Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy.
Combinations of antiretroviral drugs that prevent or delay the appearance of drug-resistant human immunodeficiency virus-type 1 (HIV-1) mutants are urgently required. Mutants resistant to 3'-azidothymidine (AZT, zidovudine) became phenotypically sensitive in vitro by mutation of residue 184 of viral reverse transcriptase to valine, which also induced resistance to (-)2'-deoxy-3'-thiacytidine (3TC). Furthermore, AZT-3TC coresistance was not observed during extensive in vitro selection with both drugs. In vivo AZT-3TC combination therapy resulted in a markedly greater decreased in serum HIV-1 RNA concentrations than treatment with AZT alone, even though valine-184 mutants rapidly emerged. Most samples assessed from the combination group remained AZT sensitive at 24 weeks of therapy, consistent with in vitro mutation studies.
Larder
B A
BA
Antiviral Therapeutic Research Unit, Wellcome Research Laboratories, Beckenham, Kent, UK.
Kemp
S D
SD
Harrigan
P R
PR
D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D003062:Codon; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D006367:HeLa Cells; D006801:Humans; D019259:Lamivudine; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D012367:RNA, Viral / Q000097:blood; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D012692:Serial Passage; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
D000998:Antiviral Agents; D003062:Codon; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase