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The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors. 1998

V Miller, and M Stürmer, and S Staszewski, and B Gröschel, and K Hertogs, and M P de Béthune, and R Pauwels, and P R Harrigan, and S Bloor, and S D Kemp, and B A Larder
Zentrum der Inneren Medizin, J.W. Goethe Universität, Frankfurt, Germany.

OBJECTIVE To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients. METHODS A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance. RESULTS The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance. CONCLUSIONS Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir.

UI MeSH Term Description Entries
D008715 Methionine A sulfur-containing essential L-amino acid that is important in many body functions. L-Methionine,Liquimeth,Methionine, L-Isomer,Pedameth,L-Isomer Methionine,Methionine, L Isomer
D004352 Drug Resistance, Microbial The ability of microorganisms, especially bacteria, to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS). Antibiotic Resistance,Antibiotic Resistance, Microbial,Antimicrobial Resistance, Drug,Antimicrobial Drug Resistance,Antimicrobial Drug Resistances,Antimicrobial Resistances, Drug,Drug Antimicrobial Resistance,Drug Antimicrobial Resistances,Drug Resistances, Microbial,Resistance, Antibiotic,Resistance, Drug Antimicrobial,Resistances, Drug Antimicrobial
D004359 Drug Therapy, Combination Therapy with two or more separate preparations given for a combined effect. Combination Chemotherapy,Polychemotherapy,Chemotherapy, Combination,Combination Drug Therapy,Drug Polytherapy,Therapy, Combination Drug,Chemotherapies, Combination,Combination Chemotherapies,Combination Drug Therapies,Drug Polytherapies,Drug Therapies, Combination,Polychemotherapies,Polytherapies, Drug,Polytherapy, Drug,Therapies, Combination Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014633 Valine A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. L-Valine,L Valine
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D015224 Dideoxynucleosides Nucleosides that have two hydroxy groups removed from the sugar moiety. The majority of these compounds have broad-spectrum antiretroviral activity due to their action as antimetabolites. The nucleosides are phosphorylated intracellularly to their 5'-triphosphates and act as chain-terminating inhibitors of viral reverse transcription. 2',3'-Dideoxynucleosides,Dideoxyribonucleosides,ddNus,2',3' Dideoxynucleosides
D015331 Cohort Studies Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. Birth Cohort Studies,Birth Cohort Study,Closed Cohort Studies,Cohort Analysis,Concurrent Studies,Historical Cohort Studies,Incidence Studies,Analysis, Cohort,Cohort Studies, Closed,Cohort Studies, Historical,Studies, Closed Cohort,Studies, Concurrent,Studies, Historical Cohort,Analyses, Cohort,Closed Cohort Study,Cohort Analyses,Cohort Studies, Birth,Cohort Study,Cohort Study, Birth,Cohort Study, Closed,Cohort Study, Historical,Concurrent Study,Historical Cohort Study,Incidence Study,Studies, Birth Cohort,Studies, Cohort,Studies, Incidence,Study, Birth Cohort,Study, Closed Cohort,Study, Cohort,Study, Concurrent,Study, Historical Cohort,Study, Incidence
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015658 HIV Infections Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS). HTLV-III Infections,HTLV-III-LAV Infections,T-Lymphotropic Virus Type III Infections, Human,HIV Coinfection,Coinfection, HIV,Coinfections, HIV,HIV Coinfections,HIV Infection,HTLV III Infections,HTLV III LAV Infections,HTLV-III Infection,HTLV-III-LAV Infection,Infection, HIV,Infection, HTLV-III,Infection, HTLV-III-LAV,Infections, HIV,Infections, HTLV-III,Infections, HTLV-III-LAV,T Lymphotropic Virus Type III Infections, Human

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