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Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults
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Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice - (09/10/21)
Abstract
JAIDS 2017 - François Raffi, MD, PhD,*Chloe Orkin, MD,Amanda Clarke, MD,‡Laurence Slama, MD,Joel Gallant, MD, MPH,kEric Daar, MD, Keith Henry, MD,# Jorge Santana-Bagur, MD,**David K. Stein, MD,Nicholaos Bellos, MD,‡‡Anthony Scarsella, MD, Mingjin Yan, PhD,kkMichael E. Abram, PhD,kkAndrew Cheng, MD, PhD,kkand Martin S. Rhee, MDkk
In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent).
At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies per milliliter [adjusted difference -0.5% (95% confidence interval: -5.3 to 4.4%)].
Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well-tolerated, and durable nucleotide reverse transcriptase inhibitor backbone.
INTRODUCTION
Although tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is a potent and generally well-tolerated nucleotide analog, it has been associated with an increased risk of nephrotoxicity and greater reductions in bone mineral density (BMD) compared with other nucleotide reverse transcriptase inhibitors.1–6 Tenofovir alafenamide (TAF) is a novel TFV prodrug that is associated with 91% lower plasma TFV levels compared with TDF,7 which leads to less adverse impact on bone and kidneys.8,9 Recent HIV treatment guidelines have either replaced TDF with TAF or include both as part of recommended initial regimens.10,11
In this large, double-blind, multicenter trial, we compared the switch to fixed-dose emtricitabine (FTC) with TAF versus continued use of fixed-dose FTC with TDF in virologically suppressed HIV-infected patients (ClinicalTrials.gov number NCT02121795). Results from week 48 were previously reported and demonstrated that switching to FTC/TAF was noninferior to continued use of FTC/TDF while remaining on the same third agent in maintaining viral suppression and led to improvements in markers of bone and renal safety.12 We present safety and efficacy data through 96 weeks, with a focus on outcomes depending on third agent.
Study Design and Participants
The design and inclusion criteria of this randomized, double-blind, multicenter, active-controlled phase 3 trial have been previously described.12 Briefly, we enrolled HIV-infected adults (aged ≥18 years) who were virologically suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months on regimens containing fixed-dose FTC with TDF and had estimated glomerular filtration rate (eGFR) >50 mL/min (calculated by the Cockcroft–Gault equation). Eligible participants were randomized (1:1) to either switch to coformulated FTC/TAF or to continue FTC/TDF without changing their third agents. Participants on boosted protease inhibitors (PIs) (atazanavir, darunavir, and lopinavir all boosted with ritonavir) who were randomly assigned to switch treatment received coformulated 200 mg FTC with 10 mg TAF; those on other third agents received coformulated 200 mg FTC with 25 mg TAF.
Participants also received placebo tablets matching the alternative treatment. The study remained blinded until the last participant receiving study drug completed week 96.
RESULTS
We noted increases from baseline in eGFR for participants who switched to FTC/TAF, mostly occurring in the first 24 weeks, as compared with minimal changes among those who remained on an FTC/TDF regimen (10.0 vs. 4.0 mL/min). We observed significant differences between groups favoring FTC/TAF in changes of total proteinuria, albuminuria, and tubular proteinuria (urine retinol-binding protein/creatinine ratio and urine β2-microglobulin/creatinine ratio) (Fig. 1). Of note, in the FTC/TDF group, albuminuria and tubular proteinuria continued to worsen in the second year. Improvement of these markers of renal safety in the FTC/TAF group was similar regardless of third agent (Table 1). No participants in the FTC/TAF group and 2 in the FTC/TDF group discontinued study drug because of renal AEs. One participant with underlying hypertension on FTC/TDF plus ritonavir-boosted darunavir had an increase in serum creatinine that led to discontinuation of study drug. The second participant on FTC/TDF plus ritonavir-boosted atazanavir had laboratory findings consistent with proximal tubulopathy (proteinuria, normoglycemic glycosuria, hypophosphatemia, and an increase in serum creatinine). No cases of proximal tubulopathy or Fanconi syndrome were reported in the FTC/TAF group.
From baseline to week 96, BMD increased in the FTC/TAF group but not in the FTC/TDF group [median change: hip 1.78% vs. -0.17% (P < 0.001) and spine 1.85% vs. -0.33% (P < 0.001)] (Fig. 1). Of note, in the FTC/TAF group, BMD continued to increase in the second year. Results were similar regardless of third agent (Table 1). More participants in the FTC/TAF group had increase in BMD of at least 3% [spine 40% vs. 18% (P < 0.001) and hip 29% vs. 11% (P < 0.001)]. There were 4 fractures (1 on FTC/TAF and 3 on FTC/TDF), all related to mechanical trauma and considered by the investigator to be unrelated to study drug.
The incidence of laboratory abnormalities through week 96 was similar for both treatment groups. Fasting lipid values increased from baseline in the FTC/TAF group while remaining stable in the FTC/TDF group at week 96 [total cholesterol, FTC/TAF 14 vs. FTC/TDF 1 mg/dL, P < 0.001; low-density lipoprotein 14 vs. 4 mg/dL, P < 0.001; high-density lipoprotein (HDL) 1 vs. -1 mg/dL, P = 0.023]; however, median changes were minimal from a clinical standpoint and the median changes in total cholesterol to HDL ratio were similar (0.1 vs. 0.1; P = 0.26). The rate of initiating lipid-modifying medications was similar between the groups at week 96 (FTC/TAF 7.2%, FTC/TDF 6.4%, P = 0.76).
DISCUSSION
Our findings demonstrated that switching to FTC/TAF was noninferior to continuing FTC/TDF in maintaining virological suppression at 96 weeks in individuals with HIV receiving a large variety of third agents. Although overall safety was similar, renal parameters improved in patients who switched to FTC/TAF, with an increase in eGFR and a reduction in proteinuria, especially in the excretion of β2-microglobulin and retinol-binding protein, which are considered specific markers of proximal tubulopathy.15 BMD also improved in patients who switched, and changes were significantly greater in the FTC/TAF group at 96 weeks, with a greater likelihood of improvement in clinical bone density status (osteoporosis, osteopenia, or normal). The efficacy and safety results, including those of bone and renal, did not differ by third agent; particularly, improvement was also seen in patients receiving a ritonavir-boosted PI.
The results for the markers of renal safety were consistent with recent data from studies comparing TAF vs. TDF as part of 2 single-tablet regimens also containing elvitegravir, cobicistat, and FTC (E/C/F/TAF vs. E/C/F/TDF). Importantly, these data corroborate the clinical data, as there were no renal discontinuations or proximal renal tubulopathy in patients receiving FTC/TAF in this study (n = 333) nor in treatment-naive patients receiving E/C/F/TAF (n = 866) through week 96.16 By contrast, 2 patients receiving FTC/TDF in this study and 6 receiving E/C/F/TDF in the treatment-naive study16 had renal discontinuations; 1 in each group had proximal renal tubulopathy. The BMD results are also reassuring in their consistency with those from E/C/F/TAF studies. One interesting aspect is the fact that there is continuous improvement over the 96-week period, with no plateau effect, and the BMD increase by week 96 (around + 2% for both hip and spine) is clinically important in this population of patients with a median previous exposure to TDF of over 5 years.
Lipids increased in the FTC/TAF group while remaining stable in the FTC/TDF group. Because TDF is associated with lower lipids, it is likely that lower TFV exposures through switching TDF to TAF is leading to increase in lipids.17–20 However, no differences in total cholesterol to HDL ratio or initiation of lipid-modifying medications were noted between groups, suggesting that the increases in lipids on switching to FTC/TDF from FTC/TDF are probably of minimal clinical relevance.
FTC/TAF is now part of recommended initial regimens in treatment guidelines; E/C/F/TAF is also one of the recommended initial regimens.10,11 In addition, FTC/TAF is available as part of rilpivirine/FTC/TAF and is being developed as part of darunavir/COBI/FTC/TAF and bictegravir/FTC/TAF. In addition, FTC/TAF uniquely provides clinicians with the flexibility to combine with other agents that are not part of currently available single-tablet regimens. Lastly, FTC/TAF is also being developed for preexposure prophylaxis of HIV infection.
The longer-term data in this study confirm the potential of FTC/TAF to be an important nucleotide reverse transcriptase inhibitor backbone in the treatment of patients with HIV, with the flexibility to be combined with a variety of third agents and safety advantages over FTC/TDF. In patients exposed to FTC/TDF for many years, who represent a large majority of patients with HIV currently in care, and in those who are aging with potential for renal and or bone comorbidities from various causes, proactive switching from FTC/TDF to FTC/TAF can improve renal and bone parameters, while maintaining antiviral efficacy.
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