Tenofovir alafenamide shows similar anti-hepatitis B activity with less kidney toxicity

A new formulation of tenofovir that can be taken at lower doses demonstrated potent activity against hepatitis B virus (HBV) similar to that of the existing formulation in a 28-day study, but with less effect on kidney function, according to a poster presented at The Liver Meeting 2013, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD), recently held in Washington, DC.

Gilead Science's tenofovir disoproxil fumarate (TDF; Viread) – the currently marketed formulation – is one of the most effective antiviral drugs for hepatitis B as well as one of the most widely used antiretrovirals for HIV. TDF is generally safe and well-tolerated, but it can cause kidney toxicity in susceptible individuals and is also associated with bone loss.

A new pro-drug formulation known as tenofovir alafenamide (TAF; formerly GS-7340) produces five-fold higher concentrations of active tenofovir diphosphate in lymphoid cells that harbour HIV, but is more stable in plasma and results in lower blood drug levels and systemic exposures than those seen with TDF. This allows for reduced dosing with potentially less detrimental effect on the kidneys and bones.

Researchers recently reported that a 10mg dose of TAF is as effective against HIV as a 300mg dose of TDF through 48 weeks in a phase 2 study, but the former has less impact on markers of kidney function and bone mineral density.

TAF also leads to higher levels of active tenofovir in hepatocytes (liver cells). At the Liver Meeting, Josh Agarwal from Kings College Hospital in London and colleagues reported findings from a study comparing TAF versus TDF for the treatment of chronic HBV infection.

This open-label phase 1b study enrolled 51 people with chronic hepatitis B who had HBV DNA levels of at least 2000 IU/ml. Most participants were men, about 60% were Asian, about 30% were black and approximately half were hepatitis B 'e' antigen negative. At baseline they had ALT levels within 10 time the upper limit of normal and creatine clearance >70 ml/min.

Participants were randomly allocated to equal-sized arms receiving TAF at doses of 8, 25, 40 or 120mg, or TDF at a dose of 300mg, for 28 days, with four weeks of post-treatment follow-up.

HBV DNA declines over 28 days were similar across all TAF dose groups, and comparable to that seen with TDF (approximately -2.5 log IU/ml). TAF pharmacokinetics, including maximum plasma concentration and area under the curve, were dose-proportional.

Overall tenofovir exposure (relative to TDF) was reduced by 97%, 92%, 81% and 33%, respectively, using TAF doses of 8, 25, 40 and 120mg. TAF doses of 25mg or lower reduced systemic tenofovir exposures to less than 8% of levels produced by 300mg TDF.

TAF was generally safe and well-tolerated over 28 days. Adverse events were generally mild to moderate and were not dose-related. No participants experienced serious adverse events or discontinued therapy for this reason. Five people who received 40 or 120mg TAF experienced grade 3-4 laboratory abnormalities, as did one person who received TDF.

No participants experienced kidney-related adverse events including creatinine increases >0.5 mg/dl from baseline, phosphorus levels <2 mg/dl or creatinine clearance <50 ml/min. TAF was associated with smaller decreases in creatine clearance than those seen with TDF; the lowest decline at 29 days was -2.0 ml/min with 25mg TAF compared to -10.4 ml/min with 300mg TDF.

"Over a 28-day dosing period, TAF was safe and well tolerated in patients with chronic HBV," the researchers concluded. "The antiviral activity of TAF did not vary by dose and was comparable to TDF."

Further clinical trials of TAF for chronic hepatitis B are planned using a selected dose of 25mg.