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Should Non-Nucleoside Reverse Transcriptase Inhibitors be Combined?

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Abstract

In the treatment of HIV-infected patients, an urgent need exists for more conveniently dosed and better tolerated regimens with improved virological and immunological efficacy. Based on preclinical studies, the combination of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was considered to fulfill this. Several clinical studies, however, have shown different results with regard to mechanism of action, pharmacokinetics, efficacy and toxicity of dual NNRTI regimens. Combinations of two NNRTIs have shown additive or synergistic inhibitory effects on the HIV-1 reverse transcriptase activity and the viral replication of HIV-1 in vitro, although antagonistic effects have also been described. When nevirapine and efavirenz were administered in combination, the exposure to efavirenz was decreased due to induction of metabolism by nevirapine. When compared with single NNRTI regimens, dual NNRTI regimens showed similar but not superior results with regard to virological and immunological success in treatment-naive and pretreated HIV-1-infected patients. However, NNRTI-associated adverse events, such as clinical hepatitis, elevated liver enzymes, rash, central nervous system toxicity and psychiatric disorders, occurred more frequently when two NNRTIs were administered concomitantly. In conclusion, regimens with both nevirapine and efavirenz seem to result in similar antiviral and immunological efficacy with an increased incidence of adverse events compared with single NNRTI regimens. The combination of two NNRTIs is therefore less desirable than other available and effective treatment options.

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References

  1. Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998 Mar; 338 (13): 853–60

    Article  PubMed  Google Scholar 

  2. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [online]. Available from URL: http://www.aidsinfo.nih.gov/guidelines/adult/AA_102904.pdf [Accessed 2004 Nov]

  3. Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003 Dec; 349 (24): 2304–15

    Article  PubMed  CAS  Google Scholar 

  4. Fischl MA, Ribaudo HJ, Collier AC, et al. A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease. J Infect Dis 2003 Sep; 188 (5): 625–34

    Article  PubMed  CAS  Google Scholar 

  5. Hammer SM, Vaida F, Bennett KK, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 2002 Jul; 288 (2): 169–80

    Article  PubMed  CAS  Google Scholar 

  6. Gulick RM, Smeaton LM, D’Aquila RT, et al. Indinavir, nevirapine, stavudine, and lamivudine for human immunodeficiency virus-infected, amprenavir-experienced subjects: AIDS Clinical Trials Group protocol 373. J Infect Dis 2001 Mar; 183 (5): 715–21

    Article  PubMed  CAS  Google Scholar 

  7. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003 May; 17 (7): 987–99

    Article  PubMed  Google Scholar 

  8. Cuzin L, Pugliese P, Bugnon F, et al. Triple NRTI vs NNRTI containing regimens as first line therapy: efficacy and durability in a prospective cohort of French HIV-infected patients [abstract no. TuPeB4533]. 15th International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  9. Moyle G, Nelson MR, Higgs C, et al. An open-label, randomis- ed comparative study of a quadruple NRTI regimen (Trizivir+tenofovir) versus a standard of care 2 class triple therapy regimen (Combivir+efavirenz) as initial therapy for HIV-1 infection. 15th International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  10. Joly V, Descamps D, Yeni P. NNRTI plus PI combinations in the perspective of nucleoside-sparing or nucleoside-failing antiretroviral regimens. AIDS Rev 2002 Jul; 4 (3): 128–39

    PubMed  Google Scholar 

  11. Fraaij PL, Neubert J, Bergshoeff AS, et al. Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children. Antivir Ther 2004 Apr; 9 (2): 297–9

    PubMed  CAS  Google Scholar 

  12. Vigouroux C, Gharakhanian S, Salhi Y, et al. Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metab 1999 Sep; 25 (3): 225–32

    PubMed  CAS  Google Scholar 

  13. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated li-podystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999 Jun 19; 353 (9170): 2093–9

    Article  PubMed  CAS  Google Scholar 

  14. Kollmann C, Tremblay C, Giguel F, et al. In vitro anti-HIV-1 synergy between non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Antivir Ther 2001 Jun; 6 (2): 143–4

    PubMed  CAS  Google Scholar 

  15. Quan Y, Motakis D, Buckheit Jr R, et al. Sensitivity and resistance to (+)-calanolide A of wild-type and mutated forms of HIV-1 reverse transcriptase. Antivir Ther 1999; 4 (4): 203–9

    PubMed  CAS  Google Scholar 

  16. Adkins JC, Noble S. Efavirenz. Drugs 1998 Dec; 56 (6): 1055–64

    Article  PubMed  CAS  Google Scholar 

  17. Clarke S, Harrington P, Barry M, et al. The tolerability of efavirenz after nevirapine-related adverse events. Clin Infect Dis 2000 Sep; 31 (3): 806–7

    Article  PubMed  CAS  Google Scholar 

  18. Havlir D, Cheeseman SH, McLaughlin M, et al. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis 1995 Mar; 171 (3): 537–45

    Article  PubMed  CAS  Google Scholar 

  19. Miller V, De Bethune MP, Kober A, et al. Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride. An-timicrob Agents Chemother 1998 Dec; 42 (12): 3123–9

    CAS  Google Scholar 

  20. de Jong MD, Vella S, Carr A, et al. High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication. J Infect Dis 1997 Apr; 175 (4): 966–70

    Article  PubMed  Google Scholar 

  21. Zhang Z, Hamatake R, Hong Z. Clinical utility of current NNRTIs and perspectives of new agents in this class under development. Antivir Chem Chemother 2004 May; 15 (3): 121–34

    PubMed  Google Scholar 

  22. King RW, Klabe RM, Reid CD, et al. Potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in combination with other human immunodeficiency virus NNRTIs, NRTIs, or protease inhibitors. Antimicrob Agents Chemother 2002 Jun; 46 (6): 1640–6

    Article  PubMed  CAS  Google Scholar 

  23. Gu Z, Quan Y, Li Z, et al. Effects of non-nucleoside inhibitors of human immunodeficiency virus type 1 in cell-free recombi-nant reverse transcriptase assays. J Biol Chem 1995 Dec; 270 6(52): 31046–51

    Google Scholar 

  24. Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 2001; 40 (12): 893–905

    Article  PubMed  CAS  Google Scholar 

  25. Murphy RL, Montaner J. Nevirapine: a review of its development, pharmacological profile and potential for clinical use. Expert Opin Invest Drugs 1996; 5 (9): 1183–99

    Article  CAS  Google Scholar 

  26. Lamson M, MacGregor T, Riska P, et al. Nevirapine induces both CYP3A4 and CYP2B6 metabolic pathways [abstract PI-79]. 100th American Society for Clinical Pharmacology and Therapeutics; 1999 Mar 18–20; San Antonio (TX)

    Google Scholar 

  27. Mouly S, Lown KS, Kornhauser D, et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther 2002 Jul; 72 (1): 1–9

    Article  PubMed  CAS  Google Scholar 

  28. Balzarini J. Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem 2004; 4 (9): 921–44

    Article  PubMed  CAS  Google Scholar 

  29. Veldkamp AI, Harris M, Montaner JS, et al. The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infect-ed persons. J Infect Dis 2001 Jul; 184 (1): 37–42

    Article  PubMed  CAS  Google Scholar 

  30. Kappelhoff BS, van Leth F, MacGregor TR, et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study [abstract no. 1239]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 29–Nov 2; Washington, DC

    Google Scholar 

  31. Olivieri J. Nevirapine + efavirenz based salvage therapy in heavily pretreated HIV infected patients. Sex Transm Infect 2002 Feb; 78 (1): 72–3

    Article  PubMed  CAS  Google Scholar 

  32. Jordan WC, Jefferson R, Yemofio F, et al. Nevirapine plus efavirenz plus didanosine: a simple, safe, and effective once-daily regimen for patients with HIV infection. J Natl Med Assoc 2003 Dec; 95 (12): 1152–7

    PubMed  Google Scholar 

  33. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001 Jan; 15 (1): 71–5

    Article  PubMed  CAS  Google Scholar 

  34. Joshi AS, Barret JS, Fiske WD, et al. Population pharmacokinetics of efavirenz in phase II studies and relationship with efficacy [abstract no. 1201]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco

    Google Scholar 

  35. Gey DC, Lorenz T, Brust J, et al. An NRTI-free regimen in HIV-patients with evidence of mitochondrial toxicity: 48 weeks results of a pilot study [abstract no. TuPeB4512]. 15th International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  36. Arranz-Caso JA, Gorgolas M, Estrada V, et al. Treatment of HIV-infected patients with a combination of efavirenz, nevirapine and nucleoside reverse transcriptase inhibitors. HIV Med 2004 Mar; 5 (2): 128–9

    Article  PubMed  CAS  Google Scholar 

  37. van Leth F, Phanuphak P, Ruxrungtham K, et al. 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 2004 Apr; 363: 1253–63

    Article  PubMed  Google Scholar 

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Acknowledgements

No sources of funding were used for this study, and the authors have no conflicts of interest that are directly relevant to the contents of this manuscript.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, Amsterdam, 1066 EC, The Netherlands

    Bregt S. Kappelhoff, Alwin D. R. Huitema & Jos H. Beijnen

  2. Department of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Faculty of Pharmaceutical Sciences, Utrecht, The Netherlands

    Jos H. Beijnen

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  1. Bregt S. Kappelhoff
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Correspondence to Bregt S. Kappelhoff.

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Kappelhoff, B.S., Huitema, A.D.R. & Beijnen, J.H. Should Non-Nucleoside Reverse Transcriptase Inhibitors be Combined?. Drugs R D 6, 61–69 (2005). https://doi.org/10.2165/00126839-200506020-00001

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