
No. 5, 2010, pp. 496-505.
http://dx.doi.org/10.1086/655681
[59] S. Padilla, F. Gutierrez, M. Masia, V. Canovas and C.
Orozco, “Low Frequency of Renal Function Impairment
During One-Year of Therapy with Tenofovir-Containing
Regimens in the Realworld: A Case-Control Study,”
AIDS Patient Care STDS, Vol. 19, No. 7, 2005, pp. 421-
424. http://dx.doi.org/10.1089/apc.2005.19.421
[60] A. Gupta, A. Bugeja and D. Kirpalani, “Tenofovir Induce
Nephrotoxicity Myth and Fact,” Saudi Journal of Kidney
Disease and Transplantation, Vol. 23. No. 1, 2012, pp.
148-149.
[61] D. Verhelst, M. Monge, J. L. Meynard , B. Fouqueray, B.
Mougenot, et al., “Fanconi Syndrome and Renal Failure in-
duced by Tenofovir: A First Case Report,” American Jour-
nal of Kidney Disease, Vol. 40, No. 6, 2002, pp. 1331-
1333. http://dx.doi.org/10.1053/ajkd.2002.36924
[62] M. Horberg, B. Tang, W. Towner, et al., “Impact of Ten-
ofovir on Renal Function in HIV-Infected, Antiretrovi-
ral-Naive Patients,” Journal Acquired Immune Deficiency
Syndrome, Vol. 53, No. 1, 2010, pp. 62-69.
http://dx.doi.org/10.1097/QAI.0b013e3181be6be2
[63] A. Milinkovic, “Proteinuria as an Early Marker of Teno-
fovir Renal Toxicity,” 14th IWCADR, 19-21 July 2012,
Washington DC, Oral Abstract 005. Antiviral Therapy,
Vol. 17, No. 2, 2012, p. 5.
[64] E. Deti, G. Chene, C. Vandenhende, et al., “Chronic Re-
nal Failure in HIV Infected Patients: Incidence and Risk
Factors (ANRS CO3 Aquitaine Cohort, France),” 17th
CROI, San Francisco, 2010.
[65] C. L. Woodward, A. M. Hall, I. G. Williams and S.
Madge, “A Copas Tenofovir-Associated Renal and Bone
Toxicity,” HIV Medicine, Vol. 10, No. 8, 2009. pp. 482-
487. http://dx.doi.org/10.1111/j.1468-1293.2009.00716.x
[66] C. Fux, M. Simcock, M. Wolbers, et al., “Tenofovir Use
Is Associated with a Reduction in Calculated Glomerular
Filtration Rates in the Swiss HIV Cohort Study,” Antivi-
ral Therapy,” Vol. 12, No. 8, 2007, pp.1165-1173.
[67] A. Mocroft, O. Kirk, P. Reiss, et al., Euro SIDA Study
Group, “Estimated Glomerular Filtration Rate, Chronic Kid-
ney Disease and Antiretroviral Drug Use in HIV-Positive
Patients,” AIDS, Vol. 24, No. 11, 2010, pp. 1667-1678.
http://dx.doi.org/10.1097/QAD.0b013e328339fe53
[68] S. Rocha, S. Xerinda, R. Marques, C. Pinero, A. Prisca,
M. Tavares, R. Serrao and C. Caldas, “Tenofovir-Asso-
ciated Nephrotoxicity in the First Year of Therapy,” AIDS
2006 XVI International ADIS Conference, Abstract No.
CD B0725.
[69] W. Manosuthi, W. Prasithsirikul, P. Tantanathip, S. Chim-
suntorn, S. Nilkamhangand and S. Sungkanuparph, “Re-
nal Impairment in HIV-1 Infected Patients Receiving
Antiretroviral Regimens Including Tenofovir in a Re-
source-Limited Setting,” Southeast Asian Journal of Tro-
pical Medicine and Public Health, Vol. 42, No. 3, 2011,
pp. 643-650.
[70] E. Overton, D. Nurutdinova, J. Freeman, W. Seyfried and
K. Mondy, “Factors Associated with Renal Dysfunction
within an Urban HIV-Infected Cohort in the Era of
Highly Active Antiretroviral Therapy,” HIV Medicine,
Vol. 10, No. 6, 2009, pp. 343-350.
http://dx.doi.org/10.1111/j.1468-1293.2009.00693.x
[71] Y. Cao, Y. Han, J. Xie, Q. Cul, et al., “Impact of a Teno-
fovir Disoprofumarate plus Ritonavir-Boosted Protease
Inbuitor-Based Regimen on Renal Function in HIV-In-
fected Individuals: A Prospective Muticentre Study,” BMC
Infectious Diseases, Vol. 13, 2013, pp. 2-8.
http://dx.doi.org/10.1186/1471-2334-13-301
[72] K. K. Patel, A. K. Patel, R. R. Ranjan, A. A. Patel and J.
K. Patel, “Tenofovir-Associated Renal Dysfunction in
Clinical Pruchice: An Observational Coliost from West-
ern,” India Journal of Sexual Transmitted Disease and
AIDS, Vol. 31, No. 1, 2010, pp. 30-34.
http://dx.doi.org/10.4103/0253-7184.68998
[73] P. Soler-patient, A. Melendo and C. Noguera-Julian, “Pros-
pective Study of Renal Function in HIV-Infected Pediat-
ric Patients Receiving Tenofovir-Containing HAART
Regimens,” AIDS, Vol. 25, No. 2, pp.171-176.
http://dx.doi.org/10.1097/QAD.0b013e328340fdca
[74] A. Hall, S. Edwards, M. Lapsley, et al., “Subclinical Tu-
bular Injury in HIV Infected Individuals on Antiretroviral
Therapy: A Cross-Sectional Analysis,” American Journal
of Kidney Disease, Vol. 54, No. 6, 2009, pp. 1034-1042.
http://dx.doi.org/10.1053/j.ajkd.2009.07.012
[75] P. Labarga, P. Barreiro, L. Martin-Carbonero, et al., “Kid-
ney Tubular Abnormalities in the Absence of Impaired
Glomerular Function in HIV Patients Treated with Teno-
fovir,” AIDS. Vol. 23, No. 6, 2009, pp. 689-696.
http://dx.doi.org/10.1097/QAD.0b013e3283262a64
[76] F. Post, G. Moyle, H. Stellbrink, et al., “Randomized
Comparison of Renal Effects, Efficacy, and Safety with
Once-Daily Abacavir/Lamivudine versus Tenofovir/Em-
tricitabine, Administered with Efavirenz, in Antiretrovi-
ral-Naive, HIV-1-Infected Adults: 48-Week Results from
the ASSERT Study,” Journal of Acquired Immune Defi-
ciency Syndrome, Vol. 55, No. 1, 2010, pp. 49-57.
http://dx.doi.org/10.1097/QAI.0b013e3181dd911e
[77] J. L. Campbell, L. Hamzah and A. Frank, “Is Tenofovir-
Related Renal Toxicity Incompletely Reversible?” Jour-
nal of Acquired Immune Deficiency Syndrome, Vol. 56,
No. 3, 2011, p. 95.
http://dx.doi.org/10.1097/QAI.0b013e318202f1b8
[78] P. De Beaudrap, M. B. Diallo, R. Landman, N. F. Guèye,
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One 661
I. Ndiaye, A. Diouf, et al., “Changes in the Renal Func-
tion after Tenofovir-Containing Antiretroviral Therapy
Initiation in a Senegalese Cohort (ANRS 1215),” AIDS
Research and Human Retroviruses, Vol. 26, No. 11, 2010,
pp. 1221-1227. http://dx.doi.org/10.1089/aid.2009.0261
[79] P. Maggi, D. Bartolozzi, P. Bonfanti, L. Calza, et al.,
“Renal Complications in HIV Disease; between Present
and Future,” AIDS Review, Vol. 14, No. 1, 2012, pp. 37-
53.
[80] B. H. Chi, A. Mwango, M. Giganti, L. B. Mulenga, B.
Tambatamba-Chapula, et al., “Early Clinical and Pro-
grammatic Outcomes with Tenofovir-Based Antiretrovi-
ral Therapy in Zambia,” Journal of Acquired Immune De-
ficiency Syndrome, Vol. 54, No. 1, 2010, pp. 63-70.
[81] L. Calza, F. Trapani, S. Tedeschi, B. Piergentili, R. Man-
fredi, V. Colangeli, et al., “Tenofovir-Induced Renal To-
xicity in 324 HIV-Infected, Antiretroviral-Naive Pa-
tients,” Scandinavian Journal Infectious Disease, Vol. 43,
No. 8, 2011. pp. 656-660.
http://dx.doi.org/10.3109/00365548.2011.572906
[82] A. Sanders, N. Munshi, S. Dhande and A. Dravid, “Teno-
fovir-Induced Acute Kidney Injury in HIV Infected Pa-
tients in Western India: A Resource Limited Setting Per-
spective,” Journal of the International AIDS Society, Vol.
15, Suppl. 4, 2012, p.1.
[83] R. Manfredi and L. Calza, “Assessment of Kidney Safety
Parameters among HIV-Infected Patients Starting a Ten-
ofovir-Containing Antiretroviral Therapy,” The Open Drug
Safety Journal, Vol. 2, 2011, pp. 21-24.
http://dx.doi.org/10.2174/1876818001102010021
[84] F. A. Dauchy, S. Lawson-Ayayi, R. de La Faille, F. Bon-
net, et al., “Increased Risk of abnormal Proximal Renal
Tubular Function with HIV Infection and Antiretroviral
Therapy,” Kidney International, Vol. 80, No. 3, 2011, pp.
302-309.
[85] T. Nishijima, H. Gatanaga, H. Komatsu, K. Tsukada, T.
Shimbo, et al., “Renal Function Declines More in Teno-
fovir than Abacavir-Based Antiretroviral Therapy in Low-
Body Weight Treatment-Naïve Patients with HIV Infec-
tion,” PLoS One, Vol. 7, No. 1, 2012, Article ID: 29977.
http://dx.doi.org/10.1371/journal.pone.0029977
[86] A. C. Chua, R. M. Llori, L. Kelvin, P. Cavailler and H.
Law, “Renal Safely of Tenofivir Containing Antiretrovi-
ral Regimen in a Singapore Cohort,” AIDS Research and
therapy, Vol. 9, No. 1, 2012, pp. 2-5.
[87] S. N. Si-Ahmed, P. Pradat, R. Zoutendijk, M. Buti, V.
Mallet, et al., “Efficacy and Tolerance of a Combination
of Tenofovir Disoproxil Fumarate plus Emtricitabine in
Patients with Chronic Hepatitis B: A European Multicen-
ter Study,” Antiviral Research, Vol. 92, No. 1, 2011, pp.
90-95. http://dx.doi.org/10.1016/j.antiviral.2011.07.003
[88] J. Gallant, M. Parish, J. Keruly and R. Moore, “Changes
in Renal Function Associated with Tenofovir Disoproxil
Fumarate Treatment, Compared with Nucleoside Rever-
se-Transcriptase Inhibitor Treatment,” Clinical Infectious
Disease, Vol. 40, No. 8, 2005, pp. 1194-1198.
http://dx.doi.org/10.1086/428840
[89] A. Judd, K. L. Boyda, W. Stohr and D. Dunn, “Effect of
Tenofovir Disoproxil Fumarate on Risk of Renal Abnor-
mality in HIV-1-Infected Children on Antiretroviral Ther-
apy: A Nested Case-Control Study,” AIDS, Vol. 24, No. 4,
2010, pp. 525-534.
http://dx.doi.org/10.1097/QAD.0b013e3283333680
[90] L. C. Herlitz, S. Mohan, M. B. Stokes, J. Radhakrishnan,
et al., “Tenofovir Nephrotoxicity: Acute Tubular Necrosis
with Distinctive Clinical, Pathological, and Mitochon-
drial Abnormalities,” Kidney International, Vol. 78, 2010,
pp. 1171-1177.
http://dx.doi.org/10.1038/ki.2010.318
[91] A. Bonjoch, P. Echeverría, N. Perez-Alvarez, J. Puig, C.
Estany, et al., “High Rate of Reversibility of Renal Dam-
age in a Cohort of HIV-Infected Patients Receiving Ten-
ofovir-Containing Antiretroviral Therapy,” Antiviral Re-
search, Vol. 96, No. 1, 2012, pp. 65-69.
http://dx.doi.org/10.1016/j.antiviral.2012.07.009
[92] D. K, Mark, G. Abby, B. Harry and R. Diane, “Teno-
fovir-Associated Proteinuria,” AIDS, Vol. 27, No. 3, 2003,
pp. 479-481.
[93] C. W. James, M. C. Steinhaus, S. Szabo and R. M. Dres-
sier, “Tenofovir-Related Nephrotoxicity: Case Report and
Review of the Literature,” Pharmacotherapy, Vol. 24, No.
8, 2004, pp. 415-418.
[94] A. Karras, M. Lafaurie, A. Furco, et al., “Tenofovir-Re-
lated Nephrotoxicity in Human Immunodefi Ciency Vi-
rus-Infected Patients: Three Cases of Renal Failure, Fan-
coni Syndrome, and Nephrogenic Diabetes Insipidus,”
Clinical Infectious Disease, Vol. 36, No. 8, 2007, pp.
1070-1073. http://dx.doi.org/10.1086/368314
[95] S. Murreno, P. Domingo, R. Palacios and J. Santos, “Re-
nal Safety of Tenofovir Disoproxil Fumarate in HIV 1
Treatment Experienced Patients with Adverse Events Re-
lated to Prior NRTI Use, Data from a Prospective Cohorts
Observation Multicentre Study,” Journal of Acquired
Immune Deficiency Syndrome, Vol. 42, No. 3, 2006, pp.
385-386.
http://dx.doi.org/10.1097/01.qai.0000221690.54349.83
[96] K. McKelvey, “Impairment of Renal Function associated
with Tenofovir Therapy,” 19th Annual Conference of the
British HIV Association (BHIVA), 16-19 April 2013,
Manchester Central Convention Complex.
[97] K. Wever, M. A. van Agtmael and A. Carr, “Incomplete
Reversibility of Tenofovir-Related Renal Toxicity in
HIV-Infected Men,” Journal of Acquired Immune Defi-
ciency Syndrome, Vol. 55, No. 1, 2010, pp.78-81.
[98] A. E. Zimmermann, T. Pizzoferrato, J. Bedford and A.
Morris, “Tenofovir-Associated Acute and Chronic Kid-
ney Disease: A Case of Multiple Drug Interactions,” Cli-
nical Infectious Diseases, Vol. 42, No. 2, 2006, pp. 283-
290. http://dx.doi.org/10.1086/499048
[99] E. J. Heathcote, P. Marcellin, M. Buti, E. Gane, R. A. De
Man, Z. Krastev, G. Germanidis, et al., “Three-Year Ef-
ficacy and Safety of Tenofovir Disoproxil Fumarate
Treatment for Chronic Hepatitis B,” Gastroenterology,
Vol. 140, No. 1, 2011, pp. 132-143.
http://dx.doi.org/10.1053/j.gastro.2010.10.011
[100] J. E. Gallant, S. Staszewski, A. L. Pozniak , E. DeJesus, J.
M. Suleiman, et al., “Efficacy and Safety of Tenofovir
DF vs Stavudine in Combination Therapy in Antiretrovi-
Open Access PP

Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part One
Open Access PP
662
ral-Naive Patients: A 3-Year Randomized Trial,” Journal
of American Medical Association, Vol. 292, No. 2, 2004,
pp. 191-201. http://dx.doi.org/10.1001/jama.292.2.191
[101] B. Young, K. Buchacz, R. Baker, et al., “Renal Function
in Tenofovir-Exposed and Tenofovir-Unexposed Patients
Receiving Highly Active Antiretroviral Therapy in the
HIV Outpatient Study,” Journal of International Associa-
tion of Physicians AIDS Care (Chic III), Vol. 6, No. 3,
2007, pp.178-187.
http://dx.doi.org/10.1177/1545109707300676
[102] B. Young, K. Buchacz, A. Moorman, K. Wood and J.
Brooks, “Renal Function in Patients with Preexisting Re-
nal Disease Receiving Tenofovir-Containing Highly Ac-
tive Antiretroviral Therapy in the HIV Outpatient Study,”
AIDS Patient Care STDS, Vol. 23, No. 8, 2009, pp. 589-
592. http://dx.doi.org/10.1089/apc.2008.0232
[103] E. P. O’Donnell, K. K. Scarsi, K. M. Darin, L. Gerzen-
shtein, et al., “Low Incidence of Renal Impairment Ob-
served in Tenofovir-Treated Patients,” Journal of Antim-
icrobial Chemotherapy, Vol. 66, No. 5, 2011. pp. 1120-
1126. http://dx.doi.org/10.1093/jac/dkr039
[104] G. Birkus, M. J. Hitchcock and T. Cihlar. “Assessment of
Mitochondrial Toxicity in Human Cells Treated with
Tenofovir: Comparison with Other Nucleoside Reverse
Transcriptase Inhibitors,” Antimicrobial Agents Chemo-
therapy, Vol. 46, No. 3, 2002, pp. 716 -723.
[105] H. Izzedine, J. S. Hulot, D. Vittecoq, et al., “Long-Term
Renal Safety of Tenofovir Disoproxil Fumarate in Anti-
retroviral-Naive HIV-1-Infected Patients: Data from a
Double-Blind Randomized Active-Controlled Multicen-
tre Study,” Nephrology Dialysis Transplantation, Vol. 20,
No. 4, 2005, pp. 743-746.
http://dx.doi.org/10.1093/ndt/gfh658
[106] J. Gallant and R. Moore, “Renal Function with Use of a
Tenofovir-Containing Initial Antiretroviral Regimen,”
AIDS, Vol. 23, No. 15, 2009, pp. 1971-1975.
http://dx.doi.org/10.1097/QAD.0b013e32832c96e9
[107] E. Martinez, J. A. Arranz, D. Podzamczer, M. Lonca, et
al., “A Simplification Trial Switching from Nucleoside
Reverse Transcriptase Inhibitors to Once-Daily Fixed-Dose
Abacavir/Lamivudine or Tenofovir/Emtricitabine in HIV-
1-Infected Patients with Virological Suppression,” Jour-
nal of Acquired Immune Deficiency Syndrome, Vol. 51,
No. 3, 2009, pp. 290-297.
http://dx.doi.org/10.1097/QAI.0b013e3181aa12d5
[108] C. T. Longenecker, R. Scherzer, P. Bacchetti, C. E. Lewis,
C. Grunfeld and M. G. Shlipak, “HIV Viremia and Changes
in Kidney Function,” AIDS, Vol. 23, No. 9, 2009, pp.
1089-1096.
http://dx.doi.org/10.1097/QAD.0b013e32832a3f24
[109] M. Ando, N. Yanagisawa, A. Ajisawa, K. Tsuchiya and K.
Nitta, “Kidney Tubular Damage in the Absence of Glome-
rular Defects in HIV Infected Patients on Highly Active
Antiretroviral Therapy,” Nephrology Dialysis Transplan-
tation, Vol. 26, No. 10, 2011, pp. 3224-3229.
http://dx.doi.org/10.1093/ndt/gfr020
[110] R. T. Schooley, P. Ruanea, R. A. Myers and G. Beall,
“Tenofovir DF in Antiretroviral-Experienced Patients:
Results from a 48-Week, Randomized, Double-Blind Stu-
dy,” AIDS, Vol. 16, No. 9, 2002, pp. 1257-1263.
http://dx.doi.org/10.1097/00002030-200206140-00008
[111] A. Gayet-Ageron, J. Ananworanich, T. Jupimai, et al.,
“No Change in Calculated Creatinine Clearance after
Tenofovir Initiation among Thai Patients,” Journal of An-
timicrobial Chemotherapy, Vol. 59, No. 5, 2007, pp.
1034-1037. http://dx.doi.org/10.1093/jac/dkm064
[112] A. Viganò, G. V. Zuccotti, L. Martelli, V. Giacomet, et
al., “Renal Safety of Tenofovir in HIV-Infected Children:
a Prospective, 96-Week Longitudinal Study,” Clinical
Drug Investigation, Vol. 27, No. 8, 2007, pp. 573-581.
http://dx.doi.org/10.2165/00044011-200727080-00006
[113] H. Bygrave, K. Kranzer, K. Hilderbrand, G. Jouquet, E.
Goemaere, et al., “Renal Safety of a Tenofovir-Con-
taining First Line Regimen: Experience from an Antiret-
roviral Cohort in Rural Lesotho,” PLoS ONE, Vol. 6, No.
3, 2011, Article ID: 17609.
http://dx.doi.org/10.1371/journal.pone.0017609
[114] L. Gerard, C. Chazallon, A. Taburet, P. Girard, et al.,
“Renal Function in Antiretroviral Experience Patients
Treated with Tenofovir/Atazanavir,” Antiviral Therapy,
Vol. 12, 2007, pp. 31-39.
[115] K. Squires, A. L. Pozniak, G. Pierone Jr., et al., “Teno-
fovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1
Infection: A Randomized Trial,” Annals of Internal Medi-
cine, Vol. 139, No. 5, 2003, pp. 313-320.
http://dx.doi.org/10.7326/0003-4819-139-5_Part_1-20030
9020-00006
[116] K. Y. Smith, P. Patel, D. Fine, et al., “Randomized, Dou-
ble-blind, Placebo-Matched, Multicenter Trial of Aba-
cavir/Lamivudine or Tenofovir/Emtricitabine with Lopi-
navir/Ritonavir for Initial HIV Treatment,” AIDS, Vol. 23,
No. 12, 2009, pp. 1547-1556.
http://dx.doi.org/10.1097/QAD.0b013e32832cbcc2
[117] J. R. Arribas, A. L. Pozniak, J. E. Gallant, et al. “Teno-
fovir Disoproxil Fumarate, Emtricitabine, and Efavirenz
Compared with Zidovudine/Lamivudine and Efavirenz in
Treatment-Naïve Patients: 144-Week Analysis,” Journal
of Acquired Immune Deficiency Syndrome, Vol. 47, No. 1,
2008, pp. 74-78.
http://dx.doi.org/10.1097/QAI.0b013e31815acab8