Tenofovir alafenamide (TAF), a new
formulation that produces higher drug levels in cells but allows for lower
dosing, was as effective as the current tenofovir disoproxil fumarate (TDF)
formulation, but had less impact on markers of kidney function and bone
turnover, researchers reported yesterday at the 53rd Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC) in Denver.
Tenofovir (Viread, also in the
Truvada, Atripla, Eviplera and Stribild coformulations) is one of the
most widely used antiretroviral drugs. It is highly effective and generally
regarded as safe and well-tolerated. However, it can cause kidney toxicity in
susceptible individuals and is associated with bone loss that begins soon after
starting treatment. The long-term consequences of these side-effects are a
growing concern in light of guidelines recommending earlier treatment initiation
and expanding use of Truvada for
pre-exposure prophylaxis (PrEP).
Gilead Sciences' new TAF formulation produces fivefold higher
concentrations of active tenofovir diphosphate in cells that harbour HIV, but
drug levels in the blood remain much lower compared with TDF. This enables
reduced dosing that is expected to have a less detrimental effect on the kidneys
Paul Sax from Brigham and Women's Hospital in Boston presented
late-breaking results from a phase 2 study comparing TAF at 10mg and TDF at
300mg, both as part of a single-tablet regimen that also includes the integrase
inhibitor elvitegravir, cobicistat (a pharmacoenhancer or 'booster') and
FTC (emtricitabine). The TDF-containing coformulation is marketed as Stribild; the TAF version is not yet
This double-blind, placebo-controlled trial included 170 previously
untreated people with HIV who were randomly assigned (2:1) to receive the TAF
or TDF coformulations once-daily for 48 weeks.
Almost all participants were men, more than two-thirds were white,
nearly one-third were black and the median age was about 35 years. The median baseline
CD4 cell count was about 390 cells/mm3 (though about 15% had less
than 200 cells/mm3) and the median viral load was approximately
40,000 copies/ml. At study entry participants had normal kidney function, with a median
estimated glomerular filtration rate (eGFR) of 115 ml/min. People with
hepatitis B or C co-infection were excluded.
At this year's Conference on Retroviruses and Opportunistic Infections (CROI 2013), Andrew Zolopa reported 24-week
interim data from the study, showing that 87% of people taking the TAF
coformulation achieved HIV RNA below 50 copies/ml compared with 90% of those
The 48-week response data presented at ICAAC showed little change: 88.4%
of people in the TAF arm and 87.9% in the TDF arm achieved undetectable viral
load in an intent-to-treat 'snapshot' analysis (90.2 vs 89.7%, respectively,
in a missing=failure analysis). CD4 cell gains at 48 weeks were 177 and 204
cells/mm3, respectively. None of these differences were statistically
More Stribild recipients
discontinued due to lack of efficacy (3.4% vs none), but more TAF recipients
stopped early due to adverse events (3.6% vs none) or had missing 48-week data
(5.4 vs 1.7%).
A total of six participants – three in each arm – who experienced
virological failure underwent resistance testing. No one in the TAF arm
developed resistance, but two people taking Stribild
showed double resistance mutations.
A total of 26 patients participated in a pharmacokinetic sub-study. The
TAF coformulation produced trough (minimum) and area under the curve (total)
tenofovir plasma concentrations of 11 ng/ml and 326 ng*hr/ml, respectively,
compared with 83 ng/ml and 3795 ng*hr/ml with Stribild. Overall plasma exposure was 91% lower with TAF.
Conversely, tenofovir diphosphate exposure in peripheral blood mononuclear cells
was 5.3-fold lower with TDF than with TAF.
The TAF and TDF coformulations were both generally safe and well-tolerated,
with most side-effects being mild or moderate. Most adverse events occurred at
similar rates in both groups, but nausea was nearly twice as common in the TAF
arm (21 vs 12%). There
were no treatment-related serious adverse events in either arm.
Laboratory abnormalities were also generally comparable in the two
treatment arms. However, more people in the TAF arm had abnormally high
low-density lipoprotein (LDL or 'bad cholesterol'). Sax explained that
tenofovir has a lipid-lowering effect in the blood, but this didn't happen to
the same extent with TAF because its plasma concentration is so much lower.
Turning to kidney function, there was less change in eGFR over time in
the TAF coformulation arm compared with the Stribild
arm (-5.5 and -10.0, respectively). Other indicators of kidney function
including protein in the urine (2.7 vs 5.2%), changes in serum creatinine
(0.9 vs 3.4%) and two exploratory urine markers of proximal renal tubulopathy (retinol
binding protein/creatinine ratio and beta microglobulin/creatinine ratio) also
favoured the TAF coformulation.
Kidney biomarker changes have been attributed to cobicistat inhibiting
renal tubule secretion, Sax noted. But it is not clear why this effect is smaller
with TAF than with TDF, since the cobicistat dose in the two coformulations is
the same. No cases
of renal tubulopathy were seen in either arm and nor did anyone discontinue
therapy due to kidney-related side-effects.
Looking at bone loss, bone mineral density, as measured by DEXA scans taken
at 24 and 48 weeks, decreased less in the TAF arm than in the TDF arm at both
the spine (-1.00 vs -3.37) and the hip (-0.62 vs -2.39). Furthermore, one-third
of participants taking the TAF coformulation experienced no change in hip bone
density compared with just 7% in the Stribild
arm. Biomarkers of bone resorption and bone formation favoured TAF over TDF (procollagen type 1 N-terminal
propeptide: 109 vs 169%; C-terminal telopeptide: 119 vs 178%). No fragility
fractures occurred in either arm of the study.
A related poster presentation showed that TAF did not lead to
unexpectedly high concentrations of tenofovir in bone-forming cells known as
primary osteoblasts, and it did not have a cytotoxic (cell-killing) effect on
these cells at clinically relevant concentrations in a laboratory study.
Treatment-naive participants taking the TAF coformulation had high levels of
viral suppression over 48 weeks, comparable to those seen with Stribild, the researchers summarised. But people taking the TAF coformulation had a smaller decrease in eGFR and significantly smaller decreases in
bone mineral density of the hip and spine.
that phase 3 studies are underway and researchers are making an
"aggressive attempt" to enrol more women.