Prospective Trials of Drug Resistance Testing

NARVAL

French investigators compared genotype (TruGene), phenotype, and standard of care in a randomized trial of 541 patients failing a 3-drug PI-containing regimen with plasma HIV-1 RNA levels >1000 copies/mL (23). Most patients were heavily pre-treated, having received a median of seven drugs. An important difference between this study and other studies is that in the phenotyping arm, investigators provided clinicians with a ranked list of possible regimens based on the fold-resistance resistance testing of the drugs; no such listing was offered to patients in the genotype or standard of care arms. Expert advice was followed by clinicians approximately 85% of the time. Patients were stratified at entry on the basis of virus load and prior treatment experience. No significant difference between arms was found at week 12 for either the percent of patients with plasma HIV-1 RNA <200 copies/mL or for the percent of patients showing a >1-log10 decrease in virus load from baseline. There was a trend favoring the genotyping arm at week 24. Significantly more patients in the genotyping arm than in the standard of care arm achieved plasma HIV-1 RNA levels <200 copies/mL at weeks 12 and 24.

A number of factors may explain the failure to find a significant benefit of resistance testing in NARVAL. Patients in this study had substantially greater prior treatment experience than in the GART and Viradapt studies. In addition, there were considerable differences between the phenotype and genotype arms in classification of patient samples with regard to resistance to d4T, 3TC, and abacavir (24). For example, 56% were considered resistant to d4T by genotype, but only 24% were resistant by phenotype. By contrast, 62% were considered 3TC-resistant by genotype compared to 81% by phenotype. In the case of abacavir, 84% were classified as resistant by genotype vs 41% by phenotype. This discrepancies could have led to incorrect treatment recommendations that may have altered the outcome of the trial. Despite these shortcomings, NARVAL does point out the importance of validating interpretation of genotypes and phenotypes on the basis of clinical outcome, and suggests that resistance testing may be less useful in highly treatment-experienced patients with few remaining treatment options.

4/15/01

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