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HIV Reports

A Randomized, Open-Label Study of the Safety


and Efficacy of Switching Stavudine or Zidovudine
to Tenofovir Disoproxil Fumarate in HIV-1infected
Children With Virologic Suppression
Xavier Saez-Llorens, MD,* Elizabeth Castao, MD,* Mobeen Rathore, MD, Joseph Church, MD,
Jaime Deville, MD, Aditya Gaur, MD, Dora Estripeaut, MD,* Kirsten White, PhD, Sarah Arterburn, MS,
Jeffrey V. Enejosa, MD,** Andrew K. Cheng, MD, PhD, Steven L. Chuck, MD, and Martin S. Rhee, MD
Background: The safety and efficacy of tenofovir disoproxil fumarate
(TDF) in HIV-1infected children have not been evaluated in a randomized
controlled trial.
Methods: Subjects (2 to <16 years) on a stavudine (d4T) or zidovudine (ZDV)
containing regimen with HIV-1 RNA <400 copies/mL were randomized to
either switch d4T or ZDV to TDF or continue d4T or ZDV. The primary endpoint was the proportion of subjects with HIV-1 RNA < 400 copies/mL at
Week 48 with a prespecified noninferiority margin of 15%. After the 48-week
randomized phase, eligible subjects were rolled over to an extension phase.
Results: Ninety-seven children (48 TDF vs. 49 d4T or ZDV) were randomized and treated. The percent of subjects who maintained virologic suppression in the TDF versus d4T or ZDV group at Week 24 were 93.8%
versus 89.8% (difference 4.0%; 95% confidence interval:: 6.9% to 14.9%)
and at Week 48 were 83.3% versus 91.8% (difference: 8.5%; 95% confidence interval: 21.5% to 4.5%; missing = failure, intent-to-treat analysis).
No subjects discontinued study drug because of an adverse event in the 48
weeks of randomized phase. Four subjects discontinued TDF because of
proximal renal tubulopathy in the extension phase.
Conclusions: Our study did not demonstrate noninferiority of TDF versus
d4T or ZDV at Week 48. Overall safety and tolerability of TDF in children
were consistent with adults. TDF may be considered as an alternative to d4T
or ZDV in HIV-infected children.

MATERIALS AND METHODS


Study Design

Key Words: tenofovir, children, antiretroviral therapy


(Pediatr Infect Dis J 2015;34:376382)

orldwide, an estimated 3.3 million children (< 15 years of


age) were living with HIV infection in 2012, mostly acquired

Accepted for publication December 13, 2013.


From the *Department of Infectious Diseases, Hospital del Nio, Panama City,
Panama; Division of Pediatric Infectious Disease and Immunology, University of Florida Health Science Center, Jacksonville, FL; Division of Clinical Immunology and Allergy, Childrens Hospital Los Angeles; Division
of Pediatric Infectious Diseases, University of California in Los Angeles,
Los Angeles, CA; Department of Infectious Diseases, St. Jude Childrens
Research Hospital, Memphis, TN; Gilead Sciences Inc., Foster City; and
**Dynavax Technologies, Berkley, CA.
Trial registration: GS-US-1040352 is registered with ClinicalTrials.gov
(NCT00528957).
All study investigators received research funding from Gilead Sciences to support their subjects participation in this study. J.V.E. and S.L.C. were previous
employees and K.W., S.A., A.K.C. and M.S.R. are current employees of the
study sponsor, Gilead Sciences Inc. and own its stocks and/or stock options.
The authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Martin S. Rhee, MD, 333 Lakeside Drive, Foster
City, CA 94404. E-mail: mrhee@gilead.com.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journals website (www.pidj.com).
Copyright 2014 by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/15/3404-0376
DOI: 10.1097/INF.0000000000000289

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through mother-to-child transmission.1 Although there are >20


antiretroviral agents approved in the United States and Europe for
treatment of HIV-1 infection in adults, the number of agents approved
for use in children is limited. Antiretroviral agents that are effective,
safe, tolerable and convenient for children are greatly needed.
Tenofovir disoproxil fumarate (TDF) has been an important
part of the nucleoside/tide reverse transcriptase inhibitor backbone
in adults because of its proven efficacy and safety.2,3 TDF 300mg
is approved for treatment of HIV-1 infection in adolescents (12
to <18 years) and pediatric formulations including 150, 200 and
250mg tablets and a 40mg/g taste-masked powder were recently
approved by the US Food and Drug Administration (FDA) for
use in children aged 2 years and older.4 Study GS-US-1040352
assessed the efficacy and safety of TDF in virologically suppressed,
treatment-experienced, HIV-infected children aged 2 to <16 years.
In addition, the pharmacokinetics (PK) of TDF oral powder were
evaluated in a PK substudy. This report presents those results
through Week 144, which consist of a 48-week randomized phase
and a 96-week extension phase.

GS-US-104-0352 is an ongoing, open-label, phase 3 clinical study conducted in the United States, United Kingdom and
Panama. The protocol was approved by ethics committees at each
site. All parents/guardians provided written informed consent; subjects who were able provided written assent. The primary endpoint
was the proportion of subjects with HIV-1 RNA <400 copies/mL
at Week 48 [missing = failure (M = F) analysis]. The planned total
duration of the study is 336 weeks, including three 96-week extensions beyond the Week 48 primary endpoint. This report presents
the efficacy and safety results of the 48-week randomized phase
and through the first 96-week extension phase.

Patients
HIV-1infected children 2 to <12 years of age were eligible if
they were virologically suppressed (HIV-1 RNA < 400 copies/mL) on
a stavudine (d4T)- or zidovudine (ZDV)-containing ART regimen for
at least 12 weeks before study entry and were nave to TDF. Subjects
who were enrolled in a pediatric rollover study for continued access to
emtricitabine were also included if they were receiving d4T or ZDV,
were 2 to < 16 years of age and metall other entry criteria. Subjects
were required to have normal serum creatinine and estimated creatinine clearance 80mL/min/1.73 m2 using the Schwartz formula.5,6
Exclusion criteria were the use of nephrotoxic or immunosuppressive
agents, history of significant bone disease or multiple fractures, any
serious medical condition, substance abuse and pregnancy or lactation. There were no criteria for CD4 cell count for study entry.

The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

Study Treatment
Subjects were randomly assigned to either switch d4T or
ZDV to TDF (TDF group) or continue d4T or ZDV (d4T or ZDV
group) in combination with their current background antiretroviral
regimen. Subjects assigned to the TDF group who weighed > 37kg
and were able to swallow a tablet were given one 300mg tablet
daily without regard to food. Those assigned to the TDF group
who weighed 37kg or were unable to swallow a tablet were given
TDF oral powder (4% weight/weight TDF) 8mg/kg once daily, up
to 300mg (7.5 scoops). The oral powder was administered as a
mixture with 24 ounces of food that does not require chewing.
To ensure complete consumption of the oral powder, water was
added and swirled within the bowl for subjects to drink, followed
by additional water. Subjects assigned to the d4T or ZDV group
continued to receive d4T or ZDV and other antiretroviral agents as
prescribed before study entry. All study drugs were dispensed in
an open-label fashion. Substitution of the subjects assigned treatment (d4T, ZDV or TDF) was not permitted during the initial 48
weeks of the study.
After completion of 48 weeks of randomized treatment, subjects who were <18 years of age were given an option to roll over
into an extension phase to continue or initiate TDF (ie, switch from
d4T or ZDV) in combination with their other antiretroviral agents.

Assessments
Clinical and laboratory evaluations including serum creatinine and phosphorous and urinanalysis (including urine protein and
glucose) were performed at screening, baseline and at each clinic
visit (Weeks 2, 4, 8, 16, 24, 36 and 48 in the randomized phase
and every 12 weeks in the extension phase). Evaluations included
review of adverse events and concomitant medications, physical
examination, hematology and chemistry profile, urinalysis, CD4
cell count, HIV-1 RNA level and study drug accountability. HIV-1
RNA plasma samples were analyzed using the Roche COBAS
Amplicor HIV-1 Monitor Ultrasensitive test (version 1.5; range:
50100,000 copies/mL). Values <50 copies/mL were imputed as 49
copies/mL. Genotypic resistance testing was performed in subjects
who discontinued because of virological failure (defined as 2 consecutive HIV-1 RNA > 1000 copies/mL that could not be attributed
to nonadherence) or had HIV-1 RNA > 400 copies/mL at Weeks
48, 96, 144 or upon early discontinuation (Monogram Biosciences,
Inc., South San Francisco, CA). PK was assessed in a subset of subjects who received TDF oral powder for at least 4 weeks during the
randomized phase. PK specimens were collected at 0, 1, 2, 4, 8 and
12 hours after TDF administration. Steady-state tenofovir (TFV)
PK parameters were estimated using WinNolin software version
5.2 (Certara, St. Louis, MO).

Statistical Analysis
All analyses were specified by protocol and performed with
SAS software version 9.1 (Cary, NC). All randomized patients
treated with at least 1 dose of study drug were included in the efficacy and safety analyses. The primary efficacy endpoint was the
percent of subjects with HIV-1 RNA <400 copies/mL at Week 48
(Days 295378) in the intent-to-treat (ITT) population, and missing
data were handled using the missing = failure (M = F) method; when
>1 HIV-1 RNA were available within Week 48 (Days 295378),
the 1 closest to the midpoint (ie, Days 336337) was used. Treatment noninferiority was determined if the lower bound of the
2-sided 95% confidence interval (CI) for the difference between
the treatment groups was greater than 15%. The difference
between the 2 proportions and its CI were calculated based on normal approximation methods for a binomial distribution. P-values
comparing treatment groups were provided using Fisher exact test.
2014 Wolters Kluwer Health, Inc. All rights reserved.

Switch to Tenofovir

We estimated that a sample size of 100 subjects (50 per group)


would have approximately 80% power to establish noninferiority
with respect to the difference in the percent of subjects with HIV-1
RNA < 400 copies/mL at Week 48 between the 2 groups. It would
be assumed that the proportion of subjects maintaining HIV-1 RNA
<400 copies/mL was 92% for subjects switching to TDF and 90%
for subjects continuing d4T or ZDV.2,3 Secondary efficacy endpoints were the percent of subjects with HIV-1 RNA <400 copies/
mL at Week 48 using the missing = excluded (M = E) method, the
percent of subjects with HIV-1 RNA <50 copies/mL (M = F, M = E)
and change from baseline in CD4 cell count at Week 48. Post hoc
analyses were performed using FDA-defined snapshot algorithm
(ITT)7; when >1 HIV-1 RNA were available within Week 48 (Days
295378), the last 1 was used.
Data from the noncomparative extension phase up to March
16, 2011, were summarized using 48 subjects who were initially
randomized to receive TDF and 41 subjects who were initially randomized to continue d4T or ZDV and were switched to TDF after
Week 48 (termed the All TDF group). To evaluate the long-term
efficacy and safety data in relation to the duration of TDF exposure, the baseline in the All TDF group was defined as the day the
subject received the first dose TDF whether in the randomized or
extension phase.
Treatment-emergent adverse events and laboratory toxicities
were summarized by incidence and grade. The severity of laboratory abnormalities was graded according to the 2004 Division of
AIDS toxicity criteria
(http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_
Pediatric_Adverse_Events.pdf). Weight and height Z-scores were
assigned using year 2000 growth charts and methods outlined by
the Center for Disease Control. Unless otherwise specified, the 2
treatment groups were compared using the Fisher exact test or the
Cochran-Mantel-Haenszel row means scores for categorical data
and using the Wilcoxon rank sum test for continuous data. P < 0.05
were considered statistically significant.

RESULTS
A total of 97 subjects (48 TDF vs. 49 d4T or ZDV) were
randomized and treated between January 10, 2007, and March
14, 2008. Among 48 subjects in the TDF group, at baseline, 6
subjects received TDF 300mg tablet and 42 received TDF oral
powder. Of the 92 subjects who completed the 48-week randomized phase, 79 subjects were enrolled in the extension phase;
38 subjects from the TDF group continued TDF and 41 subjects
from the d4T or ZDV group switched to TDF. Subject disposition
during the 48-week randomized phase and up to when the last
subject completed the first 96-week extension phase is shown in
Figure1. During the randomized phase, study drug was prematurely discontinued in 4 subjects in the TDF group (1 lack of
efficacy; 2 withdrawal of consent and 1 tolerability) and 1 subject in the d4T or ZDV group (withdrawal of consent). Baseline
demographic and laboratory characteristics were similar between
the TDF and d4T or ZDV groups, except for slightly more female
subjects in the TDF group (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B819). During the randomized
phase, the concomitant antiretroviral agents in the class of protease inhibitor or non-nucleoside reverse transcriptase inhibitor in the TDF and d4T or ZDV group were lopinavir/ritonavir
(87.5% vs. 91.8%), nevirapine (10.4% vs. 4.1%), nelfinavir
(4.2% vs. 6.1%) and efavirenz (2.1% vs. 2.0%); in the class of
nucleoside reverse transcriptase inhibitor, lamivudine (75.0% vs.
77.6%), emtricitabine (18.8% vs. 22.4%), abacavir (14.6% vs.
2.0%) and ZDV (4.2% vs. 0). No subject in either group used
didanosine during the study.
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Saez-Llorens etal

Screened (n=127)

Screen failure (n=30)


Randomized (n-97)

Allocated to switch d4T or ZDV to TDF


and treated with at least one dose (n=48)

Discontinued in randomized phase (n=4)


Efficacy (n=1)
Withdrawal of consent (n=2)
Tolerability (n=1)

Completed randomized phase (n=44)

Did not consent for 1st extension phase (n=6)

Dosed with TDF in 1st extension phase (n=38)

Discontinued in 1st extension phase (n=3)


Adverse event (n=1)
Poor adherence (n=2)

Completed 1st extension phase (n=35)

Did not consent for 2nd extension phase (n=1)


Discontinued in 2nd extension phase (n=6)
Adverse event (n=2)
Efficacy (n=1)
Poor adherence (n=3)

Ongoing in 2nd extension phase (n=28)

Allocated to remain on d4T or ZDV


and treated with at least one dose (n=49)

Discontinued in randomized phase (n=1)


Withdrawal of consent (n=1)

Completed randomized phase (n=48)

Did not consent for 1st extension phase (n=6)


Consented for extension phase but
not dosed per investigators discretion (n=1)

Dosed with TDF in 1st extension phase (n=41)

Discontinued in 1st extension phase (n=1)


Withdrawal of consent (n=1)

Completed 1st extension phase (n=40)

Discontinued in 2nd extension phase (n=2)


Adverse event (n=2)

Ongoing in 2nd extension phase (n=38)

FIGURE 1. Study flow of subjects

Efficacy
At Week 48, 83.3% of subjects (40/48) in the TDF group
and 91.8% (45/49) in the d4T or ZDV group had HIV-1 RNA <
400 copies/mL (M = F, ITT analysis) (difference: 8.5%, 95% CI:
21.5% to 4.5%; Fig.2A). Therefore, with the prespecified noninferiority margin of 15%, the study did not meet its primary endpoint at Week 48. However, the proportion of subjects with HIV-1
RNA < 400 copies/mL were similar between the TDF and d4T
or ZDV groups using the M = F analysis at Week 24 (93.8% in
TDF group vs. 89.8% in d4T or ZDV group, difference 4.0%, 95%
CI: 6.9% to 14.9%) and at all earlier time points. The percent of

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subjects with HIV-1 RNA < 50 copies/mL in the TDF and d4T or
ZDV group over 48 weeks showed similar trends (Fig.2B). In the
M = E analyses at Week 48, 90.9 % of subjects (40/44) in the TDF
group and 93.8% (45/48) in the d4T or ZDV group had HIV-1 RNA
<400 copies/mL (difference: 2.8%, 95% CI: 13.8% to 8.1%).
The median change from baseline in CD4 percent and cell count at
Week 48 was similar between the TDF and d4T or ZDV group: 0
versus 1%; 59 versus 16 cells/mm3, respectively.
In a post hoc efficacy analyses using the FDA-defined snapshot algorithm, the percent of subjects with HIV-1 RNA <400 copies/mL in the TDF and d4T or ZDV group at Week 48 were 87.5%
2014 Wolters Kluwer Health, Inc. All rights reserved.

The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

Subjects with HIV-1 RNA < 400 copies/ml (%)

Switch to Tenofovir

100

80

Difference between groups at Week 24


4.0 % (95% CI -6.9 to 14.9)

Difference between groups at Week 48


-8.5% (95% CI -21.5 to 4.5)

60
Tenofovir DF (n=48)
ZDV or d4T (n=49)

0 2 4

16

24

36

48

Weeks

FIGURE 2. Percent of subjects with


HIV-1 RNA < 400 copies/mL (panel
a) and < 50 copies/mL (panel b)
during the 48-week randomized
phase (missing = failure, ITT
analysis). Error bars represent
95% CIs.

Subjects with HIV-1 RNA < 50 copies/ml (%)

100

80

Difference between groups at Week 24


-0.4% (95% CI -15.9 to 15.1)
60
Tenofovir DF (n=48)

Difference between groups at Week 48


-14.9% (95% CI -31.0 to 1.3)

ZDV or d4T (n=49)

0 2 4

versus 89.8% (difference: 2.3%, 95% CI: 14.9% to 10.3%; see


Table, Supplemental Digital Content 2, http://links.lww.com/INF/
B820); those with HIV-1 RNA <50 copies/mL were 75.0% versus
81.6% (difference: 6.6%, 95% CI: 23.0% to 9.7%, respectively).
HIV-1 RNA results for subjects counted as failures in the
primary analysis are provided in Table1. Eight subjects in the TDF
group and 4 subjects in the d4T or ZDV group were considered
failures in the Week 48M =F analysis. There were more subjects
in the TDF group (4 of 8) than in the d4T or ZDV group (1/4)
who discontinued the study before Week 48 and were considered
failures because of missing data (Fig.1). Of these subjects with
missing Week 48 data, 2 of 4 in the TDF group and the 1 subject
in the d4T or ZDV group had HIV-1 RNA <400 copies/mL at their
last study visit. A similar number of subjects in each arm had a
Week 48 HIV-1 RNA result that was 400 copies/mL (4 in the TDF
group and 3 in the d4T or ZDV group). All 4 of the subjects in the
2014 Wolters Kluwer Health, Inc. All rights reserved.

16

24

36

48

Weeks

TDF group and 1 of the 3 subjects in the d4T or ZDV group had
an HIV-1 RNA result < 400 copies/mL at a subsequent visit while
taking their study mediations as randomized. Moreover, 2 of the
3 subjects randomized to continue d4T or ZDV who did not have
HIV-1 RNA <400 copies/mL at Week 48 later switched to TDF and
had subsequent virologic suppression to <400 copies/mL.
The long-term efficacy data were summarized using the All
TDF group (n = 89), as defined previously. The percent of subjects
with HIV-1 RNA <400 copies/mL (M = F, ITT analysis) with 48,
96 and 144 weeks of TDF exposure were 85.4%, 84.6% and 80.6%,
respectively (see Fig., Supplemental Digital Content 3, http://links.
lww.com/INF/B821). The percent of subjects with HIV-1 RNA <50
copies/mL (M = F, ITT analysis) with 48, 96 and 144 weeks of TDF
exposure were 68.5%, 73.1% and 67.2%, respectively (see Fig.,
Supplemental Digital Content 3, http://links.lww.com/INF/B821).
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Saez-Llorens etal

TABLE 1. GS-US-1040352: Outcomes for Subjects With HIV-1 RNA Levels > 400 copies/mL or Missing at Week 48
Subject

Week 48 Result

Outcome
TDF (N = 8)

HIV-1 RNA 6970 copies/mL

HIV-1 RNA 25,800 copies/mL (Day 338)

HIV-1 RNA 4170 copies/mL

HIV-1 RNA 1240 copies/mL

5*

Early d/c (last dose: Day 293; last HIV-1 RNA level on study
drug: 1220 copies/mL on Day 204)
Early d/c (last dose: Day 260; last HIV-1 RNA level on study
Withdrew consent
drug: <50 copies/mL on Day 260)
Early d/c [last dose: Day 13; last HIV-1 RNA level on study
Intolerability to oral powder (discontinued TDF because parent
drug: < 50 copies/mL on Day 15 (note: subject restarted ZDV
stopped trying to dose the child)
on Day 5; there is no postbaseline HIV-1 RNA level before
the switch)]
Early d/c (last dose: Day 42; last HIV-1 RNA level on study
TDF switched to ZDV (both TDF and ZDV taken for 1 week; HIV-1
drug: 1130 copies/mL on Day 26 and 965 copies/mL on
RNA < 400 copies/mL at follow-up visits). Note: this subject had
Day 35 (retest)
the K65R mutation early (at Week 4)
d4T or ZDV (N = 4)
HIV-1 RNA 429 copies/mL
Discontinued from study; HIV-1 RNA at last visit 2290 copies/mL
HIV-1 RNA 672 copies/mL
d4T switched to TDF (same background regimen); HIV-1
RNA < 400 copies/mL 12 weeks after switch
HIV-1 RNA 685 copies/mL
ZDV switched to TDF (same background regimen); HIV-1
RNA < 400 copies/mL 12 weeks after switch

6*
7*

8*

9
10
11
12*

Early d/c (last dose: Day 16; last HIV-1 RNA level on study
drug: < 50 copies/mL on Day 16)

Week 60 HIV-1 RNA < 400 copies/mL on same regimen (TDF + 3TC
+ LPV/r; subject also had a transient low-level increase in viral
load earlier in study)
Second Week 48 visit (Day 365) HIV-1 RNA < 400 copies/mL; TDF
switched to d4T on Day 364 (same background regimen). HIV-1
RNA < 400 copies/mL at follow-up visits
Week 60 HIV-1 RNA < 400 copies/mL on same regimen
(TDF + 3TC + LPV/r)
Week 60 HIV-1 RNA < 400 copies/mL on same regimen
(TDF + 3TC + LPV/r)
Withdrew consent

Withdrew consent

TDF, TFV disoproxil fumarate; 3TC, lamivudine; LPV/r, lopinavir/ritonavir; d4T, stavudine; ZDV, zidovudine; d/c, discontinuation.
*Subject not included in the denominator for the M = E post hoc efficacy analyses

Resistance

Safety During the 48-week Randomized Phase

During the randomized phase, 6 of 48 (12.5%) in the TDF


group and 3 of 49 (6.1%) in the d4T or ZDV group underwent genotypic resistance testing for virologic failure. Of 5 subjects in the
TDF group, 4 with data available had emergent resistance; 1 subject
in whom resistance testing failed did not have confirmed virologic
failure (HIV-1 RNA > 1000 copies/mL) but had low-level viremia
(HIV-1 RNA 1220 copies/mL) before discontinuation caused by
withdrawal of consent. Three of these subjects in the TDF group had
M184V mutation; 1 subject also had thymidine-analogue associated
mutations (M41L, L210L/W T215C/Y). The 5th subject in the TDF
group had K65R and Y181C mutation, but not M184V. One of 3
subjects with data available in the d4T or ZDV group (2 subjects had
assay failures) developed M184V and L90M mutations.
During the extension phase (ie, after the randomized phase),
17 subjects underwent genotypic resistance testing for virologic
failure while receiving TDF, including 1 subject who had resistance testing during the randomized phase and was retested during
the extension phase; 11 of 14 subjects with data available (3 subjects had assay failure) had emergent resistance. Ten subjects had
M184V mutation and 3 subjects had thymidine-analogueassociated mutations (eg, M41L, L210L/W T215C/Y).

The overall incidences of adverse events during the 48-week


randomized phase are shown (Table2). Adverse events related to
study drug were reported in 5 of 48 subjects (10.4%) in the TDF
group and 1 of 49 subjects (2.0%) in the d4T or ZDV group, most
of whom had gastrointestinal disorders [4 subjects (8.3%) vs. 0
subject (0%)]. No grade 3 or 4 adverse events were reported. No
subject discontinued the study drug because of an adverse event
during the 48-week randomized phase. No bone fractures were
reported. Serious adverse events were reported in 2 of 48 subjects
(4.2 %) in the TDF group (pneumonia and pharyngotonsilitis) and
2 of 49 subjects (4.1 %) in the d4T or ZDV group (lymphadenitis
and asthmatic crisis). None of these serious adverse events were
considered related to the study drug. There were no deaths. Similar percent of subjects in the TDF and d4T or ZDV groups experienced grade 3 or 4 laboratory abnormalities [6.3% (3/48) vs. 10.2%
(5/49), respectively].
Serum creatinine did not increase from baseline at Week 48
in either the TDF and d4T or ZDV group (median change 0.0 vs.
0.0mg/dL). No subject had a graded serum creatinine laboratory
abnormality reported during the randomized phase. The median
changes from baseline in calculated creatinine clearance in the
TDF and d4T or ZDV group were minimal at Week 48 (+5.50 vs.
+6.33mL/min/1.73 m2, respectively).
Subjects in the TDF group had decreases from baseline at
Week 48 in total cholesterol, which were not observed in the d4T or
ZDV group (median change: 14.0 vs. 3.0mg/dL, P = 0.005) and
low density lipoprotein (5.5 vs. 6.0, P = 0.025). Changes were not
different between the 2 groups for high density lipoprotein (3.5
vs. 2.0, P = 0.68) and triglycerides (21.0 vs. 3.0, P = 0.21).

Pharmacokinetics
Twenty-three subjects taking TDF oral powder (8mg/kg) for
at least 4 weeks participated in the PK substudy. TDF oral powder
was rapidly absorbed (median Tmax 1.93 hours) to achieve mean
(%CV) Cmax (maximum plasma concentration) 238.7 (53.4) ng/mL
and area under the curve of plasma concentration over time 2586.3
(40.9) ngh/mL.

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The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

TABLE 2. Adverse Events According to Study Group


Through Week 48*

Adverse event,
number (%)
Common adverse
event, number
(%)
Nasopharyngitis
Cough
Otitis media
Upper respiratory infection
Gastroenteritis
Vomiting
Diarrhea
Bronchitis
Rhinitis allergic
Sinusitis
Pyrexia

TFV Disoproxil Fumarate


Group (N = 48)

Stavudine or ZDV
Group (N = 49)

41 (85.4)

41 (83.7)

16 (33.3)

17 (34.7)

6 (12.5)
7 (14.6)
6 (12.5)

6 (12.2)
4 (8.2)
3 (6.1)

3 (6.3)
6 (12.5)
4 (8.3)
3 (6.3)
4 (8.3)
3 (6.3)
1 (2.1)

4 (8.2)
0
1 (2.0)
1 (2.0)
0
1 (2.0)
3 (6.1)

*Adverse event terms are from the Medical Dictionary for Regulatory Activities,
version 11.1.
Common events are defined as occurring in > 5% in either group.

Safety During the Extension Phase


During the extension phase, 5 subjects discontinued the
study drug because of an adverse event: 3 with hypophosphatemia
(1 of whom also had arthralgia), 1 with glycosuria and 1 with brain
neoplasm. The pertinent laboratory data at the time of discontinuation of the study drug (ie, TDF) for the 4 subjects who discontinued
because of either hypophosphatemia or glycosuria were considered
to be clinically consistent with proximal renal tubulopathy; in all 4
subjects, serum creatinine at the time of TDF discontinuation was
greater than the median at the corresponding visit in the All TDF
group (0.5mg/dL for all corresponding visits; Table3). All 4 subjects
were taking lopinavir/ritonavir concomitantly with TDF at the time
of discontinuation, and no subjects took didanosine during the study.
Three subjects experienced fracture during the extension phase, all of
which were considered to be related to high impact trauma.

DISCUSSION
As the cumulative exposure to antiretroviral agents is generally lifelong in pediatric patients who mostly acquire HIV-1 through

Switch to Tenofovir

mother-to-child transmission, it is important to establish long-term


efficacy and safety of any agent in this population. In contrast to the
extensive long-term clinical safety data available on the use of TDF
in adults, there are only limited data in pediatric patients.
In this randomized, open-label study of HIV-1infected children, the primary endpoint of noninferiority in maintaining HIV-1
RNA <400 copies/mL at Week 48 was not met when d4T or ZDV
was switched to TDF. However, at Week 24 and earlier time points,
the percent of subjects with HIV-1 RNA < 400 copies/mL were
more comparable between the 2 groups. The main reason for not
meeting the primary endpoint of noninferiority at Week 48 is likely
because of the higher number of subjects with missing HIV-1 RNA
at Week 48 in the TDF group (4 vs. 1 subjects). One of these 4
subjects in the TDF group discontinued the study drug at Week 4
because of lack of efficacy. In this subject, K65R mutation rapidly
emerged at Week 4, which suggests that most likely it was present
before baseline and led to virologic failure. The remaining 3 subjects in the TDF group and 1 subject in the d4T or ZDV group discontinued because of nonvirologic reasons (withdrawal of consent
or tolerability). Despite being counted as failures in the primary
efficacy analysis, 2 of the 4 subjects who discontinued TDF early
had evidence of virologic response, with HIV-1 RNA results <400
copies/mL at their discontinuation visits. Additionally, 2 subjects in
the d4T or ZDV group with virologic failure at Week 48 switched
to TDF and achieved suppression to <400 copies/mL, providing
further evidence of the efficacy of TDF in HIV-1infected children.
Although noncomparative, the efficacy data during the extension
phase demonstrated the long-term durability of switching d4T or
ZDV to TDF in maintaining virologic suppression.
The PK of TDF oral powder formulation was assessed in a
substudy. These results showed that the TFV exposure in children
receiving TDF oral powder 8mg/kg dose was comparable with that
of adults receiving TDF 300mg tablet.4 These data suggest that inadequate TDF dose or exposure in subjects receiving TDF oral powder
is unlikely to be the primary reason for the study not meeting its primary efficacy endpoint. Furthermore, 90.9% of subjects in the TDF
group with a Week 48 HIV-1 RNA result had virologic suppression
to 400 copies/mL, suggesting that plasma TFV concentrations
were therapeutic in most subjects randomized to receive TDF.
TDF appeared to have minimal effect on serum creatinine
and creatinine clearance. It should be noted that our study only
included those with normal renal function, and therefore, the
renal safety in children with abnormal renal function could not be
assessed. Although no subject discontinued TDF because of renal
events during the 48-week randomized phase, 4 of 89 subjects

TABLE 3. Selected Laboratory Data at Baseline and at the Time of Discontinuation of TDF on 4 Subjects
Who Discontinued the Study Drug Because of Hypophosphatemia or Glycosuria*
Subject (Age
at Baseline
and Sex)

Duration of TDF
Exposure

TDF Formulation
(mg/kg)

#1 (10-yr-old
female)
#2 (9-yrold male)

156 wks

#3 (8-yrold male)

96 wks

#4 (11-yrold male)

144 wks

300mg tablet
(7mg/kg)
Oral powder
(8mg/kg)
300mg tablet
(7mg/kg)
300mg tablet
(7mg/kg)

84 wks

Creatinine
(mg/dL)

eCrCL
(mL/min/
1.73 m2)

Phosphate
(mg/dL)

Proteinuria

Glycosuria

FTC, LPV/r

0.5 0.8

146.9 98.7

5.0 1.8

() (+)

() (+)

ABC, LPV/r

0.4 1.1

184.8 70.1

3.9 1.6

() (+)

() (+)

FTC, LPV/r

0.5 0.8

141.9 94.9

4.7 3.5

() (+)

() (+)

3TC, LPV/r

0.4 0.7

180.0 138.0

5.0 2.5

() (+)

() ()

Concomitant
ARVs

ARVs, antiretroviral agents; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; ABC, abacavir; 3TC, lamivudine; eCrCL, estimated creatinine clearance.
*When multiple visits occurred within the same visit window, the laboratory data with the greatest severity were selected.
For TDF 300mg tablet, mg/kg was calculated using the weight that was measured at the visit closest to the study drug discontinuation day. As per protocol, the dosage of TDF
oral powder was 8mg/kg.
Estimated creatinine clearance was calculated using Schwartz formula.4,5
Positive (+) proteinuria and glycosuria are defined as results greater than or equal to 1+ on urine dipstick.

2014 Wolters Kluwer Health, Inc. All rights reserved.

www.pidj.com|381

Saez-Llorens etal

The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

discontinued TDF during the extension phase because of adverse


events consistent with proximal renal tubulopathy; all 4 subjects
had at least 84 weeks of TDF exposure. It is notable that all 4 subjects were taking TDF in combination with lopinavir/ritonavir,
which can increase the systemic exposure of TFV.4 However, it is
difficult to infer any association, given that most subjects in the All
TDF group (92.1%) received lopinavir/ritonavir during the study.
Although proximal renal tubulopathy, or Fanconi syndrome, has
been reported in adults and children,811 it has rarely been observed
in clinical trial settings in adults.12 Our findings suggest that proximal renal tubulopathy can occur in children receiving TDF and can
be identified using routine laboratory testing, such as serum creatinine, serum phosphate, urine protein and/or urine glucose.
Many of the previous studies on the efficacy and/or safety
of TDF in adolescents and/or children have been cross-sectional or
noncomparative.13,14 The current study is the first randomized, activecontrolled study to evaluate the efficacy and safety of TDF compared
with other NRTIs in HIV-1infected children under the age of 12.
This is also the largest comparative study of TDF in this population.
Based on the current study, oral powder and r educed-strength tablet
formulations of TDF were approved by the US FDA for treatment of
HIV-1 infection in children aged 212 years. For children who can
swallow tablets, the reduced-strength tablets (150, 200, 250mg) can
be more convenient as it does not have to be mixed with food.
Our study demonstrated that viral suppression was maintained at Week 24 when switching d4T or ZDV to once daily TDF,
but not at Week 48. The safety profile of TDF, including renal
safety, in HIV-1infected children treated with antiretroviral agents
was generally consistent with that in adults. As pediatric formulations of TDF are now available, TDF may be an alternative to
d4T or ZDV for treatment of HIV infection in children after careful
weighing of their risks and benefits.

ACKNOWLEDGMENTS
The authors acknowledge Erin Quirk for her critical review
and editing of the article, YaPei Liu and Hiba Graham for their
assistance in article preparation and James Porter for final article
editing and distribution. In addition to the authors, the following
investigators and contributors are acknowledged for their role in
the study design, conduct and analysis of the study: from United
States, Anna Puga and Jill Foster; from United Kingdom, Delane
Shingadia.
This clinical study was sponsored by Gilead Sciences Inc.
The authors received medical writing support from Bryan Graham,
who is an employee of Gilead Sciences Inc. The study was conducted by the sponsor and developer of TFV disoproxil fumarate,
Gilead Sciences Inc. Data were collected and analyzed by the study
sponsor, and all authors had full access to the data. The corresponding author had full access to all of the data, takes responsibility for the integrity of the data and the accuracy of the data analysis
and had the final responsibility to submit the article for publication.

382|www.pidj.com

Authors contributions: X.S.-L., E.C., D.E., M.R., J.C., J.D.


and A.G. participated in the recruitment of subjects and reporting of data for those subjects. K.W., S.A., J.V.E., A.K.C. and S.L.C.
contributed to the design, conduct and analysis of the study. M.S.R.
prepared the first draft of the article. All authors participated in the
development of the article, interpretation of the data. All authors
except S.L.C., who passed away before the final version was available, approved the final article. The surviving authors honor the
memory of Steve L. Chuck whose contributions have expanded treatment options for adults and children living with HIV-1 infection.
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2014 Wolters Kluwer Health, Inc. All rights reserved.

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