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Meta-Analysis of Dolutegravir vs Guideline-Recommended Agents for Naive
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14th European AIDS Conference. October 16-19, 2013. Brussels
EACS: 48-Week Efficacy of Dolutegravir Relative to Commonly Used 3rd Agents in Treatment-Naive HIV-1-Infected Patients: A Systematic Review and Network Meta-analysis - (10/16/13)
EACS: Once-Daily Dolutegravir Versus Darunavir/Ritonavir in Antiretroviral Naïve Adults: 48 Week Subgroup Analyses from FLAMINGO - (10/17/13)
EACS: Activity of Dolutegravir (DTG) 50 mg BID vs Placebo (PBO) Over 7 Days of Functional Monotherapy in Patients Harbouring Raltegravir- and/or Elvitegravir-Resistant Virus: Primary Endpoint Results of the VIKING-4 Study (ING116529) - (10/16/13)
IDSA: Safety and Efficacy of Dolutegravir (DTG; GSK1349572) in Treatment-Experienced HIV-1 Infected Adolescents: 24-week Results from IMPAACT P1093 - (10/04/13)
Mark Mascolini
Dolutegravir, the recently licensed integrase inhibitor, proved comparable to or better than guideline-sanctioned first-line antiretroviral cornerstones in virologic response and CD4 gains, according to a meta-analysis including 46 trials [1]. Dolutegravir attained significantly better virologic suppression to a load below 50 copies at 48 weeks than regimens hinged on efavirenz, rilpivirine, or ritonavir-boosted atazanavir, darunavir, or lopinavir.
Antiretrovirals recommended as keystone agents for first-line combinations by the US DHHS or the European AIDS Clinical Society are efavirenz, rilpivirine, raltegravir, elvitegravir, and boosted atazanavir, darunavir, or lopinavir. Randomized trials have compared dolutegravir with efavirenz or raltegravir but not with the other guideline-endorsed antiretrovirals.
To get a better understanding of how first-line dolutegravir measures up to currently preferred antiretrovirals, GlaxoSmithKline researchers and collaborators conducted a systematic review of randomized controlled trials that enrolled antiretroviral-naive people at least 13 years old and included one of the comparison agents. They excluded studies of treatment interruption or switching and studies of combinations including more than one of the comparison agents.
The primary outcomes were (1) a viral load below 50 copies at week 48 figured by one of several standard methods and (2) CD4-cell change to week 48 in intention-to-treat populations. The investigators adjusted analyses for type of nucleos(t)ide backbone. The analysis focused on 81 data sources for 46 unique randomized controlled trials. Twenty-three studies had 48-week virologic suppression data and 26 had 48-week CD4-change data.
The number of trials of individual agents of interest ranged from 1 for rilpivirine to 9 for efavirenz. There were 2 trials each involving dolutegravir, elvitegravir, raltegravir, unboosted atazanavir, and darunavir.
Without considering nucleos(t)ide backbones, pooled estimates of 48-week sub-50-copy suppression were highest with dolutegravir (83%), followed by raltegravir (80%), elvitegravir (78%), rilpivirine (77%), efavirenz (74%), darunavir (73%), atazanavir (72%), and lopinavir (68%). Dolutegravir also had the highest pooled estimate of 48-week suppression when the analysis included only studies with tenofovir/emtricitabine (86%) or abacavir/lamivudine (84%).
In a backbone-adjusted analysis, odds of 48-week virologic success were greater with dolutegravir than with every comparison agent and significantly greater with dolutegravir than with every comparison agent except the two other integrase inhibitors, elvitegravir and raltegravir:
Dolutegravir vs lopinavir/ritonavir: odds ratio (OR) 2.62 (95% CI 1.63 to 3.98)
Dolutegravir vs atazanavir/ritonavir: OR 2.17 (95% CI 1.33 to 3.33)
Dolutegravir vs darunavir/ritonavir: OR 2.06 (95% CI 1.09 to 3.56)
Dolutegravir vs efavirenz: OR 1.95 (95% CI 1.34 to 2.73)
Dolutegravir vs rilpivirine: OR 1.67 (95% CI 1.03 to 2.56)
Dolutegravir vs elvitegravir/cobicistat: OR 1.56 (95% CI 0.92 to 2.46)
Dolutegravir vs raltegravir: OR 1.32 (95% CI 0.93 to 1.84)
Another backbone-adjusted analysis determined that 48-week CD4-cell gains were significantly greater with dolutegravir than with atazanavir/ritonavir, efavirenz, or lopinavir/ritonavir but not with the other comparison agents:
Dolutegravir vs atazanavir/ritonavir: mean CD4 difference 36.57 (95% CI 14.6 to 59.17)
Dolutegravir vs efavirenz: mean CD4 difference 38.62 (95% CI 19.35 to 58.15)
Dolutegravir vs lopinavir/ritonavir: mean CD4 difference 27.19 (95% CI 1.84 to 52.93)
Average 48-week CD4 gains were also greater with dolutegravir than with any other comparison agent, though those differences lacked statistical significance. CD4 gains through 48 weeks were similar with dolutegravir and raltegravir (mean difference 3.80 favoring dolutegravir, 95% CI -14.0 to 22.00).
When the CD4 analysis did not adjust for backbone agents, 48-week CD4 gains were significantly greater with dolutegravir than with atazanavir/ritonavir (mean difference 48.1), darunavir/ritonavir (mean difference 41.81), efavirenz (mean difference 50.17), elvitegravir/cobicistat (mean difference 33.37), lopinavir/ritonavir (mean difference 38.8), and rilpivirine (mean difference 33.00), but not raltegravir (mean difference 8.04 favoring dolutegravir).
Sensitivity analysis disclosed no major variation from these results. Of course findings from this type of analysis are not as robust as those from a direct randomized comparison of dolutegravir with these agents. People versed in the nuts and bolts of statistical analysis will want to know these particulars about the GlaxoSmithKline approach: "Overall relative 3rd-agent virologic suppression and CD4 change from baseline were estimated using the Bayesian fixed effect network meta-analysis methodology. Fixed effect model was chosen after consideration of population comparability and fixed and random effects model fit diagnostics (homogeneity, deviance, and fit). . . . Sensitivity analysis was conducted to assess the impact of different model specifications (ie, random effects and no backbone adjustment) on relative efficacy outcomes."
Reference
1. Patel DA, Snedecor SJ, Tang WY, et al. 48-Week efficacy of dolutegravir relative to commonly used 3rd agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. 14th European AIDS Conference. October 16-19, 2013. Brussels. Abstract PE7/7.
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