Therapeutic review: Pharmacologic consideration for the use of antiretroviral agents in the elderly

Journal of Clinical Pharmacology

Volumn 48, Issue 10, 2008, Pages 1212-1225

  Rhee, Martin S ^a   Greenblatt, David J ^b  

^a TUFTS MEDICAL CENTER   (United States)

^b TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Antiretroviral; Elderly; HIV; Pharmacokinetics

Indexed keywords

ABACAVIR; AMPRENAVIR; AMPRENAVIR PHOSPHATE; ANTIRETROVIRUS AGENT; ATAZANAVIR; DARUNAVIR; DELAVIRDINE; DIDANOSINE; EFAVIRENZ; EMTRICITABINE; ENFUVIRTIDE; INDINAVIR; LAMIVUDINE; LOPINAVIR; MARAVIROC; NELFINAVIR; NEVIRAPINE; RALTEGRAVIR; RITONAVIR; SAQUINAVIR; STAVUDINE; TENOFOVIR; TIPRANAVIR; ZIDOVUDINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT;

AGED; AGING; ARTICLE; CHRONIC DISEASE; COMORBIDITY; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; DRUG RESPONSE; DRUG USE; ELDERLY CARE; GASTROINTESTINAL DISEASE; HEMOGLOBIN BLOOD LEVEL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERBILIRUBINEMIA; HYPERLIPIDEMIA; KIDNEY FUNCTION; LACTIC ACIDOSIS; LIPODYSTROPHY; LIVER FUNCTION; LIVER TOXICITY; LONG TERM CARE; NEPHROTOXICITY; NEUROTOXICITY; PANCREATITIS; PREVALENCE; SIDE EFFECT; URINARY EXCRETION; VIRUS REPLICATION; AGE; CLINICAL TRIAL; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; PATIENT COMPLIANCE; REVIEW;

AGE FACTORS; AGED; ANTI-HIV AGENTS; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CLINICAL TRIALS AS TOPIC; COMORBIDITY; HIV INFECTIONS; HUMANS; PATIENT COMPLIANCE;

EID: 51849091134     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1177/0091270008322177     Document Type: Article

References (133)

1. Mack KA, Ory MG AIDS and older Americans at the end of the twentieth century. J Acquir Immune Defic Syndr. 2003 ; 33: S68 - S75.
2. Centers for Disease Control and Prevention. Cases of HIV infection and AIDS in the United States, 2004. HIV Surveillance Rep. 2004 ; 16: 1-46.
3. Smith G. Statement of Senator Gordon H. Smith. Aging hearing: HIV over fifty, exploring the new threat. Washington, DC: Senate Special Committee on Aging; 2005.
4. Gallant JE, DeJesus E., Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 ; 354: 251-260.
5. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004 ; 350: 1850-1861.
6. Robbins GK, De Gruttola V., Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 ; 349: 2293-2303.
7. Centers for Disease Control and Prevention. AIDS among persons aged greater than or equal to 50 years-United States, 1991-1996. MMWR Morb Mortal Wkly Rep. 1998 ; 47: 21-27.
8. Kramarow E., Lentzner H., Rooks R., Weeks J., Saydah S. Health and Aging Chartbook: Health, United States, 1999. Hyattsville, MD: National Center for Health Statistics ; 1999.
9. Sotaniemi EA, Arranto AJ, Pelkonen O., Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997 ; 61: 331-339.
10. Skiest DJ, Rubinstien E., Carley N., Gioiella L., Lyons R. The importance of comorbidity in HIV-infected patients over 55: a retrospective case-control study. Am J Med. 1996 ; 101: 605-611.
11. Saah AJ, Hoover DR, He Y., Kingsley LA, Phair JP Factors influencing survival after AIDS: report from the Multicenter AIDS Cohort Study (MACS). J Acquir Immune Defic Syndr. 1994 ; 7: 287-295.
12. Ferro S., Salit IE HIV infection in patients over 55 years of age. J Acquir Immune Defic Syndr. 1992 ; 5: 348-353.
13. Operskalski EA, Stram DO, Lee H., et al. Human immunodeficiency virus type 1 infection: relationship of risk group and age to rate of progression to AIDS. Transfusion Safety Study Group. J Infect Dis. 1995 ; 172: 648-655.
14. Phillips AN, Lee CA, Elford J., et al. More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts. J Acquir Immune Defic Syndr. 1991 ; 4: 970-975.
15. Blaxhult A., Granath F., Lidman K., Giesecke J. The influence of age on the latency period to AIDS in people infected by HIV through blood transfusion. AIDS. 1990 ; 4: 125-129.
16. Sutin DG, Rose DN, Mulvihill M., Taylor B. Survival of elderly patients with transfusion-related acquired immunodeficiency syndrome. J Am Geriatr Soc. 1993 ; 41: 214-216.
17. Rothenberg R., Woelfel M., Stoneburner R., Milberg J., Parker R., Truman B. Survival with the acquired immunodeficiency syndrome: experience with 5833 cases in New York City. N Engl J Med. 1987 ; 317: 1297-1302.
18. Gaeta TJ, LaPolla C., Melendez E. AIDS in the elderly: New York City vital statistics. J Emerg Med. 1996 ; 14: 19-23.
19. Lemp GF, Payne SF, Neal D., Temelso T., Rutherford GW Survival trends for patients with AIDS. JAMA. 1990 ; 263: 402-406.
20. Rosenberg PS, Goedert JJ, Biggar RJ Effect of age at seroconversion on the natural AIDS incubation distribution. Multicenter Hemophilia Cohort Study and the International Registry of Seroconverters. AIDS. 1994 ; 8: 803-810.
21. Stehr-Green JK, Holman RC, Mahoney MA Survival analysis of hemophilia-associated AIDS cases in the US. Am J Public Health. 1989 ; 79: 832-835.
22. Balslev U., Monforte AD, Stergiou G., et al. Influence of age on rates of new AIDS-defining diseases and survival in 6546 AIDS patients. Scand J Infect Dis. 1997 ; 29: 337-343.
23. Anastos K., Barron Y., Cohen MH, et al. The prognostic importance of changes in CD4+ cell count and HIV-1 RNA level in women after initiating highly active antiretroviral therapy. Ann Intern Med. 2004 ; 140: 256-264.
24. Egger M., May M., Chene G., et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 ; 360: 119-129.
25. Collaborative Group on AIDS. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Concerted Action on SeroConversion to AIDS and Death in Europe. Lancet. 2000 ; 355: 1131-1137.
26. Darby SC, Ewart DW, Giangrande PL, Spooner RJ, Rizza CR Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. UK Haemophilia Centre Directors' Organisation. Lancet. 1996 ; 347: 1573-1579.
27. Longini IM Jr, Clark WS, Gardner LI, Brundage JF The dynamics of CD4+ T-lymphocyte decline in HIV-infected individuals: a Markov modeling approach. J Acquir Immune Defic Syndr. 1991 ; 4: 1141-1147.
28. Hessol NA, Koblin BA, van Griensven GJ, et al. Progression of human immunodeficiency virus type 1 (HIV-1) infection among homosexual men in hepatitis B vaccine trial cohorts in Amsterdam, New York City, and San Francisco, 1978-1991. Am J Epidemiol. 1994 ; 139: 1077-1087.
29. Veugelers PJ, Page KA, Tindall B., et al. Determinants of HIV disease progression among homosexual men registered in the Tricontinental Seroconverter Study. Am J Epidemiol. 1994 ; 140: 747-758.
30. Goodkin K., Shapshak P., Asthana D., et al. Older age and plasma viral load in HIV-1 infection. AIDS. 2004 ; 18 (suppl 1). S87 - S98.
31. Grabar S., Kousignian I., Sobel A., et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age: results from the French Hospital Database on HIV. AIDS. 2004 ; 18: 2029-2038.
32. Manfredi R., Chiodo F. A case-control study of virological and immunological effects of highly active antiretroviral therapy in HIV-infected patients with advanced age. AIDS. 2000 ; 14: 1475-1477.
33. Kaufmann GR, Furrer H., Ledergerber B., et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis. 2005 ; 41: 361-372.
34. Teixeira L., Valdez H., McCune JM, et al. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. AIDS. 2001 ; 15: 1749-1756.
35. Viard JP, Mocroft A., Chiesi A., et al. Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the EuroSIDA study. J Infect Dis. 2001 ; 183: 1290-1294.
36. Tumbarello M., Rabagliati R., De Gaetano DK, et al. Older age does not influence CD4 cell recovery in HIV-1 infected patients receiving highly active antiretroviral therapy. BMC Infect Dis. 2004 ; 4: 46.
37. Perez JL, Moore RD Greater effect of highly active antiretroviral therapy on survival in people aged > or =50 years compared with younger people in an urban observational cohort. Clin Infect Dis. 2003 ; 36: 212-218.
38. Paterson DL, Swindells S., Mohr J., et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000 ; 133: 21-30.
39. Barclay TR, Hinkin CH, Castellon SA, et al. Age-associated predictors of medication adherence in HIV-positive adults: health beliefs, self-efficacy, and neurocognitive status. Health Psychol. 2007 ; 26: 40-49.
40. Ammassari A., Murri R., Pezzotti P., et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr. 2001 ; 28: 445-449.
41. Duran S., Spire B., Raffi F., et al. Self-reported symptoms after initiation of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART. HIV Clin Trials. 2001 ; 2: 38-45.
42. Gordillo V., del Amo J., Soriano V., Gonzalez- Lahoz J. Sociodemographic and psychological variables influencing adherence to antiretroviral therapy. AIDS. 1999 ; 13: 1763-1769.
43. Hinkin CH, Hardy DJ, Mason KI, et al. Medication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuse. AIDS. 2004 ; 18: S19 - S25.
44. Silverberg MJ, Leyden W., Horberg MA, DeLorenze GN, Klein D., Quesenberry CP Jr. Older age and the response to and tolerability of antiretroviral therapy. Arch Intern Med. 2007 ; 167: 684-691.
45. Shah SS, McGowan JP, Smith C., Blum S., Klein RS Comorbid conditions, treatment, and health maintenance in older persons with human immunodeficiency virus infection in New York City. Clin Infect Dis. 2002 ; 35: 1238-1243.
46. Orlando G., Meraviglia P., Cordier L., et al. Antiretroviral treatment and age-related comorbidities in a cohort of older HIV-infected patients. HIV Med. 2006 ; 7: 549-557.
47. de Maat MM, Ekhart GC, Huitema AD, Koks CH, Mulder JW, Beijnen JH Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet. 2003 ; 42: 223-282.
48. Robertson SM, Penzak SR, Pau A. Drug interactions in the management of HIV infection: an update. Expert Opin Pharmacother. 2007 ; 8: 2947-2963.
49. Ma Q., Okusanya OO, Smith PF, et al. Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors. Expert Opin Drug Metab Toxicol. 2005 ; 1: 473-485.
50. Piscitelli SC, Gallicano KD Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001 ; 344: 984-996.
51. Fichtenbaum CJ, Gerber JG Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002 ; 41: 1195-1211.
52. Tseng AL, Foisy MM Management of drug interactions in patients with HIV. Ann Pharmacother. 1997 ; 31: 1040-1058.
53. Fellay J., Marzolini C., Decosterd L., et al. Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients. Eur J Clin Pharmacol. 2005 ; 60: 865-873.
54. Mouly S., Rizzo-Padoin N., Simoneau G., et al. Effect of widely used combinations of antiretroviral therapy on liver CYP3A4 activity in HIV-infected patients. Br J Clin Pharmacol. 2006 ; 62: 200-209.
55. Yeh RF, Gaver VE, Patterson KB, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr. 2006 ; 42: 52-60.
56. von Moltke LL, Greenblatt DJ, Grassi JM, et al. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol. 1998 ; 38: 106-111.
57. Granfors MT, Wang JS, Kajosaari LI, Laitila J., Neuvonen PJ, Backman JT Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol. 2006 ; 98: 79-85.
58. Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, von Moltke LL Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 ; 33: 764-770.
59. Greenblatt DJ, He P., von Moltke LL, Court MH Cytochrome P. 450: role in the metabolism and toxicology of drugs and other xenobiotics. In Ioannides C, ed. The CYP3 Family. Cambridge, UK: Royal Society of Chemistry; 2008: 354-383.
60. Stone VE, Jordan J., Tolson J., Miller R., Pilon T. Perspectives on adherence and simplicity for HIV-infected patients on antiretroviral therapy: self-report of the relative importance of multiple attributes of highly active antiretroviral therapy (HAART) regimens in predicting adherence. J Acquir Immune Defic Syndr. 2004 ; 36: 808-816.
61. O'Brien ME, Clark RA, Besch CL, Myers L., Kissinger P. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr. 2003 ; 34: 407-414.
62. Nolan L., O'Malley K. Prescribing for the elderly: Part I. Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc. 1988 ; 36: 142-149.
63. Cuzin L., Delpierre C., Gerard S., Massip P., Marchou B. Immunologic and clinical responses to highly active antiretroviral therapy in patients with HIV infection aged >50 years. Clin Infect Dis. 2007 ; 45: 654-657.
64. Knobel H., Guelar A., Valldecillo G., et al. Response to highly active antiretroviral therapy in HIV-infected patients aged 60 years or older after 24 months follow-up. AIDS. 2001 ; 15: 1591-1593.
65. Silverberg M., Leyden W., Horberg M., Delorenze G., Klein D., Quesenberry C. Older age associated with reduced tolerability of antiretrovirals. Paper presented at: XVI International AIDS Conference ; August 13-18, 2006 ; Toronto, Canada. Abstract WEPE 0177.
66. Cicconi P., Sighinolfi L., Cozzi-Lepri A., et al. Clinical prognosis of HIV-positive patients older than 50 years in the I.CO.N.A. cohort. Paper presented at: 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment ; July 24-27, 2005 ; Rio de Janeiro, Brazil. Abstract MoPe11.6C07.
67. Hamilton MJ, Corless IB, Sefcik EF, et al. Identifying differences in older (50+) and younger persons living with HIV/AIDS. Paper presented at: XV International AIDS Conference ; July 11-16, 2004 ; Bangkok, Thailand. Abstract WePeD6492.
68. Ekong E., Akinlade O., Uwah A., Igbu T. Comparative assessment of response to HAART of the elderly and young HIV/AIDS patients in a resource-limited setting. Paper presented at: XV International AIDS Conference ; July 11-16, 2004 ; Bangkok, Thailand. Abstract ThPeB7187.
69. Martinez E., Mocroft A., Garcia-Viejo MA, et al. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet. 2001 ; 357: 592-598.
70. Mallal SA, John M., Moore CB, James IR, McKinnon EJ Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000 ; 14: 1309-1316.
71. Chene G., Angelini E., Cotte L., et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis. 2002 ; 34: 649-657.
72. Boufassa F., Dulioust A., Lascaux AS, et al. Lipodystrophy in 685 HIV-1-treated patients: influence of antiretroviral treatment and immunovirological response. HIV Clin Trials. 2001 ; 2: 339-345.
73. Heath KV, Hogg RS, Chan KJ, et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS. 2001 ; 15: 231-239.
74. Grimes RM, Otiniano ME, Rodriguez-Barradas MC, Lai D. Clinical experience with human immunodeficiency virus - in fected older patients in the era of effective antiretroviral therapy. Clin Infect Dis. 2002 ; 34: 1530-1533.
75. Almond LM, Edirisinghe D., Dalton M., Bonington A., Back DJ, Khoo SH Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals. Clin Pharmacol Ther. 2005 ; 78: 132-142.
76. Hennessy M., Clarke S., Spiers JP, et al. Intracellular accumulation of nelfinavir and its relationship to P-glycoprotein expression and function in HIV-infected patients. Antivir Ther. 2004 ; 9: 115-122.
77. Chaillou S., Durant J., Garraffo R., et al. Intracellular concentration of protease inhibitors in HIV-1-infected patients: correlation with MDR-1 gene expression and low dose of ritonavir. HIV Clin Trials. 2002 ; 3: 493-501.
78. Marzolini C., Telenti A., Decosterd LA, Greub G., Biollaz J., Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001 ; 15: 71-75.
79. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals. AIDS. 2001 ; 15: 1089-1095.
80. Fletcher CV, Anderson PL, Kakuda TN, et al. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS. 2002 ; 16: 551-560.
81. Burger D., Hugen P., Reiss P., et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS. 2003 ; 17: 1157-1165.
82. Anderson PL, Kakuda TN, Kawle S., Fletcher CV Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS. 2003 ; 17: 2159-2168.
83. Gutierrez F., Navarro A., Padilla S., et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005 ; 41: 1648-1653.
84. González de Requena, Nunez M., Jimenez-Nacher I., Soriano V. Liver toxicity caused by nevirapine. AIDS. 2002 ; 16: 290-291.
85. Dieleman JP, Gyssens IC, van der Ende ME, de Marie S., Burger DM Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients. AIDS. 1999 ; 13: 473-478.
86. Reijers MH, Weigel HM, Hart AA, et al. Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study. AIDS. 2000 ; 14: 59-67.
87. Gatti G., Di Biagio A., Casazza R., et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS. 1999 ; 13: 2083-2089.
88. González de Requena D., Bonora S., Canta F., et al. Atazanavir Ctrough is associated with efficacy and safety: definition of therapeutic range. Paper presented at: 12th Conference on Retrovirus and Opportunistic Infection ; February 22-25, 2005 ; Boston, Massachusetts. Abstract 645.
89. de Requena D., Blanco F., Garcia-Benayas T., Jimenez-Nacher I., Gonzalez-Lahoz J., Soriano V. Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir. AIDS Patient Care STDS. 2003 ; 17: 443-445.
90. Tseng A., Loufty M., Phillips E., Walker S., Rachilis A., Walmsley S. The relationship between lipid elevations and lopinavir (LPV) concentrations in HIV-infected patients on LPV/r-containing salvage regimens. Paper presented at: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy ; September 27-30, 2002 ; San Diego, California. Abstract H-1916.
91. Gutierrez F., Padilla S., Navarro A., et al. Lopinavir plasma concentrations and changes in lipid levels during salvage therapy with lopinavir/ritonavir-containing regimens. J Acquir Immune Defic Syndr. 2003 ; 33: 594-600.
92. Torti C., Quiros-Roldan E., Regazzi-Bonora M., et al. Lipid abnormalities in HIV-infected patients are not correlated with lopinavir plasma concentrations. J Acquir Immune Defic Syndr. 2004 ; 35: 324-326.
93. Clevenbergh P., Garraffo R., Dellamonica P. Impact of various antiretroviral drugs and their plasma concentrations on plasma lipids in heavily pretreated HIV-infected patients. HIV Clin Trials. 2003 ; 4: 330-336.
94. Boffito M., Bonora S., Sinicco A., et al. Lopinavir plasma concentrations and lipid elevation patterns in patients on lopinavir/ ritoanvir-containing regimens. Paper presented at: 4th International Workshop on Clinical Pharmacology of HIV Therapy ; March 27-29, 2003 ; Cannes, France. Abstract 4.4.
95. Best B., May S., Witt M., et al. Relationship between lopinavir concentration and changes in lipid levels at 24 weeks. Paper presented at: 11th Conference on Retroviruses and Opportunistic Infections ; February 8-11, 2004 ; San Francisco, California. Abstract 613.
96. 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: 743-753.
97. Stretcher BN, Pesce AJ, Frame PT, Greenberg KA, Stein DS Correlates of zidovudine phosphorylation with markers of HIV disease progression and drug toxicity. AIDS. 1994 ; 8: 763-769.
98. Yarchoan R., Pluda JM, Thomas RV, et al. Long-term toxicity/activity profile of 2,′3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet. 1990 ; 336: 526-529.
99. Fischl MA, Parker CB, Pettinelli C., et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N Engl J Med. 1990 ; 323: 1009-1014.
100. Skowron G. Biologic effects and safety of stavudine: overview of phase I and II clinical trials. J Infect Dis. 1995 ; 171: S113 - S117.
101. Browne MJ, Mayer KH, Chafee SB, et al. 2,′3′-didehydro- 3′deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. J Infect Dis. 1993 ; 167: 21-29.
102. Ho DD, Neumann AU, Perelson AS, Chen W., Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 ; 373: 123-126.
103. Coffin JM HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995 ; 267: 483-489.
104. Izopet J., Souyris C., Hance A., et al. Evolution of human immunodeficiency virus type 1 populations after resumption of therapy following treatment interruption and shift in resistance genotype. J Infect Dis. 2002 ; 185: 1506-1510.
105. Verhofstede C., Wanzeele FV, Van Der GB, De Cabooter N., Plum J. Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype. AIDS. 1999 ; 13: 2541-2546.
106. Lee CG, Gottesman MM, Cardarelli CO, et al. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry (Mosc). 1998 ; 37: 3594-3601.
107. Washington CB, Duran GE, Man MC, Sikic BI, Blaschke TF Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 ; 19: 203-209.
108. Profit L., Eagling VA, Back DJ Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors. AIDS. 1999 ; 13: 1623-1627.
109. Borkan GA, Hults DE, Gerzof SG, Robbins AH, Silbert CK Age changes in body composition revealed by computed tomography. J Gerontol. 1983 ; 38: 673-677.
110. Boffito M., Back DJ, Blaschke TF, et al. Protein binding in antiretroviral therapies. AIDS Res Hum Retroviruses. 2003 ; 9: 825-835.
111. Kim RB, Fromm MF, Wandel C., et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998 ; 101: 289-294.
112. Gupta SK, Eustace JA, Winston JA, 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. Clin Infect Dis. 2005 ; 40: 1559-1585.
113. Wynne HA, Cope LH, Mutch E., Rawlins MD, Woodhouse KW, James OF The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989 ; 9: 297-301.
114. Zoli M., Magalotti D., Bianchi G., et al. Total and functional hepatic blood flow decrease in parallel with ageing. Age Ageing. 1999 ; 28: 29-33.
115. Schmucker DL Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging. 2001 ; 18: 837-851.
116. Woodhouse K., Wynne HA Age-related changes in hepatic function: implications for drug therapy. Drugs Aging. 1992 ; 2: 243-255.
117. George J., Byth K., Farrell GC Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver. Biochem Pharmacol. 1995 ; 50: 727-730.
118. Schmucker DL, Woodhouse KW, Wang RK, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther. 1990 ; 48: 365-374.
119. Hunt CM, Westerkam WR, Stave GM Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992 ; 44: 275-283.
120. Cotreau MM, von Moltke LL, Greenblatt DJ The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet. 2005 ; 44: 33-60.
121. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003 ; 306: 287-300.
122. Rea IM, McNerlan SE, Alexander HD CD69, CD25, and HLA-DR activation antigen expression on CD3+ lymphocytes and relationship to serum TNF-alpha, IFN-gamma, and sIL-2R levels in aging. Exp Gerontol. 1999 ; 34: 79-93.
123. Gibbons S., Back D., Khoo S. Is there evidence of age-dependent variation in lopinavir or efavirenz levels in female subjects in a clinical setting? Paper presented at: 6th International Workshop on Clinical Pharmacology of HIV Therapy ; April 28-30, 2005 ; Quebec, Canada. Abstract 54.
124. O'Mara E., Randall D., Stoltz R., Geraldes M., Mummaneni V. BMS-232632: a prospective study of age and gender effects on single-dose pharmacokinetics in healthy volunteers. P aper presented at: 1st International AIDS Society Conference on HIV Pathogenesis and Treatment ; July 8-11, 2001 ; Buenos Aires, Argentina. Abstract 350.
125. Parsons T., Spritzler J., Stocker V., et al. The effect of age on lopinavir concentrations. Paper presented at: 6th International Workshop on Clinical Pharmacology of HIV Therapy ; April 28-30, 2005 ; Quebec, Canada. Abstract 40.
126. Bertz R., Lam W., Hsu A., Granneman GR, Sun E. Effects of gender, race, age and weight on the pharmacokinetics of lopinavir after single-dose kaletra (lopianvir/ritonavir) in healthy adult subjects [abstract]. Paper presented at: 2nd International Workshop on Clinical Pharmacology of HIV Therapy ; April 2-4, 2001 ; Noordwijk, The Netherlands.
127. Yamashita TE, Phair JP, Munoz A., et al. Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study. AIDS. 2001 ; 15: 735-746.
128. Manfredi R., Calza L., Cocchi D., Chiodo F. Antiretroviral treatment and advanced age: epidemiologic, laboratory, and clinical features in the elderly. J Acquir Immune Defic Syndr. 2003 ; 33: 112-114.
129. Tumbarello M., Rabagliati R., De Gaetano DK, et al. Older HIV-positive patients in the era of highly active antiretroviral therapy: changing of a scenario. AIDS. 2003 ; 17: 128-131.
130. Nogueras M., Navarro G., Anton E., et al. Epidemiological and clinical features, response to HAART, and survival in HIV-infected patients diagnosed at the age of 50 or more. BMC Infect Dis. 2006 ; 6: 159.
131. Frutos B., Perez-Elias MJ, Casado JL, et al. Elderly HIV-infected patients in the era of protease inhibitor therapy. Paper presented at: 12th International AIDS Conference ; June 28 to July 3, 1998 ; Geneva, Swizterland. Abstract 60704.
132. Jenny- Avital E., King J., Wiznia A., et al. Pharmacokinetic parameters for lopinavir/ritonavir in older (>55 years) versus younger (<35 years) HIV+ outpatients on stable lopinavir/ritonavir-containing regimens. Paper presented at: Frontiers in Drug Development for Antiretroviral Therapies (DART) ; December 10-14, 2006 ; Cancun, Mexico. Abstract 67.
133. van der Leur MR, Burger DM, la Porte CJ, Koopmans PP A retrospective TDM database analysis of interpatient variability in the pharmacokinetics of lopinavir in HIV-infected adults. Ther Drug Monit. 2006 ; 28: 650-653.