FDA analysis of predicted responses to tipranavir/r
Simon Collins, HIV i-Base
An analysis by the FDA, the US regulatory agency, of the clinical impact of resistance on the response of protease-inhibitor resistant patients to tipranavir/r (TPV/r) was published in the 11 January issue of the AIDS.
In the review of new drug applications, the FDA independently analyses resistance data, in order to characterise a new antiretroviral drugs resistance profile. The FDA emphasises that resistance testing should be included in all phases of drug development.
Because patients in the registrational RESIST studies were stratified based on T-20 use, virologic outcomes were examined in three groups: overall (All), those not receiving T-20 (No T-20), and those receiving T-20 (+T-20) as part of optimised background regimen. Many of the analyses were focused on the No T-20 group in order to assess baseline resistance predictors of TPV/r virologic outcome without the additive effect of T-20 use on the overall response.
In their summary, the researchers showed both the number and type of baseline PI mutations affected response rates to TPV/r.
Virologic response rates in TPV/r-treated participants were reduced when isolates with amino acid substitutions at positions I13, V32, M36, I47, Q58, D60, I84 or substitutions V82S/F/I/L were present at baseline. Furthermore, virologic responses to TPV/r at week 24 decreased when the number of baseline FDA-defined primary PI mutations was five or more.
In patients not using T-20, approximately 28% achieved viral load reductions of >1 log using tipranavir compared to 11% using a comparator protease inhibitor (CPI). People with five or more PI mutations at baseline without T-20 achieved a 0.86 log median decrease in viral load on TPV/r (n = 215) compared with a 0.23 log median decrease in viral load on CPI/r treatment (n = 258). However, individuals receiving T-20 (enfuvirtide) with TPV/r were able to achieve > 1.5 log10 reductions in viral load from baseline, sustained out to 24 weeks, even with five or more baseline PI mutations. They recognised that other drugs in the background therapy in addition to T-20 could also contribute to the virologic response.
The most common mutations that developed in greater than 20% of TPV/r virologic failure isolates were L33V/I/F, V82T and I84V. Other mutations that developed in 10 to 20% of isolates included L10V/I/S, I13V, E35D/G/N, I47V, K55R, V82L and L89V/M/W. These mutations had also been seen in in vitro passaging. The V82T mutation developed frequently in 34% individuals with virologic failure especially when the V82A mutation was present at baseline.
In the RESIST trials, TPV/r resistance developed in individuals with virologic failure (n = 59) at an average of 38 weeks with a median decrease of 14-fold in TPV susceptibility. The baseline mean TPV susceptibility of the virologic failure isolates was 3.3-fold. These TPV/r resistant isolates were highly cross-resistant to other PIs. Although the resistance profile in treatment-naive individuals has not been characterised, tipranavir is no longer being studied treatment naive patients because of unacceptable risk of toxicity.
Response rates to TPV/r were also examined by TPV baseline phenotype. Based on data from the RESIST trials, baseline phenotype appears to be a predictor of response to TPV. Virologic response rates to TPV/r decreased when the shift in EC50 value from reference of TPV susceptibility was greater than three.
In participants receiving TPV/r without concomitant T-20, the proportion of responders was 45% if TPV baseline susceptibility was three-fold or less. This decreased to 21% responders when TPV susceptibility was between three and ten-fold, and dropped to 0% responders for a TPV baseline susceptibility change of greater than 10-fold.
The researchers concluded that based on these results, a baseline TPV phenotype of less than three predicts the patients HIV is susceptible to TPV. A baseline phenotype of three to ten predicts decreased susceptibility to TPV and greater than ten predicts resistance to TPV (see Table 1).
Table 1: Response by baseline tipranavir phenotype in RESIST studies
|BL TPV||% of||% of responders (with T-20) b||No. BL||No. BL TPV|
|0-3||45% (74/163)||77% (46/60)||0-2||0-4|
|>3-10||21% (10/47)||43% (12/28)||3||5-7|
|>10||0 (0/8)||57% (4/7)||4||=8|
a fold change 50% effective concentration (EC50) vs wild-type
b confirmed >1 log reduction at week 24
c from L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N33D, I84V.
Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS: Volume 21(2) 11 January 2007 p 179-185.