Jim Kling

February 26, 2015

SEATTLE — Tenofovir alafenamide fumarate, a prodrug version of the antiviral tenofovir disoproxil fumarate (Viread, Gilead), has a better bone and renal safety profile when used to treat HIV than the original formulation, according to new research.

The results of two phase 3 trials comparing the new and original formulations of tenofovir were presented here at the Conference on Retroviruses and Opportunistic Infections 2015.

"One of the Achilles' heels of tenofovir disoproxil fumarate, if there is one, has been concern about bone toxicity and renal function," said Constance Benson, MD, from the University of California at San Diego, who moderated the news conference during which the findings were discussed.

That concern prompted Gilead to develop the new formulation, which is metabolized differently. Because levels of tenofovir in the plasma are more than 90% lower with the new formulation, it is thought that the agent will be less likely to cause systemic renal and bone toxicity.

A better bone and renal safety profile has already been demonstrated in a phase 2 clinical trial.

"We still want to make sure it works in HIV," lead investigator David Wohl, MD, from the University of North Carolina at Chapel Hill, told reporters attending the news conference.

Investigators conducted two identical phase 3 studies of treatment-naïve adults with HIV: one in Asia, the European Union, and North America; and the other in the European Union, Latin America, and North America. Both were powered to confirm safety and efficacy.

The 1733 patients enrolled in the two studies were randomized to receive a once-daily single-tablet regimen consisting of a combination of elvitegravir, cobicistat, and emtricitabine, plus either tenofovir alafenamide fumarate or tenofovir disoproxil fumarate.

Median age in the cohort was 34 years, 15% of the patients were women, 43% were nonwhite, and 23% had a viral load of at least 100,000 copies/mL. Median viral load was 4.8 log10 c/mL, and median CD4 count was 427 cells/µL.

At 48 weeks, the virologic response rate with the new formulation of tenofovir was noninferior to the original formulation (92% vs 90%; 95% confidence interval [CI], –0.7% to 4.7%; p = .13). Mean change in CD4 count was similar with the two formulations (211 vs 181 cells/µL; P = .024).

Table 1. Outcomes

Outcomes New Formulation, % Original Formulation, %
Virologic failure 4.0 4.0
Resistance 0.8 0.6
Treatment-related serious adverse events 0.3 0.2

 

The researchers compared virologic response rates in a number of subgroups, including age, sex, race, baseline HIV-1 RNA level, baseline CD4 cell count, geographic region (inside or outside the United States), and study drug adherence. In all subgroups, efficacy was similar.

However, the safety profile with respect to renal and bone toxicity was better with the new formulation.

Table 2. Changes in Toxic Effects

Variable New Formulation Original Formulation P Value
Mean serum creatinine (mg/dL) 0.08 0.11 <.001
Median urinary protein/creatinine ratio, % –3.00 20.00 <.001
Median urine albumin/creatinine ratio, % –5.00 7.00 .001
Bone mineral density      
   Lumbar spine, % –1.30 –2.86 <.001
   Total hip, % –0.66 –2.95 <.001

 

Rates of adverse events were similar with the new formulation and the original formulation, including diarrhea (3.3% vs 2.5%), nausea (2.2% vs 2.0%), headache (2.9% vs 2.1%), and upper respiratory tract infections (3.6% vs 3.1%).

"Tenofovir alafenamide fumarate clearly held its own against tenofovir disoproxil fumarate, which is kind of the standard-bearer in the class," said Dr Wohl.

"Having a drug that's potentially protective and that doesn't have a significant impact on renal dysfunction will be a major advantage," said Dr Benson.

Physicians are reluctant to prescribe tenofovir disoproxil fumarate to children younger than 12 years, primarily because of the potential effect on bone development. If the new formulation does reduce bone toxicity, it could help pediatric patients.

"If you're going to be using an HIV suppressive drug for a lifetime of therapy, you want to reduce the risk as much as you can," she explained.

With a better safety profile, tenofovir alafenamide fumarate is also likely to get considered as a component of pre-exposure prophylaxis combinations. "My understanding is that this is being aggressively studied by the manufacturer of the drug, so I think you'll hear much more about that in the future," said Dr Wohl.

The study was funded by Gilead Sciences, the manufacturer of both formulations. Dr Wohl reports serving as an adviser to Gilead and Janssen. Dr Benson has disclosed no relevant financial relationships.

Conference on Retroviruses and Opportunistic Infections (CROI) 2015: Abstract 113, presented February 25, 2015; Abstract 143LB, presented February 26, 2015.

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