Treatment-experienced HIV patients who switched to a tenofovir alafenamide-based regimen maintained virologic suppression and saw significant improvements in renal and bone safety, Healio reports that researchers say.
Tenofovir alafenamide (TAF), an investigational prodrug of tenofovir (TFV) coformulated with elvitegravir, cobicistat and emtricitabine (E/C/F/TAF), has demonstrated potent antiviral activity at approximately one-tenth the dose of the current TFV drug, Viread (tenofovir disoproxil fumarate, Gilead Sciences; TDF). Additionally, the reduced toxicity of TAF has made it an attractive option for treatment-experienced patients.
In one presentation, Dr Melanie Thompson, from the AIDS Research Consortium of Atlanta, discussed week 48 data from a study of virologically suppressed adults taking Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences; E/C/F/TDF) who switched to a single tablet of E/C/F/TAF. A subset of 459 virologically suppressed patients from a larger study were randomly assigned in a 2:1 ratio to receive open-label E/C/F/TAF or to remain on their TDF-based regimen. Thompson said baseline characteristics were similar between the two groups.
Results indicated patients who switched to E/C/F/TAF maintained high virologic control; 98% of those who made the switch and 97% of those who continued with E/C/F/TDF had HIV-1 RNA below 50 c/mL. No treatment-related serious adverse events were reported. Two patients discontinued treatment due to increases in serum creatinine; both of these patients belonged to the TDF arm. Additionally, “those who switched to TAF saw improvement in their kidney function, measured by serum creatinine and by urinary proteins, and they also saw improvement in bone density when they switched to TAF off of the TDF-containing regimen,” Thompson is quoted as saying.
Patients taking E/C/F/TAF had statistically significant increases in lipid levels since baseline, the clinical significance of which is still unclear, according to Thompson. Lipid-modifying medications were initiated by 7.8% of patients on a TAF-based regimen and 6.5% of patients on a TDF-based regimen.
According to Thompson, TAF delivers high levels of tenofovir directly into HIV target cells, yielding 91% lower plasma TFV levels compared with TDF. This may account for the improved safety profile of the drug. “I think what we’re seeing is that there is less circulating tenofovir, which is the active agent, in plasma, and so there is less bystander effect on these off-target organs like kidney and bone, but where we want tenofovir to be concentrated is in the lymphoid cells, and so that’s what TAF does,” she said.
The report says according to Gregory Huhn, infectious disease specialist at Mount Sinai Hospital, 135 patients on a DRV-containing regimen for at least 4 months with two prior treatment failures and resistance to at least two classes of drugs were randomly assigned to open-label E/C/F/TAF plus DRV (n = 89) or continued with their baseline regimen (BR). Huhn said baseline characteristics between the two groups were relatively well-balanced.
The median number of pills per regimen at study entry was 5, with 65% of patients taking a twice-daily regimen – a majority whom had been prescribed a TDF-based regimen. Viral suppression was maintained by week 24 in 97% of patients in the switch arm vs. 91% in the BR arm, with a proportional difference of 5.3% (95% CI, –3.4% to 17.4%). At week 48, 94% of patients who switched to a TAF-based regimen and 76% of BR patients maintained virologic control – a proportional difference of 18.3% (95% CI, 3.5% to 33%). “With these figures, statistical superiority was established in the switch arm,” Huhn said.
The researchers saw no evidence of the emergence of drug resistance in patients receiving E/C/F/TAF plus DRV. One participant with viral rebound developed resistance in the BR arm. There was a slightly higher adverse event rate in the switch arm (92% vs. 78%), “which may be due to the open-label study design in patients initiating a novel therapy,” Huhn said.
The researchers reported no serious drug-related adverse events, and no adverse events led to treatment discontinuation. Additionally, they saw no significant difference in the estimated glomerular filtration rate at week 48 with E/C/F/TAF plus DRV (+ 7.4 mL/min) vs. BR (+ 3.9 mL/min). TAF also was associated with greater treatment satisfaction among patients, the researchers said.
“For treatment-experienced individuals with two-class or greater resistance on complex, high-pill burden regimens, switching to E/C/F/TAF plus darunavir provides a simple, once-daily, two-pill option with superior efficacy and comparable tolerability,” Huhn concluded.
Background: TAF is a tenofovir (TFV) prodrug coformulated into a STR containing elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/TAF 10mg (E/C/F/TAF). . Week 48 data in adults on elvitegravir/cobicistat/emtricitabine/TDF (E/C/F/TDF) randomized to switch to a once-daily E/C/F/TAF regimen or to continue E/C/F/TDF are described.
Methods: GS-US-292-0109 is a study in virologically suppressed (HIV-1 RNA Results: At Week 48, 301/306 (98.4%) of those switched to E/C/F/TAF and 149/153 (97.4%) of those continuing E/C/F/TDF had HIV-1 RNA E/C/F/TAF patients had statistically higher changes from baseline in fasted lipid tests; the total cholesterol: HDL ratio change was: E/C/F/TAF, +0.2; E/C/F/TDF, +0.1 (p=0.48).
Conclusion: At Week 48, patients who switched from E/C/F/TDF to E/C/F/TAF remained on treatment and maintained high virologic control, had significantly improved hip/spine BMD, serum creatinine, and had significantly less general proteinuria and specific proximal tubular proteinuria than those remaining on E/C/F/TDF. Longer term data are needed to understand the clinical relevance of lipid changes in the TAF arm.
Strategic simplification of an antiretroviral regimen with high pill burden and dosing frequency is a priority for treatment-experienced patients with multi-drug resistance. A single tablet with co-formulated E/C/F/TAF has demonstrated high efficacy and improved renal and bone safety compared to E/C/F/TDF in Phase 3 clinical trials. This study evaluated the efficacy and safety of switching to E/C/F/TAF +DRV in patients with ≥ 2-class resistance, including TDF resistance mutations (K65R, ≤3 TAMs).
Virologically suppressed adults (N=135) on a DRV-containing regimen for ≥ 4months, with two prior failed regimens, and no history of Q151M, T69ins, or DRV RAMs, were randomized 2:1 to open-label E/C/F/TAF +DRV or to continue baseline regimen (BR). Week (W) 24 viral suppression (HIV-1 RNA <50c/mL) by FDA snapshot analysis and safety data are reported.
Participants were older (median age 49), 25% female, 45% black, and 14% Hispanic. At entry, the median pills/regimen was 5, with 65% taking a twice-daily regimen, and a majority (58%) on a TDF-containing regimen. Viral suppression was maintained in 96.6% (86/89) in the E/C/F/TAF +DRV arm and 91.3% (42/46) in the BR arm (95%CI: -3.4%, 17.4%). In the E/C/F/TAF +DRV arm, 2 patients had viremia at W24 but were suppressed at W36 and W48; 1 and 4 persons were missing data in the E/C/F/TAF +DRV and BR arms, respectively. There was no emergence of resistance. There were no differences in the median change in eGFR [2.5 in the E/C/F/TAF+DRV vs. -0.1mL/min in the BR arm (p=0.62)] or urine protein/creatinine (Cr) ratio [-14% in the E/C/F/TAF +DRV arm vs. -4% in BR arm (p=0.21)]. Specific markers of proximal tubular proteinuria improved with E/C/F/TAF +DRV: median urine beta-2M/Cr decreased 35% (p<.001) and median urine RBP/Cr decreased 17% (p=.019), compared to increases of 11% and 13% respectively in the BR arm. There were no drug-related SAEs and no AEs leading to treatment discontinuation.
Through W24, strategic simplification to E/C/F/TAF + DRV (two pills once daily) maintained viral suppression, and the switch to TAF was associated with significant improvement in proximal tubular proteinuria. E/C/F/TAF +DRV may offer an attractive option for treatment-experienced patients on complex multi-tablet regimens.
Objective: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug.
Design: A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study.
Methods: Treatment-naive and experienced HIV-1–positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days.
Results: Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08–1.73 log10 copies per milliliter, including a dose–response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration–time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF.
Conclusions: Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.