After three years, tenofovir alafenamide (TAF) for first-line HIV treatment was better at suppressing viral load and safer for the bones and kidneys than the older tenofovir disoproxil fumarate (TDF), researchers reported at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle. Another study showed that people with low bone density who switched from TDF to TAF saw improved bone health, including a reduction in osteoporosis.
Gilead Sciences' TDF (Viread, also in the Truvada, Atripla, Eviplera and Stribild co-formulations) has been one of the most widely used antiretroviral drugs. It is generally considered safe and well-tolerated, but it can cause kidney toxicity in susceptible individuals and bone loss soon after starting treatment.
TAF (part of the Descovy, Genvoya and Odefsey co-formulations) is a pro-drug that delivers its active agent more efficiently to HIV-infected cells. TAF produces adequate intracellular levels with much lower doses, which means lower concentrations in the blood plasma and less drug exposure for the kidneys, bones, and other organs and tissues.
At CROI 2015 researchers presented 48-week results from a pair of phase 3 studies comparing single-tablet regimens containing TAF and TDF used for initial antiretroviral therapy. At this year's meeting Jose Arribas of La Paz University Hospital in Madrid, Spain, gave an update with 144-week data.
Study 104 and Study 111 together included 1,733 previously untreated people; most were men and the median age was 34 years. They had well-controlled HIV disease with a median CD4 T-cell count of approximately 400 cells/mm3 and normal kidney function with a median estimated glomerular filtration rate (eGFR) of approximately 115 ml/min. Participants were randomly assigned to start a once-daily single-tablet regimen containing elvitegravir, cobicistat and emtricitabine with either 25mg TAF or 300mg TDF (Genvoya or Stribild).
At 48 weeks 92% of people in the TAF arm and 90% in the TDF arm achieved HIV RNA < 50 copies/ml, showing that TAF was non-inferior to TDF.
At 144 weeks the viral suppression rates were 84% and 80%, respectively, and at this point the TAF regimen was statistically superior to the TDF combo. Twelve participants (1.4%) in each arm experienced virological failure with drug resistance.
The 48-week data showed that overall drug safety profiles were similar in both arms, with few participants discontinuing treatment due to adverse events (8 on TAF and 13 on TDF). But while most discontinuations for this reason happened early in the TAF arm, they continued to occur over time in the TDF arm, so by week 144 there was a significant difference in favour of TAF.
Most notably, there were 12 kidney-related events leading to discontinuation – including four cases of renal tubulopathy – in the TDF arm but none in the TAF arm. Likewise, six people in the TDF arm but none in the TAF arm stopped early due to bone-related events. Changes in renal biomarkers were significantly smaller and there was significantly less hip and spine bone loss in the TAF arm. Fasting lipids increased more among people on TAF, however.
"These longer-term data support the use of elvitegravir/cobicistat/emtricitabine/TAF as a safe, well tolerated and durable regimen for initial and on-going HIV-1 treatment," the researchers concluded.
In addition to its benefits for first-line therapy, studies have also shown better outcomes when people on antiretroviral therapy with undetectable viral load switch from TDF to TAF. In 2015 researchers reported 48-week results from Gilead’s Study 109, a phase 3 trial in which people with viral suppression on a TDF-containing regimen either stayed on the same therapy or switched to the Genvoya TAF regimen. This study included 1,436 participants, mostly men, with a median age of about 41 years, median CD4 count of approximately 670 cells/mm3 and a median eGFR of about 106 ml/min.
After 48 weeks 97% of people who switched to the TAF co-formulation had undetectable viral load compared with 93% of those who stayed on their existing regimen – a significant difference in favour of TAF. People who switched to TAF experienced improvements in kidney function biomarkers while those who stayed on TDF worsened, and those in the TAF arm were less likely to discontinue therapy due to kidney-related adverse events.
In the overall study population spine bone mineral density (BMD) rose by a mean of +1.79% in the TAF arm but fell by -0.28% in the TDF arm; the corresponding changes in hip BMD were +1.37% and -0.26%, with both differences being statistically significant. People who switched to TAF saw significant reductions in osteoporosis (brittle bones) and osteopenia (milder bone loss).
At CROI Todd Brown of Johns Hopkins University presented 96-week bone data from participants who started with low bone density in Study 109 and Study 112, a single-arm, non-randomised study in which participants made the same TDF to TAF regimen switch.
Of the 1,117 total participants in the two trials, 214 (19%) had low BMD at baseline, based on comparison with norms of a population of the same sex and age. Low BMD was defined as having a T-score < -2.0 at the lumbar spine, total hip or femoral neck (narrow part of the hip joint); 43% had T-scores < -2.5, indicating osteoporosis. Most (85%) were men and the median age was 46 years. Two-thirds had normal body weight, a quarter were smokers and half used protease inhibitors – factors also associated with bone health.
The researchers analysed BMD changes according to DEXA scans, changes in T-scores, proportion with osteopenia or osteoporosis, and bone turnover biomarkers including procollagen 1 intact N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX).
At 96 weeks after switching from TDF to TAF, BMD increased by about 2.5% at both the lumbar spine and total hip. Over a quarter of participants (27%) experienced at least a 5% increase in spine bone density and 16% had at least a 5% gain at the hip. Among 86 participants who started with osteoporosis, 23% no longer met the criteria at week 96, though they still had osteopenia.
People with excessive phosphate excretion in the urine and higher bone turnover biomarkers were more likely to experience at least a 5% increase in BMD. People with lower hip BMD at baseline saw larger gains, though this was not the case for the spine.
"Switching from TDF to TAF may be an important treatment strategy to increase bone mineral density in those at the highest fracture risk," the researchers concluded. "Baseline urinary phosphate wasting or high bone turnover may identify TDF-treated HIV-infected patients with low BMD who may benefit the most from a switch to TAF."
Abstract 453
Two randomized, controlled, double-blinded multinational Phase 3 trials compared tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each in single-tablet regimens coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At Week (W) 48, E/C/F/TAF was statistically noninferior to E/C/F/TDF for the proportion of subjects with HIV-1 RNA ARV naïve participants randomized 1:1 to receive E/C/F/TAF (TAF) or E/C/F/TDF (TDF). W144 viral suppression (HIV-1 RNA 100,000 c/mL. Median baseline characteristics: age 34 yrs, CD4 count 405 cells/µL, and VL 4.58 log10 c/mL. At W144, TAF met prespecified criteria for both noninferiority and superiority to TDF by FDA snapshot algorithm (HIV-1 RNA Through W144, participants on E/C/F/TAF had a significantly higher rate of virologic suppression (
Authors
Jose R Arribas, Melanie Thompson, Paul E Sax, Bernhard Haas, Cheryl McDonald, David Wohl, Edwin DeJesus, Amanda Clarke, Moupali Das, Scott McCallister
Abstract 683
Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) may represent an important treatment strategy to improve bone health in HIV-infected individuals with low bone mineral density (BMD), but this has not been specifically investigated.
This analysis consisted of pooled data from two prospective Phase 3 studies (Studies 109 and 112) of HIV suppressed adults on a TDF-based regimen switching to elvitegravir, cobicistat, and emtricitabine (E/C/F) co-formulated with TAF. In adults with clinically significant low BMD by dual energy x-ray absorptiometry (T-score ≤ -2.0 at the lumbar spine, femoral neck, or total hip) at baseline (BL), we assessed percentage change in BMD and T-score at the lumbar spine and total hip and change in proportion with osteoporosis (T-score ≤ -2.5 at any site) at Weeks (W) 96. Logistic regression was used to determine BL predictors of a clinically significant improvement (≥ 5% increase) in lumbar spine and total hip BMD, adjusted for age, race, sex, and BL BMD.
Of the 1117 enrolled who switched from TDF to TAF, 214 (19%) had clinically significant low BMD at BL (median age 46 years, 85% male, 63% White, 26% smokers) with 43% (93/214) osteoporosis. The BL median (interquartile range: Q1, Q3) T-score (lowest of any 3 sites) was -2.4 (-2.8, -2.2). At the spine, the median (Q1, Q3) % BMD change at W96 was 2.53% (0.22%, 5.31%) and T-score change was 0.19 (0.02, 0.42) (all p<0.001). At total hip, BMD change at W96 was 2.39% (0.72%, 4.18%) and T-score change was 0.14 (0.04, 0.24) (all p<0.001). Of the 86 with BL osteoporosis and W96 BMD data, 23% no longer met criteria for osteoporosis at W96. Of 214 with low BMD, 24% and 15% had a clinically significant BMD increase at the spine and total hip, respectively. In multivariable analysis, BL factors associated with clinically significant BMD increase at W96 were higher fraction excretion of phosphate (FEPO4 ≥ 10%) for the hip and higher BMI (≥30 kg/m2) and procollagen type 1 N-terminal propeptide (P1NP >1.85 log10 ng/mL) levels for spine.
HIV-infected individuals with clinically significant low BMD on a TDF-based regimen who switched to E/C/F/TAF experience a ~2.5% BMD increase over 96 weeks and a reversion from osteoporosis in approximately 1/4 of patients. Baseline urinary phosphate wasting and high bone turnover may identify TDF-treated HIV-infected patients with low BMD who may benefit the most from a switch to TAF.
Authors
Todd Brown, Michael T Yin, Samir Gupta, Christine Katlama, Adriano Lazzarin, Kathy Melbourne, Calvin Cohen, YaPei Liu, Thai Nguyen-Cleary, Scott McCallister
[link url="http://www.aidsmap.com/Bone-density-improves-in-people-who-switch-from-tenofovir-DF-to-tenofovir-alafenamide/page/3125628/"]Aidsmap material[/link]
[link url="http://www.croiconference.org/sessions/significant-efficacy-long-term-safety-difference-taf-based-str-na%C3%AFve-adults"]CROI 2017 abstract 453[/link]
[link url="http://www.croiconference.org/sessions/switching-tdf-taf-hiv-infected-adults-low-bmd-pooled-analysis"]CROI 2017 abstract 683[/link]