Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy

Abstract

Efavirenz is a potent and selective nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Nucleotide sequence 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 of patients in phase II clinical studies of efavirenz combination therapy were undertaken in order to identify the spectrum of mutations in plasma-borne HIV-1 associated with virological treatment failure. A K103N substitution was the HIV-1 RT gene mutation most frequently observed among plasma samples from patients for whom combination therapy including efavirenz failed, occurring in at least 90% of cases of efavirenz-indinavir or efavirenz-zidovudine (ZDV)-lamivudine (3TC) treatment failure. V108I and P225H mutations were observed frequently, predominantly in viral genomes that also contained other nonnucleoside RT inhibitor (NNRTI) resistance mutations. L100I, K101E, K101Q, Y188H, Y188L, G190S, G190A, and G190E mutations were also observed. V106A, Y181C, and Y188C mutations, which have been associated with high levels of resistance to other NNRTIs, were rare in the patient samples in this study, both before and after exposure to efavirenz. The spectrum of mutations observed in cases of virological treatment failure was similar for patients initially dosed with efavirenz at 200, 400, or 600 mg once a day and for patients treated with efavirenz in combination with indinavir, stavudine, or ZDV-3TC. The proportion of patients carrying NNRTI resistance mutations, usually K103N, increased dramatically at the time of initial viral load rebound in cases of treatment failure after exposure to efavirenz. Viruses with multiple, linked NNRTI mutations, especially K103N-V108I and K103N-P225H double mutants, accumulated more slowly following the emergence of K103N mutant viruses.

FIG. 1

Viral load (plasma-borne HIV-1) in patient 22 in study DMP 266-003. The log₁₀ of the plasma HIV-1 viral load, as measured by the Roche Amplicor HIV-1 Monitor assay, is plotted against the number of days of therapy (two different scales). ▴, time point at which plasma virus genotype was determined. The timing of efavirenz monotherapy and efavirenz plus indinavir combination therapy is indicated by the bars. EFV, efavirenz; IDV, indinavir; q8h, every 8 h.

FIG. 2

Prevalence of NNRTI resistance mutations in the plasma-borne virus of patients for whom efavirenz treatment failed. (A) Prevalence as a function of initial efavirenz dose. Shown are the percentages of patients for whom efavirenz treatment failed in whose plasma virus the listed NNRTI mutation was detected by clonal sequencing as a function of initial efavirenz dose. Linkage of mutations is not considered. Genotypic data from patients in studies DMP 266-003, -004, and -005 are included. The efavirenz dose was changed for some patients during the study. (B) Prevalence as a function of drug regimen. Shown are the percentages of patients for whom efavirenz treatment failed in whose plasma virus the listed NNRTI mutation was detected by clonal sequencing in different efavirenz-containing drug regimens. Linkage of mutations is not considered. Genotypic data from patients in studies DMP 266-003, -004, and -005 are included.

FIG. 3

Time of appearance of NNRTI resistance mutations relative to rebound in plasma virus load in study DMP 266-004 patients for whom efavirenz combination therapy failed. (A) Time of appearance of single NNRTI resistance mutations and multiple, linked NNRTI resistance mutations. The cumulative percentage of patients with sequence data available and with linked NNRTI mutations in one or more cloned viral genomes in study DMP 266-004 is plotted as a function of the interval before or after the initial rebound in viral load which defined the treatment failure day. (B) Time of appearance of specific efavirenz-selected NNRTI resistance mutations. The cumulative percentage of patients with sequence data available and with specific NNRTI mutations in one or more cloned viral genomes in study DMP 266-004 is plotted as a function of the interval before or after the initial rebound in viral load which defined the treatment failure day. Linkage of mutations is not considered.