www.hivandhepatitis.com

ICAAC 2014: New Tenofovir Alafenamide Combo Pill Has Less Effect on Kidneys and Bones

An experimental single-tablet regimen containing a new version of tenofovir (tenofovir alafenamide or TAF) and the HIV protease inhibitor darunavir (Prezista) worked as well as a similar regimen containing the older tenofovir disoproxil fumarate (TDF) formulation,but it had less detrimental effects on kidney function and bone density, according to a study presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Washington, DC.

Tenofovir disoproxil fumarate (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs. It is highly effective and generally regarded as safe and well-tolerated, but it can cause kidney toxicity in susceptible individuals and is associated with bone loss soon after starting treatment.

TAF, being developed by Gilead Sciences, is a new formulation designed to produce higher levels of the active tenofovir diphosphate in HIV-infected cells. This allows for lower dosing that leads to reduced drug levels in blood plasma and less drug exposure for the kidneys and bones. A better-tolerated formulation of tenofovir could be particularly useful in light of the different risk-benefit calculation for HIV negative people using it for pre-exposure prophylaxis, or PrEP.

Anthony Mills of the Southern California Men's Medical Group presented the latest data from a Phase 2 study (GS-US-292-0102) evaluating a once-daily coformulation containing darunavir (800 mg) boosted with cobicistat (150 mg), TAF (10 mg), and emtricitabine (200 mg). None of the existing single-tablet regimens include an HIV protease inhibitor, an antiretroviral class with a high barrier to drug resistance.

This double-blind, placebo-controlled trial included 150 previously untreated people with HIV who were randomly assigned to receive the new TAF-containing single tablet regimen, or a regimen containing 4 daily pills: darunavir 400 mg twice-daily, cobicistat 150 mg once-daily, and Truvada (TDF 300 mg + emtricitabine 200 mg) once-daily.

To enable blinding, participants were randomized to receive either the active single-tablet regimen and placebos matching the 4-pill regimen, or else the active 4-pill regimen and a placebo matching the single-tablet regimen. That is, everyone took 5 pills daily, thus eliminating any convenience advantage of the single-tablet regimen.

More than 90% of participants were men, 60% were white, 35% were black, the median age was about 35 years, and none had hepatitis B or C coinfection. The median baseline CD4 T-cell count was approximately 400 cells/mm³. By chance, about half as many people taking the single-tablet regimen had <200 cells/mm³, but this group was more likely to have high HV viral load. The study required participants to have normal kidney function at baseline with an estimated glomerular filtration rate (eGFR) of >70 mL/min (median approximately 112 mL/min).

Results

• At 24 weeks, 75% of people taking the TAF single-tablet regimen and 74% taking the TDF 4-pill regimen had undetectable HIV RNA <50 copies/mL.
• 24-week virological failure rates were 20% and 24%, respectively.
• At 48 weeks, response rates had risen to 77% for the single-tablet regimen and 84% for the 4-pill regimen.
• 48-week virological failure rates were 16% and 12%, respectively.
• No participants with virological failure in either treatment group showed evidence of drug resistance.
• Levels of tenofovir diphosphate in peripheral blood mononuclear cells were 6.5 times higher in the TAF single-tablet regimen group compared with the TDF 4-pill regimen group.
• Conversely, plasma tenofovir levels were 91% lower with TAF compared with TDF.
• The TAF single-tablet regimen and the TDF 4-pill regimen were both generally safe and well-tolerated.
• Early discontinuation rates were similar in the 2 treatment groups (18% and 16%, respectively), with loss to follow-up and withdrawal of consent being the most common reasons.
• 2 people in each treatment group stopped early due to adverse events.
• The most common adverse events were diarrhea, fatigue, upper respiratory infections, nausea, and rash, occurring at similar rates in both treatment groups.
• Participants taking TAF showed less overall effect on kidney function than those taking TDF:

o   Serum creatinine mean change at week 48: +0.06 vs +0.09, respectively;

o   2 markers of protein in the urine (retinol binding protein/creatinine ratio and betamicroglobulin/creatinine ratio) favored TAF over TDF;

o   No differences were observed in other kidney parameters including dipstick proteinuria or excretion of phosphate or uric acid;

o   1 person receiving TDF stopped treatment early due to proximal renal tubulopathy.

• TAF also had less effect on bone mineral density (BMD) at 48 weeks as measured by DEXA scans:

o   Hip BMD decrease: -0.84 with TAF vs -3.82 with TDF;

o   Spine BMD decrease: -1.57 vs -3.62, respectively;

o   Hip BMD decrease >3%: 18% with TAF vs 62% with TDF;

o   Spine BMD decrease >3%: 33% vs 55%, respectively.

o   Hip BMD increase >3%: 5% vs 0%, respectively;

o   Spine BMD increase >3%: 11% vs 2%, respectively;

o   No bone fractures occurred in either treatment group.

• Levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were significantly higher in TAF recipients compared with TDF recipients (thought to occur because the lipid-lowering effect of tenofovir was not as great at lower plasma concentrations).

"Viral suppression rates were comparable" with the TAF-containing single-tablet regimen and the TDF-containing 4-pill regimen, the researchers concluded. "Both treatments were well tolerated with similarly low rates of adverse event-related discontinuation."

"With TAF’s potential improved renal and bone profile, along with darunavir's high resistance barrier,
a Phase 3 study of the [darunavir/cobicistat/TAF/emtricitabine] single-tablet regimen is warranted," they advised.

9/9/14

Reference

A Mills, R Ortiz, G Crofoot, et al. 48 Week Study of the First PI-based Single Tablet-Regimen (STR) Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) vs. Cobicistat (COBI)-boosted Darunavir (DRV) and Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) in Treatment-naive (TN) Adults. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-647c.