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.

DESIGN

Descriptive case series.

SETTING

Academic medical center.

PATIENTS

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.

MEASUREMENTS

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.