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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
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)
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
Switch to Tenofovir
100
80
60
Tenofovir DF (n=48)
ZDV or d4T (n=49)
0 2 4
16
24
36
48
Weeks
100
80
0 2 4
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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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)
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
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
Adverse event,
number (%)
Common adverse
event, number
(%)
Nasopharyngitis
Cough
Otitis media
Upper respiratory infection
Gastroenteritis
Vomiting
Diarrhea
Bronchitis
Rhinitis allergic
Sinusitis
Pyrexia
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.
DISCUSSION
As the cumulative exposure to antiretroviral agents is generally lifelong in pediatric patients who mostly acquire HIV-1 through
Switch to Tenofovir
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.
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The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015
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.
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