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Failure and Resistance Differences Between Darunavir and Lopinavir in TITAN
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
(Poster online at http://www.retroconference.org/2008/PDFs/874.pdf.)
Mark Mascolini
Virologic failure proved twice as likely with lopinavir/ritonavir as with darunavir/ritonavir among antiretroviral-experienced but lopinavir-naive people in the TITAN trial [1]. And when failure occurred, lower proportions of people taking darunavir than lopinavir had new primary protease inhibitor (PI) mutations or nucleoside mutations.
TITAN involved 595 PI-experienced or -naive people with a viral load above 1000 copies while taking a stable antiretroviral regimen for at least 12 weeks. Enrollees could also be on a drug holiday. Everyone had antiretroviral experience, but no one had taken lopinavir, darunavir, tipranavir, the fusion inhibitor enfuvirtide, or investigational antiretrovirals. Study participants got randomized to darunavir/ritonavir or the capsule formulation of lopinavir/ritonavir plus an optimized background regimen that could include nucleosides and a nonnucleoside but not enfuvirtide.
When TITAN began 187 people (31%) had no PI experience and 488 (82%) had virus susceptible to four or more PIs. Treatment groups did not differ substantially in median baseline primary PI mutations (0), PI resistance-associated mutations (4), or nucleoside-related mutations (2). Most study participants had virus highly susceptible to darunavir (median fold-change in susceptibility 0.6) and lopinavir (median 0.75) when TITAN began.
In short, ample proportions of study participants had virus that should have responded to a strong PI regimen. And most people did respond well, though after 48 weeks of treatment, significantly more people taking darunavir than lopinavir had a viral load below 400 copies, 77% versus 68% [2]. Defining virologic failure as never reaching a load below 400 copies or going under 400 and rebounding, the investigators counted half as many failures in the darunavir group as in the ritonavir group. And fewer PI or nucleoside mutations arose upon failure of darunavir versus ritonavir:
· Failures: 31 of 298 (10.4%) with darunavir versus 65 of 297 (21.9%) with lopinavir
· New primary PI mutations upon virologic failure: 6 of 28 (21.4%) with darunavir versus 20 of 56 (35.7%) with lopinavir
· New nucleoside mutations upon virologic failure: 4 of 28 (14.3%) with darunavir versus 15 of 56 (26.8%) with lopinavir
· Loss of susceptibility to PI in regimen (by Antivirogram): 3 of 28 (10.7%) with darunavir versus 13 of 54 (24.1%) with lopinavir
· Loss of susceptibility to nucleoside in regimen: 3 of 28 (10.7%) with darunavir versus 14 of 28 (50%) with lopinavir
Higher proportions of people with darunavir failure than with lopinavir failure retained susceptibility to fosamprenavir, atazanavir, and saquinavir. About 90% in each group retained susceptibility to tipranavir after failure. The French (ANRS) genotype-based resistance method confirmed Antivirogram-figured phenotypic estimates of resistance to PIs after failure.
One person in whom darunavir failed with the L90M mutation had that mutation at screening but not at baseline. The other five primary PI mutations spotted upon failure of darunavir were I54L in 1 person, I47V in 2, and L76V in 2--all of them darunavir-associated changes. People in whom these mutants emerged had already taken two to six PIs. Familiar lopinavir-associated mutations arose upon failure of that PI.
References
1. De Meyer S, Lathouwers E, Dierynck I, et al. Characterization of virologic failures on darunavir/ritonavir in the randomized, controlled, phase III TITAN trial in treatment-experienced patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 874.
2. Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370:49-58.
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