November 01, 2017
MILAN — When the new tenofovir alafenamide prodrug is added to emtricitabine, viral suppression is as good as it is with abacavir plus lamivudine, and bone and renal safety are similar, new research shows.
So far, the prodrug has not been associated with cardiovascular risks, as abacavir was in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study; however, long-term studies have not been completed.
"The message here is not that everyone should switch their patients from abacavir to tenofovir alafenamide," said Alan Winston, MD, from Imperial College London.
"This is now an evidence base for another option. And you've still got a triple antiretroviral regimen," he told Medscape Medical News.
Dr Winston presented 48-week data here at the 16th European AIDS Conference, although the patients will be followed for 96 weeks. The findings add to the body of evidence that tenofovir alafenamide is a meaningful nucleoside backbone for aging people living with HIV.
The Same or Better?
Many studies have already found that the prodrug is superior to the older tenofovir disoproxil fumarate formulation, Dr Winston reported.
"When you switch from tenofovir disoproxil fumarate to many other agents, we see improvement in renal and bone markers," he told the audience. But "is there still a renal or bone signal in tenofovir alafenamide, just not as pronounced as with tenofovir disoproxil fumarate? Or is tenofovir alafenamide actually quite clean when it comes to bone and renal signals?"
To examine the issue, Dr Winston and his colleagues randomized 500 adults with HIV who were being treated with abacavir and lamivudine plus another agent to stay on their current regimen or to switch to tenofovir alafenamide plus emtricitabine but continue with their third agent.
Because the abacavir and lamivudine combination is well known and considered to be "clean" of renal and bone toxicity, it is a good comparator with which to test the safety of tenofovir alafenamide, Dr Winston explained.
The patient population was older — median age was 52 years — and largely white and male. The prevalence of comorbidities, similar in the two groups, was high: 47% of the patients had hyperlipidemia, 39% had hypertension, 12% had diabetes, and 6% had cardiovascular disease.
Fewer patients in the switch group than in the nonswitch group achieved viral suppression — an HIV RNA viral load below 50 copies/mL — although the difference was not significant (90% vs 93%). It is also within the 4% noninferiority threshold specified by the US Food and Drug Administration.
Resistance rates were identical in the switch and nonswitch groups, and rates of discontinuation were similar (4% vs 3%).
"I'll remind you that this is a double-blind study, and in the abacavir–lamivudine arm, these individuals have been on that regimen for a median of 8 years," he pointed out. "So it's quite reassuring that we aren't seeing high rates of discontinuation in the interventional arm."
The majority of adverse events were nasopharyngitis, upper respiratory tract infection, diarrhea, and headache. However, some adverse events in the switch group were deemed to be related to tenofovir alafenamide, including elevated blood creatinine, anxiety, and blurred vision.
Importantly, no participant in either treatment group experienced proximal renal tubulopathy. And renal, bone mineral density, and lipid changes were similar in the two groups.
A Question About Lipids
This last measure "intrigued" Peter Reiss, MD, from the Academic Medical Center in Amsterdam. A previous study showed a bump in total cholesterol when patients switched from the older tenofovir to tenofovir alafenamide, which left physicians wondering whether tenofovir alafenamide itself is associated with dyslipidemia, he explained.
"This study confirms that that effect is actually the withdrawal of tenofovir, which reduces lipids; when you take it away, they go up," he said. So "what do we do with people with dyslipidemia?' You can still switch them to tenofovir alafenamide, but you may want to give them a statin or another lipid-lowering agent."
The results drew animated reactions from the audience, with clinicians asking for a subanalysis of the 40% of participants who had taken the older tenofovir previously (reasons for initial switch were unknown), and for more details about the renal changes. And, as with any new drug, there were questions about cost.
"In Spain, the cost of abacavir–lamivudine is about €500. Tenofovir alafenamide–emtricitabine is more than €4000," one member of the audience reported. "After your research, do you think there's any reason to change any patients from abacavir to the much more expensive therapy with tenofovir alafenamide?" he asked.
That is a really good question, Dr Winston replied.
"I don't think these data say we should go back and switch everyone's antiretroviral therapy," he emphasized. "I think these data say that, for individuals on abacavir and lamivudine, if you are worried about toxicity, or if the patient is getting older and you're worried about cardiovascular disease, then this is another option, with data behind it."
This study was funded by Gilead Sciences. Dr Winston reports financial relationships with Abbott/AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Roche, Pfizer, and ViiV Healthcare. Dr Reiss has disclosed no relevant financial relationships.
16th European AIDS Conference: Abstract PS8/4. Presented October 27, 2017.