Discovery and Development of Tenofovir Disoproxil Fumarate

Antiviral Drugs: From Basic Discovery through Clinical Trials

Volumn , Issue , 2011, Pages 85-101

  De Clercq, Erik ^a  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate development; TDF combined with ( )FTC better health outcomes at lower costs; TDF, treatment of hepatitis B PMEA (adefovir) and PMEDAP, against HBV replication

Indexed keywords

EID: 84868231786     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470929353.ch7     Document Type: Chapter

References (146)

1. DeClercq, E.;Holý, A.;Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C. A novel selective broad-spectrum anti-DNA virus agent. Nature 1986, 323, 464-467.
2. De Clercq, E. The acyclic nucleoside phosphonates from inception to clinical use: historical perspective. Antiviral Res. 2007, 75, 1-13.
3. De Clercq, E. Acyclic nucleoside phosphonates: past, present and future. Bridging chemistry to HIV, HBV, HCV, HPV, adeno-, herpes-, and poxvirus infections: the phosphonate bridge. Biochem. Pharmacol. 2007, 73, 911-922.
4. De Clercq, E.; Descamps, J.; De Somer, P.; Holý, A. (S)-9-(2,3-Dihydroxypropyl)adenine: an aliphatic nucleoside analogwith broad-spectrum antiviral activity. Science 1978, 200, 563-565.
5. De Clercq, E.; Holý, A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat. Rev. Drug Discov. 2005, 4, 928-940.
6. Pauwels, R.; Balzarini, J.; Schols, D.; Baba, M.; Desmyter, J.; Rosenberg, I.; Holý, A.; De Clercq, E. Phosphonylmethoxyethyl purine derivatives, a new class of antihuman immunodeficiency virus agents. Antimicrob. Agents Chemother. 1988, 32, 1025-1030.
7. Balzarini, J.; Naesens, L.; Herdewijn, P.; Rosenberg, I.; Holý, A.; Pauwels, R.; Baba, M.; Johns, D. G.; De Clercq, E. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc. Natl. Acad. Sci. USA 1989, 86, 332-336.
8. Balzarini, J.; Holý, A.; Jindrich, J.; Dvorakova, H.; Hao, Z.; Snoeck, R.; Herdewijn, P.; Johns, D. G.; De Clercq, E. 9-[(2R,S)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. Proc. Natl. Acad. Sci. USA 1991, 88, 4961-4965.
9. Balzarini, J.; Holý, A.; Jindrich, J.; Naesens, L.; Snoeck, R.; Schols, D.; De Clercq, E. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother. 1993, 37, 332-338.
10. Balzarini, J.; Aquaro, S.; Perno, C. -F.; Witvrouw, M.; Holý, A.; De Clercq, E. Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems. Biochem. Biophys. Res. Commun. 1996, 219, 337-341.
11. De Clercq, E. Potential of acyclic nucleoside phosphonates in the treatment of DNA virus and retrovirus infections. Expert Rev. Anti-Infect. Ther. 2003, 1, 21-43.
12. De Clercq, E.; Sakuma, T.; Baba,M.; Pauwels, R.; Balzarini, J.; Rosenberg, I.; Holý, A. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 1987, 8, 261-272.
13. Helliot, B.; Panis, B.; Frison, E.; De Clercq, E.; Swennen, R.; Lepoivre, P.; Neyts, J. The acyclic nucleoside phosphonate analogues, adefovir, tenofovir and PMEDAP, efficiently eliminate banana streak virus from banana (Musa spp.). Antiviral Res. 2003, 59, 121-126.
14. Shen, Y.; Zhukovskaya, N. L.; Zimmer, M. I.; Soelaiman, S.; Bergson, P.;Wang, C. R.; Gibbs, C. S.; Tang,W. J. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 2004, 101, 3242-3247.
15. Vela, J. E.; Miller, M. D.; Rhodes, G. R.; Ray, A. S. Effect of nucleoside and nucleotide reverse transcriptase inhibitors of HIV on endogenous nucleotide pools. Antiviral Ther. 2008, 13, 789-797.
16. Suo, Z.; Johnson, K. A. Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor,(R)-9-(2-phosphonylmethoxypropyl)adenine. J. Biol. Chem. 1998, 273, 27250-27258.
17. Cherrington, J. M.; Allen, S. J. W.; Bischofberger, N.; Chen, M. S. Kinetic interaction of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human DNA polymerases α, β and γ. Antiviral Chem. Chemother. 1995, 6, 217-221.
18. Cihlar, T.; Chen, M. S. Incorporation of selected nucleoside phosphonates and anti-human immunodeficiency virus nucleotide analogues into DNA by human DNA polymerases α, β and γ. Antiviral Chem. Chemother. 1997, 8, 187-195.
19. Birkus, G.; Hitchcock, M. J.; Cihlar, T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 2002, 46, 716-723.
20. Biesecker, G.; Karimi, S.; Desjardins, J.; Meyer, D.; Abbott, B.; Bendele, R.; Richardson, F. Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral Res. 2003, 58, 217-225.
21. Gallant, J. E.; Deresinski, S. Tenofovir disoproxil fumarate. Clin. Infect. Dis. 2003, 37, 944-950.
22. Margot, N. A.; Isaacson, E.; McGowan, I.; Cheng, A. K.; Schooley, R. T.; Miller, M. D. Genotypic and phenotypic analyses ofHIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS 2002, 16, 1227-1235.
23. Murry, J. P.; Higgins, J.; Matthews, T. B.; Huang, V. Y.; Van Rompay, K. K.; Pedersen, N. C.; North, T. W. Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. J. Virol. 2003, 77, 1120-1130.
24. Wolf, K.; Walter, H.; Beerenwinkel, N.; Keulen, W.; Kaiser, R.; Hoffmann, D.; Lengauer, T.; Selbig, J.; Vandamme, A. M.; Korn, K.; Schmidt, B. Tenofovir resistance and resensitization. Antimicrob. Agents Chemother. 2003, 47, 3478-3484.
25. Deval, J.; White, K. L.; Miller, M. D.; Parkin, N. T.; Courcambeck, J.; Halfon, P.; Selmi, B.; Boretto, J.; Canard, B. Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations. J. Biol. Chem. 2004, 279, 509-516.
26. Miller, M. D.; Margot, N.; Lu, B.; Zhong, L.; Chen, S. S.; Cheng, A.; Wulfsohn, M. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J. Infect. Dis. 2004, 189, 837-846.
27. Marchand, B.;White, K. L.; Ly, J. K.; Margot, N. A.;Wang, R.; McDermott, M.; Miller, M. D.; Götte, M. Effects of the translocation status of human immunodeficiency virus type 1 reverse transcriptase on the efficacy of excision of tenofovir. Antimicrob. Agents Chemother. 2007, 51, 2911-2919.
28. von Wyl, V.; Yerly, S.; Böni, J.; Bürgisser, P.; Klimkait, T.; Battegay, M.; Bernasconi, E.; Cavassini, M.; Furrer, H.; Hirschel, B.; et al. Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir. Clin. Infect. Dis. 2008, 46, 1299-1309.
29. de Mendoza, C.; Jiménez-Nacher, I.; Garrido, C.; Barreiro, P.; Poveda, E.; Corral, A.; Zahonero, N.; González-Lahoz, J.; Soriano, V. Changing patterns in HIV reverse transcriptase resistance mutations after availability of tenofovir. Clin. Infect. Dis. 2008, 46, 1782-1785.
30. Svarovskaia, E. S.; Feng, J. Y.; Margot, N. A.; Myrick, F.; Goodman, D.; Ly, J. K.; White, K. L.; Kutty, N.; Wang, R.; Borroto-Esoda, K.; Miller, M. D. The A62V and S68G mutations in HIV-1 reverse transcriptase partially restore the replication defect associated with the K65R mutation. J. Acquir. Immune Defic. Syndr. 2008, 48, 428-436.
31. Delaugerre, C.; Roudiere, L.; Peytavin, G.; Rouzioux, C.; Viard, J. P.; Chaix, M. L. Selection of a rare resistance profile in an HIV-1-infected patient exhibiting a failure to an antiretroviral regimen including tenofovir DF. J. Clin. Virol. 2005, 32, 241-244.
32. Kagan, R. M.; Lee, T. S.; Ross, L.; Lloyd, R. M., Jr.; Lewinski, M. A.; Potts, S. J.Molecular basis of antagonism between K70E and K65R tenofovir-associated mutations in HIV-1 reverse transcriptase. Antiviral Res. 2007, 75, 210-218.
33. Sluis-Cremer, N.; Sheen, C. W.; Zelina, S.; Torres, P. S.; Parikh, U. M.;Mellors, J.W.Molecular mechanism bywhich the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 2007, 51, 48-53.
34. Van Rompay, K. K.; Johnson, J. A.; Blackwood, E. J., Singh, R. P.; Lipscomb, J.; Matthews, T. B.; Marthas, M. L.; Pedersen,N.C.; Bischofberger,N.; Heneine,W.; North, T.W. Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection. Retrovirology 2007, 4, 25.
35. De Clercq, E. Antivirals: current state of the art. Future Virol. 2008, 3, 393-405.
36. De Clercq, E. Emerging antiviral drugs. Expert Opin. Emerging Drugs 2008, 13, 393-416.
37. Naesens, L.; Balzarini, J.; Bischofberger, N.; De Clercq, E. Antiretroviral activity and pharmacokinetcs in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl) adenine, the bis(pivaloyloxymethyl) ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine. Antimicrob. Agents Chemother. 1996, 40, 22-28.
38. Naesens, L.; Snoeck, R.; Andrei, G.; Balzarini, J.; Neyts, J.; De Clercq, E. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. Antiviral Chem. Chemother. 1997, 8, 1-23.
39. Robbins, B. L.; Srinivas, R. V.; Kim, C.; Bischofberger, N.; Fridland, A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl) adenine (PMPA), bis(isopropyloxymethylcarbonyl)-PMPA. Antimicrob. Agents Chemother. 1998, 42, 612-617.
40. Arimilli, M. N.; Kim, C. U.; Dougherty, J.; Mulato, A.; Oliyai, R.; Shaw, J. P.; Cundy, K. C.; Bischofberger, N. Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antiviral Chem. Chemother. 1997, 8, 557-564.
41. Naesens, L.; Bischofberger, N.; Augustijns, P.; Annaert, P.; Van den Mooter, G.; Arimilli, M. N.; Kim, C. U.; De Clercq, E. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl) adenine in mice. Antimicrob. Agents Chemother. 1998, 42, 1568-1573.
42. Schooley, R. T.; Ruane, P.; Myers, R. A.; Beall, G.; Lampiris, H.;Berger, D.;Chen, S. S.;Miller, M. D.; Isaacson, E.; Cheng, A. K. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002, 16, 1257-1263.
43. Squires, K.; Pozniak, A. L.; Pierone, G. Jr.; Steinhart, C. R.; Berger, D.; Bellos, N. C.; Becker, S. L.; Wulfsohn, M.; Miller, M. D.; Toole, J. J.; et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann. Intern. Med. 2003, 139, 313-320.
44. Gallant, J. E.; DeJesus, E.; Arribas, J. R.; Pozniak, A. L.; Gazzard, B.; Campo, R. E.; Lu, B.; McColl, D.; Chuck, S.; Enejosa, J.; et al. Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N. Engl. J. Med. 2006, 354, 251-260.
45. Gallant, J. E.; Staszewski, S.; Pozniak, A. L.; DeJesus, E.; Suleiman, J.M.; Miller, M. D.; Coakley, D. F.; Lu, B.; Toole, J. J.; Cheng, A. K. Efficacy and safety of tenofovir DF vs. stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004, 292, 191-201.
46. Valantin, M.-A.; De Truchis, P.; Bittar, R.; Bollens, D.; Slama, L.; Lebouché, B.; Pétour, P.; Aubron-Olivier, C.; Costagliola, D.; Katlama, C. Early improvement of triglycerides and LDL-cholesterol levels in dyslipidemic HIVinfected patients after switching NRTI backbone to tenofovir plus emtricitabine: the TOTEM randomised trial. 10th InternationalWorkshop on Adverse Drug Reactions and Lipodystrophy in HIV, London, Nov. 6-8, 2008. Poster P30.
47. Gathe, Jr. J. C. Switching HIV-infected, suppressed patients from ABC/3TC to FTC/TDF improves lipids: the SETTLE study. 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, London, Nov. 6-8, 2008. Poster P37.
48. Ribera, E.; Clotet, B.; Martinez, E.; Estrada, V.; Sanz, J.; Berenguer, J.; Rubio, R.; Pulido, F.; Larrouse, M.; Curran, A.; et al. 48 Week outcomes following switch from AZT/3TC to FTC/TDF (TVD) vs continuing on AZT/3TC: 48 week interim analysis of the RECOMB trial. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, U.K, Nov. 9-13, 2008. Poster P054.
49. TM. Future Virol. 2006, 1, 709-715.
50. Madruga, J. V. R.; Cassetti, I.; Etzel, A.; Suleiman, J.; Zhou, Y.; Cheng, A. K.; Enejosa, J. The safety and efficacy of tenofovir DF (TDF) in combination with lamivudine (3TC) and efavirenz (EFV) in antiretroviral-naïve patients through seven years. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, U.K, Nov. 9-13, 2008. Poster P004.
51. Hoetelmans, R. M.; Mariën, K.; De Pauw, M.; Hill, A.; Peeters, M.; Sekar, V.; De Doncker, P.; Woodfall, B.; Lefebvre, E. Pharmacokinetic interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in healthy volunteers. Br. J. Clin. Pharmacol. 2007, 64, 655-661.
52. Wenning, L. A.; Friedman, E. J.;Kost, J. T.;Breidinger, S. A.; Stek, J. E.; Lasseter, K. C.; Gottesdiener, K. M.; Chen, J.; Teppler, H.; Wagner, J. A.; et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob. Agents Chemother. 2008, 52, 3253-3258.
53. Ramanathan, S.; Shen,G.; Cheng, A.;Kearney, B. P. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J. Acquir. Immune Defic. Syndr. 2007, 45, 274-279.
54. Molina, J. N.; Andrade-Villanueva, J.; Echevarria, J.; Chetchotisakd, P.; Corral, J.; David, N.; Moyle, G.; Mancini, M.; Percival, L.; Yang, R.; et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008, 372, 646-655.
55. Pozniak, A. L.; Gallant, J. E.; DeJesus, E.; Arribas, J. R.; Gazzard, B.; Campo, R. E.; Chen, S. S.; McColl, D.; Enejosa, J.; Toole, J. J.; Cheng, A. K. 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. J. Acquir. Immune Defic. Syndr. 2006, 43, 535-540.
56. De Clercq, E. AIDS in the ThirdWorld: How to stop the HIV infection? Verh. K. Acad. Geneesk. Belg. 2007, 64, 65-80.
57. De Clercq, E. Anti-HIV drugs. Verh. K. Acad. Geneesk. Belg. 2007, 64, 81-104.
58. Matthias, A. A.; Hinkle, J.; Menning, M.; Hui, J.; Kaul, S.; Kearney, B. P. Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen. J. Acquir. Immune Defic. Syndr. 2007, 46, 167-173.
59. Arribas, J. R.; Pozniak, A. L.; Gallant, J. E.; DeJesus, E.; Gazzard, B.; Campo, R. E.; Chen, S. S.; McColl, D.; Holmes, C. B.; Enejosa, J.; et al. Tenofovir disoproxil fumarate, emtricabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J. Acquir. Immune Defic. Syndr. 2008, 47, 74-78.
60. DeJesus, E.; Young, B.; Flaherty, J.; Ebrahimi, R.; Maa, J.-F.; McColl, D.; Seekins, D.; Farajallah, A. Simplification of antiretroviral therapy with efavirenz/emtricitabine/tenofovir DF single tablet regimen vs. continued unmodified antiretroviral therapy in virologically-suppressed, HIV-1-infected patients. 48th Annual ICAAC/IDSA and 46th AnnualMeeting, Washington, DC, Oct. 25-28, 2008. Poster H-1234.
61. DeJesus, E.; Pozniak, A.; Gallant, J.; Arribas, J.; Zhou, Y.; Cheng, A.; Enejosa, J. The 48-week efficacy and safety of switching to fixed-dose efavirenz/emtricitabine/tenofovir DF in HIV-1-infected patients receiving HAART. 48th Annual ICAAC/IDSA and 46th Annual Meeting, Washington, DC, Oct. 25-28, 2008. Poster H-1235.
62. Léon, A.; Mallolas, J.; Martinez, E.; De Lazzari, E.; Pumarola, T.; Larrousse, M.; Milincovic, A.; Lonca, M.; Blanco, J. L.; Laguno, M.; et al. High rate of virological failure in maintenance antiretroviral therapy with didanosine and tenofovir. AIDS 2005, 19, 1695-1697.
63. Maitland, D.; Moyle, G.; Hand, J.; Mandalia, S.; Boffito, M.; Nelson, M.; Gazzard, B. Early virologic failure in HIV-1-infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS 2005, 19, 1183-1188.
64. Gallant, J. E.; Rodriguez, A. E.; Weinberg, W. G.; Young, B.; Berger, D. S.; Lim, M. L.; Liao, Q.; Ross, L.; Johnson, J.; Shaefer, M. S. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J. Infect. Dis. 2005, 192, 1921-1930.
65. Delaunay, C.; Brun-Vézinet, F.; Landman, R.; Collin, G.; Peytavin, G.; Trylesinski, A.; Flandre, P.; Miller, M.; Descamps, D. Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triplenucleoside analog therapy. J. Virol. 2005, 79, 9572-9578.
66. Ray, A. S.; Myrick, F.; Vela, J. E.; Olson, L. Y.; Eisenberg, E. J.; Borroto-Esodo, K.;Miller, M. D.; Fridland, A. Lack of a metabolic and antiviral drug interaction between tenofovir, abacavir and lamivudine. Antiviral Ther. 2005, 10, 451-457.
67. Rey, D.; Hoen, B.; Chavanet, P.; Schmitt, M. P.; Hoizey, G.; Meyer, P.; Peytavin, G.; Spire, B.; Allavena, C.; Diemer,M.; et al. High rate of early virological failure with the oncedaily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients. J. Antimicrob. Chemother. 2009, 63, 380-388.
68. Lapadula, G.; Costarelli, S.; Quiros-Roldan, E.; Calabresi, A.; Izzo, I.; Carosi, G.; Torti, C. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy-naive HIV-infected patients. Clin. Infect. Dis. 2008, 46, 1127-1129.
69. Redfield, R. R.; Morrow, J. S. Combination antiretroviral therapy with tenofovir, emtricitabine or lamivudine, and nevirapine. Clin. Infect. Dis. 2008, 47, 984-985.
70. Sattler, F. R. Pathogenesis and treatment of lipodystrophy: what clinicians need to know. Top. HIV Med. 2008, 16, 127-133.
71. Milinkovic, A.; Martinez, E.; López, S.; de Lazzari, E.; Miró, O; Vidal, S.; Blanco, J. L.; Garrabou, G.; Laguno, M.; Arnaiz, J. A.; et al. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Antiviral Ther. 2007, 12, 407-415.
72. van Griensven, J.; Zachariah, R.; Rasschaert, F.; Atté, E. F.; Reid, T. Weight evolution in HIV-1-infected women in Rwanda after stavudine substitution due to lipoatrophy: comparison of zidovudine with tenofovir/abacavir. Trans. R. Soc. Trop. Med. Hyg. 2009, 103, 613-619.
73. Purdy, J. B.; Gafni, R. I.; Reynolds, J. C.; Zeichner, S.; Hazra, R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J. Pediatr. 2008, 152, 582-584.
74. Giacomet, V.; Mora, S.; Martelli, L.; Merlo, M.; Sciannamblo, M.; Viganó, A. A 12-month treatment with tenofovir does not impair bone mineral accrual in HIV-infected children. J. Acquir. Immune Defic. Syndr. 2005, 40, 448-450.
75. Gallant, J. E.; Winston, J. A.; DeJesus, E.; Pozniak, A. L.; Chen, S. S.; Cheng, A. K.; Enejosa, J. V. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS 2008; 22, 2155-2163.
76. Viganó, A.; Zuccotti, G. V.; Martelli, L.; Giacomet, V.; Cafarelli, L.; Borgonovo, S.; Beretta, S.; Rombolá, G.;Mora, S. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clin.Drug Invest. 2007, 27, 573-581.
77. Peyriére, H.; Reynes, J.; Rouanet, I.; Daniel, N.; de Boever, C. M.; Mauboussin, J. M.; Leray, H.; Moachon, L.; Vincent, D.; Salmon-Céron, D. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J. Acquir. Immune Defic. Syndr. 2004, 35, 269-273.
78. Barrios, A.; García-Benayas, T.; González-Lahoz, J.; Soriano, V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004, 18, 960-963.
79. Karras, A.; Lafaurie, M.; Furco, A.; Bourgarit, A.; Droz, D.; Sereni, D.; Legendre, C.; Martinez, F.; Molina, J. M. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin. Infect. Dis. 2003, 36, 1070-1073.
80. Rifkin, B. S.; Perazella, M. A. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure. Am. J. Med. 2004, 117, 282-284.
81. Gaspar, G.; Monereo, A.; García-Reyne, A.; de Guzmán, M. Fanconi syndrome and acute renal failure in a patient treated with tenofovir: a call for caution. AIDS 2004, 18, 351-352.
82. Hynes, P.; Urbina, A.; McMeeking, A.; Barisoni, L.; Rabenou, R. Acute renal failure after initiation of tenofovir disoproxil fumarate. Ren. Fail. 2007, 29, 1063-1066.
83. Kapitsinou, P. P.; Ansari, N. Acute renal failure in an AIDS patient on tenofovir: a case report. J. Med. Case Rep. 2008, 2, 94.
84. Patel, S. M.; Zembower, T. R.; Palella, F.; Kanwar, Y. S.; Ahya, S. N. Early onset of tenofovir-induced renal failure: case report and review of the literature. Sci. World J. 2007, 7, 1140-1148.
85. Izzedine, H.; Isnard-Bagnis, C.; Hulot, J. S.; Vittecoq, D.; Cheng, A.; Jais, C. K.; Launay-Vacher, V.; Deray, G. Renal safety of tenofovir in HIV treatment-experienced patients. AIDS 2004, 18, 1074-1076.
86. Rollot, F.;Nazal, E.M.; Chauvelot-Moachon, L.;Kélaïdi, C.; Daniel, N.; Saba, M.; Abad, S.; Blanche, P. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin. Infect. Dis. 2003, 37, e174-e176.
87. Martinez, E.; Milinkovic, A.; de Lazzari, E.; Ravasi, G.; Blanco, J. L.; Larrousse,M.; Mallolas, J.; García, F;Miró, J. M.; Gatell, J. M. Pancreatic toxic effects associated with coadministration of didanosine and tenofovir in HIV-infected adults. Lancet 2004, 364, 65-67.
88. Callens, S.; De Schacht, C.; Huyst, V.; Colebunders, R. Pancreatitis in an HIV-infected person on tenofovir, didanosine and stavudine containing highly active antiretroviral treatment. J. Infect. 2003, 47, 188-189.
89. Murphy, M. D.; O'Hearn, M.; Chou, S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin. Infect. Dis. 2003, 36, 1082-1085.
90. Izzedine, H.; Baumelou, A.; Deray, G. Acute renal failure in HIV patients. Nephrol. Dial. Transplant. 2007, 22, 2757-2762.
91. Madeddu, G.; Bonfanti, P.; De Socio, G. V.; Carradori, S.; Grosso, C.; Marconi, P.; Penco, G.; Rosella, E.; Miccolis, S.; Melzi, S.; et al. Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project. Biomed. Pharmacother. 2008, 62, 6-11.
92. Nelson, M. R.; Katlama, C.; Montaner, J. S.; Cooper, D. A.; Gazzard, B.; Clotet, B.; Lazzarin, A.; Schewe, K.; Lange, J.; Wyatt, C.; et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007, 21, 1273-1281.
93. Mulenga, L. B.; Kruse, G.; Lakhi, S.; Cantrell, R. A.; Reid, S. E.; Zulu, I.; Stringer, E. M.; Krishnasami, Z.; Mwinga, A.; Saag, M. S.; et al. Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia. AIDS 2008, 22, 1821-1827.
94. Goicoechea, M.; Liu, S.; Best, B.; Sun, S.; Jain, S.; Kemper, C.; Witt, M.; Diamond, C.; Haubrich, R.; Louie, S. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J. Infect. Dis. 2008, 197, 102-108.
95. Libório, A. B.; Andrade, L.; Pereira, L. V.; Saches, T. R.; Shimizu, M. H.; Seguro, A. C. Rosiglitazone reverses tenofovir-induced nephrotoxicity. Kidney Int. 2008, 74, 910-918.
96. Yokota, T.; Mochizuki, S.; Konno, K.; Mori, S.; Shigeta, S.; De Clercq, E. Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis. Antimicrob. Agents Chemother. 1991, 35, 394-397.
97. Heijtink, R. A.; de Wilde, G. A.; Kruining, J.; Berk, L.; Balzarini, J.; De Clercq, E.; Holý, A.; Schalm, S. W. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res. 1993, 21, 141-153.
98. Heijtink, R. A.; Kruining, J.; de Wilde, G. A.; Balzarini, J.; De Clercq, E.; Schalm, S. W. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitisBvirus infections in tissue culture. Antimicrob. Agents Chemother. 1994, 38, 2180-2182.
99. Ying, C.; De Clercq, E.; Neyts, J. Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis B virus activity in cell culture. J. Viral Hepatitis 2000, 7, 79-83.
100. Ying, C.; De Clercq, E.; Nicholson,W.; Furman, P.; Neyts, J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J. Viral Hepatitis 2000, 7, 161-165.
101. Lada, O.; Benhamou, Y.; Cahour, A.; Katlama, C.; Poynard, T.; Thibault, V. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antiviral Ther. 2004, 9, 353-363.
102. Hadziyannis, S. J.; Tassopoulos, N. C.; Heathcote, E. J.; Chang, T. T.; Kitis, G.; Rizzetto, M.; Marcellin, P.; Lim, S. G.; Goodman, Z.; Wulfsohn, M. S.; et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 2003, 348, 800-807.
103. Marcellin, P.; Chang, T. T.; Lim, S. G.; Tong, M. J.; Sievert, W.; Shiffman, M. L.; Jeffers, L.; Goodman, Z.; Wulfsohn, M. S.; Xiong, S.; et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 2003, 348, 808-816.
104. Hadziyannis, S. J.; Tassopoulos, N. C.; Heathcote, E. J.; Chang, T. T.; Kitis, G.; Rizzetto, M.; Marcellin, P.; Lim, S. G.; Goodman, Z.; Ma, J.; et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 2005, 352, 2673-2681.
105. Delaney, W. E. IV; Ray, A. S.; Yang, H.; Qi, X.; Xiong, S.; Zhu, Y.; Miller, M. D. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob. Agents Chemother. 2006, 50, 2471-2477.
106. Ristig, M. B.; Crippin, J.; Aberg, J. A.; Powderly, W. G.; Lisker-Melman, M.; Kessels, L.; Tebas, P. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J. Infect. Dis. 2002, 186, 1844-1847.
107. Dore, G. J.; Cooper, D. A.; Pozniak, A. L.; DeJesus, E.; Zhong, L.; Miller, M. D.; Lu, B.; Cheng, A. K. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapynaive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J. Infect. Dis. 2004, 189, 1185-1192.
108. Peters,M. G.; Andersen, J.; Lynch, P.; Liu, T.; Alston-Smith, B.; Brosgart, C. L.; Jacobson, J. M.; Johnson, V. A.; Pollard, R. B.; Rooney, J. F.; et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006, 44, 1110-1116.
109. Matthews, G. V.; Avihingsanon, A.; Lewin, S. R.; Amin, J.; Rerknimitr, R.; Petcharapirat, P.; Marks, P.; Sasadeusz, J.; Cooper, D. A.; Bowden, S.; et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology 2008, 48, 1062-1069.
110. Lacombe,K.; Gozlan, J.; Boyd, A.; Boelle, P.Y.; Bonnard, P.; Molina, J. M.;Miailhes, P., Lascoux-Combe, C.; Serfaty, L.; Zoulim, F.; Girard, P.M. Comparison of the antiviral activity of adefovir and tenofovir on hepatitis B virus in HIV-HBVcoinfected patients. Antiviral Ther. 2008, 13, 705-713.
111. Matthews, G. V.; Cooper, D. A.; Dore, G. J. Improvements in parameters of end-stage liver disease in patients with HIV/HBV-related cirrhosis treated with tenofovir. Antiviral Ther. 2007, 12, 119-122.
112. Mallet, V. O.; Dhalluin-Venier, V.; Verkarre, V.; Correas, J. M.; Chaix, M. L.; Viard, J. P.; Pol, S. Reversibility of cirrhosis in HIV/HBV coinfection. Antiviral Ther. 2007, 12, 279-283.
113. van Bömmel, F. ;Wünsche; T.;Mauss, S.; Reinke, P.; Bergk, A.; Schürmann, D.; Wiedenmann, B.; Berg, T. Comparison of adefovir and tenofovir in the treatment of lamivudineresistant hepatitis B virus infection. Hepatology 2004, 40, 1421-1425.
114. Kuo, A.; Dienstag, J. L.; Chung, R. T. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin. Gastroenterol. Hepatol. 2004, 2, 266-272.
115. Marcellin, P.; Heathcote, E. J.; Buti, M.; Gane, E.; de Man, R. A.; Krastev, Z.; Germanidis, G.; Lee, S. S.; Flisiak, R.; Kaita,K.; et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N. Engl. J. Med. 2008, 359, 2442-2455.
116. Marcellin, P.; Buti, M.; Krastev, Z.; Gurel, S.; Balabanska, R.; Dusheiko, G.; Myers, R.; Heathcote, E. J.; Sorbel, J.; Anderson, J.; et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-negative patients with chronic hepatitis B (Study 102). 59th Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov. 4, 2008. Oral Presentation 146.
117. Heathcote, E. J.; Gane, E.; deMan, R.; Chan, S.; Sievert,W.; Mauss, S.; Marcellin, P.; Sorbel, J.; Anderson, J.; Mondou, E.; et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAgpositive patients with chronic hepatitis B (Study 103). 59th Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov. 4, 2008. Oral Presentation 158.
118. Snow-Lampart, A.; Chappell, B.; Curtis,M.; Zhu, Y.; Heathcote, J.; Marcellin, P.; Borroto-Esoda, K.Week 96 resistance surveillance for HBeAg positive and negative subjects with chronic HBV infection randomized to receive tenofovir DF 300 mg QD. 59th Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov. 4, 2008. Poster 977.
119. Curtis, M.; Hinkle, J.; Harris, J.; Borroto-Esoda, K.; Zhu, Y. Tenofovir is equally active in vitro against wild-type HBV clinical isolates of genotypes A-H. 59th Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov 4, 2008. Poster 955.
120. Lee, S.; Heathcote, E. J.; Sievert, W.; Rinh, H.; Kaita, K.; Younossi, Z.; George, M.; Shiffman, M.; Marcellin, P.; Sorbel, J.; et al. Tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) in Asians with HBeAg-positive and HBeAg-negative chronic hepatitis B participating in Studies 102 and 103. 59th Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov. 4, 2008. Poster 980.
121. Deniz, B.; Everhard, F. Cost effectiveness simultation analysis of tenofovir disoproxil fumarate (TDF), lamivudine (LAM), adefovir dipivoxil (ADV) and entecavir (ETV) in HBeAg negative patients with chronic hepatitis B (CHB) in the USA. 59th AnnualMeeting of the American Association for the Study of the Liver Diseases (AASLD), San Francisco, Oct. 31-Nov. 4, 2008. Poster 976.
122. Reijnders, J. G.; Janssen, H. L. Potency of tenofovir in chronic hepatitis B: mono or combination therapy. J. Hepatol. 2008, 48, 383-386.
123. Tan, J.; Degertekin, B.; Wong, S. N.; Husain, M.; Oberhelman, K.; Lok, A. S. Tenofovir monotherapy is effective in hepatitisBpatientswith antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J. Hepatol. 2008, 48, 391-398.
124. Lai, C. L.; Yuen, M. F. Chronic hepatitis B: new goals, new treatment. N. Engl. J. Med. 2008, 359, 2488-2491.
125. Tsai, C.-C.; Follis, K. E.; Sabo, A.; Beck, T. W.; Grant, R. F.; Bischofberger, N.; Benveniste, R. E.; Black, R. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 1995, 270, 1197-1198.
126. Otten, R. A.; Smith, D. K.; Adams, D. R.; Pullium, J. K.; Jackson, E.; Kim, C. N.; Jaffe, H.; Janssen, R.; Butera, S.; Folks, T. M. Efficacy of postexposure prophylaxis after intravaginal exposure of pig-tailed macaques to a humanderived retrovirus (human immunodeficiency virus type 2). J. Virol. 2000, 74, 9771-9775.
127. Van Rompay, K. K.; McChesney, M. B.; Aguirre, N. L.; Schmidt, K. A.; Bischofberger, N.; Marthas, M. L. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J. Infect. Dis. 2001, 184, 429-438.
128. Mayer, K. H.;Masiankowski, L. A.; Gai, F.; El-Sadr,W. M.; Justman, J.; Kwiecien, A.; Masse, B.; Eshleman, S. H.; Hendrix, C.; Morrow, K.; et al. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS 2006, 20, 543-551.
129. Cranage, M.; Sharpe, S.; Herrera, C.; Cope, A.; Dennis, M.; Berry, N.; Ham, C.; Heeney, J.; Rezk, N.; Kashuba, A.; et al. Prevention of SIV rectgal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Med. 2008, 5, e157.
130. Denton, P.W.; Estes, J.D.; Sun, Z.;Othieno, F. A.;Wei, B. L.; Wege,A.K.; Powell, D. A.; Payne,D.; Haase, A.T.;Garcia, J. V. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med. 2008, 5, e16.
131. Garcia-Lerma, J. G.; Otten, R. A.; Qari, S. H.; Jackson, E.; Cong, M. E.; Masciotra, S.; Luo, W.; Kim, C.; Adams, D. R.; Monsour, M.; et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008, 5, e28.
132. Paxton, L. A.; Hope, T.; Jaffe, H. W. Pre-exposure prophylaxis for HIV infection: What if it works ? Lancet 2007, 370, 89-93.
133. + cell depletion after chemoprophylaxis-induced protection from mucosal infection in rhesus macaques. AIDS Res. Hum. Retrovir. 2008, 24, 543-546.
134. Peterson, L.; Taylor, D.; Roddy, R.; Belai, G.; Phillips, P.; Nanda, K.; Grant, R.; Clarke, E. E.; Doh, A. S.; Ridzon, R.; et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin. Trials 2007, 2, e27.
135. Olmscheid, B.; Zhang, S. Use of tenofovir disoproxil fumarate (TDF) in pregnancy: findings from the Antiretroviral Pregnancy Registry (APR). 48th Annual ICAAC/IDSA and 46th Annual Meeting, Washington, DC, Oct. 25-28, 2008. Posters H-456 and 976.
136. Nurutdinova, D.; Onen, N. F.; Hayes, E.; Mondy, K.; Overton, E. T. Adverse effects of tenofovir use in HIVinfected pregnant women and their infants. Ann. Pharmacother. 2008, 42, 1581-1585.
137. Van Rompay, K. K.; Durand-Gasselin, L.; Brignolo, L. L.; Ray, A. S.; Abel, K.; Cihlar, T.; Spinner, A.; Jerome, C.; Moore, J.; Kearney, B. P.; 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.
138. De Clercq, E.Anti-HIV drugs: 25 compounds approvedwitin 25 years after the discovery of HIV. Int. J. Antimicrob. Agents 2009, 33, 307-320.
139. Hirsch, M. S. Initiating therapy: when to start, what to use. J. Infect. Dis. 2008, 197 (Suppl. 3), S252-S260.
140. Willig, J. H.; Abroms, S.; Westfall, A. O.; Routman, J.; Adusumilli, S.; Varshney, M.; Allison, J.; Chatham, A.; Raper, J. L.; Kaslow, R. A.; et al. Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy. AIDS 2008, 22, 1951-1960.
141. Young, B.; DeJesus, E.; Morales-Ramirez, J.; Flaherty, J.; Ebrahimi, R.; Maa, J.-F.; McColl, D.; Seekins, D.; Farajallah, A. Simplification of antiretroviral therapy with efavirenz/emtricitabine/tenofovir DF single tablet regimen vs. continued antiretroviral therapy in suppressed HIV-1-infected patients. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Nov. 9-13, 2008. Poster P061.
142. Hodder, S.; Mounzer, K.; DeJesus, E.; Maa, J.-F.; Ebrahimi, R.; Grimm, K.; Flaherty, J.; Farajallah, A. Patient reported outcomes after simplification to a single tablet regimen of efavirenz (EFV)/emtricitabine (FTC)/tenofovir DF (TDF). 9th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Nov. 9-13, 2008. Poster P063.
143. Pozniak, A. Tenofovir: What have over 1 million years of patient experience taught us? Int. J. Clin. Pract. 2008, 62, 1285-1293.
144. Brogan,A. J.; Everhard, F.; Talbird, S. E.;Hutt, E.; Zimovetz, E. NRTI Backbone pairs for treatment-naive adults with HIV infection: a UK economic evaluation. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Nov. 9-13, 2008. Poster P306.
145. Brogan, A. J.; Everhard, F.; Talbird, S. E.; Hutt, E. Costeffectiveness of tenofovir/emtricitabine compared with other NRTI pairs in treatment-naïve adults with HIV infection in the United States. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Nov. 9-13, 2008. Poster P309.
146. Rosen, S.; Long, L.; Fox, M.; Sanne, I. Cost and costeffectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa. J. Acquir. Immune Defic. Syndr. 2008, 48, 224-344.