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Lower Failure and Resistance Rates With Darunavir Than Lopinavir at 96 Weeks of TITAN
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
After 96 weeks TITAN trial investigators counted almost half as many virologic failures with darunavir as with lopinavir in antiretroviral-experienced but lopinavir-naive study participants [1]. Genotypic and phenotypic resistance proved much less common after darunavir failure than after lopinavir failure. These differences held true when the researchers limited the analysis to people with a 10-fold or less decrease in susceptibility to lopinavir or who had used no protease inhibitors (PIs) or one PI when TITAN began.
TITAN randomized 595 treatment-experienced but lopinavir-naive people to 600/100 mg of darunavir/ritonavir twice daily or 400/100 mg of lopinavir/ritonavir twice daily (in the old capsule formulation) plus an optimized background regimen. Everyone had a viral load above 1000 copies after at least 12 weeks on a stable failing regimen. Viral loads averaged about 20,000 in both treatment groups when the study began. About one third of participants in both groups had never taken a PI, one third had taken one PI, and one third had taken two or more PIs. The median number of PI resistance mutations stood at 4 in both groups. Twenty-nine people in each group (10%) had more than 10-fold loss of susceptibility to lopinavir, while only 1% to 2% had more than 10-fold resistance to darunavir.
After 96 weeks a time-to-loss-of-virologic response analysis figured a 67% sub-400-copy response rate to darunavir and a 59% response rate to lopinavir, a significant difference both in a noninferiority analysis (P < 0.001) and in a superiority analysis (P = 0.034) [2]. (These results rest on a logistic regression model including use of a nonnucleoside in the background regimen as a factor and starting viral load as a covariate.)
Among people with one or more primary PI mutations when TITAN began, 68% taking darunavir and 38% taking lopinavir had a week-96 viral load below 50 copies (P < 0.0001). Among people with no PI experience before the trial, 69% taking lopinavir and 56% taking darunavir had a sub-50 load at week 96, a difference that got close to statistical significance (P = 0.078). Among people who used one or more PIs before entering TITAN, 62% taking darunavir versus 49% taking lopinavir had a week-96 load under 50 copies (P = 0.007).
In the resistance analysis [1] the investigators defined virologic failure as a rebound from below 400 copies or never reaching a sub-400 load after week 16. With this yardstick they measured a 26% failure rate with lopinavir (76 of 297 people) and a 14% rate with darunavir (41 of 298) (P < 0.001). When the researchers looked only at people with 10-fold or lower resistance to lopinavir before TITAN began, 60 of 261 lopinavir takers (23%) and 35 of 263 darunavir takers (13%) had a virologic failure (P < 0.01). And when they limited the analysis to people who had used one or no PIs before the trial, 43 of 208 (21%) in the lopinavir arm had a virologic failure, compared with 25 of 202 (12%) in the darunavir arm (P < 0.05).
Among all people with virologic failure, primary PI mutations emerged in 33% taking lopinavir and 15% taking darunavir (P < 0.05), while nucleoside mutations arose in 26% taking lopinavir and 8% taking darunavir (P < 0.05). When the investigators confined this analysis to people with 10-fold or less resistance to lopinavir at study entry, primary PI mutations emerged in 29% taking lopinavir and 3% taking darunavir (P < 0.01). Rates of emergent nucleoside mutations in this analysis were 23% with lopinavir and 6% with darunavir (P < 0.05).
Antivirogram-measured susceptibility to the PI or the nucleosides in the regimen showed that fewer people in whom darunavir failed lost PI susceptibility (8% versus 31% with lopinavir, P < 0.05) or nucleoside susceptibility (11% versus 36%, P < 0.05). The susceptibility advantage with darunavir remained statistically significant in analyses limited to people with 10-fold or less resistance to lopinavir at study entry, or with pre-TITAN use of one or no PIs.
References
1. De Meyer S, Lathouwers E, Dierynck I, et al. Resistance development in virological failures with DRV/r or LPV/r: 96-week analysis of the phase III TITAN trial in treatment experienced patients. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract O424.
2. Banhegyi D, Katlama C, Da Cunha C, et al. Phase III TITAN week 96 final analysis: efficacy/safety of darunavir/ritonavir versus lopinavir/ritonavir in lopinavir/ritonavir-naive, treatment experienced patients. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P022.
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