Brief Report: Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Adults With Renal Impairment: 96-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study

Frank A Post, Pablo Tebas, Amanda Clarke, Laurent Cotte, William R Short, Michael E Abram, Shuping Jiang, Andrew Cheng, Moupali Das, Marshall W Fordyce, Frank A Post, Pablo Tebas, Amanda Clarke, Laurent Cotte, William R Short, Michael E Abram, Shuping Jiang, Andrew Cheng, Moupali Das, Marshall W Fordyce

Abstract

Tenofovir disoproxil fumarate is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30-69 mL/min who switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001), and significant increases in hip and spine bone mineral density through 96 weeks (P < 0.001). Eighty-eight percent maintained HIV-1 RNA <50 c/mL at week 96. These longer-term results support the use of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in HIV-infected individuals with mild-moderately impaired renal function.

Conflict of interest statement

F.A.P. reports receiving research grant to institution from Gilead and ViiV, and personal fees from Gilead, ViiV, Janssen, MSD, and Abbvie. P.T. reports receiving consulting fees from Merck and research grant to institution for Gilead trials and has serve on adjudication committee for GlaxoSmithKline. L.C. has received research grants from MSD, and ViiV; personal fees from Mylan; and nonfinancial support from MSD, ViiV, Janssen, Gilead, and BMS. M.E.A., S.J., A. Cheng, M.D., and M.W.F. are employees of Gilead and hold stock interest in the company. The remaining authors have no conflicts of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
A, eGFRCKD-EPI, sCr: changes over time no significant change from baseline in eGFRCKD-EPI, sCr was observed through 96 weeks. *P-values for differences between baseline and week 96 based on the 2-sided Wilcoxon signed-rank test. B, eGFRCKD-EPI, cysC: changes over time. A significant improvement in eGFRCKD-EPI, cysC was observed in patients whose preswitch regimen contained TDF. *P-values for differences between baseline and week 96 based on the 2-sided Wilcoxon signed-rank test. C, Changes in eGFR by baseline eGFR strata.
FIGURE 2.
FIGURE 2.
Renal biomarkers: changes from baseline to week 96. *All changes statistically significant; †all changes not statistically significant with exception of β2m:Cr. β2m, β2-microglobulin; RBP, retinol-binding protein. Normal range is ≤200 mg/g for urine protein to creatinine ratio and 300 μg/g and/or RBP:Cr >159 μg/g are consistent with proximal tubular dysfunction.,

References

    1. Schwartz EJ, Szczech LA, Ross MJ, et al. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol. 2005;16:2412–2420.
    1. Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease in HIV infection: an urban epidemic. AIDS. 2007;21:2101–2103.
    1. Linley L, Prejean J, Qian A, et al. Racial/ethnic disparities in HIV diagnoses among persons aged 50 years and older in 37 US States, 2005–2008. Am J Public Health. 2012;102:1527–1534.
    1. Adekeye OA, Heiman HJ, Onyeabor OS, et al. The new invincibles: HIV screening among older adults in the US. PLoS One. 2012;7:e43618.
    1. Hall AM, Hendry BM, Nitsch D, et al. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011;57:773–780.
    1. D:A:D Study Group, Sabin CA, Worm SW, Reiss P, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371:1417–1426.
    1. Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016;316:191–210.
    1. Van Rompay KK, Durand-Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother. 2008;52:3144–3160.
    1. Fux CA, Simcock M, Wolbers M, et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the swiss HIV cohort study. Antivir Ther. 2007;12:1165–1173.
    1. Goicoechea M, Liu S, Best B, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis. 2008;197:102–108.
    1. Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther. 2008;83:265–272.
    1. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385:2606–2615.
    1. Ray AS, Cihlar T, Robinson KL, et al. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother. 2006;50:3297–3304.
    1. Bam RA, Yant SR, Cihlar T. Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther. 2014;19:687–692.
    1. Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune Defic Syndr. 2016;72:58–64.
    1. Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16:43–52.
    1. Rivero A, Pulido F, Caylá J, et al. ; Grupo de Estudio de Sida (GESIDA), Secretaría del Plan Nacional sobre el Sida. The Spanish AIDS study group and Spanish national AIDS plan (GESIDA/Secretaría del Plan Nacional sobre el Sida) recommendations for the treatment of tuberculosis in HIV-infected individuals (updated january 2013) [in Spanish]. Enferm Infecc Microbiol Clin. 2013;31:672–684.
    1. Antinori A, Marcotullio S, Andreoni M, et al. ; Italian HIV Guidelines Working Group. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2015. New Microbiol. 2016;39:93–109.
    1. Snopková S, Rozsypal H, Aster V, et al. Guidelines for caring for HIV-infected adults and post-exposure prophylaxis of HIV infection [Article in Czech]. Klin Mikrobiol Infekc Lek. 2016;22:20–38.
    1. German-Austrian HIV Treatment Guidelines. 2016. Available at: . Accessed September 10, 2016.
    1. Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48 week results from a single-arm, multi-center, open-label, phase 3 study. J Acquir Immune Defic Syndr. 2016;71:530–537.
    1. Tungsiripat M, Kitch D, Glesby MJ, et al. A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206. AIDS. 2010;24:1781–1784.
    1. Santos JR, Saumoy M, Curran A, et al. The lipid-lowering effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial. Clin Infect Dis. 2015;61:403–408.
    1. Behrens G, Maserati R, Rieger A, et al. Switching to tenofovir/emtricitabine from abacavir/lamivudine in HIV-infected adults with raised cholesterol: effect on lipid profiles. Antivir Ther. 2012;17:1011–1020.
    1. Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis. 2003;42:617–622.
    1. Kudo K, Konta T, Mashima Y, et al. The association between renal tubular damage and rapid renal deterioration in the Japanese population: the takahata study. Clin Exp Nephrol. 2011;15:235–241.

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