CROI 2015: Tenofovir Alafenamide as Effective but Safer for Kidneys and Bones than TDF

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Tenofovir alafenamide (TAF), a new formulation that has lower concentrations in the blood but reaches higher levels in cells, is as effective as the older version, tenofovir disoproxil fumarate (TDF), according to a report at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle. A second study showed that TAF has less detrimental effects on the kidneys and bones compared with TDF. TAF has been submitted for approval in the U.S. and Europe.

Gilead Sciences' tenofovir disoproxil fumarate (Viread) is one of the most widely used antiretroviral drugs. It is a component of the Truvada coformulation -- used for both HIV treatment and pre-exposure prophylaxis (PrEP) -- and of the single-tablet regimens Atripla, Compera, and Stribild. TDF is highly potent and generally safe and well-tolerated, but it can cause kidney and bone toxicity in some patients.

TAF is a new pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells infected with HIV. TAF produces adequate intracellular levels with lower doses, which means lower concentrations in the blood plasma and less drug exposure for the kidneys, bones and other organs and tissues. A Phase 2 clinical trial previously showed that a regimen of TAF plus emtricitabine, elvitegravir, and cobicistat was comparable to TDF/emtricitabine/elvitegravir/cobicistat (Stribild) but caused less kidney impairment and bone loss.

David Wohl from the University of North Carolina presented combined primary results from 2 Phase 3 studies (GS-US-292-0104 and GS-US-292-0111) looking at the antiviral activity and overall safety of TAF in a new single-tablet regimen. Paul Sax from Brigham and Women's Hospital in Boston followed the next day with data on TAF's effects on kidneys, bones, and lipids.

Study 104 and Study 111 were randomized controlled trials conducted in Europe (both), North America (both), Latin America (Study 111), and Asia (Study 104). Together they included 1733 previously untreated participants with similar characteristics in both trials.

Most (85%) were men, one-quarter were black, 19% were Hispanic/Latino, and the median age was 34 years. They had well-controlled HIV disease with a median viral load of 4.58 log copies/mL and a median CD4 cell counts of approximately 400 cells/mm3. They had normal kidney function at baseline with a median estimated glomerular filtration rate (eGFR) of approximately 115 mL/min.

Participants were randomly assigned to receive a once-daily single-tablet regimen containing emtricitabine, elvitegravir, and cobicistat with either 10 mg TAF or 300 mg TDF. The primary analysis was done at week 48 of treatment.

Efficacy and Overall Safety Results

"Nothing stood out" in terms of adverse events association with TAF that have not already been seen with TDF, Wohl said.

Kidney, Bone, and Lipid Results

In a separate report, Sax described kidney, bone, and lipid-related adverse events and toxicities.

A pharmacokinetic analysis confirmed that TAF produced lower plasma levels of tenofovir than TDF, but intracellular levels were 4 times higher with TAF; the steady-state tenofovir concentration was 91% lower with TAF compared to TDF.

Looking at kidney-related side-effects, eGFR decreased -- indicating worsening function -- by -6.6% in the TAF arm and by -11.2% in the TDF arm by week 48. The change occurred during the first few weeks of treatment and then stabilized.

In the TAF arm there were no kidney-related adverse events leading to treatment discontinuation. 3 people had hypophosphataemia and 2 had protein in their urine. In the TDF arm, there were 4 kidney-related discontinuations: 2 cases of kidney failure, 1 person with decreased eGFR, and 1 with nephropathy. In addition, 1 patient had subclinical tubulopathy, 4 had hypophosphataemia, and 2 each had glucose and protein in their urine. No one in either arm, however, had overt tubulopathy or Fanconi syndrome.

Turning to bone effects, DEXA measurements were done at baseline and at weeks 24 and 48. People taking TAF experienced smaller average decreases in bone mineral density at 48 weeks than people taking TDF at both the spine (-1.30 vs -2.86) and the hip (-0.66 vs -2.95). Spinal bone loss started soon after starting treatment, reaching a plateau at 24 weeks. Hip bone mineral density continued to fall through week 48, but much more steeply in the TDF arm.

However, not everyone experienced bone loss. In the TAF group, 26% had spine bone loss and 17% had hip bone loss of at least 3%. Bone loss occurred more often in the TDF arm, with 45% and 50% having at least a 3% decrease at the spine and hip, respectively. A small proportion of participants actually gained bone density: 7% at both the spine and hip in the TAF arm, and 3% at both sites in the TDF arm.

Finally, researchers looked at blood lipid levels, which are known to play a role in cardiovascular disease. Levels of total, LDL ("bad") and HDL ("good") cholesterol, as well as triglycerides, rose by small amounts across the board, but more so in the TAF arm; total-to-HDL cholesterol ratio stayed about the same.

Sax suggested that the lipid differences might be occurring because tenofovir reduces lipid levels, but the lower concentration produced by TAF does so less compared with TDF.

Conclusions

Wohl’s team concluded that the TAF and TDF coformulations led to "high and similar response rates, irrespective of age, sex, race, HIV-1 RNA, and CD4 cell count," with "low rates of virological failure, with resistance <1% in both arms."

"Efficacy was very comparable and clearly TAF held its own against TDF," Wohl said at a CROI press conference. "This is very reassuring data as we think about TAF as a component of antiretroviral therapy."

Sax’s team concluded that "detailed protocol-specified renal [kidney] and bone endpoints confirmed the favorable safety and tolerability profile of TAF." Compared with TDF, TAF demonstrated no discontinuations due to renal adverse events; significantly smaller decreases in eGFR; significantly less proteinuria, albuminuria, and tubular proteinuria; significantly less impact on spine and hip bone mineral density; and greater increases in fasting lipids.

Sax explained at the press conference that while the long-term clinical effects are not yet known, this analysis "strongly suggests [TAF] will be safer in the long run for the kidneys and bones than TDF."

Based on these favorable findings, Gilead has submitted the TAF coformulation for regulatory review in the U.S. Europe. The U.S. Food and Drug Administration (FDA) is expected to make a decision by November 2015.

Stand-alone TAF is also being developed as a treatment for hepatitis B virus (HBV) infection. In addition, the company is developing a dual coformulation of TAF and emtricitabine, which will be the successor to Truvada.

Asked about the role of TAF as PrEP for HIV prevention, Marshall Fordyce from Gilead said at the press conference that the company is collaborating with the U.S. Centers for Disease Control and Prevention (CDC) on a study of emtricitabine and TAF for PrEP in macaque monkeys. Fordyce noted that the TAF combination "will have the same development pathway" as TDF for PrEP, presumably suggesting that Gilead will not conduct PrEP trials itself. "To reproduce iPrEx [with the new formulation] would be a large undertaking," he stated.

SEE ALSO: CROI 2015: Antiretrovirals in the Pipeline: New Tenofovir and HIV Maturation Inhibitor [VIDEO]

2/27/15

References

D Wohl, A Pozniak, M Thompson, et al. Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 113LB.

P Sax, M Saag, MT Yin, et al. Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 143LB.