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Changes in Darunavir (Prezista) Resistance Score after Previous Failure of Boosted Tipranavir (Aptivus) in Multidrug-resistant HIV Patients

Darunavir (Prezista) and tipranavir (Aptivus) are the most recently-approved protease inhibitors. Boosted with low-dose ritonavir (Norvir), they both exhibit activity against multidrug-resistant strains of HIV. However, researchers have not yet clearly defined the optimal sequencing of these 2 antiretroviral agents when used in salvage regimens for highly treatment-experienced patients [1,2].

The aim of the current study, published in the February issue of the Journal of Acquired Immune Deficiency Syndromes, was to evaluate changes in resistance to darunavir/ritonavir in patients who had experienced treatment failure on a tipranavir/ritonavir-containing regimen, and to assess virological response to darunavir/ritonavir-containing regimens after tipranavir/ritonavir failure.

Samples were obtained both at baseline and at the time of treatment failure from 47 patients on a failing tipranavir/ritonavir-containing regimen. HIV genotypes were evaluated using the Stanford mutation score; patients were ranked on the basis of tipranavir/ritonavir and darunavir/ritonavir resistance as susceptible (class 1), potential low-level resistance (class 2), low-level resistance (class 3), intermediate-level resistance (class 4), and high-level resistance (class 5). Values are expressed as median (interquartile range) or as frequency (%).

Results

• At baseline (tipranavir initiation), the scoring for tipranavir/ritonavir resistance was:
• class 3 = 4 (8.5%);
• class 4 = 31 (66%);
• class 5 = 12 (25.5%).
• Corresponding scores for darunavir/ritonavir resistance were:
• class 2 = 1 (2%);
• class 3 = 12 (25.5%);
• class 4 = 32 (68%);
• class 5 = 2 (4.5%).
• At the time of tipranavir/ritonavir failure, a shift toward a higher tipranavir/ritonavir resistance class was seen in 16 patients (34.1%) (P = 0.001).
• A shift toward a higher darunavir/ritonavir resistance class was observed in 9 patients (19.2%) (P = 0.2381).
• After tipranavir/ritonavir failure, 25 of 47 patients (53%) were treated with a darunavir/ritonavir-containing regimen.
• After 24 weeks (on-treatment analysis), the median HIV RNA decrease was 3.04 log10 copies/mL in the darunavir/ritonavir group versus -0.04 log10 copies/mL in patients not switched to a darunavir/ritonavir-containing regimen (P < 0.0001).
• The average CD4 count increase was 126 cells/mm3 in the darunavir/ritonavir group versus -42 cells/mm3 in the comparison arm (P < 0.0001).

In their discussion, the authors noted that the reverse transcriptase (RT) mutation Q151M complex confers high-level resistance to all nucleoside reverse transcriptase inhibitors (NRTIs), and a study showed that patients harboring the Q151M mutation had reduced response to rescue treatment [3].

In this study, none of the patients presenting with the Q151M mutation at baseline reached viral loads below 50 copies/mL while on tipranavir/ritonavir-containing regimens, according to the researchers. All study participants increased their tipranavir/ritonavir resistance score, and 6 of 7 patients (85.7%) had a worsened darunavir/ritonavir resistance score.

"The absence of an optimal [NRTI] backbone seems to be the main reason for the poor virological response and the consequent accumulation of new protease mutation in these patients," wrote the authors.

Based on these findings, they concluded that treatment with tipranavir/ritonavir did not significantly increase the darunavir/ritonavir resistance score and did not preclude the efficacy of subsequent treatment with darunavir/ritonavir.

Finally, they stated, "The only independent predictor of an increase in darunavir/ritonavir resistance score after failure [of] tipranavir/ritonavir-containing regimens was the presence of the Q151M mutation at baseline," adding that [56%] of the 24 patients treated with darunavir/ritonavir after tipranavir/ritonavir failure showed a 24-week virological response."

Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy.

1/27/09

Reference

V Spagnuolo, N Gianotti, E Seminari, and others. Changes in Darunavir/r Resistance Score after Previous Failure to Tipranavir/r in HIV-1-Infected Multidrug-Resistant Patients [Brief Report]. Journal of Acquired Immune Deficiency Syndromes 50(2): 192-195. February 2009.

Other citations

1. CB Hicks, P Cahn, DA Cooper, and others. Durable efficacy of tipranavir-ritonavir in combination with an optimized background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 368: 466-475. 2006.

2. B Clotet, N Bellos, JM Molina, and others. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 369: 1169-1178. 2007.

3. M Zaccarelli, CF Perno, F Forbici, and others. Q151M-mediated multi-nucleoside resistance: prevalence, risk factors, and response to salvage therapy. Clinical Infectious Diseases 38: 433-437. 2004.