ZIDOVUDINE RESISTANCE MUTATIONS AND HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 DNA BURDEN - LONGITUDINAL EVALUATION OF 6 PATIENTS UNDER TREATMENT

Zidovudine (ZDV) is by far the most widely used drug to counteract hum an immunodeficiency virus type 1 (HIV-1) infection, both in monotherap y and in combination therapy regimens, However, the majority of patien ts under prolonged ZDV therapy have been shown to harbour HIV-1 mutant genomes displaying reduced sensitivity to the drug in vitro, In order to investigate the pathogenic role of in vitro resistance to ZDV, six HIV-1-infected ZDV-treated subjects were evaluated longitudinally (me an follow-up 28.5 months, range 12-39 months) for HIV-1 DNA load in pe ripheral blood mononuclear cells (PBMC) and for the presence of HIV-1p ol gene mutations responsible for ZDV resistance, Quantitation of HIV- 1 DNA was performed by competitive polymerase chain reaction (cPCR) an d the pol genotype was determined by direct sequencing of PCR products , All of the six patients developed one or more of the HIV-1 pol mutat ions known to confer resistance to ZDV in vitro (Met41 --> Leu, Asp67 --> Asn, Lys70 --> Arg, Thr215 --> Phe/Tyr, Lys219 --> Gln/Glu), A tem poral association was found between HIV-1 DNA burden and the level of ZDV resistance, as predicted on the basis of the pol genotype (genotyp ic resistance), Both virus load and ZDV resistance were inversely corr elated with CD4+ cell counts, These results are compatible with a dire ct in vivo pathogenetic role for pol gene mutations shown to be involv ed in resistance to ZDV in vitro, Monitoring the degree of genotypic r esistance to ZDV and to other antiretroviral drugs should be considere d in designing protocols for the management of treated patients.