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Single-Tablet D/C/F/TAF Strong Through 48 Weeks in Naive AMBER Group
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16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
Over 90% of previously untreated adults had an undetectable viral load after 48 weeks of a once-daily single-tablet regimen including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (D/C/F/TAF) in the international AMBER trial [1]. D/C/F/TAF proved noninferior to the comparator regimen, darunavir/cobicistat plus emtricitabine/tenofovir disoproxil fumarate (F/TDF).
Switching to D/C/F/TAF (800/150/200/20 mg once daily) proved noninferior to maintaining a suppressive regimen including a boosted protease inhibitor plus F/TDF in the phase 3 EMERALD trial [2]. The European Union has licensed single-tablet D/C/F/TAF, which is under regulatory review in the United States.
AMBER, a phase 3 double-blind North American/European trial, randomized antiretroviral-naive adults with HIV susceptible to darunavir, emtricitabine, and tenofovir to D/C/F/TAF or darunavir/cobicistat plus F/TDF for 48 weeks, after which everyone could receive D/C/F/TAF. The primary endpoint was proportion of participants with a viral load below 50 copies at 48 weeks by an FDA snapshot analysis, with a noninferiority margin of 10%. Of the 362 people randomized to D/C/F/TAF, 339 (93.6%) continued the regimen for 48 weeks. Among 363 people randomized to D/C plus F/TDF, 335 (92.3%) continued treatment for 48 weeks.
Median age stood at 34 in both the D/C/F/TAF group and the control group, about 88% in both arms were men, about 83% white, and 11% black. Median pretreatment CD4 count measured 461.5 in the D/C/F/TAF group and 440 in the control group, while respective viral loads were 4.4 and 4.6 log10 copies/mL (about 25,000 and 40,000 copies). The study excluded people with HBV or HCV infection, and pretreatment renal function was excellent (overall median estimated glomerular filtration rate [eGFR] 119 mL/min). While 16% of participants had pretreatment nonnucleoside mutations, 5% had pretreatment nucleos(t)ide mutations.
After 48 weeks 91.4% in the D/C/F/TAF arm and 88.4% in the control arm had a viral load below 50 copies in an intention-to-treat analysis (difference 2.7, 95% confidence interval -1.6 to 7.1), a result establishing the noninferiority of D/C/F/TAF to D/C plus F/TDF. In a per-protocol analysis, week 48 sub-50-copy response rates were 94.0% with D/C/F/TAF and 92.2% with the control regimen. Response rates did not vary significantly by age over versus under 50, gender, race, baseline CD4 count above or below 200, or baseline viral load above or below 100,000 copies.
One person randomized to D/C/F/TAF (0.3%) and none randomized to the comparator regimen stopped treatment because of lack of efficacy. Nine people (2.5%) in both study arms had a last viral load above 50 copies in the week-48 window. Among 7 people on D/C/F/TAF with virologic failure and paired screening and endpoint genotypes, M184I/V was the only emergent resistance mutation detected.
Nineteen people (5.2%) randomized to D/C/F/TAF and 22 (6.1%) randomized to the control arm had 1 or more grade 3 or 4 adverse events. Respective numbers with 1 or more serious adverse events were 17 (4.7%) and 21 (5.8%). Seven people (1.9%) stopped D/C/F/TAF for adverse events (6 rash, 1 diarrhea), compared with 16 people (4.4%) randomized to D/C plus F/TDF (7 rashes, 2 toxic skin eruptions, 2 neoplasms).
After 48 weeks eGFR based on serum creatinine or serum cystatin C was significantly higher in the D/C/F/TAF arm (P < 0.0001 and P = 0.001). No renal adverse events suggested proximal renal tubulopathy or led to treatment discontinuation. Average 48-week changes in 4 urinary tubular proteinuria markers consistently and significantly favored D/C/F/TAF. Spine and hip bone mineral density hardly changed through 48 weeks while declining with the control regimen (P = 0.004 between regimens at the spine, P < 0.0001 between regimens at the hip). A small difference in total-to-high-density lipoprotein cholesterol ratio significantly favored the control regimen but was not clinically relevant (4.0 versus 3.9).
The researchers proposed that single-tablet D/C/F/TAF combines darunavir's efficacy and high genetic barrier to resistance with TAF's safety advantages in antiretroviral-naive people.
References
1. Gallant J, Orkin C, Molina JM, et al. Week 48 results of AMBER: A phase 3, randomised, double-blind trial in antiretroviral treatment (ART)-naive HIV-1-infected adults to evaluate the efficacy and safety of the once-daily, single-tablet regimen (STR) of darunavir/ cobicistat/ emtricitabine/ tenofovir alafenamide (D/C/F/TAF) versus darunavir/cobicistat (DRV/c) plus emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF). 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PS8/2.
2. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2017 Oct 5. pii: S2352-3018(17)30179-0. doi 10.1016/S2352-3018(17)30179-0. Epub ahead of print. http://www.natap.org/2017/IDWeek/IDWeek_11.htm
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