Switching Tenofovir/Emtricitabine plus Lopinavir/r to Raltegravir plus Darunavir/r in Patients with Suppressed Viral Load Did Not Result in Improvement of Renal Function but Could Sustain Viral Suppression: A Randomized Multicenter Trial

<div><p>Background</p><p>Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load.</p> <p>Methods</p><p>This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation.</p> <p>Results</p><p>58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD).</p> <p>Conclusions</p><p>Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load.</p> <p>Trial Registration</p><p><a href="http://clinicaltrials.gov" target="_blank">ClinicalTrials.gov</a> NCT01294761 <a href="http://clinicaltrials.gov/ct2/show/nct01294761?term=spare&rank=2" target="_blank"><u>http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2</u></a>, Umin Clinical Trials Registry UMIN000005116 <a href="http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=r000006083&language=j" target="_blank"><u>http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J</u></a>)</p> </div

Median changes in markers of renal tubular function between baseline and 48 weeks.

<p>(A) Urinary β2 microglobulin, (B) Urinary albumin, (C) Percent tubular resorption of phosphate, (D) Urinary N-acetyl-β-D-glucosaminidase. RAL, raltegravir; DRV/r, ritonavir-boosted darunavir; LPV/r, ritonavir-boosted lopinavir; TVD, fixed dose of tenofovir/emtricitabine.</p

Proportion of patients with HIV RNA <50 copies/ml at 24 and 48 weeks.

<p>(A) Per protocol analysis. (B) Intention-to-treat analysis. VL, viral load; RAL, raltegravir; DRV/r, ritonavir-boosted darunavir; LPV/r, ritonavir-boosted lopinavir; TVD, fixed dose of tenofovir/emtricitabine.</p