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CD4 Gains and Side Effect Rates Differ With Age in Phase 3 QUAD Trials
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
A two-trial analysis of QUAD (elvitegravir/cobicistat plus tenofovir/emtricitabine [TDF/FTC]) showed that people over 50 years old had a virologic response rate similar to younger people in both the QUAD arms and the comparison arms [1]. But older people gained fewer CD4 cells through 48 weeks, while side effect rates varied by regimen and age.
Two phase 3 trials demonstrated that QUAD, the first fixed-dose formulation including an integrase inhibitor, is noninferior to two standard first-line regimens at 48 weeks: efavirenz plus TDF/FTC (coformulated at Atripla) [2] and atazanavir/ritonavir plus TDF/FTC [3]. To compare outcomes in trial participants 50 and older with outcomes in younger participants, QUAD researchers conducted this analysis.
The QUAD-Atripla review involved 49 people 50 or older in the QUAD arm and 299 younger than 50. Respective numbers in the Atripla arm were 56 and 296. In the QUAD-atazanavir study there were 48 people 50 or older in the QUAD arm and 305 younger than 50. Respective numbers in the atazanavir arm were 48 and 307.
Proportions of study participants who had a viral load below 50 copies in a 48-week snapshot analysis did not differ much between 50-plus and under-50 people in the QUAD arm of the QUAD-Atripla study (86% versus 88%), in the Atripla arm (82% versus 84%), in the QUAD arm of the QUAD-atazanavir study (94% versus 89%), or in the atazanavir arm (88% versus 87%).
Average CD4 gains were lower in people 50 and older than in younger trial participants regardless of the regimen, a finding that may reflect slowing thymic output of T cells with age. In the QUAD-Atripla comparison, CD4 gains at week 48 averaged 199 with QUAD in people 50 and older, 246 with QUAD in younger people, 194 with Atripla in the older group, and 208 with Atripla in the younger group. In the QUAD-atazanavir trial, average CD4 gains in younger people were similar with QUAD and atazanavir (212 and 213). In older people average CD4 gains were lower than in younger people and nonsignificantly lower with QUAD than atazanavir (176 versus 200, P = 0.38).
In the QUAD-Atripla study, adverse events leading to discontinuation were more frequent among older people in the QUAD arm (6.1% versus 3.3% in younger people) and in the Atripla arm (10.7% versus 4.1%). In the QUAD-atazanavir study, QUAD takers 50 or older had a slightly lower rate of adverse events leading to discontinuation than younger people (2.1% versus 3.9%), but in the atazanavir arm the older group had a higher dropout rate (9% versus 4.9%). Serious adverse event rates were similar across arms and age groups in this trial, at about 8%.
In the QUAD-Atripla study, median change in estimated glomerular filtration rate (eGFR) was greater in the QUAD arms (-12.0 for 50 and older, -14.8 for younger) than in the Atripla arm (-7.5 for 50 and older, -1.6 for younger). Cobicistat and TDF both lower eGFR, but cobicistat has little impact on actual GFR [4]. Median changes in eGFR in the QUAD-atazanavir study did not differ much by age or regimen (-10.2 for 50 and older with QUAD, -13.4 for younger with QUAD, -7.3 for 50 and older with atazanavir, and -10.0 for younger with atazanavir).
In the QUAD-Atripla study, rash and neuropsychiatric side effects were less frequent with QUAD than with Atripla. In the QUAD arm those side effects were less frequent in the older group than the younger group (32.7% versus 44.5% for neuropsychiatric side effects, and 10.2% versus 18.1% for rash).
Changes in fasting triglycerides through 48 weeks went in different directions in the different treatment arms, depending on age. Among people under 50 in the QUAD-Atripla study, triglycerides rose less than 10 mg/dL in both the QUAD arm and the Atripla arm, and these gains did not differ significantly between arms. Among people 50 or older in that study, triglycerides climbed about 20 mg/dL with QUAD versus about 5 mg/dL with Atripla, but that difference lacked statistical significance (P = 0.13). Among younger people in the QUAD-atazanavir study, triglycerides jumped about 25 mg/dL with atazanavir versus less than 10 mg/dL with QUAD, a significant difference (P = 0.001). But in the older group in this study triglycerides climbed about 15 mg/dL with QUAD while falling marginally with Atripla (P = 0.001).
The slower CD4 gains and higher side effect rates in people over 50 in this 48-week analysis differ from results of a 96-week comparison of the nonnucleosides rilpivirine and efavirenz (reviewed separately by NATAP) [5]. In the rilpivirine-efavirenz two-trial analysis, CD4 gains were not blunted with age and side effects were generally similar across age groups.
References
1. Richmond GJ, Ruane P, Robbins W, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) demonstrates comparable efficacy and favorable tolerability to efavirenz/emtricitabine/ tenofovir DF in patients ≥50 years. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-879.
2. Sax PE, DeJesus E, Mills A, Zolopa A, et al; GS-US-236-0102 study team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379:2439-2448. Erratum in Lancet. 2012;380:730.
3. DeJesus E, Rockstroh JK, Henry K, et al; GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379:2429-2438.
4. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61:32-40.
5. Ryan R, Dayaram Y, Schaible D, et al. Older patients showed similar efficacy and safety results compared to younger participants over 96 weeks in the phase III ECHO and THRIVE trials of treatment-naive HIV-1-infected patients treated with rilpivirine or efavirenz. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-880.
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