A total of 312 subjects were randomized from 76 North American centers. One subject randomized to FTC/TDF withdrew consent before receiving study treatment and was excluded from the efficacy 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). Demographic and baseline disease characteristics are summarized in Table .
Baseline Demographics and Characteristics
At week 48, TLOVR responses were 133 of 155 (86.4%) for the FTC/TDF arm compared to 130 of 156 (83.3%) with continued 3TC/ABC, representing a treatment difference of 3.0% (95% CI, −5.1% to 11.2%), establishing noninferiorty. Additionally, 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 ). All 3 subjects who experienced virologic failure in the FTC/TDF arm had low-level viremia (range, 209–452 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 discontinued study drug early, and 8 subjects experienced viremia (range, 272–6430 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 specific boosted PI regimen was associated with virologic failure.
Virologic response and virologic failure by Kaplan-Meier through week 48.
Abbreviations: CI, confidence interval; FTC/TDF,emtricitabine/tenofovir disoproxil fumarate; HIV-1, human immunodeficiency virus type 1; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir; TLOVR, time to loss of virologic response.
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 subjects who were suppressed at screening but above the HIV-1 RNA value of 200 copies/mL at baseline, 2 were virologic successes 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/mm3 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 modification between arms during the study. No differences in HDL (P
= .26), TG (P
= .074) or HDL/TC ratio (P
= .17) were observed (Supplement 1
At baseline, there was no difference in the distribution across National Cholesterol Education Program (NCEP) categories between the 2 treatment groups; NCEP sets cholesterol guidelines in the United States [16
]. At week 48, a higher percentage of subjects who switched to FTC/TDF were in the desirable NCEP categories for TC and TG compared 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 ).
Fasting total cholesterol and triglycerides by National Cholesterol Education Program classification.
Abbreviations: FTC/TDF, emtricitabine/tenofovir disoproxil fumarate; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir.
Switching to FTC/TDF resulted in improvements in the predicted risk for CHD outcomes as measured by Framingham 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 calculated Framingham Scores in the 3TC/ABC group fluctuated about the baseline level with no statistically significant changes from baseline observed. The difference between groups for the predicted risk of CHD (regardless of method of calculation) only achieved statistical significance at week 24 (P < .05). The FTC/TDF group further demonstrated a shift from higher risk Framingham categories to lower risk categories (Figure ).
Categorical shifts by Framingham 10-year risk scores from baseline to week 48.
Abbreviations: CHD, coronary heart disease; FTC/TDF, emtricitabine/tenofovir disoproxil fumarate; PI, protease inhibitor; 3TC/ABC, lamivudine/abacavir.
The safety and tolerability for both treatment arms in SWIFT were consistent with the known safety profiles of FTC/TDF and 3TC/ABC (Table ). 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 ). There was one pregnancy in the 3TC/ABC arm with a spontaneous abortion, which was considered unrelated to the study drug.
Summary of Adverse Events (Treated Analysis Set)
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 treatment-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, flatulence, 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 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 decreased eGFR (grade 1 decrease at discontinuation).
Modest decreases from baseline through week 48 in creatinine clearance by the CG method (GFRCG
) using ideal body weight occurred within both treatment arms, FTC/TDF (GFRCG
−8.3 mL/minutes, P
< .001) and 3TC/ABC (GFRCG
−4.5 mL/minutes, P
= .002). When compared across arms, a statistically significant difference was observed between the groups (P
= .012). MDRD GFR estimates gave similar results (Supplement 2
Treatment emergent laboratory abnormalities were comparable between the groups. Most laboratory abnormalities were grade 1 or 2, and most common was elevated bilirubin, primarily in subjects on ATV + RTV. There was no grade 2 or higher changes in SCr throughout the study. Grade 1 SCr laboratory 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 ). No patients had confirmed normoglycemic glucosuria in either arm.
Change From Baseline in Urine Protein by Grade
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 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 ), although there was a trend for differences in fibrinogen (median change, FTC/TDF −10 mg/dL, 3TC/ABC −1 mg/dL, P = .062) at week 48.
Cardiovascular Biomarkers Change From Baseline at Week 48a