Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate in Single Tablet Regimens for Initial HIV-1 Therapy: A Randomized Phase 2 Study

Paul E. Sax, MD; Andrew Zolopa, MD; Indira Brar, MD; Richard Elion, MD; Roberto Ortiz, MD; Frank Post, MD, PhD, FCP (SA); Hui Wang, PhD; Christian Callebaut, PhD; Hal Martin, MD, MPH; Marshall W. Fordyce, MD; Scott McCallister, MD


J Acquir Immune Defic Syndr. 2014;67(1):52-58. 

In This Article

Abstract and Introduction


Objectives: To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection.

Design: Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study.

Methods: Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks.

Results: Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (<50 HIV copies per milliliter) at week 24 (86.6%; 89.7%) and at week 48 (88.4%; 87.9%), and had similar improvements in CD4 at week 48 (177; 204), respectively. Both treatments were well tolerated, and most adverse events were self-limiting and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had smaller reductions in estimated creatinine clearance (-5.5 vs. -10.1 mL/min, P = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip (-0.62% vs. -2.39%, P < 0.001) and spine (-1.00% vs. -3.37%, P < 0.001). Patients on E/C/F/TAF had higher increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both.

Conclusions: Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density.


Currently available antiretroviral regimens have led to marked declines in the morbidity and mortality of patients living with HIV-1[1–3] and decreased risk of HIV-1 transmission.[4–6] This success has shifted clinical attention toward antiretroviral drug regimens that optimize tolerability, long-term safety, and durable efficacy. Morbidity and mortality are increasingly driven by non-AIDS associated comorbidities, which are observed earlier than in age-matched controls, despite durable suppression with the best available antiretroviral therapy (ART).[1,2,7–10] Current guidelines recommend that patients begin ART earlier and stay on it continuously,[11] so the contribution of specific antiretroviral agents to long-term morbidity and mortality is increasingly important. In regimens of comparable efficacy, pill burden, dose frequency, safety, and tolerability are significant factors affecting maximal adherence over the long term.[12–14] Single-tablet regimens (STRs) represent a simple and convenient way for patients to maximize adherence and to control their HIV for many years.

Current Department of Health and Human Services guidelines recommend tenofovir disoproxil fumarate (TDF) as a preferred component of the nucleotide reverse-transcriptase inhibitor (NRTI) backbone for HIV-1–positive treatment-naive patients.[11] Despite a favorable safety and tolerability profile, TDF has been associated with nephrotoxicity,[15,16] requires dose adjustment as creatinine clearance falls <50 mL/min,[17] and has been shown to result in a greater decline in bone mineral density (BMD) relative to some other NRTIs.[18,19]

Tenofovir (TFV) is a nucleotide analog HIV-1 reverse transcriptase inhibitor. TDF, the first-generation prodrug of TFV, undergoes rapid metabolism in the plasma after oral administration.[20] TFV is then distributed intracellularly, where it is phosphorylated to the active moiety TFV diphosphate (TFV-DP). TFV alafenamide (TAF, formerly GS-7340) is a next-generation oral prodrug of TFV that may offer improved safety and efficacy. Relative to TDF, TAF is more stable in plasma and is predominantly metabolized intracellularly to TFV by cathepsin A.[20–22] This intracellular drug metabolism results in higher intracellular levels of the active metabolite TFV-DP and lower plasma levels of TFV, relative to TDF.[20,21]

Both nonhuman primate studies and human clinical studies have shown a relationship between plasma TFV levels and renal toxicity.[23–25] Because TFV (but not TAF) actively enters renal tubular cells via organic anion transporters 1 and 3, the reduced TFV levels that occur with TAF may be clinically manifest as reduced nephrotoxicity.[26,27] The higher intracellular TFV-DP levels may result in improved antiviral potency. In a 10-day monotherapy study in HIV-1–positive patients, those who received 25 mg of TAF had an approximately 0.5 log10 greater decline in plasma HIV-1 RNA than did patients who received the standard 300-mg dose of TDF.[28] In vitro, higher intracellular TFV-DP levels enable TAF to retain activity against viruses that have reduced susceptibility to TDF,[29] suggesting the potential use of TAF in a broader range of patients.

Because cobicistat increases the bioavailability of TAF by approximately 2.2-fold via the inhibition of P-glycoprotein intestinal secretion, the 10-mg dose of TAF delivered by the E/C/F/TAF STR is equivalent to the 25-mg dose of TAF.[28,30,31] To confirm the antiviral activity and safety profile of TAF compared with that of TDF, we conducted a randomized, double-blind Phase 2 clinical trial of 2 STRs—elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TAF 10 mg (E/C/F/TAF) compared with elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TDF 300 mg (E/C/F/TDF), licensed as Stribild (Gilead Sciences, Foster City, CA). The primary objective of this study, GS-292-0102, was to evaluate the efficacy and safety of TAF relative to TDF, both as part of an elvitegravir-based STR in treatment-naive patients at 24 weeks, with a particular focus on virologic, renal, and bone endpoints. Here, we report the efficacy and safety data from this study through 48 weeks.