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No Resistance to Darunavir or Lopinavir After 96 Weeks in ARTEMIS
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7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
No major protease mutations arose upon failure of darunavir/ritonavir or lopinavir/ritonavir in a 96-week analysis of the ARTEMIS trial, which enrolled previously untreated people [1]. In all darunavir and lopinavir failures analyzed to date, HIV remained susceptible to all protease inhibitors (PIs)--including the study PI--after failure. These results do not make it easier to explain why ARTEMIS researchers recorded significantly more failures with lopinavir than with darunavir at 96 weeks. Some evidence suggested worse adherence to lopinavir can be blamed.
ARTEMIS randomized 689 antiretroviral-naive people to 800/100 mg of darunavir/ritonavir once daily or to 400/100 mg of lopinavir/ritonavir twice daily or 800/200 mg once daily. People could switch from the lopinavir/ritonavir capsule to the tablet when it became available. Everyone also took tenofovir and emtricitabine. Trial participants began treatment with an average viral load of about 4.85 log (70,000 copies) and a median CD4 count of 228 in the darunavir group and 218 in the lopinavir group. About 60% in each treatment arm had subtype B virus, and fewer than 10% in each arm had AIDS.
After 48 weeks, 84% taking darunavir and 78% taking lopinavir had a viral load below 50 copies in a time-to-loss of virologic response (TLOVR) analysis, a result demonstrating the noninferiority of first-line darunavir to lopinavir [2]. Among people who began treatment with a viral load above 100,000 copies, the 48-week response rate was significantly better with darunavir than lopinavir (79% versus 67%, P < 0.05).
A week-96 TLOVR analysis determined that 79% taking darunavir and 71% taking lopinavir had a viral load under 50 copies [1]. The estimated difference in response for darunavir versus lopinavir for superiority came to 8.3% (95% confidence interval 1.8 to 14.7, P = 0.012).
Erkki Lathouwers and ARTEMIS colleagues defined failure as never reaching a viral load under 50 copies or reaching that benchmark but rebounding after week 12. By those criteria, they counted 40 failures among 343 people taking darunavir (11.7%) and 59 failures among 346 lopinavir takers (17.1%). A slightly higher proportion of failures in each group could be attributed to rebound, but half of these rebounds (12 of 24 on darunavir and 16 of 33 on lopinavir) involved transient blips above the 50-copy mark. All blippers regained an undetectable viral load. So these protocol-defined failures were not clinical failures and may not have been noticed in practice. The investigators did not analyze how eliminating blippers would affect 96-week virologic results.
Among people in whom darunavir failed, 1 (2.5%) had two pretreatment PI mutations, I84V and L90M, and 1 (2.5%) had the reverse transcriptase mutations M41L, L210W, and T215D/S/Y before starting therapy. One person in whom lopinavir failed (1.7%) had the reverse transcriptase T69D mutation before beginning treatment.
Lathouwers had genotypes for 19 people in whom darunavir failed with a load between 50 and 1000 copies and 12 people with failure at a load above 1000. Failure genotypes in the lopinavir group were available for 20 people with a load between 50 and 1000 and for 26 with a load above 1000. None of these genotypes showed a major PI mutation. One person on darunavir had the minor L10V mutation, and 2 people on lopinavir had the minor A71V/T mutation. Other people whose darunavir or lopinavir regimen failed had minor PI mutations that can be attributed to natural evolution of the virus.
Nucleoside resistance mutations emerged in 2 people whose darunavir regimen faltered (M184V and M184V/I) and in 5 whose lopinavir regimen failed (K70E, M184I, and M184V in 3 patients). Among all people whose virus was phenotyped for susceptibility to PIs before treatment and after failure, HIV always remained susceptible to all PIs, including the two study PIs.
Drug level monitoring found suboptimal concentrations of darunavir in 8 of 40 people (20%) whose regimen failed and in 11 of 303 (3.7%) without virologic failure. Lopinavir concentrations were low in 19 of 59 people (32.2%) with virologic failure and in 24 of 287 (8.6%) without failure. These findings suggest that poor adherence explains a larger proportion of lopinavir failures than darunavir failures. Results of an adherence scale (M-MASRI) supported that possibility. Nine of 38 people (23.7%) in whom darunavir failed had a suboptimal score versus 23 of 58 (39.7%) in whom lopinavir failed. However, suboptimal M-MASRI scores were also relatively frequent in people without virologic failure of darunavir (17.1%) or lopinavir (20.5%).
References
1. Lathouwers E, De Meyer S, Dierynck I, et al. Week 96 resistance analysis of the phase III ARTEMIS trial in treatment-naive patients with virological failure. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 58.
2. Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22:1389-1397.
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