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Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor–Based Single-Tablet Regimen for Initial HIV-1 Therapy

A Randomized Phase 2 Study

Mills, Anthony MD*; Crofoot, Gordon Jr MD, PA; McDonald, Cheryl MD; Shalit, Peter MD, PhD§; Flamm, Jason A. MD; Gathe, Joseph Jr MD; Scribner, Anita MD#; Shamblaw, David MD**; Saag, Michael MD††; Cao, Huyen MD‡‡; Martin, Hal MD‡‡; Das, Moupali MD, MPH‡‡; Thomas, Anne BS‡‡; Liu, Hui C. MD, PhD‡‡; Yan, Mingjin PhD‡‡; Callebaut, Christian PhD‡‡; Custodio, Joseph PhD‡‡; Cheng, Andrew MD, PhD‡‡; McCallister, Scott MD‡‡

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1, 2015 - Volume 69 - Issue 4 - p 439-445
doi: 10.1097/QAI.0000000000000618



Antiretroviral therapy (ART) has markedly reduced AIDS-related morbidity and mortality, and non-AIDS comorbidities are increasingly common.1–4 Current Department of Health and Human Services (DHHS) ART guidelines recommend initiation of ART for all HIV-positive individuals regardless of CD4 count.5 Non-AIDS comorbidities are observed earlier in HIV-positive individuals than in age-matched controls.3,6 As a result, new ARV drug development must optimize long-term safety and tolerability while maintaining durable suppression.5

Tenofovir disoproxil fumarate (TDF) is an oral prodrug of tenofovir (TFV), a nucleotide analog HIV-1 reverse transcriptase inhibitor approved in 2001. TDF is a safe potent nucleotide analog HIV-1 reverse transcriptase inhibitor that is available in a single-tablet regimen (STR) combined with 2 of the 3 classes of guideline-recommended third agents, non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine), and the integrase strand transfer inhibitor [elvitegravir boosted by cobicistat (COBI, C)]. Currently, there is no Food and Drug Administration (FDA)-approved protease inhibitor (PI)–containing STR.5

TDF undergoes rapid metabolism to TFV in plasma after oral administration.7 TFV then is distributed intracellularly, where it is phosphorylated to the active moiety TFV-diphosphate (TFV-DP). Tenofovir alafenamide (TAF, formerly GS-7340) is a next-generation oral prodrug of TFV that has increased stability in plasma compared with TDF, and in contrast to TDF, TAF is metabolized to TFV intracellularly, rather than in the plasma, before phosphorylation to the active moiety TFV-DP in key target cells such as lymphocytes and macrophages.7–9 Relative to TDF, TAF delivers substantially higher intracellular levels of the active metabolite TFV-DP and lower plasma levels of TFV.7,8 As a result, the dose of TAF is less than one-tenth the dose of TDF, which has allowed for the development of a PI-containing STR.

In a phase 2 randomized controlled trial (RCT) that directly compared TAF with TDF within an STR, HIV-positive treatment-naive adults in the TAF group had a reduced change in creatinine, less proteinuria including less proximal tubular proteinuria, and a reduced change in bone mineral density (BMD), as compared with the TDF group.10 This study is the second phase 2 RCT that directly compares the pharmacokinetics, renal, and bone effects of the 2 different TFV prodrugs. However, this is the first study that tests a PI, darunavir (DRV, D) boosted by COBI, as the third agent in an STR with emtricitabine (FTC, F) and TAF. DRV is a PI with a high genetic barrier to resistance.5 A PI-based STR containing TAF offers a promising addition to current treatment options by providing a backbone with potentially fewer renal and bone long-term complications while offering a third agent with a high barrier to resistance in a single tablet, both important features for patients.


This was a randomized, double-blinded multicenter active-controlled study that was approved by the US FDA and by institutional review boards at all sites (, number NCT01565850). Participants were HIV-positive treatment-naive adults older than 18 years with plasma HIV-1 RNA ≥5000 copies per milliliter and CD4+ cell count >50 cells per microliter. Genotype sensitivity to DRV, TDF, and FTC, and estimated glomerular filtration rate (eGFR) by Cockcroft–Gault formula (eGFRCG) ≥70 mL/min were required. Patients who were pregnant, hepatitis B or C coinfected, or had a new AIDS-defining condition within 30 days of screening were excluded.

Eligible participants were randomized centrally by a third party interactive voice/web response, stratified by HIV-1 RNA (≤100,000 copies/mL or >100,000 copies/mL) and race (black and nonblack). The TAF group received the D/C/F/TAF STR, 2 matched DRV 400 mg placebos, COBI placebo, and F/TDF placebo, whereas the TDF group received the D/C/F/TAF STR placebo, 2 DRV 400 mg tablets, COBI tablet, and F/TDF tablet, for a total of 5 tablets daily for each arm.

Randomized participants were seen at screening, baseline, and at weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, and then every 12 weeks until unblinding. The study was conducted from April 2012 to February 2014. Laboratory analyses (hematology, serum chemistries, CD4+ cell count, urinalysis, and urine renal biomarkers; Covance Laboratories, Indianapolis, IN), HIV-1 RNA (TaqMan 2.0; Roche Diagnostics, Indianapolis, IN), and physical examinations were performed at all visits. HIV-1 genotypes (reverse transcriptase and protease) were tested at screening (GenoSure MG; Monogram Biosciences, South San Francisco, CA). Any patient with confirmed virologic failure [2 consecutive viral load (VL) samples >50 copies/mL] and an HIV RNA >400 copies/mL at week 8 or later had the second, confirmatory, sample sent for resistance analysis by GeneSeq Integrase, PhenoSense GT, and PhenoSense Integrase (Monogram Biosciences, South San Francisco, CA). Dual-energy x-ray absorptiometry was used to measure BMD at the hip and lumbar spine before study drug administration at baseline, weeks 24 and 48 (read centrally by BioClinica, Newtown, PA), with investigators and patients blinded to the results. Blood for bone biomarkers was collected and analyzed at baseline, weeks 24 and 48 (Synarc, Lyon, France). Trough pharmacokinetics (PK) samples were collected at week 8, 24, and 48 visits, and population PK samples were collected at weeks 2, 4, 12, 16, 24, and 40. An intensive pharmacokinetic substudy was performed on a subset of patients at week 4 or 8 and included peripheral blood mononuclear cell (PBMC) sampling for intracellular TFV-DP levels at the sites that could perform PBMC processing.

The primary objective was to evaluate the efficacy of a regimen containing D/C/F/TAF (TAF group) vs. DRV + COBI + F/TDF (TDF group) in HIV-1 infected ART-naive adult participants, as determined by the achievement of HIV-1 RNA <50 copies per milliliter at week 24 (primary end point) and week 48 (secondary end point) using intent to treat analysis with the US FDA snapshot algorithm.11 The baseline HIV-1 RNA stratum and race weighted difference in the response rate and its 95% confidence intervals (CI) were calculated based on the stratum-adjusted Mantel–Haenszel proportion. Although this phase 2 study was not sufficiently powered for noninferiority, the standard noninferiority margin of −12% was prespecified [ie, noninferiority would be established if the lower bound of the 2-sided 95% CI of the weighted difference in response rates (TAF − TDF) was >−12%]. The FDA snapshot outcomes were also analyzed by subgroups of demographic and disease characteristics, and adherence.

The safety and tolerability outcomes were summarized using standard descriptive methods. Safety analyses included available data from all participants who consented to participate, were randomized, and received at least 1 dose of study medication; participants who prematurely discontinued study drug were followed for 30 days after drug discontinuation. In a subset of participants, PK of TAF, TFV, DRV, COBI, and FTC was assessed. The area under the concentration versus time curve over the dosing interval (AUCtau) of TFV and intracellular TFV-DP were compared using ANOVA.


Of the 232 treatment-naive adults screened, 153 were randomized 2:1 to TAF (N = 103) vs. TDF (N = 50) (see Figure S1, Supplemental Digital Content, Baseline demographic and general disease characteristics were similar between groups (Table 1). The majority of participants were male with a median age of 33 years. Approximately one-third of participants were black/African American and approximately 21% were of Hispanic ethnicity. The median VL at baseline was 4.66 log10 copies per milliliter, and median CD4 count was 384 cells per microliter with 80% of participants having an HIV-1 RNA VL ≤100,000 copies/mL and 14% of participants having a CD4 <200 cells per microliter. The median eGFRCG values were similar in the 2 treatment groups: TAF 116.0 mL/min and TDF 109.6 mL/min.

Baseline Demographic and Disease Characteristics

At week 24, 74.8% on TAF vs. 74.0% on TDF were virally suppressed (HIV-1 RNA <50 copies/mL); the weighted difference in response rate (TAF − TDF) was 3.3% (95% CI: −11.4 to 18.1) with a prespecified >−12% margin (Fig. 1). At week 48, 76.7% on TAF vs. 84.0% on TDF were virally suppressed; the weighted difference in response rate was −6.2% (95% CI: −19.9 to 7.4). The difference in virologic response rates at week 48 was primarily driven by the higher rate of participants in the TAF group (6.8%) compared with the TDF group (2%) who discontinued study drug with last available VL <50 copies/mL (eg due to reasons other than virologic failure such as loss to follow-up or investigator's discretion). At both weeks 24 and 48, there were no significant differences in virologic suppression by prespecified subgroup analyses by demographic and disease characteristics, or adherence.

Virologic outcomes HIV-1 RNA <50 copies/mL at weeks 24 and 48, FDA snapshot, intent to treat analysis.

Median adherence to study treatment as measured by pill count was high and similar in the 2 treatment arms (TAF 98.8% vs. TDF 98.6%) until week 24 and similarly high and equivalent until week 48 (TAF 98.8%, TDF 98.2%). Mean CD4+ cell count increase from baseline was 186 (95% CI: 157 to 215) cells per microliter in the TAF arm vs. 139 (95% CI: 85 to 193) cells per microliter in the TDF arm (P = 0.11) at week 24 and continued to increase similarly until week 48 to 231 (95% CI: 201 to 262) cells per microliter in the TAF arm vs. 212 (95% CI: 167 to 257) cells per microliter in the TDF arm (P = 0.50).

Among those who had virologic failure, none had the emergence of resistance. Through week 48, 8 participants met criteria for resistance analysis because of virologic rebound: 7 were confirmed as a virologic rebound with a subsequent VL ≥50 copies per milliliter and 1 was lost to follow-up. Genotypic analysis in these 8 participants revealed no development of resistance to TDF, TAF, FTC, or DRV.

Median duration of study drug exposure was 68.0 weeks in the TAF group and 69.1 weeks in the TDF group. Both treatments were generally well tolerated, as demonstrated by the low percentages of participants in either arm (TAF vs. TDF) who had serious adverse events (SAEs): 4.9% (5) vs. 4.0% (2) or discontinued study drug due to AEs: 1.9% (2) vs. 4.0% (2). The safety profiles of both arms (TAF vs. TDF) were similar, with 92.2% (95) vs. 94.0% (47) participants reporting any treatment-emergent AE and 6.8% (7) vs. 8.0% (4) reporting a grade 3 or 4 AE. Most AEs were of mild or moderate severity. The AEs reported for at least 10% of participants in the TAF group were diarrhea (21.4%, 22 participants), upper respiratory tract infection (15.5%, 16 participants), fatigue (13.6%, 14 subjects), nausea (12.6%, 13 participants), and rash (11.7%, 12 participants). The AEs occurring in at least 10% of the TDF group were diarrhea (26.0%, 13 participants), fatigue (18.0%, 9 participants), upper respiratory tract infection (14.0%, 7 participants), flatulence (12.0%, 6 participants), and nausea, pain in extremity, vitamin D deficiency, and vomiting (each in 10.0%, 5 participants). Supplemental Table S1 (see Supplemental Digital Content, ( summarizes AEs occurring in at least 5% of participants in either arm. Two participants in each group had AEs leading to discontinuation (TAF: rash, substance dependence; TDF: worsening of diarrhea, proximal renal tubulopathy). There were no deaths.

An intensive PK analysis was conducted in a subset of 32 participants. The plasma exposures {mean [percent coefficient of variation (%CV)] systemic AUCtau} of DRV [99,301.8 (45.3) ng·h−1·mL−1], COBI [8744.5 (43.9) ng·h−1·mL−1], and FTC [11,918.0 (35.9) ng·h−1·mL−1] were consistent with historical data for these agents12–15 (see Table S2, Supplemental Digital Content, For TAF, the median (Q1, Q3) plasma half-life was 0.45 (0.38, 0.66) hours, no drug was detectable 8 hours after administration, and the mean (%CV) AUClast was 130.5 (34.1) ng·h−1·mL−1. Participants in the TAF group had a greater than 90% lower mean (%CV) systemic TFV AUCtau [339.0 (37.1) ng·h−1·mL−1] than those in the TDF group [3737.0 (26.8) ng·h−1·mL−1] (Fig. 2; see Table S3, Supplemental Digital Content, The PBMC TFV-DP AUCtau (TAF 14 participants; TDF 8 participants) was markedly higher in participants receiving TAF compared with participants receiving TDF. The TFV-DP AUCtau GLSM ratio of 652.09% reflected intracellular concentrations of TFV-DP that were 6.5-fold higher in the TAF group compared with the TDF group.

Mean (SD) plasma TFV concentrations.

Serum creatinine increased and creatinine clearance decreased in both arms. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% CI: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% CI: 0.05 to 0.14) for TDF (P = 0.053) (see Figure S2, Supplemental Digital Content, Increases were observed at week 2 for each treatment group and remained stable through week 48 (see Figure S2, Supplemental Digital Content, The median decrease in eGFRCG from baseline was smaller for TAF: −2.9 vs. −10.6 mL/min for TDF (P = 0.017).

The effect of TAF vs. TDF on proximal renal tubular function was assessed by evaluating changes in the urine ratios of the tubular proteins: retinol binding protein (RBP) and β-2 microglobulin (β-2M). The increase from baseline to week 48 in urine RBP/Cr ratio was smaller for the TAF group compared with that for the TDF group (median percent change: TAF 9%, TDF 54%; P = 0.003) (see Figure S3, Supplemental Digital Content, From baseline to week 48, the urine β-2M/Cr ratio decreased for the TAF group and slightly increased for the TDF group (median percent change: TAF −42.0% vs. TDF 2.3%; P = 0.002) (see Figure S3, Supplemental Digital Content, There were no differences in the changes from baseline between arms for other renal parameters measured: treatment-emergent dipstick proteinuria, urine albumin/Cr or urine protein/Cr ratios, and fractional excretion of phosphate or uric acid (see Table S4, Supplemental Digital Content,

There was a significantly smaller decline in BMD in the TAF group compared with the TDF group at both the hip (−0.84% vs. −3.82%, P < 0.001) and lumbar spine (−1.57% vs. −3.62%, P = 0.003) at week 48; these percent changes were also present and statistically significantly different between groups at week 24 (Fig. 3). At week 48, fewer participants in the TAF group compared with the TDF group had BMD declines of >3% from baseline at the hip (18.3% vs. 61.7%) (P < 0.001) and lumbar spine (32.5% vs. 55.3%) (P = 0.002). At weeks 24 and 48, consistent with the smaller reductions in BMD, markers of bone turnover were lower in participants on TAF vs. TDF. At week 48, pro-collagen Type 1 N-terminal propeptide (P1NP), a marker of bone formation, increased 4.7% from baseline for TAF vs. 52.5% for TDF (P < 0.001), whereas C-terminal telopeptide, a marker of bone resorption, increased 23.2% from baseline for TAF vs. 74.4% for TDF (P < 0.001). There were no fractures in either group.

Mean (95% CI) percentage change from baseline in BMD by DEXA. DEXA, dual-energy x-ray absorptiometry.

There were greater increases in the fasting lipid parameters in the TAF group compared with the TDF group at week 48 (Table 2). There was a median increase in the TAF group's total cholesterol of 40 mg/dL as compared with 5 mg/dL in the TDF group (P < 0.001), low-density lipoprotein (LDL) [TAF 26 mg/dL vs. 4 mg/dL in TDF (P < 0.001)], high-density lipoprotein (HDL) [TAF 7 mg/dL vs. 3 mg/dL in TDF (P = 0.009)], and triglycerides [TAF 29 mg/dL vs. −5 mg/dL in TDF (P = 0.007)]. There were no differences in the total cholesterol/HDL ratio or fasting glucose. The majority of reported lipid-related AEs and laboratory abnormalities were nonserious and mild in severity. There were no differences in the number of participants who were initiated on lipid-lowering medications during the study [TAF, 7 (6.8%) vs. TDF, 4 (8%) (P = 0.75)]. There were no treatment-related cardiovascular events.

Median Change in Fasting Metabolic Assessments at Week 48


This phase 2 study, a direct comparison of 2 TFV prodrugs, TAF and TDF, combined with FTC and DRV boosted by COBI, demonstrated similar virologic suppression rates in both arms at week 24, which were consistent with other DRV studies.16,17 There was a difference in virologic suppression rates at week 48, primarily because of a higher rate of loss to follow-up in the TAF group, and these participants had a lower virologic suppression rate than participants in the comparably designed phase 2 study of TAF vs. TDF in an integrase-based STR.10 There was no evidence of development of virologic resistance to any ARVs in either arm. Both treatments were well tolerated with expected AEs based on the profiles of the individual ARVs. There were similarly low rates of AE-related discontinuation.

As expected, the plasma exposures of DRV, COBI, and FTC were consistent with historical data for these agents. As observed in the previous phase 2 comparison of TAF with TDF, this study confirmed that TAF is able to deliver both higher intracellular TFV-DP concentrations and lower plasma TFV exposure, with accompanying statistically significant improvements in renal and bone parameters in the TAF group.10 The more favorable renal and bone profile for participants on TAF is likely due to the lower circulating plasma TFV and its relationship to renal and bone effects.18–24

Early, small increases in creatinine were expected in both treatment arms because of the known nonpathologic inhibitory effect of COBI on tubular creatinine secretion.25 However, after week 2, participants receiving TAF had less increase in serum creatinine compared with those receiving TDF, despite otherwise receiving the same ART components. Corresponding differences were also observed for eGFRCG. The mechanism for this difference is currently unknown but may be associated with lower plasma TFV exposure with TAF. TFV in plasma is actively transported into the proximal renal tubular cell through organic anion transporter (OAT) 1 and OAT 3, but TAF is not a substrate for these transporters.22

General and specific tubular proteinuria were assessed by urine albumin/Cr and urine protein/Cr, and urine RBP/Cr and urine β-2M/Cr ratios, respectively; each urine protein concentration was divided by urine creatinine to standardize urinary concentration.26 There were no differences in general proteinuria; however, differences between treatment arms in markers of renal tubular proteinuria, urinary RBP/Cr and β-2M/Cr ratios, were statistically significant, favoring TAF. The mechanism of proximal tubular dysfunction is thought to be due to TFV-induced mitochondrial DNA depletion in the proximal tubules, and the lower plasma TFV exposure with TAF may explain the difference between treatment arms.27 Although the long-term clinical relevance of these specific, renal tubular biomarkers is not well established, the findings favoring TAF are consistent with the previous phase 2 study and suggest that TAF may have less effect than TDF on proximal renal tubular cell function.

HIV-positive individuals have lower BMD and higher fracture rates than age-matched HIV-uninfected controls.6,28 Initiation of ART increases bone turnover: TDF-containing regimens lead to greater changes in bone turnover markers and greater BMD declines than regimens without TDF.23,24,29–33 In this study, declines in hip and spine BMD over 48 weeks were smaller in the TAF group than in the TDF group; the BMD findings were supported by significantly less change in markers of bone turnover in the TAF group. The magnitude of BMD declines in the TAF group is among the lowest seen when naive participants have been evaluated by dual-energy x-ray absorptiometry.23,24,34,35 Although the mechanism of TFV-mediated BMD loss is not well understood, there may be a contribution from TFV-related urinary phosphate wasting leading to hypophosphatemia and osteomalacia.36,37

The lower plasma TFV exposure from TAF as compared with TDF may also explain the statistically significant increases in total cholesterol, LDL, HDL, and triglycerides in the TAF group compared with the TDF group. Lipid parameters improve when HIV-positive individuals switch to TDF.38–43 Adding TDF to a fully suppressive regimen decreases total cholesterol by 36.5 mg/dL and LDL by 20 mg/dL.44 In contrast, the discontinuation of TDF is associated with an increase in total cholesterol of 21 mg/dL and LDL by 17 mg/dL.45 This effect is also seen in HIV-negative persons: the metabolic substudy of iPrEx found that initiating FTC/TDF in HIV-negative males showed statistically significant decreases in total cholesterol and LDL cholesterol at week 24, which resolved by week 96. Despite the differences in lipid parameters by arm, there were no differences in the initiation of cholesterol-lowering medications by arm and there were no treatment-emergent cardiovascular events.

There were some limitations of this study. This small phase 2 RCT was not powered to evaluate noninferiority but rather to provide clinical data that would guide planning phase 3 studies. The study procedures required that each participant take more tablets (5) than is currently standard practice for the initial treatment of naive patients, a design requirement that may have contributed to reduced adherence and participant self-discontinuation. Relatively few women enrolled; therefore, generalization of these data to women may not be possible. These limitations will be addressed in the planned larger phase 3 studies.


This is the second study that demonstrates improved bone and renal safety parameters with TAF as compared with TDF, confirmed in the presence of a different third agent, DRV. These results suggest that the planned phase 3 studies of the D/C/F/TAF STR are warranted. With TAF's improved renal and bone safety profile, along with DRV's high barrier to resistance, the D/C/F/TAF STR is a promising HIV treatment option.


The authors thank all the participants who volunteered to be in this trial, the study staff who supported the ethical and efficient conduct of the trial, and Kris Dalmacio for her help in preparation of the figures.


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tenofovir alafenamide; GS-7340; darunavir; cobicistat; single-tablet regimen

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