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Single-Tablet HIV Regimen Shows Promise in Late-Stage Studies

Trials meet 48-week primary objectives

Positive results have been reported from two phase III clinical trials (Studies 104 and 111) evaluating an investigational once-daily single-tablet regimen containing tenofovir alafenamide (TAF, Gilead Sciences) for the treatment of human immunodeficiency virus-1 (HIV-1) infection in treatment-naïve adults.

The studies demonstrated that the single-tablet regimen, consisting of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TAF 10 mg (E/C/F/TAF), was non-inferior to elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg (Stribild, Gilead), based on the proportion of patients with HIV RNA levels (viral load) of less than 50 copies/mL after 48 weeks of therapy. In addition, E/C/F/TAF demonstrated more favorable renal and bone safety compared with Stribild.

In Study 104, 93.1% (405/435) of patients treated with E/C/F/TAF compared with 92.4% (399/432) of patients treated with Stribild achieved HIV RNA of less than 50 copies/mL at week 48. In Study 111, 91.6% (395/431) of patients treated with E/C/F/TAF compared with 88.5% (385/435) of patients treated with Stribild achieved HIV RNA of less than 50 copies/mL at week 48.

Laboratory abnormalities were generally similar for both regimens, with the exception of renal and bone safety indicators, which favored the TAF-based regimen. A statistically significant difference was observed in the median change in the estimated glomerular filtration rate (eGFR) from baseline to week 48, favoring the TAF-based regimen: –6.8 mL/min for E/C/F/TAF vs. –10.4 mL/min for Stribild in Study 104 (P < 0.001), and –5.7 mL/min for E/C/F/TAF vs. –11.9 mL/min for Stribild in Study 111 (P < 0.001).

In addition, patients treated with the TAF-based regimen experienced a significantly smaller median percentage decrease from baseline in lumbar-spine bone mineral density compared with the Stribild group (–1.19 vs. –2.67 in Study 104 [P < 0.001], and –1.11 vs. –2.81 in Study 111 [P < 0.001]), as well as a significantly smaller median percentage decrease from baseline in hip bone mineral density (–0.77 vs. –3.24 in Study 104 [P < 0.001], and –0.74 vs. –2.78 in Study 111 [P < 0.001]).

In Study 104, median changes from baseline in total fasting cholesterol, in high-density lipoprotein cholesterol (HDL-C) (“good” cholesterol), and in low-density lipoprotein cholesterol (LDL-C ) (“bad” cholesterol) were, respectively, 30, 7, and 15 mg/dL for E/C/F/TAF and 12, 3, and 2 mg/dL for Stribild (total cholesterol, P < 0.001; HDL-C, P < 0.001; and LDL-C, P < 0.001). In Study 111, median changes from baseline in total cholesterol, HDL-C, and LDL-C were, respectively, 27, 7, and 11 mg/dL for E/C/F/TAF and 14, 4, and 2 mg/dL for Stribild (total cholesterol, P < 0.001; HDL-C, P < 0.001; and LDL-C, P < 0.001).

Based on the results from Studies 104 and 111 and from additional ongoing trials, a regulatory application for E/C/F/TAF is expected to be submitted to the FDA in the fourth quarter of 2014.

TAF is a nucleotide reverse transcriptase inhibitor (NtRTI). It is an investigational prodrug of tenofovir, the active agent in Viread (tenofovir disoproxil fumarate, Gilead), which is also an NtRTI.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds, which interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir is approved under the trade name Vitekta in Europe, Australia, and Canada, and is currently under review by the FDA.

Cobicistat is a cytochrome P450 3A (CYP3A) inhibitor. It boosts blood levels of the HIV protease inhibitors atazanavir and darunavir by suppressing CYP3A, an enzyme that metabolizes these drugs in the body. Cobicistat acts only as a pharmacokinetic enhancer and has no antiviral activity. It is approved under the trade name Tybost in Europe, Australia, and Canada, and is currently under review by the FDA.

Source: Gilead Sciences; September 24, 2014.

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