Current HIV/AIDS Reports

, Volume 1, Issue 3, pp 116–121 | Cite as

Management of HIV-infected patients with multidrug-resistant virus

  • Marianne Harris
  • Julio S. G. Montaner
Article

Abstract

Treatment-experienced patients with HIV may harbor virus that has accumulated several mutations conferring decreased susceptibility to one or more antiretroviral drugs. For clinicians treating these patients, identifying a tolerable antiretroviral regimen with a reasonable chance of a durable virologic effect represents a major challenge. The first priority is to identify and correct the mechanisms responsible for previous treatment failure. Resistance testing and drug level monitoring may be useful in this setting. The patient’s history of antiretroviral drug tolerability, comorbidities, and concomitant medications should be considered. Patients embarking on multiple-drug regimens will require close monitoring for adherence, toxicities, and drug-drug interactions. The guiding principle when constructing a rescue or salvage regimen is to achieve a cumulative activity score greater than 2, recognizing that some agents will have only partial activity. Some new drugs are available that may be helpful if used carefully with an active background regimen.

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References and Recommended Reading

  1. 1.
    Mocroft A, Ledergerber B, Viard JP, et al.: Time to triple drug class failure after initiation of HAART [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  2. 2.
    Fessel WJ, Rhee SY, Hurley L, et al.: High-level dual and triple class multi-drug resistance in a large health maintenance organization: prevalence, risk factors, and response to salvage therapy [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  3. 3.
    Yeni PG, Hammer SH, Carpenter CC, et al.: Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002, 288:222–235.PubMedCrossRefGoogle Scholar
  4. 4.
    Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.AIDSinfo.nih.gov. Accessed November 10, 2003.Google Scholar
  5. 5.
    Jemsek J, Hutcherson P, Harper E: Poor virologic responses and early emergence of resistance in treatment naïve HIV infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  6. 6.
    Landman R, Peytavin G, Descamps D, et al.: Low genetic barrier to resistance is a possible cause of early virologic failures in once-daily regimens of abacavir, lamivudine, and tenofovir: the Tonus study [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  7. 7.
    Parikh U, Koontz D, Sluis-Cremer N, et al.: K65R: a multinucleoside resistance mutation of increasing prevalence exhibits bi-directional phenotypic antagonism with TAM [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  8. 8.
    Viread Product Monograph. Foster City, CA: Gilead Sciences, Inc.; 2003.Google Scholar
  9. 9.
    Back D, Gatti G, Fletcher C, et al.: Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 2002, 16(Suppl 1):S5-S37.PubMedCrossRefGoogle Scholar
  10. 10.
    Chesney M: Adherence to HAART regimens. AIDS Patient Care STDS 2003, 17:169–177.PubMedCrossRefGoogle Scholar
  11. 11.
    Hogg RS, Yip B, Chan KJ, et al.: Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001, 286:2568–2577. Analysis of a population of more than 1200 antiretroviral-naïve adults demonstrating consistently low rates of HIV disease progression to AIDS or death among those patients who start antiretroviral therapy with CD4 cell counts of 200/mm3 or greater. This is the first major study that led to changes in treatment guidelines to now recommend that antiretroviral therapy can be deferred in asymptomatic patients until the CD4 approaches this threshold.PubMedCrossRefGoogle Scholar
  12. 12.
    Toulson AR, Harrigan PR, Yip B, et al.: Evaluation of outcomes following structured treatment interruption (STI) among patients with prior nadir CD4 > 200 cells/mm3 [abstract]. Paper presented at the 13th Annual Canadian Conference on HIV/ AIDS Research. Montreal, Canada; May 13–16, 2004.Google Scholar
  13. 13.
    Clavel F, Hance AJ: HIV drug resistance. N Engl J Med 2004, 350:1023–1035.PubMedCrossRefGoogle Scholar
  14. 14.
    Hirsch MS, Brun-Vezinet F, Clotet B, et al.: Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis 2003, 37:113–128.PubMedCrossRefGoogle Scholar
  15. 15.
    Larder B, De Vroey V, Dehertogh P, et al.: Predicting HIV-1 phenotypic resistance from genotype using a large phenotype-genotype relational database. Antiviral Ther 1999, 4(Suppl 1):41.Google Scholar
  16. 16.
    Perez-Elias MJ, Garcia-Arota I, Munoz V, et al.: Phenotype or virtual phenotype for choosing antiretroviral therapy after failure: a prospective randomized study. Antiviral Ther 2003, 8:577–584.Google Scholar
  17. 17.
    Miller V, Sabin C, Hertogs K, et al.: Virological and immunological effects of treatment interruptions in HIV-infected patients with treatment failure. AIDS 2000, 14:2857–2867.PubMedCrossRefGoogle Scholar
  18. 18.
    Kearney M, Palmer S, Maldarelli F, et al.: Single-genome sequencing is more sensitive than standard genotype analysis for detection of HIV-1 drug-resistance mutations [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  19. 19.
    Mellors J, Palmer S, Nissley D, et al.: Low-frequency NNRTIresistant variants contribute to failure of efavirenz-containing regimens [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  20. 20.
    Charpentier C, Morand-Joubert L, Chene G, et al.: Detection of pre-existing minority viral populations contributing to the evolution of resistance to protease inhibitors [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  21. 21.
    Lawrence J, Mayers D, Hullsiek KH, et al.: Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003, 349:837–846. A randomized study in which 270 patients with multidrug-resistant HIV received multiple-drug rescue therapy, selected using phenotypic and genotypic information, preceded or not preceded by a 4-month treatment interruption. Treatment interruption before rescue therapy was associated with greater rates of HIV disease progression and no demonstrable immunologic, virologic, or quality-of-life benefits.PubMedCrossRefGoogle Scholar
  22. 22.
    Ruiz L, Ribera E, Bonjoch A, et al.: Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis 2003, 188:977–985.PubMedCrossRefGoogle Scholar
  23. 23.
    Katlama C, Dominguez S, Gourlain K, et al.: Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). AIDS 2004, 18:217–226.PubMedCrossRefGoogle Scholar
  24. 24.
    Hirschel B: Beware of drug holidays before HIV salvage therapy. N Engl J Med 2003, 349:827–828.PubMedCrossRefGoogle Scholar
  25. 25.
    Montaner JS, Harrigan PR, Jahnke N, et al.: Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens. AIDS 2001, 15:61–69.PubMedCrossRefGoogle Scholar
  26. 26.
    Miller V, Cozzi-Lepri A, Hertogs K, et al.: HIV drug susceptibility and treatment response to mega-HAART regimens in patients from the Frankfurt HIV cohort. Antiviral Ther 2000, 5:49–55.Google Scholar
  27. 27.
    DeGruttola V, Dix L, D’Aquila R, et al.: The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antiviral Ther 2000, 5:41–48.Google Scholar
  28. 28.
    Mauss S, Schmutz G, Kuschak D: Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir? AIDS 2002, 16:296–297.PubMedCrossRefGoogle Scholar
  29. 29.
    Basso S, Solas C, Quinson AM, et al.: Pharmacokinetic interaction between lopinavir/r and amprenavir in salvage therapy. J Acquir Immune Defic Syndr 2002, 31:115–117.PubMedGoogle Scholar
  30. 30.
    Wynn Vezina HE, Brundage RC, Bushman L, Fletcher CV: Pharmacologic management of the drug-drug interaction between lopinavir/ritonavir and amprenavir [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  31. 31.
    Corbett AH, Davidson L, Park JJ, et al.: Dose separation strategies to overcome pharmacokinetic interaction of a triple protease inhibitor regimen containing fosamprenavir, lopinavir, and ritonavir [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  32. 32.
    Wire MB, Naderer OJ, Masterman AL, et al.: The pharmacokinetic interaction between GW433908 and lopinavir/ ritonavir (APV10011 and APV10012) [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  33. 33.
    Deeks SG, Wrin T, Liegler T, et al.: Virologic and immunologic consequences of discontinuing combination antiretroviraldrug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001, 344:472–480.PubMedCrossRefGoogle Scholar
  34. 34.
    Deeks SG, Barbour JD, Grant RM, Martin JM: Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002, 16:201–207.PubMedCrossRefGoogle Scholar
  35. 35.
    Squires K, Pozniak AL, Pierone G Jr, et al.: Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003, 139:313–320.PubMedGoogle Scholar
  36. 36.
    Coca S, Perazella MA: Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci 2002, 324:342–344.PubMedCrossRefGoogle Scholar
  37. 37.
    Verhelst D, Monge M, Meynard JL, et al.: Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002, 40:1331–1333.PubMedCrossRefGoogle Scholar
  38. 38.
    Peyriere H, Reynes J, Rouanet I, et al.: Renal tubular dysfunction associated with tenofovir therapy: report of seven cases. J Acquir Immune Defic Syndr 2004, 35:269–273.PubMedCrossRefGoogle Scholar
  39. 39.
    Harris M, Yip B, Zalunardo N, et al.: Increases in creatinine during therapy with tenofovir DF [abstract]. Antiviral Ther 2003, 8(Suppl 1):S197.Google Scholar
  40. 40.
    Reyataz Product Monograph. Montreal, Canada: Bristol-Myers Pharmaceutical Group; 2003.Google Scholar
  41. 41.
    Haas DW, Zala C, Schrader S, et al.: Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 2003, 17:1339–1349.PubMedCrossRefGoogle Scholar
  42. 42.
    Badaro R, DeJesus E, Lazzarin A, et al.: Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS AI424-045 [abstract]. Antiviral Ther 2003, 8(Suppl 1):S212-S213.Google Scholar
  43. 43.
    DeJesus E, Grinsztejn B, Rodriguez C, et al.: Efficacy and safety of atazanavir with ritonavir or saquinavir vs lopinavir/ ritonavir in patients who have experienced virologic failure on multiple HAART regimens: 48-week results from BMS A1424-045 [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.Google Scholar
  44. 44.
    Lalezari JP, Henry K, O’Hearn M, et al.: Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003, 348:2175–2185. One of two large randomized international studies demonstrating the 24-week immunologic and virologic benefits of enfuvirtide, in addition to an optimized background regimen of three to five antiretroviral drugs in heavily treatment-experienced patients. These studies led to the regulatory approval of enfuvirtide, the first HIV-1 fusion inhibitor.PubMedCrossRefGoogle Scholar
  45. 45.
    Lazzarin A, Clotet B, Cooper D, et al.: Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003, 348:2186–2195. One of two large randomized international studies demonstrating the 24-week immunologic and virologic benefits of enfuvirtide, in addition to an optimized background regimen of three to five antiretroviral drugs in heavily treatment-experienced patients. These studies led to the regulatory approval of enfuvirtide, the first HIV-1 fusion inhibitor.PubMedCrossRefGoogle Scholar
  46. 46.
    Katlama C, Arasteh K, Clotet B, et al.: Enfuvirtide TORO studies: 48 week results confirm 24-week findings [abstract]. Paper presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France; July 13–16, 2003.Google Scholar
  47. 47.
    Montaner J, DeMasi R, Delehanty J, et al.: Analysis of virological response of enfuvirtide in TORO: implications for patient management [abstract]. Antiviral Ther 2003, 8(Suppl 1):S212.Google Scholar
  48. 48.
    Yeni P: Tipranavir: a protease inhibitor from a new class with distinct antiviral activity. J Acquir Immune Defic Syndr 2003, 34:S91-S94.PubMedCrossRefGoogle Scholar
  49. 49.
    Gathe J, Kohlbrenner VM, Pierone G, et al.: Tipranavir/ ritonavir demonstrates potent efficacy in multiple protease inhibitor-experienced patients: BI 1182.52 [abstract]. Paper presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 10–14, 2003.Google Scholar
  50. 50.
    Leith J, Walmsley S, Katlama C, et al.: Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51 [abstract]. Paper presented at the 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy; March 11–13, 2004.Google Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Marianne Harris
  • Julio S. G. Montaner
    • 1
  1. 1.British Columbia Centre for Excellence in HIV/AIDSProvidence Health Care/University of British ColumbiaVancouverCanada

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