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Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 1-2

Improving the Renal Profile of a Human Immunodeficiency Virus Drug Combination Through Prodrug Alteration

Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, USA

Date of Web Publication1-Feb-2016

Correspondence Address:
Sam Harirforoosh
Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Box 70594, Johnson City, TN 37614-1708
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-2916.175388

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How to cite this article:
Murrell DE, Harirforoosh S. Improving the Renal Profile of a Human Immunodeficiency Virus Drug Combination Through Prodrug Alteration. J Integr Nephrol Androl 2016;3:1-2

How to cite this URL:
Murrell DE, Harirforoosh S. Improving the Renal Profile of a Human Immunodeficiency Virus Drug Combination Through Prodrug Alteration. J Integr Nephrol Androl [serial online] 2016 [cited 2023 Feb 2];3:1-2. Available from: http://www.journal-ina.com/text.asp?2016/3/1/1/175388

Human immunodeficiency virus (HIV) continues to alter the lives of countless individuals, who once infected, live on a continuum between viral suppression and acquired immunodeficiency syndrome. The former being achieved via the use of various antiretrovirals beginning with the release of zidovudine over a quarter-century ago; whereas the latter may result from treatment failure or lack of treatment such as in the absence of diagnosis or the inaccessibility of medication. As no cure is yet available, regimens must be continued lifelong. Thus, contemporary treatment is given as a combination of agents from various antiretroviral drug classes in an effort to reduce the likelihood of viral resistance. Although highly effective in reducing plasma HIV viral load, side effect profiles and safety issues can limit the use of some drugs. [1]

Two treatment options, Stribild (Gilead, Foster City, CA, USA) and its younger sibling Genvoya (Gilead, Foster City, CA, USA), were approved for use in the United States by the Food and Drug Administration in August 2012 and November 2015, respectively. [2],[3] Both combination regimens contain an integrase strand transfer inhibitor (elvitegravir), a pharmacoenhancer (cobicistat), and a nucleoside reverse transcriptase inhibitor (emtricitabine) along with tenofovir, a nucleotide transcriptase inhibitor. [3],[4] The variation distinguishing regimens lie in the prodrug formulation of tenofovir, tenofovir disoproxil fumarate in Stribild and tenofovir alafenamide in Genvoya.

Although having been used in HIV treatment for more than a decade, tenofovir may present with toxicities ranging from kidney dysfunction to reduced bone density. [5],[6] The tenofovir disoproxil fumarate form found in Stribild is given at a dose of 300 mg, which yields a substantial systemic tenofovir exposure. This extended exposure is thought to bring about both the change in renal function as well as bone mineral density. [4] The advent of Genvoya introduced a new tenofovir prodrug, tenofovir alafenamide, which is given in a dose of 10 mg. [5] Although this reduction in dose automatically reduces the amount of tenofovir available in the systemic circulation, this form also exhibits a different drug release behavior compared to its predecessor. Tenofovir alafenamide has been shown to present with higher intracellular tenofovir diphosphate, the active reverse transcriptase agent, concentrations, at lower circulating tenofovir levels compared to the previous salt form. [5] Reduced severity of observed bone density changes and renal adverse effects, when using tenofovir alafenamide, have been attributed to the reduction in tenofovir plasma concentration. [4]

The prescribing information of Genvoya indicates initiation of this drug in patients with reduced glomerular filtration rate (GFR) of ≥30 mL/min compared to the indications of Stribild (≥70 mL/min). [2],[3] This would suggest that Genvoya, rather than Stribild, should be used for renally impaired treatment-naive patients with a GFR between 30 and 70 mL/min. In addition, considering the wider range of acceptable GFR values, Genvoya may be continued in an individual who is experiencing GFR reduction due to negatively influencing conditions whereas Stribild in a similar situation may have been discontinued.

As a result of more effective treatments, HIV-positive individuals are living longer, healthier lives; however, the frequency and severity of side effects may increase with physiological changes associated with aging and the increased likelihood of comorbidities. [7] The availability of safe, effective lifelong treatment options is of increasing concern to the HIV health care provider. Thus, another benefit of a lower GFR cut-off would be the utility of Genvoya in patients who may present with decreasing renal function as a result of aging. This would apply both to those newly diagnosed at an advanced age as well as those who may experience age-related changes that necessitate regimen change.

Genvoya may also be beneficial when a patient switches from Stribild specifically following discontinuation as a result of decreased renal function. Such a switch would likely decrease the opportunity for viral resistance as the active drugs, which currently confer viral suppression, would not be altered. This would prevent patient exposure to different medications that may need to be employed in the event of future regimen complications. A patient may also expect a similar side effect profile which may lessen patient anxiety concerning new medications.

The substitution of tenofovir alafenamide for tenofovir disoproxil fumarate in Genvoya may yield important benefits over its predecessor such as reduced renal and bone toxicity, greater utility in renally impaired and/or an aging population, and good candidacy for limiting new drug exposures following renally prompted Stribild discontinuation.

  References Top

Gandhi M, Greenblatt RM, Bacchetti P, Jin C, Huang Y, Anastos K, et al. A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis 2012;206:1453-61.  Back to cited text no. 1
Genvoya Prescribing Information [Gilead Sciences]. Available from: http://www.gilead.com/~/media/files/pdfs/medicines/hiv/genvoya/genvoya_pi.pdf?la=en. [Last accessed on 2015 Dec 14].  Back to cited text no. 2
Murrell DE, Moorman JP, Harirforoosh S. Stribild: A review of component characteristics and combination drug efficacy. Eur Rev Med Pharmacol Sci 2015;19:904-14.  Back to cited text no. 3
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, 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;385:2606-15.  Back to cited text no. 4
Markowitz M, Zolopa A, Squires K, Ruane P, Coakley D, Kearney B, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother 2014;69:1362-9.  Back to cited text no. 5
Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Mansky KC. Tenofovir-associated bone density loss. Ther Clin Risk Manag 2010;6:41-7.  Back to cited text no. 6
Dumond JB, Adams JL, Prince HM, Kendrick RL, Wang R, Jennings SH, et al. Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: A pilot study. HIV Med 2013;14:401-9.  Back to cited text no. 7

This article has been cited by
1 HIV Integrase Inhibitor Pharmacogenetics: An Exploratory Study
Derek E. Murrell,David B. Cluck,Jonathan P. Moorman,Stacy D. Brown,Ke-Sheng Wang,Michelle M. Duffourc,Sam Harirforoosh
Clinical Drug Investigation. 2019;
[Pubmed] | [DOI]


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