Diagnostik der Resistenz bei der AIDS-Therapie

 

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Monitoring der antiretroviralen Therapie

Neueste Daten nationaler und lokaler Zentren deuten darauf hin, dass die Zahl der HIV-1-infizierten Patienten, die an AIDS versterben, in Deutschland drastisch zurückgegangen ist, während dies bei der Zahl der HIV-Neuinfektionen nicht der Fall ist [35]. Der Erfolg der verlangsamten Krankheitsprogression bei HIV-infizierten Patienten ist auf die Einführung und Anwendung der »highly active antiretroviral therapy« (HAART) zurückzuführen [6] [16]. Diese Therapieform umfasst die gleichzeitige Gabe von Medikamenten, die unterschiedliche Zielpunkte im Replikationszyklus des HI-Virus angreifen. Es werden nukleosidale Reverse Transkriptase-Inhibitoren (NRTI), kombiniert mit Protease-Inhibitoren (PI) oder nichtnukleosidalen RT (NNRTI), eingesetzt [11] [Tab. 1]. Diese Medikamentenkombination führt bei vielen HIV-infizierten Patienten zu einer drastischen Reduktion der Zahl an freien Virionen im Blut (Viruslast), z. T. bis unter die Nachweisgrenze der zur Zeit gängigen Testsysteme [32] [Tab. 2] . HIV-Patienten, die mit einer HAART behandelt werden, sind weniger anfällig für opportunistische Infektionen und zeigen eine verlangsamte Krankheitsprogression zum Stadium AIDS [33]. Die Viruslast (Anzahl der aus Plasmaproben extrahierbaren HIV-1-RNA-Kopien) und die Zahl der CD₄-positiven Zellen (Hauptzielzellen des HI-Virus) im Blut HIV-infizierter Patienten gelten als wichtigste Laborparameter und sollten in regelmäßigen Abständen zur Bewertung des Krankheitsstatus bestimmt werden [4] [16] [30].

Literatur

• 1 Antonelli G, Turriziani O, Verri A. et al . Long-term exposure to Zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase.  AIDS Res Hum Retrov. 1996;  12 223-228
  Google Scholar
• 2 Back D J. Pharmacological issues relating to viral resistance.  Infection. 1999;  27 S42-44
  Google Scholar
• 3 Baxter J D, Mayers D L, Wentworth D N. et al . A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS.  AIDS. 2000;  14 83-93
  Google Scholar
• 4 Berger A, Preiser W, Doerr H W. The role of viral load determination for the management of human immunodeficiency virus, hepatitis B virus and hepatitis C virus infection.  J Clin Virol. 2001;  20 23-30
  Google Scholar
• 5 Bradley G, Juranka P F, Ling V. Mechanisms of multidrug resistance.  Biochem Biophys Acta. 1988;  948 87-128
  Google Scholar
• 6 Brockmeyer N H, Salzberger B, Doerr H W, Marcus U, Brodt H R. Antiretrovirale Therapie der HIV-Infektion.  Deutsches Ärzteblatt. 2001;  4 A175-A81
  Google Scholar
• 7 Cinatl J  Jr, Cinatl J, Weber B. et al . Decreased anti-human immunodeficiency virus type-1 activities of 2’,3’-dideoxynucleoside analogs in Molt-4 cell sublines resistant to 2’,3’-dideoxynucleoside analogs.  Acta Virol. 1993;  37 360-368
  Google Scholar
• 8 Cinatl J  Jr, Gröschel B, Zehner R. et al . HIV resistance to AZT in MOLT-4/8 cells is associated with the lack of AZT phosphorylation and is bypassed by AZT-monophosphate SATE-prodrugs.  Antivir Chem Chemoth. 1997;  8 343-352
  Google Scholar
• 9 Clevenbergh P, Durant J, Halfon P. et al . Persisting long-term benefit of antiretroviral genotypic guided treatment for HIV-infected patients failing HAART.  Antiviral Ther (Abstract 60). 1999;  4 42
  Google Scholar
• 10 Cohen C, Dessler H, Hunt S. et al . Phenotypic resistance testing significantly impoves response to therapy: final analysis of a randomized trial (VIRA3001).  Antivir Ther. 2000;  5 67
  Google Scholar
• 11 Draenert R, Goebel F D. Empfehlungen und Perspektiven der antiretroviralen Therapie.  Dtsch Med Wochenschr. 2001;  126 539-543
  Google Scholar
• 12 Durant J, Clevenbergh P, Halfon P. et al . Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial.  Lancet. 1999;  353 2195-2199
  Google Scholar
• 13 Eberlein B, Baur A, Neundorfer M, Jahn G. Expression of human immunodeficiency virus (HIV) in naturally infected peripheral blood mononuclear cells: comparison of a standard co-culture technique with a newly developed microculture method.  Virus Res. 1991;  19 153-161
  Google Scholar
• 14 EuroGuidelines Group for HIV resistance . Clinical and laboratory guidelines for the use of HIV-1 drug resistance testing as part of treatment management: recommendations for the European setting.  AIDS. 2001;  15 309-320
  Google Scholar
• 15 Font E, Rosario O, Santana J, Garcia H, Sommadossi J P, Rodriguez J F. Determination of zidovudine triphosphate intracellular concentrations in peripheral blood mononuclear cells from human immunodeficiency virus-infected individuals by tandem mass spectrometry.  Antimicrob Agents Chemother. 1999;  43 2964-2968
  Google Scholar
• 16 Deutsche AIDS-Gesellschaft (DAIG). Osterreichische AIDS-Gesellschaft (OAG) . German-Austrian guidelines for antiretroviral therapy in HIV infection. June 1999.  Eur J Med Res. 2000;  5 129-138
  Google Scholar
• 17 Gröschel B, Cinatl J, Cinatl J  Jr. Viral and cellular factors for resistance against antiretroviral agents.  Intervirology. 1997;  40 400-407
  Google Scholar
• 18 Gröschel B, Cinatl J, Miller V, Doerr H W, Cinatl J  Jr. Activity of thymidine kinase 1 in PBMCs of HIV-1 infected patients: novel therapy marker.  Infection. 2000;  28 209-213
  Google Scholar
• 19 Gröschel B, Himmel N, Cinatl J. et al . ddC- and 3TC-bis(SATE) monophosphate prodrugs overcome cellular resistance mechanisms to HIV-1 associated with cytidine kinase deficiency.  Nucleos Nucleot. 1999a;  18 9219-9226
  Google Scholar
• 20 Gröschel B, Meier C, Zehner R, Cinatl J, Doerr H W, Cinatl J  Jr. Effects of cycloSal-d4TMP derivatives in H9 cells with induced AZT resistance phenotype.  Nucleos Nucleot. 1999b;  18 933-936
  Google Scholar
• 21 Hammer S M, Squires K E, Hughes M D. et al . A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team.  N Engl J Med. 1997;  337 725-733
  Google Scholar
• 22 Hertogs K, de Bethune M P, Miller V. et al . A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs.  Antimicrob Agents Chemother. 1998;  42 269-276
  Google Scholar
• 23 Hertogs K, Bloor S, De Vroey V. et al . A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V.  Antimicrob Agents Chemother. 2000;  44 568-573
  Google Scholar
• 24 Jacobsson B, Britton S, He Q, Karlsson A, Eriksson S. Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.  AIDS Res Hum Retroviruses. 1995;  11 805-811
  Google Scholar
• 25 Japour A J, Mayers D L, Johnson V A. et al . Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group.  Antimicrob Agents Chemother. 1993;  37 1095-1101
  Google Scholar
• 26 Kellam P, Larder B A. Recombinant virus-assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates.  Antimicrob Agents Chemother. 1994;  38 23-30
  Google Scholar
• 27 Kim R B, Fromm M F, 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
  Google Scholar
• 28 Larder B A, Darby G, Richmann D D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prologned therapy.  Science. 1989;  243 1731-1734
  Google Scholar
• 29 Martinez-Picado J, DePasquale M P, Kartsonis N. et al . Antiretroviral resistance during successful therapy of HIV type 1 infection.  Proc Natl Acad Sci USA. 2000;  97 10 948-10 953
  Google Scholar
• 30 Mellors J W, Rinaldo C R, Gupta P, White R M, Todd J A, Kingsley L A. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.  Science. 1996;  272 1167-1170
  Google Scholar
• 31 Miller V, de Bethune M P, 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.  Antimicrob Agents Chemother. 1998;  42 3123-3129
  Google Scholar
• 32 Miller V, Sabin C A, Phillips A N. et al . The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load.  AIDS. 2000;  14 2129-2136
  Google Scholar
• 33 Palella F J, Delaney K M, Moorman A C. et al . Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  N Engl J Med. 1998;  338 853-860
  Google Scholar
• 34 Petropoulos C J, Parkin N T, Limoli K L. et al . A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1.  Antimicrob Agents Chemother. 2000;  44 920-928
  Google Scholar
• 35 Robert Koch Institut .Berichte des AIDS-Zentrums im Robert Koch Institut über aktuelle epidemiologische Daten in Deutschland (Stand 31.12.2000). Epidemiologisches Bulletin/Sonderausgabe A 2001;27Feb: 1-16
  Google Scholar
• 36 Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger U M, Schwab M. Frequency of C34/35T polymorphism of MDR1 gene in African people.  Lancet. 2001;  358 383-384
  Google Scholar
• 37 Schuetz J D, Connelly M C, Sun D. et al . A MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs.  Nat Med. 1999;  5 1048-1051
  Google Scholar
• 38 Spielhofen A, Gröschel B, Cinatl J  Jr, Doerr H W. Genotypic and phenotypic resistance testing PCR negative HIV-1 patients on HAART.  J Clin Virol. 2000;  18 48
  Google Scholar
• 39 Spina C A, Prince H E, Richman D D. Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro.  J Clin Invest. 1997;  99 1774-1785
  Google Scholar
• 40 Stuyver L, Wyseur A, Rombout A. et al . Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene.  Antimicrob Agents Chemother. 1997;  41 284-291
  Google Scholar
• 41 Tremblay C L, Giguel F, Merrill D P. et al . Marked differences in quantity of infectious human immunodeficiency virus type 1 detected in persons with controlled plasma viremia by a simple enhanced culture method.  J Clin Microbiol. 2000;  38 4246-4248
  Google Scholar
• 42 Vahey M, Nau M E, Barrick S. et al . Performance of the Affymetrix GeneChip HIV PRT 440 platform for antiretroviral drug resistance genotyping of human immunodeficiency virus type 1 clades and viral isolates with length polymorphisms.  J Clin Microbiol. 1999;  37 2533-2537
  Google Scholar
• 43 Walter H, Schmidt B, Korn K, Vandamme A M, Harrer T, Uberla K. Rapid, phenotypic HIV-1 drug sensitivity assay for protease and reverse transcriptase inhibitors.  J Clin Virol. 1999;  13 71-80
  Google Scholar
• 44 Wijnholds J, Mol C A, van Deemter L. et al . Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs.  Proc Natl Acad Sci USA. 2000;  97 7476-7481
  Google Scholar
• 45 Wilson J W, Bean P, Robins T, Graziano F, Persing D H. Comparative evaluation of three human immunodeficiency virus genotyping systems: the HIV-GenotypR method, the HIV PRT GeneChip assay, and the HIV-1 RT line probe assay.  J Clin Microbiol. 2000;  38 3022-3028
  Google Scholar
• 46 Wong J K, Hezareh M, Gunthard H F. et al . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia.  Science. 1997;  278 1291-1295
  Google Scholar
• 47 Zhang Y M, Imamichi H, Imamichi T. et al . Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites.  J Virol. 1997;  71 6662-6670
  Google Scholar

Korrespondenz

Dr. Bettina Gröschel

Institut für Medizinische Virologie, Johann Wolfgang Goethe-Universität Frankfurt/Main

Paul-Ehrlich Straße 40

60596 Frankfurt/Main

Phone: 069/6301-7747

Fax: 069/6301-4302

Email: Groeschel@em.uni-frankfurt.de