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Novel Antiretroviral Cuts HIV DNA in PBMCs When Added to Solo Darunavir
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16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
ABX464, a novel antiretroviral that modulates HIV RNA splicing, cut total HIV DNA in peripheral blood mononuclear cells (PBMCs) when added to boosted darunavir monotherapy in a double-blind placebo-controlled trial [1]. But despite the DNA drop, adding ABX484 to darunavir did not delay viral rebound when both drugs stopped.
This investigational antiretroviral disrupts HIV RNA splicing by inhibiting HIV Rev activity. A prior phase 2a study found that ABX464 monotherapy reduces HIV load in a dose-dependent manner in previously untreated people with good safety and tolerability [2]. The new phase 2a trial aimed to assess the impact of ABX464 on HIV DNA in PBMCs and sustained viral suppression after treatment stops, as well as safety and tolerability.
This double-blind trial randomized people with an undetectable viral load on boosted-darunavir monotherapy 3-to-1 to ABX464 or placebo for 28 days, followed by suspension of all therapy. Treatment would resume when the viral load rebounded above 1000 copies. Researchers measured total HIV DNA and integrated HIV DNA in PBMCs collected in samples drawn on day 0 and day 28. They defined responders as people with a minimum 50-copy drop and more than a 25% drop in total HIV DNA copies.
The 30 trial participants lived in Spain, Belgium, or France. Six people received 50 mg of ABX464 once daily and 16 got 150 mg once daily. Two people got a 50-mg placebo dose and 6 got 150 mg of placebo. Everyone had a plasma viral load below 50 copies on boosted-darunavir monotherapy. Median age ranged from 43 to 50 across the four treatment groups, 28 people (93%) were men, and 27 (90%) were white. Median CD4 count stood above 700 in all study arms.
No serious adverse events were related to study drugs. One person stopped ABX464 before day 28 because of treatment-related grade 2 abdominal pain and grade 1 epigastric pain. One episode of grade 3 fatigue was judged related to ABX464 at the 150-mg dose. All told, 8 treatment-emergent adverse events arose among 16 people (50%) in the 150-mg ABX464 arm, and one emerged among 6 people in the 150-mg placebo group.
Two of eight people (25%) dropped out of the placebo group because of poor adherence. Two of 22 (9%) stopped ABX464 because of (1) viral rebound before day 28 and (2) the grade 1 and 2 adverse events noted above. Among 6 people who completed treatment in the placebo arm, the researchers excluded 2 from HIV DNA analysis because they had fewer than 50 copies/million PBMCs. The same reason resulted in exclusion of 5 people from the 20 completers in the ABX464 arm. This left 4 evaluable placebo participants and 15 evaluable ABX464 participants.
Average time to rebound after treatment stopped did not differ much between the ABX464 group (13 days) and the placebo group (14 days). Eight of 15 people taking ABX464 (53%) were responders, compared with 0 of 4 taking placebo. Among the 8 ABX464 responders, total DNA fell by an average 186 copies/million PBMCs (38%). In the 7 ABX464 nonresponders and 4 placebo nonresponders, total DNA rose by averages of 67 and 58 copies/million PBMCs. Integrated DNA dropped by an average 131 copies/million cells in 7 ABX464 responders (55%).
The researchers noted that the substantial drop in the HIV DNA reservoir with ABX464 for 28 days was not enough to delay viral rebound. But they believe their study is the first to produce a signal "demonstrating the reduction of HIV reservoirs in patients with a therapeutic candidate." Three larger clinical trials of ABX464 are under way or planned.
References
1. Vandekerckhove L, Rutsaert S, Paredes R, et al. ABX464 decreases total HIV DNA in PBMCs when administered during 28 days to HIV-infected patients who are virologically suppressed. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract 1/7.
2. Steens JM, Scherrer D, Gineste P, et al. Safety, pharmacokinetics, and antiviral activity of a novel HIV antiviral, ABX464, in treatment-naive HIV-infected subjects in a phase 2 randomized, controlled study. Antimicrob Agents Chemother. 2017;61(7). pii: e00545-17. http://aac.asm.org/content/61/7/e00545-17.long
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