Background:  Increased plasma drug concentrations and baseline genotype and phenotype often affect HIV virologic response outcome. We explored the relationship between virologic response to tipranavir at week 24 and pharmacokinetic and resistance parameters.

Methods:  Resistance analyses were performed on 2 phase III trials, RESIST 1 and 2, which were multicentered, multinational, randomized, controlled, and open-label studies in highly treatment-experienced HIV-infected patients. Analyses evaluated virologic response (proportion of responders with a ≥1 log₁₀ reduction of viral load from baseline) based on the C_min, inhibitory quotient (IQ = C_min/ protein binding corrected IC₅₀ value) and genotypic IQ (GIQ = C_min/number of baseline PI mutations). 

Results:  The median C_min, IQ, and GIQ values for 301 patients were 34 mg/mL, 76, and 7.8, respectively. Response rates were 38% for patients with C_min values <34 mg/mL and 58% in patients with C_min values ≥34 mg/mL. Response rates for patients with 1 to 2 protease inhibitor (PI) mutations in their HIV were not affected by C_min values. However, better response rates were seen for patients with 3 to 4 baseline PI mutations if they had C_min values ≥34 mg/mL (64% vs 39%). In patients with ≥5 baseline PI mutations, response rates were reduced to approximately 30% regardless of the C_min value, unless there was concomitant enfuvirtide use. Patients with IQ values ≥76 had virologic response rates of 64%, while those with IQ values <76 had reduced virologic response rates of 29%. Similar to the IQ and C_min analyses, response rates increased as the GIQ increased. The response rate was 62% for patients with a GIQ ³7.8 compared to 34% for patients with a GIQ <7.8.

Conclusions:  Overall, response rates increased as plasma concentration increased. However, the number of baseline PI mutations and baseline tipranavir susceptibility also affected response rates to tipranavir. Therefore the IQ and GIQ, which incorporate measurements of both baseline resistance and minimum plasma concentrations, may be useful tools to predict HIV virologic response outcomes. Consistent results were seen for the IQ and GIQ analyses. Generally in clinical practice, more patients receive genotypic testing compared to phenotypic testing; therefore, the GIQ might be more available and affordable to use in the management of HIV infection; however, further confirmatory data are needed.