Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients.
BACKGROUND
Drug resistance of HIV-1 is an obstacle to the long-term efficacy of antiretroviral therapy.


OBJECTIVE
To characterize reverse transcriptase and protease genes of multidrug-resistant HIV-1 isolates.


METHODS
Descriptive case series.


METHODS
Academic medical center.


METHODS
Four consecutive patients with HIV-1 infection were selected because they had previously received many antiretroviral drugs and had not achieved plasma HIV-1 RNA suppression despite treatment with several three-drug combinations.


METHODS
Reverse transcriptase sequencing, protease sequencing, and drug susceptibility testing of HIV-1.


RESULTS
Isolates of HIV-1 from the four patients shared seven protease mutations and eight reverse transcriptase mutations. These mutations were present in biological clones and at three time points in three of the patients. Susceptibility testing showed high-level resistance (30-fold to >100-fold) to zidovudine, lamivudine, saquinavir, indinavir, and nelfinavir and lower-level resistance (3-fold to 5-fold) to didanosine, zalcitabine, and stavudine.


CONCLUSIONS
Simultaneous resistance to almost all available antiretroviral drugs may occur in HIV-1. The concordance and persistence of mutations in drug-resistant HIV-1 isolates suggest that some combinations of reverse transcriptase and protease mutations give the virus a selective advantage in the presence of various drug combinations.
Shafer
R W
RW
Stanford University Medical Center, California 94305, USA. rshafer@cmgm.stanford.edu
Winters
M A
MA
Palmer
S
S
Merigan
T C
TC
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D010450:Endopeptidases / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012367:RNA, Viral / Q000097:blood
D019380:Anti-HIV Agents; D012367:RNA, Viral; D054303:HIV Reverse Transcriptase; D010450:Endopeptidases