MILAN — A single pill that packs the punch of a boosted protease inhibitor but poses fewer risks for renal and bone mineral density toxicity than current backbone therapies might now be possible, results from the AMBER trial show.
The single-pill combination of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (Symtuza, Janssen Pharmaceuticals) “combines the efficacy of a high barrier to resistance of darunavir with the safety advantages of TAF in treatment-naïve adults,” said Chloe Orkin, MD, from Barts Health National Health Service Trust in London.
“This is the first once-daily single-tablet regimen that includes a boosted PI,” she said here at the 16th European AIDS Conference.
Results from AMBER support findings from the phase 3 noninferiority EMERALD study by Dr Orkin’s team (Lancet HIV. Published online October 5, 2017), presented at ID Week last month, which demonstrated that the combination is effective in maintaining viral suppression in treatment-experienced people living with HIV.
At the ID Week presentation, clinicians called the results “important.” But as the US Food and Drug Administration considers approving the combination, physicians are wondering when to use the new, more expensive combination and when to stick with tried-and-true medications.
Single Tablet, Multiple Findings
In the 48-week randomized controlled AMBER trial, 725 treatment-naïve patients infected with HIV were randomized to one of two treatment regimens. In the single-tablet group, 362 patients received the new pill, which contained darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg. In the control group, 363 patients received three pills: cobicistat, darunavir, and a combination of emtricitabine plus tenofovir disoproxil fumarate.
Mean viral load in the study cohort was log 4.52 copies/mL, and median CD4 count was 453 cells/mm³. Most participants were healthy, with no bone mineral density or renal problems, and all had CD4 counts above 50 cells/mm³.
At 48 weeks, the rate of viral suppression, defined as a viral load below 50 copies/mL, was similar in the single-tablet and control groups (91.4% vs 88.4%). This difference is within the 10% noninferiority threshold and is statistically significant.
Increases in median CD4 counts were also similar in the single-tablet and control groups (171 vs 158 cells/mm³).
Interestingly, Dr Orkin pointed out, the efficacy of darunavir in this trial was better than it has been in any previous randomized controlled trial.
“This is partly a function of the drugs being better, and partly a function of our ability to support patients better,” she explained.
Safety First
One patient developed a treatment-resistant mutation to emtricitabine, but none of the participants developed resistance to tenofovir alafenamide, tenofovir disoproxil fumarate, or darunavir.
Viral failure was higher in the single-tablet group than in the control group (4.4% vs 3.3%), although both rates were low, Dr Orkin noted.
The drugs in both treatment groups were well tolerated. There were no deaths during the study period and few serious adverse events that led to discontinuation in the single-tablet and control groups (4.7% vs 5.8%). The most common adverse events in the two groups were diarrhea, rash, and nausea.
No patients developed clinically relevant bone or renal toxicities, but lab measures revealed more adverse renal and bone mineral density changes in the control group than in the single-table group, although lipid measures were improved. This has become a common story with regimens that contain tenofovir disoproxil fumarate.
Praise and Caution
Results from this study of the “first single-tablet regimen with a boosted PI” are “important,” Peter Reiss, MD, from the Academic Medical Center in Amsterdam, said after the presentation.
This pill is something that Roy Gulick, MD, from the Weill Medical School of Cornell University in New York City, is looking forward to offering his patients — but not necessarily just new patients.
“It’s nice to have a once-a-day option,” he told Medscape Medical News. “I have a few patients who I’m waiting to switch to this.”
However, he added, as a boosted protease inhibitor regimen, it’s a bit of an outlier. “The field is moving away from PI regimens, so it’s unclear what it will mean.”
It is also unclear whether the improvements in lab values are relevant in healthy patients, said Jens Lundgren, MD, from the University of Copenhagen.
“I think the overriding philosophy in HIV medicine is to make taking medicine as simple and easy as possible,” he explained. “But if you have a person who’s at essentially zero risk of having something clinically meaningful happen, then the lab differences may not be as relevant as if you’re starting patients with comorbidities on treatment — people whose kidney function is threatened and who are at imminent risk of cardiovascular disease.”
People without current kidney or bone problems should not be excluded from receiving the new pill, he emphasized. But in his many years treating people with HIV, he explained, he’s seen new drugs come with promises of fewer adverse effects, and usually, eventually, some downside to those regimens appear.
“You clearly want to protect kidney function. You clearly want to prevent people from contracting cardiovascular disease. You clearly want to prevent them from getting bone fractures,” Dr Lundgren told Medscape Medical News.
“But it is not a slam dunk to say, ‘it’s unacceptable to use TDF.’ Of course it is not; it’s a perfectly good drug. It’s a balance in HIV medicine between the well-tested, well-studied drug that we’ve used for years — for which we know the benefits and we know the problems — and the new drugs, which are typically very appealing.”
The message is that it comes down, once again, to clinical judgment. “You have to be thoughtful,” he said.
This study was funded by Janssen Pharmaceuticals. Dr Orkin reports acting as an advisor, consultant, or speaker for AbbVie, BMS, Gilead Science, Janssen Pharmaceuticals, Merck, and ViiV Healthcare. Dr Reiss, Dr Gulick, Dr Lundgren have disclosed no relevant financial relationships.
16th European AIDS Conference: Abstract PS8/2. Presented October 27, 2017.
Follow Medscape on Twitter @Medscape and Heather Boerner @HeatherBoerner
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