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Switch to Boosted PI/3TC Noninferior to Triple Therapy in 4-Trial Analysis
  16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
Individual patient data meta-analysis of four randomized trials determined that switching to dual therapy with a ritonavir-boosted protease inhibitor (PI) plus lamivudine (3TC) is virologically noninferior to maintaining standard PI triple therapy according to former and current FDA endpoints [1]. Gender, HCV status, and type of PI did not affect virologic outcomes.
Four trials found switching to dual therapy with a boosted PI plus 3TC virologically noninferior to continued PI-based triple therapy with a noninferiority margin of 12%. But researchers who conducted this meta-analysis noted that all these trials had fewer than 150 participants in each arm and that efficacy of dual therapy remains uncertain in subgroups of people with HIV. Furthermore, the FDA updated its guidelines for switch trials in 2015, setting a sterner noninferiority margin of 4%.
Researchers in the Spanish GESIDA group aimed to address these issues in an individual patient data meta-analysis of trials testing a switch from a stable boosted-PI triple-therapy regimen to PI/3TC dual therapy in adults. The primary endpoint was noninferiority of a switch to dual therapy versus continued triple therapy with the current FDA endpoint of a 4% noninferiority margin for virologic failure, defined as a viral load at or above 50 copies at week 48 in a snapshot analysis.
The researchers identified four randomized controlled trials with 1051 participants that met their inclusion criteria. The trials were DUAL (n = 249), SALT (n = 286), OLE (n = 250), and ATLAS (n = 266), which tested boosted lopinavir, atazanavir, or darunavir. Median ages in the pooled dual-therapy and triple-therapy arms were 44 and 45, about three quarters of participants were men, and just under one quarter had HCV infection. Median CD4 count stood at 592 in the pooled dual-therapy arms and 612 in the pooled triple-therapy arms. About three quarters of all participants took tenofovir disoproxil fumarate as part of their triple regimen.
A 48-week pooled analysis found that 4% of participants randomized to switch to PI/3TC dual therapy versus 3.04% randomized to maintain triple therapy had a viral load at or above 50 copies (difference 0.9%, 95% confidence interval [CI] -1.3% to 3.2%), a result establishing the noninferiority of triple therapy by the newer FDA standard. This outcome difference was not significantly affected by the individual PI used (ritonavir-boosted lopinavir, atazanavir, or darunavir), by gender, or by HCV status.
After 48 weeks 84.7% randomized to dual therapy and 83.2% assigned to maintain triple therapy had a viral load below 50 copies in a pooled analysis (difference 1.47%, 95% CI -2.9% to 5.8%), confirming the noninferiority of dual therapy with a 12% noninferiority margin. Again, results of this secondary analysis were not affected by type of PI, gender, or HCV status.
CD4 gains through 48 weeks tended to favor the dual-therapy group (+29.6 CD4s with dual therapy versus +13.8). Changes in low-density lipoprotein cholesterol significantly favored the triple-therapy group (+6.9 with dual therapy versus -1.01 mg/dL), as did changes in triglycerides (+8.77 with dual therapy versus -4.75). Change in glomerular filtration rate significantly favored the dual-therapy arms (+3.32 with dual therapy versus -1.89 mL/min).
1. Perez-Molina JA, Pulido F, Di Giambenedetto S, et al. Individual patient data meta-analysis of randomized controlled trials of dual therapy with a boosted protease inhibitor plus lamivudine for maintenance of virological suppression (Gesida Study 9717). 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PS1/1.