Human immunodeficiency virus type 1 expressing the lamivudine-associated M184V mutation in reverse transcriptase shows increased susceptibility to adefovir and decreased replication capability in vitro.
In a phase II study of 6-12 months of adefovir dipivoxil treatment in human immunodeficiency virus (HIV)-infected patients, HIV from 8 of 29 patients developed mutations in reverse transcriptase (RT) potentially attributable to adefovir dipivoxil therapy. Recombinant HIV from pre- and posttreatment plasma samples from these 8 patients showed no change or minor decreases in adefovir susceptibility, consistent with the durable antiviral effect observed. Additionally, HIV from 8 patients developed the M184V RT mutation because of concomitant lamivudine use. Recombinant HIV pairs from all 4 patients with zidovudine-resistant HIV showed statistically significant increases in adefovir susceptibility of 3- to 4-fold (to near wild type IC50), and HIV pairs from 2 of 4 patients with zidovudine-sensitive HIV showed a 2- to 3-fold increase in susceptibility. In growth kinetics studies, expression of the M184V RT mutation resulted in attenuated viral growth in peripheral blood mononuclear cell cultures. These studies suggest that patients possessing HIV with zidovudine and lamivudine resistance mutations may benefit from adefovir dipivoxil therapy.
Miller
M D
MD
Gilead Sciences, Foster City, California, USA. Michael_Miller@gilead.com
Anton
K E
KE
Mulato
A S
AS
Lamy
P D
PD
Cherrington
J M
JM
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D063065:Organophosphonates; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D015215:Zidovudine / Q000627:therapeutic use
D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D000225:Adenine; C106812:adefovir dipivoxil