Large Study Backs Switch to Next-Gen Tenofovir for HIV

Pam Harrison

July 29, 2015

VANCOUVER, British Columbia — Tenofovir alafenamide maintains viral suppression at least as well as standard tenofovir (Viread, Gilead), has potential bone- and renal-sparing effects, and is not associated with additional adverse events, according to the largest switch study of its kind.

The randomized open-label trial, presented here at the 8th International AIDS Society Conference, was completed by 1196 virologically suppressed HIV-infected patients. All had been on a regimen that included tenofovir disoproxil fumarate (TDF) for at least 96 weeks, and all had a viral load below 50 copies/mL of HIV-1 RNA during that period.

At study entry, 31.9% of the patients were on a regimen of elvitegravir, cobicistat, emtricitabine, and TDF; 26.1% were on a regimen of efavirenz, emtricitabine, and TDF; 26.8% were on a regimen ritonavir-boosted atazanavir, emtricitabine, and TDF; and 15.0% were on a regimen of cobicistat-boosted atazanavir, emtricitabine, and TDF.

"CD4 counts were generally high, reflecting at least 96 weeks of successful therapy," reported lead investigator Anthony Mills, MD, from the Southern California Men's Medical Group in Los Angeles.

After randomization, 799 patients were switched to a regimen of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and the prodrug tenofovir alafenamide 10 mg for 48 weeks, and 397 patients remained on their TDF regimen.

At 48 weeks, more patients in the prodrug group than in the TDF groups had an HIV-1 RNA level below 50 copies/mL, which was the primary study end point (97% vs 93%; P < .001). In addition, more patients receiving the prodrug regimen met the primary end point than those receiving the efavirenz, emtricitabine, and TDF regimen (96% vs 90%; P = .02).

Virologic response was better with the prodrug regimen than with boosted atazanavir plus emtricitabine and TDF (P = .02). However, there was no difference in response when either the prodrug or TDF was added to the elvitegravir, cobicistat, and emtricitabine regimen (96% vs 97%).

At some point during the trial, 20% to 30% of participants in each group experienced grade 2 to 4 laboratory abnormalities. Elevations in bilirubin were more common in the TDF groups than in the prodrug group.

Prodrug Effects on Bone

Because the study participants had received at least 96 weeks of TDF treatment, there was a slight decrease (–0.28%) in spine bone mineral density at week 48, Dr Mills reported. But when the prodrug was added to the elvitegravir, cobicistat, and emtricitabine regimen, there was an increase in spine bone mineral density of at least 2%.

Similarly, there was a slight decrease in hip bone mineral density (–0.26%) at week 48 in the TDF groups. But with the prodrug regimen, there was a significant 1.37% increase in hip bone mineral density, resulting in a 1.6% difference in hip bone mineral density between the prodrug group and the TDF groups (P < .001).

"At baseline, approximately 35% of participants were found to have osteopenia and approximately 7% were osteoporotic," Dr Mills reported. At week 48, there was no change in these percentages in the TDF groups, but there was a "marked" decrease in the percent of patients with osteopenia in the prodrug group, and a decrease in the percent of patients with osteoporosis.

All improvements in renal function favored the prodrug regimen, indicating that both proteinuria and tubular proteinuria were diminished after the introduction of the prodrug.

Table. Median Change From Baseline to Week 48

Ratios Prodrug Group, % TDF Groups, % P Value
Urine protein:creatinine –18.5 9.4 <.001
Urine albumin:creatinine –18.4 5.3 <.001
Retinal binding protein:creatinine –32.9 15.7 <.001
Beta₂-microglobulin:creatinine –49.2 14.4 <.001

 

The prodrug regimen was effective across the board, "regardless of the patient's age, but I think it's important to think about long-term effects on bone and the kidney," Dr Mills explained. "Particularly for women and for patients who are at risk for either bone or kidney issues, I think the prodrug provides us with a really great new option for many patients."

Plasma levels were 90% lower with the prodrug than with TDF, which potentially reduces off-target adverse events.

Renal toxicity from TDF is pretty rare, said David Wohl, MD, from the AIDS Clinical Trials Unit at the University of North Carolina at Chapel Hill.

Renal Toxicity Rare

"The problem is that many of our patients are already at risk for renal problems, and it's sometimes hard to differentiate between toxicity from a drug that a person is on and their own intrinsic pathological reasons to have renal problems," he told Medscape Medical News.

The main reason HIV-infected patients are at elevated risk for kidney disease has less to do with toxic effects from a drug like TDF, and more to do with traditional risk factors for kidney disease, Dr Wohl explained.

"We know that people who are infected with HIV have HIV in the kidney, and there can be direct effects from that," he said.

In addition, "there are all sorts of other risk factors for kidney disease, including an aging patient population and a disproportionate number of people with HIV being African American, so we're seeing this constellation of risk factors within our patient population that puts them at risk for kidney disease," he said.

Bone mineral density loss is a lot more common than renal toxicity in TDF-treated patients, he added. Although modest, the data suggest that there is some leaching of bone with longer-term TDF therapy.

When asked who this new formulation might benefit most, Dr Wohl told Medscape Medical News that physicians might want to give everyone the new tenofovir.

"Time will tell," he said. The tenofovir prodrug "is a new and improved TDF; it has everything we want from TDF, but it's better tolerated and easier to coformulate."

Another way to look at the issue is "who do we keep on the old formulation of TDF," he said. "I don't see why you would want to keep someone on a drug that has more toxicity, even if it's not very common, when you have a new formulation that purportedly doesn't have that toxicity, or at least not to the same extent."

This study was funded by Gilead Sciences. Dr Mills reports financial relationships with Gilead, Merck, BMS, and Janssen. Dr Wohl reports receiving research funding from Gilead through his university, and sitting on a number of advisory boards, including Gilead and Janssen.

8th International AIDS Society (IAS) Conference: Abstract TUAB0102. Presented July 21, 2015.

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