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IDWeek 2015: Studies Continue to Support Tenofovir Alafenamide as it Nears Approval

A single-tablet regimen containing a new formulation of tenofovir maintained viral suppression when switching from other combinations and was associated with improved kidney function and bone health, according to studies presented at IDWeek 2105 last week in San Diego. Other research showed that the new formulation works better than the old one for black patients and for older people, and that it can be safely used with sofosbuvir/ledipasvir (Harvoni) for hepatitis C treatment.

Gilead Sciences' tenofovir alafenamide or TAF is a new pro-drug formulation that delivers the active agent to HIV-infected cells more efficiently than the current tenofovir disoproxil fumarate or TDF (Viread, also in Truvada, Atripla, Complera, and Stribild). TAF produces adequate intracellular drug levels with smaller doses, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

TAF vs TDF Coformulations

TAF dominated the sole IDWeek oral abstract session on antiretroviral therapy, with 3 presentations.

Melanie Thompson from theAIDS Research Consortium of Atlanta presented findings from a sub-group analysis of the Phase 3 GS-US-292-0109 trial, which evaluated a new single-tablet regimen containing 150 mg elvitegravir, 150 mg cobicistat (a booster), 200 mg emtricitabine, and 10 mg TAF in more than 1400 people currently taking TDF-containing regimens. Results from the larger study were presented at the International AIDS Society Conference this summer in Vancouver.

This open-label sub-study looked at 459 HIV-positive people with undetectable viral load taking the currently marketed Stribild single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and 300 mg TDF. In this head-to-head comparison participants were randomly assigned to either stay on Stribild or switch to the new TAF-containing pill. (Another sub-study presented at last month's ICAAC meeting compared the same TAF-containing combo to the coformulation of efavirenz, emtricitabine, and TDF, marketed as Atripla.)

Over 90% of participants were men, 70% were white, and the median age was about 40 years. The median CD4 count was high at approximately 690 cells/mm³. They were required to have near-normal kidney function with an estimated glomerular filtration rate (eGFR) of >50 mL/min (median 103 mL/min).

Results

• At week 48 after randomization, 98% of participants who switched to the TAF-containing coformulation maintained viral suppression, as did 97% of those continuing on Stribild, showing that the TAF was non-inferior to TDF.
• Just 0.7% of people in both groups experience virological failure.
• The new coformulation was generally safe and well-tolerated, with no treatment-related serious adverse events.
• There were no notable differences in most adverse events between the TAF and TDF groups.
• Serum creatinine (a measure of kidney function) improved significantly starting at week 2 in participants who switched to the TAF-containing pill compared to those who stayed on Stribild (mean change -0.01 vs +0.03 mg/dL).
• Urine protein markers -- and tubular proteinuria in particular -- also significantly improved in people who switched.
• 2 people in the TDF arm, but none in the TAF arm, discontinued treatment due to serum creatinine increases.
• DXA bone scans showed that bone mineral density (BMD) also improved significantly among people who switched to the TAF-containing coformulation.
• Spine BMD increased by +1.33% in the TAF arm while falling by -0.50% in the TDF arm.
• Hip BMD also improved, rising by +1.15% in the TAF arm while falling by -0.24% in the TDF arm.
• As a result, fewer people in the TAF group had spine or hip osteopenia at week 48.
• Blood lipid levels rose overall among people taking the TAF pill, with increases in total cholesterol, LDL (bad) cholesterol, and triglycerides.
• However, changes in the total-to-HDL (good) cholesterol ratio were similar in both arms.
• 7.8% of TAF recipients and 6.5% of people taking TDF started lipid-modifying medications.

In both the overall GS-US-292-0109 study population and among prior Stribild users, those switching to the new TAF-containing coformulation "maintained virologic success," the researchers concluded, and "[t]he change from TDF to TAF resulted in ~90% reduction in plasma [tenofovir] levels, associated with significant changes in renal and bone safety."

Simplified Regimen for Drug-Resistant Patients

In a second study presented in the same session, Gregory Huhnfrom the Ruth M. Rothstein CORE Center in Chicago and colleagues looked at a simplified TAF-containing antiretroviral regimen for people with highly resistant HIV.

People who are starting HIV treatment for the first time can usually take a once-daily single-tablet regimen such as Stribild or Atripla. But those who are heavily treatment-experienced with virus that has developed resistance to multiple drugs must still sometimes take complex regimens with many pills and more frequent dosing.

This open-label study included 135 adults with HIV; about 75% were men, 45% were black, and the median age was about 49 years -- reflecting the fact that some had been HIV-positive for a long time and likely had received earlier suboptimal treatment.

All had viral suppression for at least 4 months on a regimen containing the HIV protease inhibitor darunavir (Prezista). They had been on at least 2 prior failed regimens and had resistance to at least 2 antiretroviral drug classes, including some tenofovir resistance (e.g., K65R or <3 thymidine mutations), but no evidence of Q151M, T69ins, or darunavir resistance mutations. At study entry they were taking a median of 5 pills, about 40% took 6 or more pills, and 65% were on twice-daily regimens.

Participants were randomly assigned to either stay on their baseline regimen or switch to a simpler 2-pill once-daily regimen consisting of the elvitegravir/cobicistat/emtricitabine/TAF coformulation plus darunavir.

At 24 weeks, 97% of people who switched to the TAF-containing coformulation plus darunavir had undetectable viral load, as did 91% who stayed on their old regimen, not a significant difference. But by 48 weeks the difference was greater -- 90% vs 72%, respectively, using a <20 copies/mL cut-off -- demonstrating that the simplified regimen was statistically superior. No new drug resistance mutations were seen in the TAF arm, but 1 person with viral rebound developed resistance on their old regimen.

The simplified regimen was generally well-tolerated with no drug-related serious adverse events or events leading to treatment discontinuation. Overall, more people in the TAF-containing arm reported adverse events (92% vs 78%), which might be due to starting new drugs, which can often cause transient side effects during the first few weeks.

Participants who switched to the TAF-containing pill showed more favorable changes in eGFR (+7.4 vs +3.9 mL/min at 48 weeks; not significant) and improvement in tubular proteinuria compared to those who stayed on their old regimen. People who switched also reported significantly more improvement in treatment satisfaction scores than those who stayed on their old regimen.

"For treatment-experienced individuals with >2 class resistance on complex, high-pill burden regimens, switching to [elvitegravir/cobicistat/emtricitabine/TAF plus darunavir] provides a simple, once-daily, 2-pill option with superior efficacy and comparable tolerability," the researchers concluded.

First-line TAF

Two posters at the conference presented data from sub-group analyses of a pair of Phase 3 trials (Study 104 and Study 111) evaluating the elvitegravir/cobicistat/emtricitabine/TAF coformulation taken as a first antiretroviral regimen.

In these studies treatment-naive participants with near-normal kidney function were randomly assigned to take the TAF-containing pill or Stribild. As described at the Conference on Retroviruses and Opportunistic Infections earlier this year, both coformulations demonstrated similar high efficacy (92% vs 90%). Treatment was generally safe and well-tolerated and overall drug safety profiles were similar in both arms, but TAF had less detrimental effects on the kidneys and bones than TDF. 

In the first planned sub-group analysis, David Wohl from the University of North Carolina and colleagues looked at outcomes among black patients, a group at higher risk for kidney disease compared to white patients.

A quarter (n=436) of the 1733 combined total participants in the 2 trials self-identified as black. At 48 weeks 88% of black patients taking TAF and 83% taking TDF achieved viral suppression -- not a significant difference. But response rates were significantly lower for black people in both treatment arms than those of non-black patients (94% vs 93%, respectively).

Black participants were more likely than non-blacks to experience both virological treatment failure and to be lost to follow up, and they were less likely to achieve 95% or better treatment adherence (68% vs 86%).

Treatment was safe and well-tolerated among black participants and there were no cases of proximal renal tubulopathy (a type of kidney damage). Like the study population as a whole, black patients showed a smaller decrease in eGFR and more improvement in proteinuria in the TAF compared to the TDF arm. Decreases in bone density -- which typically declines after starting tenofovir -- were smaller in the TAF arm than in the TDF arm, and black patients experienced changes similar to those seen in non-blacks.

Eric Daar from UCLA's Los Angeles Biomedical Research Institute and colleagues conducted a similar sub-group analysis of people age 50 or older, noting that the risk of kidney problems and other comorbidities rises with age.

About 12% (n=203) of the 1733 total participants were age 50 or above. At 48 weeks 94% people taking TAF and 91% taking TDF achieved viral suppression -- similar to the efficacy in the study population as a whole. 

Again treatment was generally well-tolerated; 1 person in the TAF arm and 4 in the TDF arm experienced adverse events leading to study discontinuation. Mean changes in eGFR were -5.8 vs -11.7 mL/min, respectively, and TAF was associated with improved tubular proteinuria. TAF recipients also had smaller BMD decreases at the spine (-1.47% vs -2.77%) and hip (-0.31% vs -2.54%).

"These findings demonstrate an important safety improvement of TAF relative to TDF in patients >50 years, which is of particular importance as the population living with HIV ages and experiences more non-AIDS related conditions," the researchers concluded.

TAF Coformulations and Harvoni

Finally, Joseph Custodioof Gilead and colleagues looked at potential drug-drug interactions between the elvitegravir/cobicistat/emtricitabine/TAF coformulation or another single-tablet regimen containing the NNRTI rilpivirine with emtricitabine and TAF, and the sofosbuvir/ledipasvir combination pill used to treat hepatitis C.

Using a P-glycoprotein (Pgp) inhibitor like ledipasvir with a Pgp substrate like TAF may be complicated by drug interactions, the researchers noted as background. Identifying such interactions is important because nearly a third of HIV-positive people are coinfected with hepatitis C and could benefit from simultaneous treatment for both viruses.

In 2 randomized crossover studies, 30 healthy volunteers received the elvitegravir TAF combo and 42 received the rilpivirine TAF combo, both taken alone or in combination with sofosbuvir/ledipasvir once-daily with food for 10 or 11 days. About 70% of the volunteers were men, two-thirds were white, and the average age was about 33 years.

The combined treatments were generally safe and well-tolerated; no one taking the elvitegravir TAF combo and 2 people taking the rilpivirine TAF combo discontinued due to adverse events. 

Sofosbuvir/ledipasvir did not affect tenofovir pharmacokinetics in the study using the elvitegravir TAF combo. Tenofovir exposure did increase when the rilpivirine TAF combo was taken with sofosbuvir/ledipasvir. However, it remained well below tenofovir levels when using TDF and the researchers considered the change "not clinically meaningful."

The elvitegravir TAF combo-- but not the rilpivirine TAF combo -- raised sofosbuvir and ledipasvir exposure, which was attributed to the effects of the pharmaco-enhancer cobicistat. Here too, levels remained within a safe range and the changes were not deemed clinically relevant.

The researchers concluded that "exposure of all agents [is] expected to be in a range associated with efficacy and safety," and "no dose adjustments [are] needed."

Based on favorable study finding to date, Gilead has requested U.S. and European regulatory approval of the elvitegravir/cobicistat/emtricitabine/TAF single-tablet regimen, and the Food and Drug Administration is scheduled to make a decision in November.

In addition, the company has also requested approval of the rilpivirine/emtricitabine/TAF coformulation, another TAF single-tablet regimen containing darunavir, and a dual coformulation of TAF and emtricitabine that would be a successor to Truvada. Stand-alone TAF is also being developed as a treatment for hepatitis B.

10/14/15

References

M Thompson, J Morales-Ramirez, C McDonald, et al.Switching from a Tenofovir Disoproxil Fumarate (TDF) to a Tenofovir Alafenamide (TAF)-Based Single Tablet Regimen (STR): Week 48 Data in HIV-1 Infected Virologically Suppressed Adults. Abstract 725.

G Huhn, P Tebas, J Gallant, et al. Strategic Simplification: The Efficacy and Safety of Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) plus Darunavir (DRV) in Treatment-Experienced HIV-1 infected Adults (NCT01968551). Abstract 726.

D Wohl, J Gathe, M Thompson, et al. Safety and Efficacy of TAF vs TDF Single-Tablet Regimen in HIV-1 Treatment-Naive Black and Nonblack Patients Through Week 48. Abstract 1073.

ES Daar, M Saag, B Trottier, et al. Influence of Age on Outcomes in HIV-Infected Adults Initiating Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate With Elvitegravir, Cobicistat, and Emtricitabine. Abstract 1074.

J Custodio, E Doyle, PS Pang, et al. Lack of Drug Interactions betweenBoosted and Unboosted Tenofovir Alafenamide-based Antiretroviral Single Tablet Regimens (Emtricitabine/Rilpivirine/Tenofovir Alafenamide and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) and the anti-HCV Single Tablet Regimen Ledipasvir/Sofosbuvir. Abstract 727.