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Tenofovir Nephrotoxicity: 2011 Update

DOI: 10.1155/2011/354908

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Abstract:

Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study. 1. Tenofovir Tenofovir disoproxil fumarate is an orally bioavailable prodrug of tenofovir, an acyclic nucleotide analogue reverse-transcriptase inhibitor (NtRTI) structurally similar to adefovir and cidofovir [1] (Figure 1). Acyclic nucleotides differ in their side chains: hydroxy phosphonomethoxypropyl (HPMP) for cidofovir, phosphonomethoxyethyl (PME) for adefovir and phosphonomethoxypropyl (PMP) for tenofovir [2]. Tenofovir diphosphate is a structural analog of deoxyadenosine-5′-triphosphate, the usual substrate for viral RNA-directed DNA polymerase, and is a weak inhibitor of mammalian DNA α- and β-polymerases and mitochondrial DNA γ-polymerase [3]. Figure 1: Chemical structure of the three main nephrotoxic acyclic nucleotide analogs, adefovir, cidofovir and tenofovir, as well as less nephrotoxic tenofovir derivatives under development. A lesser uptake by proximal tubular cells can be achieved by either esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids (hexadeciloxypropyl-tenofovir, CMX157) or by ribose-modification (GS-9148 and its oral prodrug GS-9131). Tenofovir was the first (2001), and remains the only, NtRTI approved by the US Food and Drug Administration (FDA) for the treatment of HIV infection [1]. Tenofovir was also approved for treatment of chronic hepatitis B in adults in 2008 [4]. Tenofovir is now a widely used component of antiretroviral regimens for both treatment-naive and experienced patients on the basis of its

References

[1]  J. E. Gallant and S. Deresinski, “Tenofovir disoproxil fumarate,” Clinical Infectious Diseases, vol. 37, no. 7, pp. 944–950, 2003.
[2]  K. Y. Hostetler, “Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art,” Antiviral Research, vol. 82, no. 2, pp. A84–A98, 2009.
[3]  G. Birkus, M. J. M. Hitchcock, and T. Cihlar, “Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 3, pp. 716–723, 2002.
[4]  E. A. Belongia, J. Costa, and I. F. Gareen, “NIH consensus development statement on management of hepatitis B,” NIH Consens State Sci Statements, vol. 25, pp. 1–29, 2008.
[5]  Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 2011, http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
[6]  S. Rodriguez-Nvoa, E. Alvarez, P. Labarga, and V. Soriano, “Renal toxicity associated with tenofovir use,” Expert Opinion on Drug Safety, vol. 9, no. 4, pp. 545–559, 2010.
[7]  M. R. Nelson, C. Katlama, J. S. Montaner et al., “The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years,” AIDS, vol. 21, no. 10, pp. 1273–1281, 2007.
[8]  M. Goicoechea, S. Liu, B. Best et al., “Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy,” Journal of Infectious Diseases, vol. 197, no. 1, pp. 102–108, 2008.
[9]  T. Cihlar, E. S. Ho, D. C. Lin, and A. S. Mulato, “Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs,” Nucleosides, Nucleotides and Nucleic Acids, vol. 20, no. 4–7, pp. 641–648, 2001.
[10]  A. S. Ray, T. Cihlar, K. L. Robinson et al., “Mechanism of active renal tubular efflux of tenofovir,” Antimicrobial Agents and Chemotherapy, vol. 50, no. 10, pp. 3297–3304, 2006.
[11]  J. E. Gallant, M. A. Parish, J. C. Keruly, and R. D. Moore, “Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment,” Clinical Infectious Diseases, vol. 40, no. 8, pp. 1194–1198, 2005.
[12]  J. E. Gallant, S. Staszewski, A. L. Pozniak et al., “Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial,” Journal of the American Medical Association, vol. 292, no. 2, pp. 191–201, 2004.
[13]  A. Karras, M. Lafaurie, A. Furco et al., “Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus,” Clinical Infectious Diseases, vol. 36, no. 8, pp. 1070–1073, 2003.
[14]  C. W. James, M. C. Steinhaus, S. Szabo, and R. M. Dressler, “Tenofovir-Related nephrotoxicity: case report and review of the literature,” Pharmacotherapy, vol. 24, no. 3, pp. 415–418, 2004.
[15]  A. Malik, P. Abraham, and N. Malik, “Acute renal failure and fanconi syndrome in an AIDS patient on tenofovir treatment—case report and review of literature,” Journal of Infection, vol. 51, no. 2, pp. e61–e65, 2005.
[16]  B. Young, K. Buchacz, A. Moorman, K. C. Wood, and J. T. Brooks, “Renal function in patients with preexisting renal disease receiving tenofovir-containing highly active antiretroviral therapy in the HIV outpatient study,” AIDS Patient Care and STDS, vol. 23, no. 8, pp. 589–592, 2009.
[17]  H. Izzedine, A. Baumelou, and G. Deray, “Acute renal failure in HIV patients,” Nephrology Dialysis Transplantation, vol. 22, no. 10, pp. 2757–2762, 2007.
[18]  J. L. Martin, C. E. Brown, N. Matthews-Davis, and J. E. Reardon, “Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis,” Antimicrobial Agents and Chemotherapy, vol. 38, no. 12, pp. 2743–2749, 1994.
[19]  A. Gayet-Ageron, J. Ananworanich, T. Jupimai et al., “No change in calculated creatinine clearance after tenofovir initiation among Thai patients,” Journal of Antimicrobial Chemotherapy, vol. 59, no. 5, pp. 1034–1037, 2007.
[20]  H. Izzedine, C. Isnard-Bagnis, J. S. Hulot et al., “Renal safety of tenofovir in HIV treatment-experienced patients,” AIDS, vol. 18, no. 7, pp. 1074–1076, 2004.
[21]  A. L. Pozniak, J. E. Gallant, E. DeJesus et al., “Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes—a 96-week analysis,” Journal of Acquired Immune Deficiency Syndromes, vol. 43, no. 5, pp. 535–540, 2006.
[22]  R. D. Cooper, N. Wiebe, N. Smith, P. Keiser, S. Naicker, and M. Tonelli, “Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients,” Clinical Infectious Diseases, vol. 51, pp. 496–505, 2010.
[23]  L. C. Herlitz, S. Mohan, M. B. Stokes, J. Radhakrishnan, V. D. D'Agati, and G. S. Markowitz, “Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities,” Kidney International, vol. 78, no. 11, pp. 1171–1177, 2010.
[24]  D. Lebrecht, A. C. Venhoff, J. Kirschner, T. Wiech, N. Venhoff, and U. A. Walker, “Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats,” Journal of Acquired Immune Deficiency Syndromes, vol. 51, no. 3, pp. 258–263, 2009.
[25]  A. B. Libório, L. Andrade, L. V. B. Pereira, T. R. C. Sanches, M. H. Shimizu, and A. C. Seguro, “Rosiglitazone reverses tenofovir-induced nephrotoxicity,” Kidney International, vol. 74, no. 7, pp. 910–918, 2008.
[26]  T. Cihlar, G. LaFlamme, R. Fisher et al., “Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 1, pp. 150–156, 2009.
[27]  J. J. Kohler, S. H. Hosseini, A. Hoying-Brandt et al., “Tenofovir renal toxicity targets mitochondria of renal proximal tubules,” Laboratory Investigation, vol. 89, no. 5, pp. 513–519, 2009.
[28]  D. M. Fine, M. A. Perazella, G. M. Lucas, and M. G. Atta, “Renal disease in patients with HIV infection: epidemiology, pathogenesis and management,” Drugs, vol. 68, no. 7, pp. 963–980, 2008.
[29]  H. Izzedine, M. Harris, and M. A. Perazella, “The nephrotoxic effects of HAART,” Nature Reviews Nephrology, vol. 5, no. 10, pp. 563–573, 2009.
[30]  H. Izzedine, V. Thibault, M. A. Valantin, G. Peytavin, L. Schneider, and Y. Benhamou, “Tenofovir/probenecid combination in HIV/HBV-coinfected patients: how to escape fanconi syndrome recurrence?” AIDS, vol. 24, no. 7, pp. 1078–1079, 2010.
[31]  J. P. Lalezari, R. J. Stagg, B. D. Kuppermann et al., “Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS: a randomized, controlled trial,” Annals of Internal Medicine, vol. 126, no. 4, pp. 257–263, 1997.
[32]  J. M. Irizarry-Alvarado, J. P. Dwyer, L. M. Brumble, S. Alvarez, and J. C. Mendez, “Proximal tlibular dysfunction associated with tenofovir and didanosine causing fanconl syndrome and diabetes insipidus: a report of 3 cases,” AIDS Reader, vol. 19, no. 3, pp. 114–121, 2009.
[33]  H. Peyrière, J. Reynes, I. Rouanet et al., “Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases,” Journal of Acquired Immune Deficiency Syndromes, vol. 35, no. 3, pp. 269–273, 2004.
[34]  A. E. Zimmermann, T. Pizzoferrato, J. Bedford, A. Morris, R. Hoffman, and G. Braden, “Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions,” Clinical Infectious Diseases, vol. 42, no. 2, pp. 283–290, 2006.
[35]  S. K. Gupta, “Tenofovir-associated fanconi syndrome: review of the FDA adverse event reporting system,” AIDS Patient Care and STDs, vol. 22, no. 2, pp. 99–103, 2008.
[36]  A. Papaleo, J. Warszawski, R. Salomon et al., “Increased β-2 microglobulinuria in human immunodeficiency virus-1-infected children and adolescents treated with tenofovir,” Pediatric Infectious Disease Journal, vol. 26, no. 10, pp. 949–951, 2007.
[37]  H. Gatanaga, N. Tachikawa, Y. Kikuchi et al., “Urinary β2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate,” AIDS Research and Human Retroviruses, vol. 22, no. 8, pp. 744–748, 2006.
[38]  S. Perrot, E. Aslangul, T. Szwebel, N. Caillat-Vigneron, and C. Le Jeunne, “Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient,” Journal of Clinical Rheumatology, vol. 15, no. 2, pp. 72–74, 2009.
[39]  M. J. Parsonage, E. G. L. Wilkins, N. Snowden, B. G. Issa, and M. W. Savage, “The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy,” HIV Medicine, vol. 6, no. 5, pp. 341–346, 2005.
[40]  K. K. A. Van Rompay, L. L. Brignolo, D. J. Meyer et al., “Biological effects of short-term or prolonged administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to newborn and infant rhesus macaques,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 5, pp. 1469–1487, 2004.
[41]  A. B. Castillo, A. F. Tarantal, M. R. Watnik, and R. Bruce Martin, “Tenofovir treatment at 30?mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta),” Journal of Orthopaedic Research, vol. 20, no. 6, pp. 1185–1189, 2002.
[42]  FDA., “Tenofovir disoproxil fumarate,” in Metting PotFADPAC, US Food and Drug Administration, 2001.
[43]  R. T. Schooley, P. Ruane, R. A. Myers et al., “Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study,” AIDS, vol. 16, no. 9, pp. 1257–1263, 2002.
[44]  A. Ortiz, P. Justo, A. Sanz et al., “Tubular cell apoptosis and cidofovir-induced acute renal failure,” Antiviral Therapy, vol. 10, no. 1, pp. 185–190, 2005.
[45]  J. R. Arribas, A. L. Pozniak, J. E. Gallant et al., “Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-Week analysis,” Journal of Acquired Immune Deficiency Syndromes, vol. 47, no. 1, pp. 74–78, 2008.
[46]  A. Winston, J. Amin, P. W. G. Mallon et al., “Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy,” HIV Medicine, vol. 7, no. 2, pp. 105–111, 2006.
[47]  P. Barditch-Crovo, S. G. Deeks, A. Collier et al., “Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults,” Antimicrobial Agents and Chemotherapy, vol. 45, no. 10, pp. 2733–2739, 2001.
[48]  E. Kinai and H. Hanabusa, “Progressive renal tubular dysfunction associated with long-term use of tenofovir DF,” AIDS Research and Human Retroviruses, vol. 25, no. 4, pp. 387–394, 2009.
[49]  A. D. Rule, “Understanding estimated glomerular filtration rate: implications for identifying chronic kidney disease,” Current Opinion in Nephrology and Hypertension, vol. 16, no. 3, pp. 242–249, 2007.
[50]  P. E. Sax, J. E. Gallant, and P. E. Klotman, “Renal safety of tenofovir disoproxil fumarate,” AIDS Reader, vol. 17, no. 2, pp. 99–104, 2007.
[51]  A. Ortiz, J. P. Oliveira, C. Wanner, B. M. Brenner, S. Waldek, and D. G. Warnock, “Recommendations and guidelines for the diagnosis and treatment of fabry nephropathy in adults,” Nature Clinical Practice Nephrology, vol. 4, no. 6, pp. 327–336, 2008.
[52]  K. Bhaskaran, O. Hamouda, M. Sannes et al., “Changes in the risk of death after HIV seroconversion compared with mortality in the general population,” Journal of the American Medical Association, vol. 300, no. 1, pp. 51–59, 2008.
[53]  A. S. Go, G. M. Chertow, D. Fan, C. E. McCulloch, and C. Y. Hsu, “Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization,” New England Journal of Medicine, vol. 351, no. 13, pp. 1296–1370, 2004.
[54]  J. Rojas-Rivera, C. De La Piedra, A. Ramos, A. Ortiz, and J. Egido, “The expanding spectrum of biological actions of vitamin D,” Nephrology Dialysis Transplantation, vol. 25, no. 9, pp. 2850–2865, 2010.
[55]  P. Labarga, P. Barreiro, L. Martin-Carbonero et al., “Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir,” AIDS, vol. 23, no. 6, pp. 689–696, 2009.
[56]  S. Rodríguez-Nóvoa, P. Labarga, V. Soriano et al., “Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a harmacogenetic study,” Clinical Infectious Diseases, vol. 48, no. 11, pp. e108–e116, 2009.
[57]  K. Buchacz, B. Young, R. K. Baker et al., “Renal function in patients receiving tenofovir with ritonavir/lopinavir or ritonavir/atazanavir in the HIV Outpatient Study (HOPS) cohort,” Journal of Acquired Immune Deficiency Syndromes, vol. 43, no. 5, pp. 626–628, 2006.
[58]  S. Badiou, C. Merle De Boever, N. Terrier, V. Baillat, J. P. Cristol, and J. Reynes, “Is tenofovir involved in hypophosphatemia and decrease of tubular phosphate reabsorption in HIV-positive adults?” Journal of Infection, vol. 52, no. 5, pp. 335–338, 2006.
[59]  R. Jones, J. Stebbing, M. Nelson et al., “Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study,” Journal of Acquired Immune Deficiency Syndromes, vol. 37, no. 4, pp. 1489–1495, 2004.
[60]  F. Zoulim, S. Radenne, and C. Ducerf, “Management of patients with decompensated hepatitis B virus association cirrhosis,” Liver Transplantation, vol. 14 Suppl 2, pp. S1–7, 2008.
[61]  P. Bonfanti, G. V. De Socio, S. Carradori et al., “Tenofovir renal safety in HIV-infected patients: results from the SCOLTA project,” Biomedicine and Pharmacotherapy, vol. 62, no. 1, pp. 6–11, 2008.
[62]  R. L. Mehta, J. A. Kellum, S. V. Shah et al., “Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury,” Critical Care, vol. 11, no. 2, article R31, 2007.
[63]  J. W. Sons, Ed., Mitochondrial Dysfunction in Drug-Induced Toxicity, John Wiley & Sons, Hoboken, NJ, USA, 2008.
[64]  N. Tanji, K. Tanji, N. Kambham, G. S. Markowitz, A. Bell, and V. D. D'Agati, “Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion,” Human Pathology, vol. 32, no. 7, pp. 734–740, 2001.
[65]  E. J. Fisher, K. Chaloner, D. L. Cohn et al., “The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial,” AIDS, vol. 15, no. 13, pp. 1695–1700, 2001.
[66]  M. A. Perazella, “Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy,” Kidney International, vol. 78, no. 11, pp. 1060–1063, 2010.
[67]  W. Lewis, B. J. Day, and W. C. Copeland, “Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective,” Nature Reviews Drug Discovery, vol. 2, no. 10, pp. 812–822, 2003.
[68]  J. D. Stumpf and W. C. Copeland, “Mitochondrial DNA replication and disease: insights from DNA polymerase mutations,” Cellular and Molecular Life Sciences, vol. 68, no. 2, pp. 219–233, 2011.
[69]  T. N. Kakuda, “Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity,” Clinical Therapeutics, vol. 22, no. 6, pp. 685–708, 2000.
[70]  G. Moyle, “Mechanisms of HIV and nucleoside reverse transcriptase inhibitor injury to mitochondria,” Antiviral Therapy, vol. 10, no. 2, pp. M47–M52, 2005.
[71]  J. K. Min, C. Jardel, C. Barthélémy et al., “Mitochondrial DNA content, an inaccurate biomarker of mitochondrial alteration in human immunodeficiency virus-related lipodystrophy,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 5, pp. 1670–1676, 2008.
[72]  R. Ferraresi, L. Troiano, M. Pinti et al., “Resistance of mtDNA-depleted cells to apoptosis,” Cytometry Part A, vol. 73, no. 6, pp. 528–537, 2008.
[73]  C. C. Kujoth, A. Hiona, T. D. Pugh et al., “Medicine: mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging,” Science, vol. 309, no. 5733, pp. 481–484, 2005.
[74]  H. Lee, J. Hanes, and K. A. Johnson, “Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase,” Biochemistry, vol. 42, no. 50, pp. 14711–14719, 2003.
[75]  H. C. F. C?té, A. B. Magil, M. Harris et al., “Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy,” Antiviral Therapy, vol. 11, no. 1, pp. 79–86, 2006.
[76]  A. B. Sanz, B. Santamaría, M. Ruiz-Ortega, J. Egido, and A. Ortiz, “Mechanisms of renal apoptosis in health and disease,” Journal of the American Society of Nephrology, vol. 19, no. 9, pp. 1634–1642, 2008.
[77]  S. Coca and M. A. Perazella, “Rapid communication: a cute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity,” American Journal of the Medical Sciences, vol. 324, no. 6, pp. 342–344, 2002.
[78]  S. Rodríguez-Nóvoa, P. Labarga, A. D'Avolio et al., “Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations,” AIDS, vol. 24, no. 7, pp. 1064–1066, 2010.
[79]  S. K. Gupta, J. A. Eustace, J. A. Winston et al., “Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV medicine association of the infectious diseases society of america,” Clinical Infectious Diseases, vol. 40, no. 11, pp. 1559–1585, 2005.
[80]  European AIDS Clinical Society. Prevention and Management of Non-Infectious Co-Morbidities in HIV, 2009, http://www.europeanaidsclinicalsociety.org/guidelinespdf/2_Non_Infectious_Co_Morbidities_in_HIV.pdf.
[81]  F. J. De La Prada álvarez, A. M. Prados, A. Tugores, M. Uriol, C. Saus, and A. Morey, “Acute renal failure and proximal renal tubular dysfuntion in a patient with acquired immunodeficiency syndrome treated with tenofovir,” Nefrologia, vol. 26, no. 5, pp. 626–630, 2006.
[82]  E. Blind, K. Dunder, P. A. De Graeff, and E. Abadie, “Rosiglitazone: a European regulatory perspective,” Diabetologia, vol. 54, no. 2, pp. 213–218, 2011.
[83]  E. R. Lanier, R. G. Ptak, B. M. Lampert et al., “Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 7, pp. 2901–2909, 2010.

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