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TAF noninferior to TDF through 48 weeks in elvitegravir combination
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
Tenofovir alafenamide (TAF), a second-generation tenofovir engineered to skirt the renal and bone side effects of tenofovir disoproxil fumarate (TDF), proved virologically noninferior to TDF in two 48-week trials that compared the drugs as part of a single-tablet regimen with elvitegravir, cobicistat, and emtricitabine.
Prior research showed that TAF dumps 90% less tenofovir into plasma than TDF as it gets drug into target cells more efficiently. Two phase 3 double-blind double-dummy trials randomized antiretroviral-naive people to TAF or TDF in the single-tablet once-daily elvitegravir/cobi/FTC formulation. Everyone had a viral load at or above 1000 copies and an estimated glomerular filtration rate at or above 50 mL/min.
The trials excluded people with HBV or HCV [2]. For now, whether TAF measures up to TDF in anti-HBV activity remains unknown, though a question of intense study. Whether TAF outperforms TDF in renal and bone safety will be learned at another CROI presentation still embargoed at the time of this efficacy report.
The primary endpoint of the TAF-TDF trials was the proportion of people with a viral load below 50 copies at 48 weeks in an FDA snapshot analysis. The investigators prespecified combined analysis of these two phase 3 trials, detailed here.
The combined trials randomized 866 people to TAF and 867 to TDF. Median ages of the two groups stood at 33 and 35, 85% in both groups were men, about 25% black, and 19% Hispanic/Latino. Median pretreatment CD4 counts stood at 404 in the TAF arm and 406 in the TDF arm. Pretreatment viral loads were 4.58 log (about 38,000 copies) in both arms.
Through 48 weeks 5% stopped treatment in the TAF arm and 8% stopped in the TDF arm. Adverse events explained 8 TAF withdrawals and 13 TDF withdrawals. Lack of efficacy accounted for 2 TAF dropouts and 3 TDF dropouts.
After 48 weeks 92% in the TAF arm and 90% in the TDF arm met the sub-50-copy primary endpoint. The difference between arms (2.0%, 95% confidence interval -0.7% to 4.7%) established the virologic noninferiority of TAF to TDF in this single-tablet combination given to previously untreated people. Virologic response rates did not differ between study arms when the investigators stratified participants by pretreatment viral load above or below 100,000 copies, baseline CD4 count above or below 200, age above or below 50, sex, or race.
Forty percent randomized to TAF and 42% randomized to TDF had a drug-related adverse event, 8% and 9% had any grade 3 or 4 adverse event, 8% and 7% had any serious adverse event, 0.3% and 0.2% had any drug-related serious adverse event, and 0.9% and 1.5% stopped treatment for any adverse event. No bone or renal events (including proximal tubulopathy) developed. Grade 3 or 4 lab abnormalities emerged in 20% in each study arm, including creatine kinase elevation in 7% on TAF and 6% on TDF.
CROI: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy - (02/26/15)
CROI: Safety of Tenofovir Alafenamide in Renal Impairment - (02/27/15)
CROI: Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - (02/27/15)
CROI: Gilead Announces Phase 3 Results for Investigational Once-Daily Single Tablet HIV Regimen Containing Tenofovir Alafenamide (TAF) - (02/27/15)
References
1. Wohl D, Pozniak A, Thompson M, et al. Tenofovir alafenamide (TAF) in a single-tablet regimen in initial HIV-1 therapy. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 113LB.
2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01780506 and https://clinicaltrials.gov/ct2/show/NCT01797445
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