JAC Advance Access originally published online on May 22, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):220-221; doi:10.1093/jac/dkl203
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Correspondence |
Comment on: Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir
1 University of Colorado at Denver and Health Sciences Center Box C238, 4200 East Ninth Avenue, Denver, CO 80262, USA 2 Human Pharmacokinetics, Tibotec Inc. 1020 Stony Hill Road, Suite 300, Yardley, PA 19067, USA
*Corresponding author. Tel: +1-303-315-1720; Fax: +1-303-315-1721; E-mail: peter.anderson{at}uchsc.edu
Keywords: pharmacokinetics , pharmacodynamics , drug interactions
Sir,
Barreiro and Soriano present an interesting hypothesis for what seems to be a paradoxical depletion of CD4+ cells in the face of virological suppression when the combination of didanosine and tenofovir is used.1 The central tenet of their hypothesis is the inhibition of purine nucleoside phosphorylase (PNP) by tenofovir or its metabolites such that an accumulation of deoxyribonucleotides, particularly dGTP, leads to a specific T-lymphocytopenia. This situation is akin to congenital immunodeficiency disorders caused by deficiency in PNP activity. We reported a similar hypothesis earlier and are encouraged to see that the issue has not been forgotten.2 In our report, we also linked the pharmacology of PNP inhibition to the poor antiviral response to triple nucleoside reverse transcriptase inhibitor (NRTI) therapies that included tenofovir and other purine analogue NRTIs. We reasoned that poor antiviral potency would be a natural consequence of raised dGTP and dATP levels with which purine analogue NRTIs compete for HIV reverse transcriptase-catalysed incorporation. Subsequently, several articles have also demonstrated that tenofovir plus didanosine are not optimally potent when combined with non-NRTIs.1
Unfortunately, the mechanism(s) for the poor responses and the paradoxical CD4 declines have not been determined. Studies have not detected intracellular pharmacokinetic interactions between tenofovir and the other NRTI components in patients.1,3 Furthermore, in vitro data are available for the effects of tenofovir and purine analogue combinations on viral replication and intracellular endogenous nucleotide pools. These studies were not discussed by Barreiro and Soriano. IL-2 and phytohaemagglutinin (PHA)-stimulated PBMCs or CEM-CCRF and MT-4 cells were cultured over 24–48 h with various concentrations of tenofovir alone or in combination with other NRTIs (abacavir, didanosine, lamivudine and combinations thereof). No anti-HIV antagonism was noted for various combinations of tenofovir and these other NRTIs. Measurements of intracellular 2'-deoxynucleotides and ribonucleotides appeared unchanged in the presence of tenofovir with and without the other NRTIs. One of these studies used ribavirin, hydroxyurea and methotrexate as positive controls and found these molecules to significantly change intracellular endogenous nucleotide pools, as expected.4,5
Whether these in vitro findings put the PNP inhibition hypothesis to rest is debatable. In vitro cellular pharmacology findings do not always predict what happens in the human body. As one illustration, stavudine and zidovudine were found to be additive against HIV replication with in vitro studies similar to those described above, but studies in patients found the combination to be antagonistic against HIV.6
It is likely that the cellular pharmacology of tenofovir in combination with these other NRTIs in patients is at the heart of these undesirable responses whether or not PNP inhibition plays a role. Other pharmacological factors that are important to consider include differences in NRTI phosphorylation among different cell types. For example, the active intracellular phosphates for tenofovir, abacavir, lamivudine and didanosine, which were all present in some combination(s) for the undesirable clinical responses described above, are at the highest level relative to their endogenous counterparts in resting cells.7,8 Perhaps there is a disproportionate level of these pharmacologically active NRTI-triphosphates in resting versus activated cells. This potential compartmentalization of high or low intracellular NRTI-triphosphate concentrations could explain toxicity and suboptimal potency in various tissues and cells depending on their activation state.7,9 Furthermore, in terms of the suboptimal potency of didanosine plus tenofovir, the combination of therapeutic doses of two adenosine analogues may be less potent than therapeutic doses of analogues of two different bases (such as thymidine and cytidine). This is because the receptor theory of pharmacology asserts that maximum effects could have been reached with one adenosine analogue leaving little additional effect from the second adenosine analogue. Finally, another hypothesis for the triple NRTI failures is a low genetic barrier to resistance whereby the individual components select for similar mutations creating a synergic selection of specific mutations such as M184V or K65R.1
In summary, it is important to understand the pharmacological mechanism(s) for these undesirable patient responses so that rational strategies can be devised to manage these problems clinically and to avoid similar problems in the future. These needs also underscore the importance of translational research to bridge bench-top findings to the clinical setting.
Transparency declarations
P. L. A. has received research grant support from Bristol-Myers Squibb and GlaxoSmithKline. T. N. K. is an employee of Tibotec, Inc.
References
1
Barreiro P and Soriano V. (2006) Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir. J Antimicrob Chemother 57:806–9.
2 Kakuda TN, Anderson PL, Becker SL. (2004) CD4 cell decline with didanosine and tenofovir and failure of triple nucleoside/nucleotide regimens may be related. AIDS 18:2442–4.[Medline]
3 Hawkins T, Veikley W, St C, laire RL 3rd, et al. (2005) Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J Acquir Immune Defic Syndr 39:406–11.[CrossRef][Web of Science][Medline]
4 Vela JE, Miller MD, Rhodes GR, et al. (2005) Effect of tenofovir in combination with other anti-HIV NRTIs on intracellular nucleotide pools. Programs and Abstracts of the Forty-fifth Interscience Conference Antimicrobial Agents and ChemotherapyWashington, DC, USA (American Society for Microbiology, Washington, DC, USA) pp. 292 Poster H-1901.
5 Lanier ER, Hazen R, Ross L, et al. (2005) Lack of antagonism between abacavir, lamivudine, and tenofovir against wild-type and drug-resistant HIV-1. J Acquir Immune Defic Syndr 39:519–22.[Medline]
6 Ray AS. (2005) Intracellular interactions between nucleos(t)ide inhibitors of HIV reverse transcriptase. AIDS Rev 7:113–25.[Medline]
7 Anderson PL, Kakuda TN, Lichtenstein KA. (2004) The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis 38:743–53.[CrossRef][Medline]
8 Robbins BL, Wilcox CK, Fridland A, et al. (2003) Metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells. Pharmacotherapy 23:695–701.[CrossRef][Medline]
9 Kuritzkes DR. (2005) Less than the sum of its parts: failure of a tenofovir-abacavir-lamivudine triple-nucleoside regimen. J Infect Dis 192:1867–8.[Medline]
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