Human immunodeficiency virus type 1 mutations selected in patients failingefavirenz combination therapy

Efavirenz is a potent acid selective nonnucleoside inhibitor of human immun odeficiency virus type 1 (HTV-1) reverse transcriptase (RT). Nucleotide seq uence analyses of the protease and RT genes (coding region for amino acids 1 to 229) of multiple cloned HIV-1 genomes from virus found in the plasma o f patients in phase II clinical studies of efavirenz combination therapy we re undertaken in order to identify the spectrum of mutations in plasma-born e HIV-1 associated with virological treatment failure. A K103N substitution was the HIV-1 RT gene mutation most frequently observed among plasma sampl es from patients for whom combination therapy including efavirenz failed, o ccurring in at least 90% of cases of efavirenz-indinavir or efavirenz-zidov udine (ZDV)-lamivudine (3TC) treatment failure. V108I and P225H mutations w ere observed frequently, predominantly in viral genomes that also contained other nonnucleoside RT inhibitor (NNP1TI) resistance mutations. L100I, K10 1E, K101Q, Y188H, Y188L, G190S, G190k and G190E mutations were also observe d. V106A, Y181C, and Y188C mutations, which have been associated with high levels of resistance to other NNRTIs, were rare in the patient samples in t his study, both before and after exposure to efavirenz, The spectrum of mut ations observed in cases of virological treatment failure was similar for p atients initially dosed with efavirenz at 200, 400, or 600 mg once a day an d for patients treated with efavirenz in combination with indinavir, stavud ine, or ZDV-3TC. The proportion of patients carrying NNRTI resistance mutat ions, usually K103N, increased dramatically at the time of initial viral lo ad rebound in cases of treatment failure after exposure to efavirenz, Virus es with multiple, linked NNRTI mutations, especially K103N-V108I and K103N- P225H double mutants, accumulated more slowly following the emergence of K1 03N mutant viruses.