Article

SWIFT: Prospective 48-Week Study to Evaluate Efficacy and Safety of Switching to Emtricitabine/Tenofovir From Lamivudine/Abacavir in Virologically Suppressed HIV-1 Infected Patients on a Boosted Protease Inhibitor Containing Antiretroviral Regimen

Department of Infectious Diseases, University of Miami School of Med, Miami, FL, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 01/2013; 56(11). DOI: 10.1093/cid/cis1203
Source: PubMed
ABSTRACT
Background. In the United States, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone with lamivudine/abacavir (3TC/ABC) as a commonly used alternative. For patients infected with human immunodeficiency virus (HIV-1) virologically suppressed on a boosted protease inhibitor (PI) + 3TC/ABC regimen, the merits of switching to FTC/TDF as the NRTI backbone are unknown.
Methods. SWIFT was a prospective, randomized, open-label 48-week study to evaluate efficacy and safety of switching to FTC/TDF. Subjects receiving 3TC/ABC + PI + ritonavir (RTV) with HIV-1 RNA < 200 c/mL ≥3 months were randomized to continue 3TC/ABC or switch to FTC/TDF. The primary endpoint was time to loss of virologic response (TLOVR) with noninferiority measured by delta of 12%. Virologic failure (VF) was defined as confirmed rebound or the last HIV-1 RNA measurement on study drug ≥200 c/mL.
Results. In total, 311 subjects were treated in this study (155 to PI + RTV + FTC/TDF, 156 to PI + RTV + 3TC/ABC). Baseline characteristics were similar between the arms: 85% male, 28% black, median age, 46 years; and median CD4 532 cells/mm3. By TLOVR through week 48, switching to FTC/TDF was noninferior compared to continued 3TC/ABC (86.4% vs 83.3%, treatment difference 3.0% (95% confidence interval, −5.1% to 11.2%). Fewer subjects on FTC/TDF experienced VF (3 vs 11; P = .034). FTC/TDF showed greater declines in fasting low-density lipoproteins (LDL), total cholesterol (TC), and triglycerides (TG) with significant declines in LDL and TC beginning at week 12 with no TC/HDL ratio change. Switching to FTC/TDF showed improved NCEP thresholds for TC and TG and improved 10-year Framingham TC calculated scores. Decreased epidermal growth factor receptor (eGFR) was observed in both arms with a larger decrease in the FTC/TDF arm.
Conclusions. Switching to FTC/TDF from 3TC/ABC maintained virologic suppression, had fewer VFs, improved lipid parameters and Framingham scores but decreased eGFR.
ClinicalTrials.gov identifier. NCT00724711.

Full-text

Available from: John F Flaherty, Jan 07, 2014
MAJOR ARTICLE HIV/AIDS
SWIFT: Prospective 48-Week Study to Evaluate
Efcacy and Safety of Switching to Emtricitabine/
Tenofovir From Lamivudine/Abacavir in
Virologically Suppressed HIV-1 Infected Patients
on a Boos ted Protease Inhibitor C ontaining
Antiretroviral Regimen
R. Campo,
1
E. DeJesus,
2
U. F. Bredeek,
3
K. Henry,
4
H. Khanlou,
5
K. Logue,
6
C. Brinson,
7
P. Benson,
8
L. Dau,
9
H. Wang,
10
K. White,
11
J. Flaherty,
12
T. Fralich,
9
B. Guyer,
9
and D. Piontkowsky
9
1
Department of Infectious Diseases, University of Miami School of Medicine, Florida;
2
Department of Infectious Disease, Orlando Immunology Center,
Florida,
3
Department of Infectious Diseases, Metropolis Medical, San Francisco, California,
4
Department of Internal Medicine HIV Program, Hennepin
County Medical Center, Minneapolis, Minnesota,
5
Medical Institute of Immunology and Infectious Diseases, Los Angeles, California;
6
Department of
Medicine, St. Clair Medical Associates, Toronto, Ontario, Canada;
7
Central Texas Clinical Research, Austin, Texas,
8
Be Well Medical Center, Berkley,
Michigan,
9
Department of Medical Affairs,
10
Department of Biostatistics,
11
Department of Clinical Virology, and
12
Department of Clinical Research,
Gilead Sciences, Inc, Foster City, California
Background. In the United States, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a preferred nucleo-
side reverse tr anscriptase inhibitor (NRTI) backbone with lamivudine/aba cavir (3TC/ABC) as a commonly used alter-
native. For patients infected with human immunodeciency virus (HIV-1) virologically suppressed on a boosted
protease inhibitor (PI) + 3TC/ABC regimen, the merits of switching to FTC/TDF as the NRTI backbone are unknown.
Methods. SWIFT w as a prospectiv e, r andomized, open-label 48-week study to evaluate efcacy and safety of
switching to FTC/TDF. Subjects receiving 3TC/ABC + PI + ritonavir (RTV) with HIV-1 RNA < 200 c/mL 3months
were randomized to continue 3TC/ABC or switch to FTC/TDF. The primary endpoint was time to loss of virologic
response (TLOVR) with noninferiority measured by delta of 12%. Virologic failure (VF) was dened as conrmed
rebo und or the last HIV-1 RNA measur ement on study drug 200 c/mL.
Results. In total, 311 subjects were treated in this study (155 to PI + RTV + FTC/TDF, 156 to PI + RTV + 3TC/
ABC). Baseline characteristics were similar between the arms: 85% male, 28% black, median age, 46 years; and median
CD4 532 cells/mm
3
. By TLOVR through week 48, switching to FTC/TDF was noninferior compared to continued
3TC/ABC (86.4% vs 83.3%, treatment difference 3.0% (95% condence interval, 5.1% to 11.2%). Fe w er subjects on
FTC/TDF experienced VF (3 vs 11; P = .034). FTC/TDF showed greater declines in fasting low-density lipoproteins
(LDL), total cholesterol (TC), and triglycerides (TG) with signicant declines in LDL and TC beginning at week 12
with no TC/HDL ratio change. Switching to FTC/TDF showed improved NCEP thresholds for TC and TG and im-
proved 10-year Framingham TC calculated scores. Decreased epidermal gr owth factor receptor (eGFR) was observed
in both arms with a larger decrease in the FTC/TDF arm.
Conclusions. Switching to FT C/TDF from 3TC/ABC maintained vir ologic suppression, had few er VFs, improv ed
lipid parameters and Framingham scor es but decr eased eGFR.
ClinicalTrials.go v identier. NCT00724711.
Keywords. HIV-1; FTC/TDF; 3TC/ABC; virologic failure; switch.
Received 6 August 2012; accepted 7 December 2012; electronically published
29 January 2013.
Correspondence: Rafael E. Campo, MD, University of Miami School of Medi-
cine, Department of Infectious Diseases, 1120 NW 14th St, Ste 853, Miami,
FL 33136 (rcampo@med.miami.edu).
Clinical Infectious Diseases 2013;56(11):163745
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. This is an Open Access article distributed under the
terms of the Creative Commons Attribution License (http://creativecommons.org/
licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in
any medium, provided the original work is properly cited.
DOI: 10.1093/cid/cis1203
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Page 1
Fixed-dose combination (FDC) antiretrovirals such as emtrici-
tabine/tenofovir disoproxil fumarate (FTC/TDF) and lamivu-
dine/abacavir (3TC/ABC) allow simplication of regimens to
potentially improve outcomes by augmenting adherence [1].
Comparative studies of FTC/TDF to 3TC/ABC-containing
regimens tend to favor the FTC/TDF arm in regards to efca-
cy and/or safety [2, 3].
In a large, prospective, treatment-naive trial, subjects with
baseline HIV-1 RNA >100 000 c/mL had a lower rate of viro-
logic failure on FTC/TDF compared to 3TC/ABC-containing
regimens [3]. Similarly, the BICOMBO study showed that vi-
rologically suppressed subjects on a 3TC-containing regimen
had a lower rate of virologic failure when switched to FTC/
TDF compared to 3TC/ABC-containing regimens [2]. In fact,
the 3TC/ABC arm was not noninferior or comparable to the
FTC/TDF arm [2]. The total cholesterol (TC), low-density li-
poprotein (LDL) cholesterol, and triglycerides (TG) were sig-
nicantly lower for subjects on FTC/TDF compared to 3TC/
ABC [4]. In another study ROCKET 2, virologically sup-
pressed subjects with dyslipidemia on lopinavir/ritonavir
(LPV/r) also showed signicant declines in TC, LDL, and TG
levels 12 weeks following switch to FTC/TDF-compared to
3TC/ABC-containing regimens [5]. Other studies support
similar lipid improvement with FTC/TDF [3, 6]. Finally, some
but not all studies have shown an association of 3TC/ABC use
with an increased relative risk rate of myocardial infarction
(MI) [713].
US treatment Guidelines list FTC/TDF as a preferred and
3TC/ABC as an alternative NRTI backbone [1, 14]. In light of
this, we undert ook a prospective, randomized, open-label trial
(SWIFT) to evaluate the virologic efcacy and safety potentials
and risks of a nucleos(t)ide backbone switch from 3TC/ABC
to FTC/TDF in virologically suppressed subjects receiving a
ritonavir-boosted protease inhibitor (PI) based regimen.
METHODS
The SWIFT study was a 48 week prospective, randomized,
openlabel, multicenter study to evaluate the safety and efca-
cy of switching FDCs from 3TC/ABC to FTC/TDF in virolog-
ically suppressed, HIV-1 infected patients maintained on their
boosted PI. Eligible subjects were 18 years old, males and
nonpregnant females, receiving 3TC/ABC plus a boosted PI
with HIV-1 RNA < 200 copies/mL for at least 3 months prior
to study entry and < 200 copies/mL at screening by the COBAS
TaqMan version 1.0 assay (TaqMan). Subjects had to have an
estimated glomerular ltration rate (eGFR) 50 mL/minutes
by the Cockcroft-Gault (CG) method, AST and ALT 5 times
the upper limit of normal, and, if receiving lipid-lowering
agents, the drug and dose had to be stable for 3 months.
Subjects were excluded if they were receiving antiretroviral
agents in addition to 3TC/ABC plus a boosted PI, had known
historical resistance to any of the study agents including resis-
tance mutations to FTC/TDF (including K65R, M184V/I, or
multiple thymidine analogs) or PIs. Subjects were stratied by
LPV/r versus other PIs, and by co-morbidities (diabetes melli-
tus, hyperlipidemia and cardiovascular disease). Antiviral ef-
cacy was assessed by serial measurements of plasma HIV-1
RNA at baseline, and weeks 4, 12, 24, 36, and 48, and at early
study discontinuation, if it occurred. Subjects with HIV-1
RNA >200 copies/mL had the test repeated at the investiga-
tors discretion.
The primary objective was to assess non-inferiority of
FTC/TDF relative to 3TC/ABC measured by the proportion
of subjects who maintained HIV-1 RNA < 200 c/mL through
week 48 (intent-to-treat, missing = failure). Secondary objec-
tives included evaluation of safety and tolerability, changes in
CD4 cell count, assessment of eGFR using the CG, and the
abbreviated modied diet in renal disease (M DRD) methods,
and evaluation of change in fasting lipid parameters (TG,
TC, LDL, HDL, TC: HDL). In a subset, certain cardiovascular
biomarkers (high-sensitivity C-reactive protein [hsCRP], inter-
leukin 6 [IL-6], interleukin 10 [IL-10], tumor necrosis factor α
[TNF-α], and brinogen) were explored over the 48 weeks.
Changes in the risk of coronary heart disease (CHD) outcomes
were determined by 10-year Framingham risk scores [15, 16].
STATISTICAL ANALYSIS
The treated analysis set, used for safety and outcome summa-
ries, includes subjects who were randomized and received at
least 1 dose of study drug. The intent to treat (ITT) analysis
set, used for efcacy analysis, excludes those with major proto-
col violations from the treated analysis set.
The primary endpoint was the proportion of subjects with
HIV-1 RNA < 200 c/mL through week 48 by time to loss of
virologic response (TLOVR) algorithm. TLOVR responders
were those who completed the study and maintained HIV-1
RNA < 200 c/mL through week 48 without intervening VF. VF
was dened as conrmed on-study HIV-1 RNA 200 c/mL on 2
successive occasions or the last on-study HIV-1 RNA 200 c/mL.
Subjects were considered failures in the TLOVR analysis if they
experienced VF, discontinued study medication before week
48, or changed to a new antiretroviral (ARV) regimen. A 2-
sided exact 95% condence interval (CI) for the difference in
treatment group response rate (FTC/TDF minus 3TC/ABC)
was constructed using inverted 2 one-sided tests with the stan-
dardized statistics. The FTC/TDF group was considered non-
inferior to the 3TC/ABC group if the lower con dence bound
of the responder difference was greater than 12%.
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Descriptive statistics summarize secondary efcacy end-
points. Condence intervals (95%) and tests of signicance, all
2-sided were also used for measure of interest of secondary
efcacy endpoints. Observed values and changes from baseline
in the risk of CHD outcomes for the 10-year Framingham risk
score were analyzed. The Framingham risk score was calculat-
ed based on using both the fasting TC score and also based on
the fasting LDL score approaches. Framingham risk scores
were summarized using descriptive statistics and differences
between treatment groups and were compared using Wilcoxon
rank sum test.
The HIV-1 RNA threshold for VF was amended in the pro-
tocol 1 year into the study from 50 c/mL to 200 c/mL based
on data regarding discordance between the COBAS Amplicor
and the TaqMan HIV-1 test. The data showed an increased
rate of samples with >50 c/mL in the TaqMan assay that
were < 50 c/mL in the COBAS Amplicor assay [17]. This
protocol change was consistent with the ACTG standard of
< 200 c/mL [18]. Subjects meeting criteria for VF had geno-
typic resistance testing performed on their last available
plasma sample if HIV-1 RNA >1000 c/mL.
RESULTS
A total of 312 subjects were randomized from 76 North
American centers. One subject randomized to FTC/TDF with-
drew consent before receiving study treatment and was exclud-
ed from the efcacy and safety analysis. Overall, 311 subjects
were randomized and treated (155 started FTC/TDF and 156
continued 3TC/ABC). One subject randomized to FTC/TDF
was excluded from the ITT analysis set for a major protocol
violation (documented prior resistance to study drug). Demo-
graphic and baseline disease characteristics are summarized in
Table 1.
Table 1. Baseline Demographics and Characteristics
Characteristic FTC/TDF + PI/r (N = 155) 3TC/ABC + PI/r (N = 156) Total (N = 311)
Age, median (range), years 46 (22, 66) 46 (22, 75) 46 (22, 75)
Male sex, No. (%) 129 (83) 134 (86) 263 (85)
Race, No. (%)
White 96 (62) 106 (68) 202 (65)
Black 43 (28) 44 (28) 87 (28)
Asian 4 (3) 3 (2) 7 (2)
Other 12 (8) 3 (2) 15 (5)
Ethnicity
Hispanic/Latino 38 (25) 36 (23) 74 (24)
Non-Hispanic/Latino 117 (76) 120 (77) 237 (76)
HIV-1 RNA c/mL, No. (%)
<50 139 (90) 145 (93) 284 (91)
50 to < 200 13 (8) 10 (6) 23 (8)
200 3 (2) 1 (1) 4 (1)
Time since first ARV therapy, median (IQR), years 4 (2.5, 6.9) 3.7 (2.5, 6.7) 3.8 (2.5, 6.7)
CD4 cell count, median (IQR), cells/mm
3
532 (354, 725) 532 (382, 728) 532 (363, 725)
Comorbidities, No. (%)
Hyperlipidemia 81 (52) 96 (62) 177 (57)
Hypertension 51 (33) 51 (33) 102 (33)
Diabetes 15 (10) 17 (11) 32 (10)
Lipid modifying agent, No. (%) 67 (43) 80 (51) 147 (47)
PI stratification
Lopinavir/ritonavir 48 (31) 53 (34) 101 (32)
Non-lopinavir/ritonavir 107 (51) 103 (49) 210 (68)
Atazanavir/ritonavir 62 (40) 60 (38) 122 (78)
Fosamprenavir/ritonavir 34 (22) 31 (20) 65 (40)
Darunavir/ritonavir 9 (6) 11 (7) 20 (13)
Other PI 2 (1) 1 (1) 3 (2)
eGFR Cockcroft-Gault, mL/min (IQR) 95 (79110) 96 (77113)
Abbreviations: ARV, antiretroviral; eGFR, epidermal growth factor receptor; FTC/TDF, emtricitabine/tenofovir disoproxil fumarate; HIV-1, human immunodeficiency
virus; IQR, interqu artile range; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir.
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Efcacy Results
At week 48, TLOVR responses were 133 of 155 (86.4%) for
the FTC/TDF arm compared to 130 of 156 (83.3%) with con-
tinued 3TC/ABC, representing a treatment difference of 3.0%
(95% CI, 5.1% to 11.2%), establishing noninferiorty. Addi-
tionally, fewer people had virologic failure in the FTC/TDF
arm vs 3TC/ABC, 3/155 (1.9%) vs 11/156 (7.1%); P = .034
through week 48 (Figure 1). All 3 subjects who experienced
virologic failure in the FTC/TDF arm had low-level viremia
(range, 209452 copies/mL); low adherence was not reported
in these subjects with low-level viremia. Two were receiving
atazanavir/ritonavir and 1 boosted fosamprenavir. Of the 11
subjects with virologic failure in the 3TC/ABC arm, 3 discon-
tinued study drug early, and 8 subjects experienced viremia
(range, 2726430 copies/mL) at the week 48 visit. Of these 11
subjects, 5 were receiving atazanavir/ritonavir, 4 lopinavir/
ritonavir, 1 fosamprenavir/ritonavir, and 1 darunavir/ritonavir.
No specic boosted PI regimen was associated with virologic
failure.
Four virologic failure subjects had HIV-1 RNA values above
1000 copies/mL and had genotypic and phenotypic analyses: 1
subject in the FTC/TDF arm and 3 subjects in the 3TC/ABC
arm. No genotypic resistance to study drugs was observed in
any subject in either arm through week 48. Note, of the 4 sub-
jects who were suppressed at screening but above the HIV-1
RNA value of 200 copies/mL at baseline, 2 were virologic suc-
cesses due to post-baseline ongoing virologic suppression, 1
was a virologic failure due to detectable but low-level viremia
at week 48 while on FTC/TDF, and 1 subject was excluded
from the ITT analysis set due to a major protocol violation.
Changes in CD4 count at week 48 were similar between
treatment arms with median (IQR) changes of 8 (49, 80)
and 39 (41, 125) cells/mm
3
for the FTC/TDF and the 3TC/
ABC arms, respectively (P = .10).
Subjects who switched to FTC/TDF from 3TC/ABC showed
reductions from baseline at week 48 in fasting TC (median
change of 21 mg/dL vs 3 mg/dL with 3TC/ABC, P < .001),
and LDL (7 mg/dL vs 2 mg/dL with 3TC/ABC; P = .007).
There were no differences in lipid lowering agent modication
between arms during the study. No differences in HDL
(P = .26), TG (P = .074) or HDL/TC ratio (P = .17) were ob-
served (Supplement 1).
At baseline, there was no difference in the distribution
across National Cholesterol Education Program (NCEP) cate-
gories between the 2 treatment groups; NCEP sets cholesterol
guidelines in the United States [16]. At week 48, a higher per-
centage of subjects who switched to FTC/TDF were in the de-
sirable NCEP categories for TC and TG com pared to those
who remained on 3TC/ABC (TC: 62% vs 45% < 200 mg/dL,
P = .005; TG: 60% vs 41% < 150 mg/dL, P = .003) (Figure 2).
Switching to FTC/TDF resulted in improvements in the
predicted risk for CHD outcomes as measured by Framing-
ham Risk Scores. Mean (SD) change from baseline in risk by
the TC formula was 1.0 (4.32) for the FTC/TDF arm at week
12 (P = .008); this reduction was also maintained through
week 48 with a mean (SD) change from baseline of 1.2
(4.39) and P = .006. When the LDL formula was used, mean
(SD) change from baseline in Framingham risk was 0.9
(3.07) for the FTC/TDF arm at week 12 (P < .001) and was
0.5 (3.93) at week 48 (P = .21). The mean change for all
Figure 1. Virologic response and virologic failure by Kaplan-Meier through week 48. Abbreviations: CI, condence interval; FTC/TDF,emtricitabine/tenofo-
vir disoproxil fumarate; HIV-1, human immunodeciency virus type 1; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir; TLOVR, time to loss of virologic
response.
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calculated Framingham Scores in the 3TC/ABC group uctu-
ated about the baseline level with no statistically signicant
changes from baseline observed. The difference between
groups for the predicted risk of CHD (regardless of method of
calculation) only achieved statistical signicance at week 24
(P < .05). The FTC/TDF group further demonstrated a shift
from higher risk Framingham categories to lower risk catego-
ries (Figure 3).
Adverse Events
The safety and tolerability for both treatment arms in SWIFT
were consistent with the known safety proles of FTC/TDF
and 3TC/ABC (Table 2). Similar percentages of subjects in
each arm reported any serious adverse event (SAE), any
adverse event (AE), or any Grade 3 or 4 treatment-emergent
AE. Three subjects died during the study: 1 subject in the
FTC/TDF group (suicide) and 2 subjects in the 3TC/ABC
group (homicide, lymphoma). None of the deaths or SAEs
was considered by the investigator to be related to study
(Table 3). There was one pregnancy in the 3TC/ABC arm
with a spontaneous abortion, which was considered unrelated
to the study drug.
The percentage of subjects who discontinued study drug
due to an AE was higher in the FTC/TDF group [4.5% (n =7/
155)], compared to the 3TC/ABC [1.9% (n = 3/156)]. Rash,
which was reported in 1.3% (2 subjects) in the FTC/TDF arm,
was the only AE reported in more than 1 subject that resulted
in study drug discontinuation. A higher percentage of treat-
ment-emergent AEs considered related to study drug by the
investigator were reported in the FTC/TDF than in the 3TC/
ABC group, 10.3% (n = 16) vs 3.8% (n = 6). Adverse events
considered related to the study drug in more than 1 subject
included nausea, headache, and dizziness (1.9%, 3 subjects
each); diarrhea, atulence, malaise, and rash (1.3%, 2 subjects
each) in the FTC/TDF group; and diarrhea (1.3%, 2 subjects)
in the 3TC/ABC group.
There were no differences observed in renal adverse events
between arms (FTC/TDF 4.5% [n = 7]; 3TC/ABC 5.1%
[n = 8]). Three subjects in the FTC/TDF arm had renal AEs
reported as related to study drug by the investigator: renal
Figure 2. Fasting total cholesterol and triglycerides by National Cholesterol Education Program classication. Abbreviations: FTC/TDF, emtricitabine/te
nofovir disoproxil fumarate; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir.
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impairment (baseline serum creatinine [SCr] of 1.0 mg/dL
which subsequently increased to 1.3 mg/dL then decreased to
1.1 mg/dL), abnormal urine odor, and increased SCr with de-
creased eGFR (grade 1 decrease at discontinuation).
Modest decreases from baseline through week 48 in
creatinine clearance by the CG method (GFR
CG
) using id eal
body weight occurred within both treatment arms, FTC/TDF
(GFR
CG
8.3 mL/minutes, P < .001) and 3TC/ABC (GFR
CG
4.5 mL/minutes, P = .002). When compared across arms, a
statistically signicant difference was observed between the
groups (P = .012). MDRD GFR estimates gave similar results
(Supplement 2).
Treatment emergent laboratory abnormalities were compa-
rable between the groups. Most laboratory abnormalities were
grade 1 or 2, and most common was elevated bilirubin, pri-
marily in subjects on ATV + RTV. There was no grade 2 or
higher changes in SCr throughout the study. Grade 1 SCr lab -
oratory changes occurred in 3.2% of subjects on FTC/TDF
and 1.9% on 3TC/ABC. No clinically relevant changes in
serum phosphorus and in hypophosphatemia were observed.
There was no difference in development of proteinuria
between the 2 arms when analyzed by change in grade from
baseline (Table 4). No patients had conrmed normoglycemic
glucosuria in either arm.
Given previous reports of increased risks for cardiovascular
events, including myocardial infarction, associated with ARV
regimens containing ABC, we explored changes in commonly
used surrogate cardiovascular biomarkers in a subset of 159 of
Figure 3. Categorical shifts by Framingham 10-year risk scores from baseline to week 48. Abbreviations: CHD, coronary heart disease; FTC/TDF, emtricita-
bine/tenofovir disoproxil fumarate; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir.
Table 2. Summary of Adverse Events (Treated Analysis Set)
Adverse Event
Category, No. (%)
a
FTC/TDF + PI/r
(N = 155)
3TC/ABC + PI/r
(N = 156)
Total
(N = 311)
Adverse event 112 (72.3%) 120 (76.9%) 232 (74.6%)
Grade 3 or 4 adverse
event
13 (8.4%) 16 (10.3%) 29 (9.3%)
Adverse event related
to study drug
16 (10.3%) 6 (3.8%) 22 (7.1%)
Grade 3 or 4 adverse
event related to
study drug
1 (0.6%) 0 1 (0.3%)
Serious adverse event 12 (7.7%) 11 (7.1%) 23 (7.4%)
Serious adverse event
related to study drug
000
Adverse event leading
to study drug
discontinuation
7 (4.5%) 3 (1.9%) 10 (3.2%)
Death during study 1 (0.6%) 2 (1.3%) 3 (1.0%)
Abbreviations: FTC/TDF,emtricitabine/tenofovir disoproxil fumarate; PI,
protease inhibitor; 3TC/ABC,lamivudine/abacavir.
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312 (51%) patients, 81 randomized to FTC/TDF and 78 to
3TC/ABC. No differences at week 48 compared to baseline
were observed between treatment arms for hsCRP, IL-10, IL-6,
and TNF-α (Table 5), although there was a trend for differenc-
es in brinogen (median change, FTC/TDF 10 mg/dL, 3TC/
ABC 1 mg/dL, P = .062) at week 48.
DISCUSSION
In this large, prospective, randomized trial, the rst study spe-
cically designed to evaluate the efcacy and safety of
switching from 3TC/ABC to FTC/TDF in HIV-1-infected sub-
jects suppressed on a PI + RTV containing regimen, we have
demonstrated that FTC/TDF is noninferior to remaining on
3TC/ABC in maintaining treatment response by TLOVR with
fewer VFs, as well as a lower risk of emergent resistance
through 48 weeks. Efcacy and virologic failure rates in sub-
jects on FTC/TDF compared to 3TC/ABC arm were compara-
ble to results seen with this FDC seen in the BICOMBO and
ASSERT trials [2, 19].
We did observe slightly higher rates of discontinuation due
to AEs and mild AEs considered study drug-related in the
FTC/TDF vs 3TC/ABC arms. This nding is not unexpected
as previous studies demonstrate an increase in certain adverse
events when stable subjects are switched to a new therapy.
Modest declines in eGFR occurred in both arms with the
degree of decline signicantly greater in FTC/TDF-treated
subjects; however, values remained in the normal range. Long-
term studies have shown that the use of TDF may be associat-
ed with initial declines in GFR within the rst few months of
starting TDF, which then stabilize [2022]. Importantly, there
were no differences between arms in emergent proteinuria
and or normoglycemic glycosuria (Table 4).
Table 4. Change From Baseline in Urine Protein by Grade
Urine Protein Change in Grade
a
2 1 0 +1 +2 +3
FTC/TDF (n = 148) 2 11 107 25 3
3TC/ABC (n = 151) 1 15 114 21 0
Total (N = 299) 3 26 221 46 3
Cochran-Mantel-Haenssel statistics (based on table scores).
Abbreviations: FTC/TDF,emtricitabine/tenofovir disoproxil fumarate; 3TC/ABC,
lamivudine/abacavir.
a
Nonzero correlation value 1.5674, P = .2106; row mean scores diff 1.5674,
P = .2106.
Table 5. Cardiovascular Biomarkers Change From Baseline at
Week 48
a
Cardiovascular Biomarkers,
Median (Q1, Q3) FTC/TDF + PI/r 3TC/ABC + PI/r
C-reactive protein (mg/dL) N = 69
0.013
(0.123,
0.054)
N=57
0.006
(0.078,
0.113)
P = .19
Fibrinogen (mg/dL) N = 64
10
(50, 31)
N=56
1
(19, 54)
P = .062
IL-10-INF (pg/mL) N = 68
0.0
(0.0, 0.0)
N=56
0.0
(0.4, 0.0)
P = .22
IL-6-INF (pg/mL) N = 68
0.0
(0.4, 0.2)
N=56
0.0
(1.2, 0.2)
P = .58
TNF-α-INF (pg/mL) N = 68
0.0
(0.0, 0.0)
N=56
0.0
(0.0, 0.0)
P = .69
P-values for comparison between treatment groups are from Wilcoxon rank-
sum test.
Abbreviations: 3TC/ABC, lamivudine/abacavir; FTC/TDF, emtricitabine/tenofovir
disoproxil fumarate; IL, interleukin; INF, interferon; PI, protease inhibitor; TNF,
tumor necrosis factor.
a
Missing = excluded analysis.
Table 3. Disposition of Subjects
Subject Disposition
a
FTC/
TDF + PI/r
3TC/
ABC + PI/r Total
Subjects randomized 156 156 312
Subjects randomized but not
treated
101
Subjects treated 155 156 311
Completed 48 weeks of study
b
138 (89.0) 139 (89.1) 277 (89.1)
Discontinued study drug
prematurely
17 (11.0) 17 (10.9) 34 (10.9)
Primary reason for premature discontinuation of study
Adverse event 7 (4.5) 3 (1.9) 10 (3.2)
Death 0 0 0
Pregnancy 0 1 (0.6) 1 (0.3)
Lack of efficacy 0 1 (0.6) 1 (0.3)
Investigators discretion 0 3 (1.9) 3 (1.0)
Withdrew consent 5 (3.2) 4 (2.6) 9 (2.9)
Lost to follow-up 4 (2.6) 5 (3.2) 9 (2.9)
Subject noncompliance 0 0 0
Protocol violation 1 (0.6) 0 1 (0.3)
Study discontinued by
sponsor
000
Abbreviations: FTC/TDF,emtricitabine/tenofovir disoproxil fumarate; PI,
protease inhibitor; 3TC/ABC,lamivudine/abacavir.
a
All percentages are based on the No. of subjects in the treated analysis set.
b
Subjects completed 48 weeks of the study if the subject completed the
protocol-planned duration of the study based on the study completion form.
HIV/AIDS
CID 2013:56 (1 June)
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Page 7
Comorbidities (FTC/TDF vs 3TC/ABC) were common in
our study population, including diabetes (10% vs11%), hyper-
lipidemia (52% vs 62%), and hypertension (33% vs 33%). Ad-
ditionally, 3.2% in both arms had a history of MI. As with
previous studies, we demonstrated lipid benets when switch-
ing to FTC/TDF [36]. Signicant declines in LDL and
TC were observed by week 12 in the FTC/TDF arm and sig-
nicant reductions in TC, LDL, and TG were seen at week 48.
By NCEP category criteria [16], higher percentages showed
improvements in TC and LDL, as well as improvement (shift
from a higher risk to a lower risk category) in the predicted
risk for CHD outcomes with FTC/TDF as seen in other com-
parative studies [2, 5]. In an ad hoc analysis, we found that the
predicted Framingham 10-yr Risk Score was more favorable
when switching FTC/TDF; particularly, for those with comor-
bidities, whites, and regimens with a PI other than LPV/r.
Such an improvement in Framingham scores is perhaps one
of the most novel benets of switching from an 3TC/ABC to
FTC/TDF-containing regimen. It is however, worthwhile to
note that the small number of subjects on LPV/r and other
confounding factors at baseline may make this a weaker corre-
lation and may limit these results from being generalized.
Finally, the changes from baseline in commonly used surro-
gate cardiovascular biomarkers (hsCRP, IL-10, IL -6, TNF-α,
and brinogen) between the FTC/TDF and 3TC/ABC arm in a
subset of 159 subjects were not signicant except a trend toward
signicance with brinogen (P = .062) (Table 5), perhaps with a
larger sample size it may have achieved signicance.
The SWIFT study showed that high rates of virologic sup-
pression were well maintained through 48 weeks with fewer vi-
rologic failures in subjects who switched to FTC/TDF, and also
this regimen is well tolerated. Decreases in creatinine clearance
did occur with both treatments and were greater in the FTC/
TDF arm. In the FTC/TDF arm, improvements in certain lipid
parameters and in other measures including in NCEP catego-
ries and Framingham predicted risk for CHD outcomes were
noted [15, 16]. In summary, switching patients on a boosted PI
regimen to FTC/TDF from 3TC/ABC is associated with im-
portant metabolic benets without loss of virologic control.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online
(http://cid.oxfordjournals.org/). Supplementary materials consist of data
provided by the author that are published to benet the reader. The
posted materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or messages
regarding errors should be addressed to the author.
Notes
Disclosures. F. B. received travel support to his institution from Me-
tropolis Medical. R. C. received institutional grant support for
participation in the studys clinical trials. E. D. J. received travel support
through his institution from Gilead. K. H. received institutional grand
support from the Minneapolis Medical Research Foundation and also re-
ceived travel support from Gilead.
Potential conicts of interest. All authors: No reported conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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