Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Journal of Antimicrobial Chemotherapy

Volumn 66, Issue 2, 2011, Pages 240-250

  Anderson, Peter L ^a   Kiser, Jennifer J ^a   Gardner, Edward M ^a,b   Rower, Joseph E ^a   Meditz, Amie ^a   Grant, Robert M ^c  

^a UNIVERSITY OF COLORADO   (United States)

^b DENVER PUBLIC HEALTH   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Clinical pharmacology; Intracellular pharmacology; Nucleoside analogue pharmacology; Pharmacodynamics; Pharmacogenomics; Pharmacokinetics

Indexed keywords

ADEFOVIR; EMTRICITABINE; EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; INDINAVIR; LAMIVUDINE; TENOFOVIR; TENOFOVIR DISOPROXIL; ZIDOVUDINE;

ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONCENTRATION RESPONSE; DRUG ACCUMULATION; DRUG DISPOSITION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENTIATION; DRUG RESPONSE; DRUG SAFETY; DRUG UPTAKE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; KIDNEY TUBULE DISORDER; NEPHROTOXICITY; NONHUMAN; PHARMACOGENETICS; RACE DIFFERENCE; RANDOMIZED CONTROLLED TRIAL (TOPIC); SEX DIFFERENCE; SINGLE NUCLEOTIDE POLYMORPHISM; TREATMENT OUTCOME;

ADENINE; CHEMOPREVENTION; DEOXYCYTIDINE; DRUG INTERACTIONS; FEMALE; FOOD-DRUG INTERACTIONS; HIV INFECTIONS; HUMANS; MALE; PHOSPHONIC ACIDS;

EID: 78651417113     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dkq447     Document Type: Article

References (98)

1. UNAIDS. 09 AIDS Epidemic Update. November 2009. http://data.unaids.org/pub/Report/2009/2009_epidemic_update_en.pdf (15 March 2010, date last accessed).
2. Rotheram-Borus MJ, Swendeman D, Chovnick G. The past, present, and future of HIV prevention: integrating behavioral, biomedical, and structural intervention strategies for the next generation of HIV prevention. Annu Rev Clin Psychol 2009; 5: 143-67.
3. Dolin R. HIV vaccine trial results-an opening for further research. N Engl J Med 2009; 361: 2279-80.
4. Cohen MS, Gay C, Kashuba AD et al. Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med 2007; 146: 591-601.
5. Garcia-Lerma JG, Paxton L, Kilmarx PH et al. Oral pre-exposure prophylaxis for HIV prevention. Trends Pharmacol Sci 2010; 31: 74-81.
6. AVAC Global Advocacy for HIV Prevention. Ongoing PrEP Trials. http://www.avac.org/ht/d/sp/i/3507/pid/3507 (15 March 2010, date last accessed).
7. Panlilio AL, Cardo DM, Grohskopf LA et al. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005; 54 (RR-9): 1-17.
8. Public Health Services Task Force. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States-Living Document. http://www.AIDSinfo.NIH.gov (15 March 2010, date last accessed).
9. Smith DK, Grohskopf LA, Black RJ et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep 2005; 54 (RR-2): 1-20.
10. Peterson L, Taylor D, Roddy 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.
11. Calmy A, Hirschel B, Cooper DA et al. A new era of antiretroviral drug toxicity. Antivir Ther 2009; 14: 165-79.
12. Anderson PL. Pharmacologic perspectives for once-daily antiretroviral therapy. Ann Pharmacother 2004; 38: 1924-34.
13. Back DJ, Burger DM, Flexner CW et al. The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing. J Acquir Immune Defic Syndr 2005; 39 Suppl 1: S1-23, quiz S24-5.
14. Derdelinckx I, Wainberg MA, Lange JMA et al. Criteria for drugs used in pre-exposure prophylaxis trials against HIV infection. PLoS Med 2006; 3: e454.
15. Abbas UL, Anderson RM, Mellors JW. Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings. PLoS ONE 2007; 2: e875.
16. Paltiel AD, Freedberg KA, Scott CA et al. HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis 2009; 48: 806-15.
17. Liu AY, Grant RM, Buchbinder SP. Preexposure prophylaxis for HIV: unproven promise and potential pitfalls. JAMA 2006; 296: 863-5.
18. Hendrix CW, Cao YJ, Fuchs EJ. Topical microbicides to prevent HIV: clinical drug development challenges. Annu Rev Pharmacol Toxicol 2009; 49: 349-75.
19. Guest G, Shattuck D, Johnson L et al. Acceptability of PrEP for HIV prevention among women at high risk for HIV. J Womens Health 2010; 19: 791-8.
20. Robbins BL, Srinivas RV, Kim C et al. 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: 612-7.
21. Wang LH, Begley J, St Claire RL III et al. Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection. AIDS Res Hum Retroviruses 2004; 20: 1173-82.
22. Cihlar T, Ray AS. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res 2010; 85: 39-58.
23. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 2004; 43: 595-612.
24. Naesens L, Bischofberger N, Augustijns P et al. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl) 9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob Agents Chemother 1998; 42: 1568-73.
25. Furman PA, Fyfe JA, St Clair MH et al. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 1986; 83:8333-7.
26. Gao WY, Agbaria R, Driscoll JS et al. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem 1994; 269: 12633-8.
27. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22: 685-708.
28. Maagaard A, Kvale D. Mitochondrial toxicity in HIV-infected patients both off and on antiretroviral treatment: a continuum or distinct underlying mechanisms? J Antimicrob Chemother 2009; 64: 901-9.
29. Mallon PW, Unemori P, Sedwell R et al. In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA. J Infect Dis 2005; 191: 1686-96.
30. Kohler JJ, Lewis W. A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen 2007; 48: 166-72.
31. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46: 716-23.
32. Johnson AA, Ray AS, Hanes J et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001; 276: 40847-57.
33. Feng JY, Murakami E, Zorca SM et al. Relationship between antiviral activity and host toxicity: comparison of the incorporation efficiencies of 2′,3′-dideoxy-5-fluoro-3′-thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase. Antimicrob Agents Chemother 2004; 48: 1300-6.
34. Ray AS, Cihlar T, Robinson KL et al. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 2006; 50: 3297-304.
35. Rodríguez-Nóvoa S, Labarga P, Soriano V et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis 2009; 48: e108-16.
36. Lebrecht D, Venhoff AC, Kirschner J et al. Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats. J Acquir Immune Defic Syndr 2009; 51: 258-63.
37. 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: 3144-60.
38. Arribas JR, Pozniak AL, Gallant JE et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr 2008; 47:74-8.
39. Nelson MR, Katlama C, Montaner JS et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007; 21: 1273-81.
40. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 2009; 1-161. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (15 March 2010, date last accessed).
41. Robbins B, Greenhaw J, Connelly M et al. Metabolic pathways for activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. Antimicrob Agents Chemother 1995; 39: 2304-8.
42. Hunsucker SA, Mitchell BS, Spychala J. The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther 2005; 107: 1-30.
43. Podgorska M, Kocbuch K, Pawelczyk T. Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters. Acta Biochim Pol 2005; 52: 749-58.
44. Jung N, Lehmann C, Rubbert A et al. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 2008; 36: 1616-23.
45. Wijnholds J, Mol CA, van Deemter L et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 2000; 97: 7476-81.
46. Kis O, Robillard K, Chan GNY et al. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci 2010; 31: 22-35.
47. Bazzoli C, Jullien V, Le Tiec C et al. Intracellular pharmacokinetics of antiretroviral drugs in HIV-infected patients, and their correlation with drug action. Clin Pharmacokinet 2010; 49: 17-45.
48. Bethell R, De Muys J, Lippens J et al. In vitro interactions between apricitabine and other deoxycytidine analogues. Antimicrob Agents Chemother 2007; 51: 2948-53.
49. Hazen R, Lanier ER. Relative anti-HIV-1 efficacy of lamivudine and emtricitabine in vitro is dependent on cell type. J Acquir Immune Defic Syndr 2003; 32: 255-8.
50. Guo Y, Kotova E, Chen Z-S et al. MRP8, ATP-binding cassette C11 (ABCC11), isacyclicnucleotide efflux pump and a resistancefactor for fluoropyrimidines 2′,3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. JBiol Chem 2003; 278: 29509-14.
51. Hopper-Borge E, Xu X, Shen T et al. Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res 2009; 69: 178-84.
52. Cihlar T, Ho ES, Lin DC et al. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 2001; 20: 641-8.
53. Barditch-Crovo P, Deeks SG, Collier A et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001; 45: 2733-9.
54. Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of nucleoside-and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis 2004; 38: 743-53.
55. Anderson PL, Kakuda TN, Kawle S et al. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 2003; 17: 2159-68.
56. Hawkins T, Veikley W, St Claire RL III et al. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J Acquir Immune Defic Syndr 2005; 39: 406-11.
57. Becher F, Landman R, Mboup S et al. Monitoring of didanosine and stavudine intracellular triphosphorylated anabolite concentrations in HIV-infected patients. AIDS 2004; 18: 181-7.
58. Pruvost A, Negredo E, Benech H et al. Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2005; 49: 1907-14.
59. Kiser JJ, Aquilante CL, Anderson PL et al. Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 47: 298-303.
60. Garcia-Lerma G, Cong M, Zheng Q et al. Efficacy of intermittent prophylaxis with tenofovir and emtricitabine against rectal SHIV transmission in macaques and relationship to systemic and mucosal drug levels. In: Abstracts of the Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, 2010. Abstract 83. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
61. Goicoechea M, Jain S, Bi L et al. Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients. AIDS 2010; 24: 707-16.
62. Van Rompay KK. Antiretroviral drug studies in nonhuman primates: a valid animal model for innovative drug efficacy and pathogenesis experiments. AIDS Rev 2005; 7: 67-83.
63. Philpott S, Weiser B, Tarwater P et al. CC chemokine receptor 5 genotype and susceptibility to transmission of human immunodeficiency virus type 1 in women. J Infect Dis 2003; 187: 569-75.
64. Hirbod T, Broliden K. Mucosal immune responses in the genital tract of HIV-1-exposed uninfected women. J Intern Med 2007; 262: 44-58.
65. Lockman S, Shapiro RL, Smeaton LM et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356: 135-47.
66. Supervie V, Garcia-Lerma JG, Heneine W et al. HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis. Proc Natl Acad Sci USA 2010; 107: 12381-6.
67. Borroto-Esoda K, Vela JE, Myrick F et al. In vitro evaluation of the anti-HIV activity and metabolic interactions of tenofovir and emtricitabine. Antivir Ther 2006; 11: 377-84.
68. Bousquet L, Pruvost A, Guyot A-C et al. Combination of tenofovir and emtricitabine plus efavirenz: in vitro modulation of abc transporter and intracellular drug accumulation. Antimicrob Agents Chemother 2009; 53: 896-902.
69. Vourvahis M, Tappouni HL, Patterson KB et al. The pharmacokinetics and viral activity of tenofovir in the male genital tract. J Acquir Immune Defic Syndr 2008; 47: 329-33.
70. Dumond JB, Yeh RF, Patterson KB et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre-and post-exposure prophylaxis. AIDS 2007; 21: 1899-907.
71. Cranage M, Sharpe S, Herrera C et al. Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Med 2008; 5: e157.
72. Subbarao S, Ramos A, Kim C et al. Direct stringency comparison of two macaque models (single-high vs. repeat-low) for mucosal HIV transmission using an identical anti-HIV chemoprophylaxis intervention. J Med Primatol 2007; 36: 238-43.
73. Garcia-Lerma JG, Otten RA, Qari SH et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008; 5: e28.
74. Tsai C-C, Emau P, Follis KE et al. Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl)adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J Virol 1998; 72: 4265-73.
75. Van Rompay KK, Kearney BP, Sexton JJ et al. Evaluation of oral tenofovir disoproxil fumarate and topical tenofovir GS-7340 to protect infant macaques against repeated oral challenges with virulent simian immunodeficiency virus. J Acquir Immune Defic Syndr 2006; 43: 6-14.
76. Garcia-Lerma JG, Cong ME, Mitchell J et al. Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection. Sci Transl Med 2010; 2: 14ra4.
77. Karim QA, Karim SS, Frohlich JA et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329: 1168-74.
78. Kashuba A, Abdool Karim E, Kraft E et al. Do systemic and genital tract tenofovir concentrations predict HIV seroconversion in the CAPRISA 004 tenofovir gel trial? In: Abstracts of the Eighteenth International AIDS Conference, Vienna, Austria, 2010. Abstract TUSS0503.
79. Durand-Gasselin L, Da Silva D, Benech H et al. Evidence and possible consequences of the phosphorylation of nucleoside reverse transcriptase inhibitors in human red blood cells. Antimicrob Agents Chemother 2007; 51: 2105-11.
80. Kiser JJ, Fletcher CV, Flynn PM et al. Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection. Antimicrob Agents Chemother 2008; 52: 631-7.
81. Pruvost A, Negredo E, Theodoro F et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother 2009; 53: 1937-43.
82. Darque A, Valette G, Rousseau F et al. Quantitation of intracellular triphosphate of emtricitabine in peripheral blood mononuclear cells from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1999; 43: 2245-50.
83. Kuklenyik Z, Martin A, Pau C-P et al. On-line coupling of anion exchange and ion-pair chromatography for measurement of intracellular triphosphate metabolites of reverse transcriptase inhibitors. J Chromatogr B 2009; 877: 3659-66.
84. Durand-Gasselin L, Van Rompay KKA, Vela JE et al. Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys. Mol Pharm 2009; 6: 1145-51.
85. Stein DS, Moore KH. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy 2001; 21: 11-34.
86. Anderson PL, Zheng JH, King T et al. Concentrations of zidovudine-and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS 2007; 21: 1849-54.
87. Dumond JB, Reddy YS, Troiani L et al. Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men. J Acquir Immune Defic Syndr 2008; 48: 156-62.
88. Balzarini J, Van Herrewege Y, Vanham G. Metabolic activation of nucleoside and nucleotide reverse transcriptase inhibitors in dendritic and Langerhans cells. AIDS 2002; 16: 2159-63.
89. Fletcher CV, King T, Bushman LR et al. Compartmental kinetics of intracellular tenofovir. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, 2008. Abstract 754. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
90. Saavedra-Lozano J, McCoig CC, Cao Y et al. Zidovudine, lamivudine, and abacavir have different effects on resting cells infected with human immunodeficiency virus in vitro. Antimicrob Agents Chemother 2004; 48: 2825-30.
91. Robbins BL, Wilcox CK, Fridland A et al. metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells. Pharmacotherapy 2003; 23: 695-701.
92. Hunt PW, Brenchley J, Sinclair E et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197: 126-33.
93. Lee WA, Martin JC. Perspectives on the development of acyclic nucleotide analogs as antiviral drugs. Antiviral Res 2006; 71: 254-9.
94. Anderson PL. Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs. Curr Opin HIV AIDS 2008; 3: 258-65.
95. Abla N, Chinn LW, Nakamura T et al. The human multidrug resistance protein 4 (MRP4, ABCC4): functional analysis of a highly polymorphic gene. J Pharmacol Exp Ther 2008; 325: 859-68.
96. Lamba JK, Crews K, Pounds S et al. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther 2007; 323: 935-45.
97. Anderson PL, Lamba J, Aquilante CL et al. Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J Acquir Immune Defic Syndr 2006; 42: 441-9.
98. Izzedine H, Hulot JS, Villard E et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis 2006; 194: 1481-91.