Summary
Zidovudine (ZDV) is by far the most widely used drug to counteract human immunodeficiency virus type 1 (HIV-1) infection, both in monotherapy and in combination therapy regimens. However, the majority of patients under prolonged ZDV therapy have been shown to harbour HIV-1 mutant genomes displaying reduced sensitivity to the drugin vitro. In order to investigate the pathogenic role ofin vitro resistance to ZDV, six HIV-1-infected ZDV-treated subjects were evaluated longitudinally (mean follow-up 28.5 months, range 12–39 months) for HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) and for the presence of HIV-1pol gene mutations responsible for ZDV resistance. Quantitation of HIV-1 DNA was performed by competitive polymerase chain reaction (cPCR) and thepol genotype was determined by direct sequencing of PCR products. All of the six patients developed one or more of the HIV-1pol mutations known to confer resistance to ZDVin vitro (Met41→Leu, Asp67→Asn, Lys70→Arg, Thr215→Phe/Tyr, Lys219→Gln/Glu). A temporal association was found between HIV-1 DNA burden and the level of ZDV resistance, as predicted on the basis of thepol genotype (genotypic resistance). Both virus load and ZDV resistance were inversely correlated with CD4+ cell counts. These results are compatible with a directin vivo pathogenetic role forpol gene mutations shown to be involved in resistance to ZDVin vitro. Monitoring the degree of genotypic resistance to ZDV and to other antiretroviral drugs should be considered in designing protocols for the management of treated patients.
Zusammenfassung
Zidovudin (ZDV) ist das Medikament, das weitaus am häufigsten in Monotherapie oder Kombinationstherapie zur Behandlung von Infektionen durch HIV-1 eingesetzt wird. Unter Langzeitbehandlung mit ZDV wurden jedoch bei der Mehrzahl der Patienten HIV-1-Mutanten mit reduzierterIn-vitro-Empfindlichkeit gegen das Medikament nachgewiesen. Um die pathogene Bedeutung derIn vitro-Resistenz gegen ZDV zu untersuchen, wurden die HIV-1 DNA-Last in mononukleären Zellen des peripheren Blutes und das Vorliegen von für die ZDV-Resistenz verantwortlichen HIV-1pol-Genmutationen bei sechs HIV-infizierten Patienten unter ZDV-Therapie in einer Längsschnittstudie (mit mittlerer Beobachtungszeit von 28.5 Monaten, Bereich 12–39 Monate) gemessen. Die quantitative Bestimmung der HIV-1 DNA erfolgte durch kompetitive Polymerasekettenreaktion (cPCR). Derpol-Genotyp wurde durch direkte Sequenzierung der PCR-Produkte ermittelt. Alle sechs Patienten entwickelten eine oder mehrere der HIV-1 Mutationen, deren Assoziation mitIn vitro-Resistenz gegen ZDV bekannt ist (Met41→Leu, Asp67→Asn, Lys70→Arg, Thr215→Phe/Tyr, Lys219→Gln/Glu). Zwischen dem auf der Basis derpol-Genotypen (Genotypresistenz) vorhergesagten Spiegel der ZDV-Resistenz und der HIV-1 DNA-Last fand sich eine zeitliche Assoziation. Sowohl die Viruslast wie auch die ZDV-Resistenz standen in umgekehrter Beziehung zu den CD4+-Zellzahlen. Diese Ergebnisse sind mit direkten pathogenenin vivo-Effekten der für die ZDV-Resistenzin vitro verantwortlichenpol-Genmutationen vereinbar. Das Monitoring des Ausmaßes genotypischer Resistenz gegen ZDV und andere antiretrovirale Substanzen sollte bei der Entwicklung von Behandlungsprotokollen berücksichtigt werden.
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Zazzi, M., Catucci, M., De Milito, A. et al. Zidovudine resistance mutations and human immunodeficiency virus type 1 DNA burden: Longitudinal evaluation of six patients under treatment. Infection 24, 419–425 (1996). https://doi.org/10.1007/BF01713041
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DOI: https://doi.org/10.1007/BF01713041