Skip to main content
SpringerLink
Log in

Pharmacodynamics of Antiretroviral Agents

  • Protocol
  • First Online:
Antibiotic Pharmacodynamics

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

  • 1561 Accesses

Abstract

The identification of drug targets against the human immunodeficiency virus has led to the development and approval of several antiretroviral agents. Drug monotherapy and non-adherence to prescribed regimen have led to the emergence of drug resistance and current drug regimens consisting of at least three drugs are recommended. The relationship between drug exposure or concentrations and response has been described for most agents, both as single agents and in combination with other drugs. The introduction of fixed-dose formulation and the fact that new drugs are only tested in combination with other antiretrovirals introduces issues in determining the exact pharmacodynamics of single agents. However, favorable responses such as viral suppression, now defined as HIV-1 RNA level <20–50 copies/mL, and restoration of immune function as evidenced by increased CD4+ cell counts, remain the benchmark in efficacy comparison. Further, HIV-RNA levels, CD4+ cell counts, and resistance-associated mutations at baseline often predict virological failure or success of HIV drugs. Although therapeutic drug monitoring may have advantages in specific populations, it is not indicated for routine use and has limited utility for some drug classes such as nucleoside reverse transcriptase inhibitors and protease inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Centers for Disease Control (CDC) (1981) Pneumocystis pneumonia--Los Angeles. MMWR Morb Mortal Wkly Rep 30:250–252

    Google Scholar 

  2. Reeves JD, Doms RW (2002) Human immunodeficiency virus type 2. J Gen Virol 83:1253–1265

    Article  CAS  PubMed  Google Scholar 

  3. Marlink R, Kanki P, Thior I, Travers K, Eisen G, Siby T et al (1994) Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 265:1587–1590

    Article  CAS  PubMed  Google Scholar 

  4. Andersson S, Norrgren H, Dias F, Biberfeld G, Albert J (1999) Molecular characterization of human immunodeficiency virus (HIV)-1 and -2 in individuals from Guinea-Bissau with single or dual infections: predominance of a distinct HIV-1 subtype A/G recombinant in West Africa. Virology 262:312–320

    Article  CAS  PubMed  Google Scholar 

  5. Raboud JM, Montaner JS, Conway B, Rae S, Reiss P, Vella S et al (1998) Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy. AIDS 12:1619–1624

    Article  CAS  PubMed  Google Scholar 

  6. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents [Internet]. AIDSinfo. [cited 2013 May 23]. Available from http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0

  7. WHO|HIV/AIDS [Internet]. World Health Organization. [cited 2013 Mar 15]. Available from http://www.who.int/mediacentre/factsheets/fs360/en/index.html

  8. Cattaneo D, Gervasoni C, Meraviglia P, Landonio S, Fucile S, Cozzi V et al (2012) Inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1-infected subjects. J Antimicrob Chemother 67:460–464

    Article  CAS  PubMed  Google Scholar 

  9. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL et al (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317:185–191

    Article  CAS  PubMed  Google Scholar 

  10. Katlama C, Ingrand D, Loveday C, Clumeck N, Mallolas J, Staszewski S et al (1996) Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group. JAMA 276:118–125

    Article  CAS  PubMed  Google Scholar 

  11. Eron JJ, Benoit SL, Jemsek J, MacArthur RD, Santana J, Quinn JB et al (1995) Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 333:1662–1669

    Article  CAS  PubMed  Google Scholar 

  12. Staszewski S, Loveday C, Picazo JJ, Dellarnonica P, Skinhøj P, Johnson MA et al (1996) Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group. JAMA 276:111–117

    Article  CAS  PubMed  Google Scholar 

  13. Staszewski S, Hill AM, Bartlett J, Eron JJ, Katlama C, Johnson J et al (1997) Reductions in HIV-1 disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials. AIDS 11:477–483

    Article  CAS  PubMed  Google Scholar 

  14. Katzenstein DA, Hughes M, Albrecht M, Hammer S, Para M, Murphy R et al (2000) Virologic and CD4+ cell responses to new nucleoside regimens: switching to stavudine or adding lamivudine after prolonged zidovudine treatment of human immunodeficiency virus infection. ACTG 302 Study Team. AIDS Clinical Trials Group. AIDS Res Hum Retroviruses 16:1031–1037

    Article  CAS  PubMed  Google Scholar 

  15. WHO|Summary: Consolidated guidelines on the use of ARV drugs for treating and preventing HIV infection [Internet]. WHO. [cited 2014 Jan 27]. Available from http://www.who.int/hiv/pub/guidelines/arv2013/short_summary/en/index.html

  16. Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Liou SH et al (1992) A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. N Engl J Med 327:581–587

    Article  CAS  PubMed  Google Scholar 

  17. Bristol-Myers Squibb Company (2000) A randomized study of the long term suppression of plasma HIV RNA levels by triple combination regimens in treatment naive subjects [Internet]. Available from http://ctr.bms.com/OneBmsCtd/ResultDetailAction.do?prodid=7&trialid=723

  18. VIDEX EC (didanosine USP) Prescribing Information [Internet]. [cited 2014 Feb 4]. Available from packageinserts.bms.com/pi/pi_videx_ec.pdf

  19. Velen K, Lewis JJ, Charalambous S, Grant AD, Churchyard GJ, Hoffmann CJ (2013) Comparison of tenofovir, zidovudine, or stavudine as part of first-line antiretroviral therapy in a resource-limited-setting: a cohort study. PLoS One 8:e64459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Spruance SL, Pavia AT, Mellors JW, Murphy R, Gathe J Jr, Stool E et al (1997) Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Bristol-Myers Squibb Stavudine/019 Study Group. Ann Intern Med 126:355–363

    Article  CAS  PubMed  Google Scholar 

  21. Katlama C, Valantin MA, Matheron S, Coutellier A, Calvez V, Descamps D et al (1998) Efficacy and tolerability of stavudine plus lamivudine in treatment-naive and treatment-experienced patients with HIV-1 infection. Ann Intern Med 129:525–531

    Article  CAS  PubMed  Google Scholar 

  22. Acosta EP, Balfour HH Jr (2003) Intermittent administration of high-dose stavudine to nucleoside-experienced individuals infected with HIV-1. J Acquir Immune Defic Syndr 33:343–348

    Article  CAS  PubMed  Google Scholar 

  23. EPIVIR (lamivudine) Prescribing Information [Internet]. [cited 2014 Feb 4]. Available from www.viivhealthcare.com/media/32160/us_epivir.pdf

  24. Henry K, Wallace RJ, Bellman PC, Norris D, Fisher RL, Ross LL et al (2001) Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET Study. J Infect Dis 183:571–578

    Article  CAS  PubMed  Google Scholar 

  25. Grant PM, Tierney C, Budhathoki C, Daar ES, Sax PE, Collier AC et al (2013) Early virologic response to abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202. HIV Clin Trials 14:284–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Behrens G, Maserati R, Rieger A, Domingo P, Abel F, Wang H et al (2012) Switching to tenofovir/emtricitabine from abacavir/lamivudine in HIV-infected adults with raised cholesterol: effect on lipid profiles. Antivir Ther 17:1011–1020

    Article  CAS  PubMed  Google Scholar 

  27. Ford N, Shubber Z, Hill A, Vitoria M, Doherty M, Mills EJ et al (2013) Comparative efficacy of Lamivudine and emtricitabine: a systematic review and meta-analysis of randomized trials. PLoS One 8:e79981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weller S, Radomski KM, Lou Y, Stein DS (2000) Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 44:2052–2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang LH, Begley J, St Claire RL III, Harris J, Wakeford C, Rousseau FS (2004) Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection. AIDS Res Hum Retroviruses 20:1173–1182

    Article  CAS  PubMed  Google Scholar 

  30. Moyle GJ, Stellbrink H-J, Compston J, Orkin C, Arribas JR, Domingo P et al (2013) 96-Week results of abacavir/lamivudine versus tenofovir/emtricitabine, plus efavirenz, in antiretroviral-naive, HIV-1-infected adults: ASSERT study. Antivir Ther 18:905–913

    Article  CAS  PubMed  Google Scholar 

  31. Nishijima T, Takano M, Ishisaka M, Komatsu H, Gatanaga H, Kikuchi Y et al (2013) Abacavir/lamivudine versus tenofovir/emtricitabine with atazanavir/ritonavir for treatment-naive Japanese patients with HIV-1 infection: a randomized multicenter trial. Intern Med 52:735–744

    Article  CAS  PubMed  Google Scholar 

  32. Goicoechea M, Jain S, Bi L, Kemper C, Daar ES, Diamond C et al (2010) Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients. AIDS 24:707–716

    Article  CAS  PubMed  Google Scholar 

  33. VIREAD® (tenofovir disoproxil fumarate) Prescribing Information [Internet]. [cited 2013 Nov 5]. Available from gilead.com/pdf/viread_pi.pdf

  34. Peeters M, Gueye A, Mboup S, Bibollet-Ruche F, Ekaza E, Mulanga C et al (1997) Geographical distribution of HIV-1 group O viruses in Africa. AIDS 11:493–498

    Article  CAS  PubMed  Google Scholar 

  35. Viramune® (nevirapine) Prescribing Information [Internet]. Available from http://www.viramune.com/Landingpage.html

  36. Von Hentig N, Carlebach A, Gute P, Knecht G, Klauke S, Rohrbacher M et al (2006) A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy. Br J Clin Pharmacol 62:552–559

    Article  CAS  Google Scholar 

  37. Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B et al (1998) A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. JAMA 279:930–937

    Article  CAS  PubMed  Google Scholar 

  38. Harris M, Patenaude P, Cooperberg P, Filipenko D, Thorne A, Raboud J et al (1997) Correlation of virus load in plasma and lymph node tissue in human immunodeficiency virus infection. INCAS Study Group. Italy, Netherlands, Canada, Australia, and (United) States. J Infect Dis 176:1388–1392

    Article  CAS  PubMed  Google Scholar 

  39. Lange JMA (2003) Efficacy and durability of nevirapine in antiretroviral drug näive patients. J Acquir Immune Defic Syndr 34(Suppl 1):S40–S52

    Article  CAS  PubMed  Google Scholar 

  40. Van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B et al (2004) Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 363:1253–1263

    Article  PubMed  CAS  Google Scholar 

  41. Conway B (2000) Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and delavirdine. Clin Infect Dis 30(Suppl 2):S130–S134

    Article  CAS  PubMed  Google Scholar 

  42. Kuritzkes DR, Bassett RL, Johnson VA, Marschner IC, Eron JJ, Sommadossi JP et al (2000) Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370. AIDS 14:1553–1561

    Article  CAS  PubMed  Google Scholar 

  43. Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H et al (2000) Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 182:1375–1384

    Article  CAS  PubMed  Google Scholar 

  44. Ngaimisi E, Habtewold A, Minzi O, Makonnen E, Mugusi S, Amogne W et al (2013) Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: a parallel-group prospective cohort study in two sub-Saharan Africa populations. PLoS One 8:e67946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J et al (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341:1865–1873

    Article  CAS  PubMed  Google Scholar 

  46. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA III et al (2004) Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 350:1850–1861

    Article  CAS  PubMed  Google Scholar 

  47. Kakuda TN, Wade JR, Snoeck E, Vis P, Schöller-Gyüre M, Peeters MP et al (2010) Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther 88:695–703

    Article  CAS  PubMed  Google Scholar 

  48. Kakuda T, Sekar V, Vis P, Coate B, Ryan R, Anderson D et al (2012) pharmacokinetics and pharmacodynamics of darunavir and etravirine in HIV-1-infected, treatment-experienced patients in the gender, race, and clinical experience (GRACE) trial. AIDS Res Treat 2012:186987

    PubMed  PubMed Central  Google Scholar 

  49. Di Perri G, Green B, Morrish G, Hill A, Faetkenheuer G, Bickel M et al (2013) Pharmacokinetics and pharmacodynamics of etravirine 400 mg once daily in treatment-naïve patients. HIV Clin Trials 14:92–98

    Article  PubMed  CAS  Google Scholar 

  50. Edurant® (rilpivirine) Prescribing Information [Internet]. [cited 2013 Nov 5]. Available from http://www.edurant.com/patients/full-product-information

  51. Nelson MR, Elion RA, Cohen CJ, Mills A, Hodder SL, Segal-Maurer S et al (2013) Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies. HIV Clin Trials 14:81–91

    Article  CAS  PubMed  Google Scholar 

  52. Cohen CJ, Andrade-Villanueva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K et al (2011) Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet 378:229–237

    Article  CAS  PubMed  Google Scholar 

  53. Molina J-M, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M et al (2011) Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet 378:238–246

    Article  CAS  PubMed  Google Scholar 

  54. Molina J-M, Clumeck N, Orkin C, Rimsky LT, Vanveggel S, Stevens M et al (2014) Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤100,000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials. HIV Med 15:57–62

    Article  CAS  PubMed  Google Scholar 

  55. Chiba M, Hensleigh M, Lin JH (1997) Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. Biochem Pharmacol 53:1187–1195

    Article  CAS  PubMed  Google Scholar 

  56. Fitzsimmons ME, Collins JM (1997) Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4 potential contribution to high first-pass metabolism. Drug Metab Dispos 25:256–266

    CAS  PubMed  Google Scholar 

  57. Koudriakova T, Iatsimirskaia E, Utkin I, Gangl E, Vouros P, Storozhuk E et al (1998) Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 26:552–561

    CAS  PubMed  Google Scholar 

  58. Mathias AA, German P, Murray BP, Wei L, Jain A, West S et al (2010) Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther 87:322–329

    Article  CAS  PubMed  Google Scholar 

  59. Lepist E-I, Phan TK, Roy A, Tong L, Maclennan K, Murray B et al (2012) Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob Agents Chemother 56:5409–5413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Le Moing V, Chêne G, Carrieri MP, Alioum A, Brun-Vézinet F, Piroth L et al (2002) Predictors of virological rebound in HIV-1-infected patients initiating a protease inhibitor-containing regimen. AIDS 16:|21–29

    Article  PubMed  Google Scholar 

  61. Paredes R, Mocroft A, Kirk O, Lazzarin A, Barton SE, Van Lunzen J et al (2000) Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study. Arch Intern Med 160:1123–1132

    Article  CAS  PubMed  Google Scholar 

  62. Schapiro JM, Winters MA, Stewart F, Efron B, Norris J, Kozal MJ et al (1996) The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med 124:1039–1050

    Article  CAS  PubMed  Google Scholar 

  63. INVIRASE® (saquinavir mesylate) Prescribing Information [Internet]. Available from www.gene.com/gene/products/information/invirase/pdf/pi.pdf

  64. Piketty C, Race E, Castiel P, Belec L, Peytavin G, Si-Mohamed A et al (1999) Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy. AIDS 13:F71–F77

    Article  CAS  PubMed  Google Scholar 

  65. Viracept® (nelfinavir mesylate) Prescribing Information [Internet]. Available from www.viivhealthcare.com/media/32259/us_viracept.pdf

  66. Kurowski M, Kaeser B, Sawyer A, Popescu M, Mrozikiewicz A (2002) Low-dose ritonavir moderately enhances nelfinavir exposure. Clin Pharmacol Ther 72:123–132

    Article  CAS  PubMed  Google Scholar 

  67. Moyle GJ, Youle M, Higgs C, Monaghan J, Prince W, Chapman S et al (1998) Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus. J Clin Pharmacol 38:736–743

    Article  CAS  PubMed  Google Scholar 

  68. Saag MS, Tebas P, Sension M, Conant M, Myers R, Chapman SK et al (2001) Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511). AIDS 15:1971–1978

    Article  CAS  PubMed  Google Scholar 

  69. Gathe JC Jr, Ive P, Wood R, Schürmann D, Bellos NC, DeJesus E et al (2004) SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 18:1529–1537

    Article  CAS  PubMed  Google Scholar 

  70. King MS, Bernstein BM, Walmsley SL, Sherer R, Feinberg J, Sanne I et al (2004) Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients. J Infect Dis 190:280–284

    Article  CAS  PubMed  Google Scholar 

  71. Yeh KC, Deutsch PJ, Haddix H, Hesney M, Hoagland V, Ju WD et al (1998) Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 42:332–338

    CAS  PubMed  PubMed Central  Google Scholar 

  72. CRIXIVAN® (Indinavir sulfate) Prescribing Information [Internet]. Available from www.merck.com/product/usa/pi_circulars/c/crixivan/crixivan_pi.pdf

  73. Easterbrook PJ, Newson R, Ives N, Pereira S, Moyle G, Gazzard BG (2001) Comparison of virologic, immunologic, and clinical response to five different initial protease inhibitor-containing and nevirapine-containing regimens. J Acquir Immune Defic Syndr 27:350–364

    Article  CAS  PubMed  Google Scholar 

  74. Casado JL, Moreno A, Sabido R, Martí-Belda P, Antela A, Dronda F et al (2000) A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response. HIV Clin Trials 1:13–19

    Article  CAS  PubMed  Google Scholar 

  75. Campo RE, Moreno JN, Suarez G, Miller N, Kolber MA, Holder DJ et al (2003) Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures. AIDS 17:1933–1939

    Article  CAS  PubMed  Google Scholar 

  76. Cressey TR, Plipat N, Fregonese F, Chokephaibulkit K (2007) Indinavir/ritonavir remains an important component of HAART for the treatment of HIV/AIDS, particularly in resource-limited settings. Expert Opin Drug Metab Toxicol 3:347–361

    Article  CAS  PubMed  Google Scholar 

  77. Pulido F, Delgado R, Pérez-Valero I, González-García J, Miralles P, Arranz A et al (2008) Long-term (4 years) efficacy of lopinavir/ritonavir monotherapy for maintenance of HIV suppression. J Antimicrob Chemother 61:1359–1361

    Article  CAS  PubMed  Google Scholar 

  78. Lopez-Cortes LF, Ruiz-Valderas R, Sánchez-Rivas E, Lluch A, Gutierrez-Valencia A, Torres-Cornejo A et al (2013) Lopinavir plasma concentrations and virological outcome with lopinavir-ritonavir monotherapy in HIV-1-infected patients. Antimicrob Agents Chemother 57:3746–3751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang K, D’Argenio DZ, Acosta EP, Sheth AN, Delille C, Lennox JL et al (2014) Integrated population pharmacokinetic/viral dynamic modelling of lopinavir/ritonavir in HIV-1 treatment-naïve patients. Clin Pharmacokinet 53:361–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bertz RJ, Persson A, Chung E, Zhu L, Zhang J, McGrath D et al (2013) Pharmacokinetics and pharmacodynamics of atazanavir-containing antiretroviral regimens, with or without ritonavir, in patients who are HIV-positive and treatment-naïve. Pharmacotherapy 33:284–294

    Article  CAS  PubMed  Google Scholar 

  81. Goutelle S, Baudry T, Gagnieu M-C, Boibieux A, Livrozet J-M, Peyramond D et al (2013) Pharmacokinetic-pharmacodynamic modeling of unboosted Atazanavir in a cohort of stable HIV-infected patients. Antimicrob Agents Chemother 57:517–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Falcoz C, Jenkins JM, Bye C, Hardman TC, Kenney KB, Studenberg S et al (2002) Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers. J Clin Pharmacol 42:887–898

    Article  CAS  PubMed  Google Scholar 

  83. Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD et al (2004) Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob Agents Chemother 48:791–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. LEXIVA (fosamprenavir calcium) Prescribing Information [Internet]. Available from http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021548s031,022116s015lbl.pdf

  85. Molina J-M, Ait-Khaled M, Rinaldi R, Penco G, Baril J-G, Cauda R et al (2009) Fosamprenavir/ritonavir in advanced HIV disease (TRIAD): a randomized study of high-dose, dual-boosted or standard dose fosamprenavir/ritonavir in HIV-1-infected patients with antiretroviral resistance. J Antimicrob Chemother 64:398–410

    Article  CAS  PubMed  Google Scholar 

  86. Quercia R, Garnier E, Ferré V, Morineau P, Bonnet B, Soulard C et al (2005) Salvage therapy with ritonavir-boosted amprenavir/fosamprenavir: virological and immunological response in two years follow-up. HIV Clin Trials 6:73–80

    Article  PubMed  Google Scholar 

  87. Thaisrivongs S, Strohbach JW (1999) Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor. Biopolymers 51:51–58

    Article  CAS  PubMed  Google Scholar 

  88. Larder BA, Hertogs K, Bloor S, Van den Eynde CH, DeCian W, Wang Y et al (2000) Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 14:1943–1948

    Article  CAS  PubMed  Google Scholar 

  89. Rusconi S, La Seta Catamancio S, Citterio P, Kurtagic S, Violin M, Balotta C et al (2000) Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother 44:1328–1332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McCallister S, Valdez H, Curry K, MacGregor T, Borin M, Freimuth W et al (2004) A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 35:376–382

    Article  CAS  PubMed  Google Scholar 

  91. Goebel FD, MacGregor TR, Sabo JP, Castles M, Johnson PA, Legg D et al (2010) Pharmacokinetic characterization of three doses of tipranavir boosted with ritonavir on highly active antiretroviral therapy in treatment-experienced HIV-1 patients. HIV Clin Trials 11:28–38

    Article  CAS  PubMed  Google Scholar 

  92. Markowitz M, Slater LN, Schwartz R, Kazanjian PH, Hathaway B, Wheeler D et al (2007) Long-term efficacy and safety of tipranavir boosted with ritonavir in HIV-1-infected patients failing multiple protease inhibitor regimens: 80-week data from a phase 2 study. J Acquir Immune Defic Syndr 45:401–410

    Article  CAS  PubMed  Google Scholar 

  93. Orkin C, DeJesus E, Khanlou H, Stoehr A, Supparatpinyo K, Lathouwers E et al (2013) Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med 14:49–59

    Article  CAS  PubMed  Google Scholar 

  94. Mills AM, Nelson M, Jayaweera D, Ruxrungtham K, Cassetti I, Girard P-M et al (2009) Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 23:1679–1688

    Article  CAS  PubMed  Google Scholar 

  95. Fourie J, Flamm J, Rodriguez-French A, Kilby D, Domingo P, Lazzarin A et al (2011) Effect of baseline characteristics on the efficacy and safety of once-daily darunavir/ritonavir in HIV-1-infected, treatment-naïve ARTEMIS patients at week 96. HIV Clin Trials 12:313–322

    Article  CAS  PubMed  Google Scholar 

  96. Arastéh K, Yeni P, Pozniak A, Grinsztejn B, Jayaweera D, Roberts A et al (2009) Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther 14:859–864

    Article  PubMed  CAS  Google Scholar 

  97. Pozniak A, Opravil M, Beatty G, Hill A, De Béthune M-P, Lefebvre E (2008) Effect of baseline viral susceptibility on response to darunavir/ritonavir versus control protease inhibitors in treatment-experienced HIV type 1-infected patients: POWER 1 and 2. AIDS Res Hum Retroviruses 24:1275–1280

    Article  CAS  PubMed  Google Scholar 

  98. Isentress Package Insert [Internet]. [cited 2013 Mar 15]. Available from http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022145s004lbl.pdf

  99. Markowitz M, Morales-Ramirez JO, Nguyen B-Y, Kovacs CM, Steigbigel RT, Cooper DA et al (2006) Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 43:509–515

    Article  CAS  PubMed  Google Scholar 

  100. Miller M, Witmer M, Stillmock K, Felock P, Etco L, Flynn J et al (2006) Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor. [cited 2013 May 23]. Available from http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2191670

  101. Rizk ML, Hang Y, Luo W-L, Su J, Zhao J, Campbell H et al (2012) Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients. Antimicrob Agents Chemother 56:3101–3106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Eron JJ Jr, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker L-G et al (2011) Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis 11:907–915

    Article  CAS  PubMed  Google Scholar 

  103. Charpentier C, Fagard C, Colin C, Katlama C, Molina J-M, Jacomet C et al (2013) Role of baseline HIV-1 DNA level in highly-experienced patients receiving raltegravir, etravirine and darunavir/ritonavir regimen (ANRS139 TRIO trial). PLoS One 8:e53621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H et al (2011) Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis 53:807–816

    Article  CAS  PubMed  Google Scholar 

  105. Gotuzzo E, Markowitz M, Ratanasuwan W, Smith G, Prada G, Morales-Ramirez JO et al (2012) Sustained efficacy and safety of raltegravir after 5 years of combination antiretroviral therapy as initial treatment of HIV-1 infection: final results of a randomized, controlled, phase II study (Protocol 004). J Acquir Immune Defic Syndr 61:73–77

    Article  CAS  PubMed  Google Scholar 

  106. Kozal MJ, Lupo S, DeJesus E, Molina J-M, McDonald C, Raffi F et al (2012) A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results. HIV Clin Trials 13:119–130

    Article  CAS  PubMed  Google Scholar 

  107. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC et al (2011) Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 25:2113–2122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ofotokun I, Sheth AN, Sanford SE, Easley KA, Shenvi N, White K et al (2012) A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses 28:1196–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gallien S, Braun J, Delaugerre C, Charreau I, Reynes J, Jeanblanc F et al (2011) Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial. J Antimicrob Chemother 66:2099–2106

    Article  CAS  PubMed  Google Scholar 

  110. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D et al (2012) Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 379:2439–2448

    Article  CAS  PubMed  Google Scholar 

  111. Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B et al (2011) Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 25:F7–F12

    Article  CAS  PubMed  Google Scholar 

  112. DeJesus E, Rockstroh JK, Henry K, Molina J-M, Gathe J, Ramanathan S et al (2012) Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 379:2429–2438

    Article  CAS  PubMed  Google Scholar 

  113. Molina J-M, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu Y-P et al (2012) Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 12:27–35

    Article  CAS  PubMed  Google Scholar 

  114. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T et al (2010) Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 54:254–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Garrido C, Villacian J, Zahonero N, Pattery T, Garcia F, Gutierrez F et al (2012) Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother 56:2873–2878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Canducci F, Ceresola ER, Saita D, Castagna A, Gianotti N, Underwood M et al (2013) In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J Antimicrob Chemother 68:2525–2532

    Article  CAS  PubMed  Google Scholar 

  117. Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A et al (2013) Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 207:740–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R et al (2014) Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 210:354–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Stellbrink H-J, Reynes J, Lazzarin A, Voronin E, Pulido F, Felizarta F et al (2013) Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS 27:1771–1778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM et al (2013) Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 13:927–935

    Article  CAS  PubMed  Google Scholar 

  121. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F et al (2013) Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 369:1807–1818

    Article  CAS  PubMed  Google Scholar 

  122. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF et al (2013) Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 382:700–708

    Article  CAS  PubMed  Google Scholar 

  123. FUZEON ®(enfuvirtide) for injection Prescribing Information [Internet]. [cited 2013 Nov 5]. Available from www.gene.com/gene/products/information/fuzeon/pdf/pi.pdf

  124. Chan DC, Chutkowski CT, Kim PS (1998) Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proc Natl Acad Sci U S A 95:15613–15617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM et al (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46:1896–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Descamps D, Assoumou L, Masquelier B, Marcelin A-G, Saidi S, Tamalet C et al (2008) HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide. J Antimicrob Chemother 62:451–455

    Article  CAS  PubMed  Google Scholar 

  127. Zhang X, Nieforth K, Lang J-M, Rouzier-Panis R, Reynes J, Dorr A et al (2002) Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: inverse Gaussian density absorption and 2-compartment disposition. Clin Pharmacol Ther 72:10–19

    Article  CAS  PubMed  Google Scholar 

  128. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY et al (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4:1302–1307

    Article  CAS  PubMed  Google Scholar 

  129. Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC et al (2002) The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 18:685–693

    Article  CAS  PubMed  Google Scholar 

  130. Wheeler DA, Lalezari JP, Kilby JM, Wheat J, Delehanty J, DeMasi R et al (2004) Safety, tolerability, and plasma pharmacokinetics of high-strength formulations of enfuvirtide (T-20) in treatment-experienced HIV-1-infected patients. J Clin Virol 30:183–190

    Article  CAS  PubMed  Google Scholar 

  131. Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R et al (2003) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8:279–287

    CAS  PubMed  Google Scholar 

  132. Lalezari JP, Henry K, O’Hearn M, Montaner JSG, Piliero PJ, Trottier B et al (2003) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348:2175–2185

    Article  CAS  PubMed  Google Scholar 

  133. Mould DR, Zhang X, Nieforth K, Salgo M, Buss N, Patel IH (2005) Population pharmacokinetics and exposure-response relationship of enfuvirtide in treatment-experienced human immunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 77:515–528

    Article  CAS  PubMed  Google Scholar 

  134. Soy D, Aweeka FT, Church JA, Cunningham CK, Palumbo P, Kosel BW et al (2003) Population pharmacokinetics of enfuvirtide in pediatric patients with human immunodeficiency virus: searching for exposure-response relationships. Clin Pharmacol Ther 74:569–580

    Article  CAS  PubMed  Google Scholar 

  135. Hardy WD, Gulick RM, Mayer H, Fätkenheuer G, Nelson M, Heera J et al (2010) Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr 55:558–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fätkenheuer G, Nelson M, Lazzarin A, Konourina I, Hoepelman AIM, Lampiris H et al (2008) Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 359:1442–1455

    Article  PubMed  Google Scholar 

  137. Jacqmin P, Wade JR, Weatherley B, Snoeck E, Marshall S, McFadyen L (2013) Assessment of Maraviroc exposure-response relationship at 48 weeks in treatment-experienced HIV-1-infected patients in the MOTIVATE studies. CPT Pharmacometrics Syst Pharmacol 2:e64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Merck Sharp and Dohme Corp., Kenilworth, NJ, USA

    Kajal B. Larson

  2. Division of Pharmacology and Toxicology, School of Medicine, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall 268, Birmingham, AL, 35294, USA

    Edward P. Acosta

Authors
  1. Kajal B. Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward P. Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward P. Acosta .

Editor information

Editors and Affiliations

  1. College of Pharmacolgy,Univ of Minnesota, Dept of Experimental and Clinical Pharma, Minneapolis, Minnesota, USA

    John C. Rotschafer

  2. Division of Infectious Diseases, University of Wisconsin, Madison, Wisconsin, USA

    David R. Andes

  3. College of Pharmacy and Medicine, University of Illinois, Chicago, Illinois, USA

    Keith A. Rodvold

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Larson, K.B., Acosta, E.P. (2016). Pharmacodynamics of Antiretroviral Agents. In: Rotschafer, J., Andes, D., Rodvold, K. (eds) Antibiotic Pharmacodynamics. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3323-5_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3323-5_19

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3321-1

  • Online ISBN: 978-1-4939-3323-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation