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RNA and CD4 Responses, Side Effect Rates, Similar Across Age Groups in Rilpivirine Trials
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
Virologic and CD4 responses of antiretroviral-naive people starting rilpivirine or efavirenz in phase 3 trials did not differ by age group [1], according to a 96-week analysis of ECHO [2] and THRIVE [3]. Rates of drug-related adverse events were generally higher with efavirenz than with rilpivirine but did usually not vary much by age.
Rilpivirine, the most recently licensed nonnucleoside reverse transcriptase inhibitor (NNRTI), proved noninferior to efavirenz at 48 weeks in these trials. The virologic failure rate was somewhat higher with rilpivirine in both ECHO and THRIVE essentially in the patients with baseline viral load >100,000 c/ml, and rilpivirine safety profiles were better. Study participants also took tenofovir/emtricitabine (TDF/FTC) in ECHO and TDF/FTC or abacavir/lamivudine in THRIVE.
Because hepatic, renal, and immune functions decline with age, and because comorbidity rates increase, Janssen researchers conducted this post hoc analysis of virologic, immunologic, and adverse event outcomes by age in ECHO and THRIVE participants [1].
The investigators stratified participants into those younger than 30 (174 rilpivirine and 171 efavirenz), and those 30 to 39 (256 and 248), 40 to 49 (187 and 206), and 50 or older (69 and 57). Of the 3168 people analyzed, 12% were 40 to 49 years old and 4% were 50 or older. Median overall pretreatment viral load stood at 100,000 copies and median CD4 count at 256.
At week 96 proportions of participants with a viral load below 50 copies by snapshot analysis were largely consistent across age groups and between rilpivirine and efavirenz, ranging from 73.7% (with efavirenz in the youngest age group) to 84.2% (with efavirenz in the oldest age group). Median CD4-cell gains were also consistent across age groups and between rilpivirine and efavirenz. Notably, CD4 gains were not blunted in the older age groups, despite a presumed decline in thymic T-cell output: 237 with rilpivirine and 278 with efavirenz in the 50-and-older group; 248 and 267 in the 40-to-49 group; 275 and 229 in the 30-to-39 group; and 266 and 256 in the under-30 group.
Rates of antiretroviral-related side effects were generally lower with rilpivirine than with efavirenz in all age groups, and those rates did not vary much by age. For grade 2 to 4 adverse events at least possibly related to study drugs, incidence by age was always lower in the rilpivirine arms:
-- Under 30 years old: 4.6% rilpivirine versus 12.9% efavirenz
-- 30 to 39 years old: 2.0% rilpivirine versus 10.1% efavirenz
-- 40 to 49 years old: 4.8% rilpivirine versus 8.3% efavirenz
-- 50 and older: 1.4% rilpivirine versus 8.8% efavirenz
Rates of serious adverse events were lower with rilpivirine than efavirenz in the under-30 group but similar with the two drugs in the three older groups:
-- Under 30 years old: 6% rilpivirine versus 11% efavirenz
-- 30 to 39 years old: 9% rilpivirine versus 10% efavirenz
-- 40 to 49 years old: 11% rilpivirine versus 11% efavirenz
-- 50 and older: 15% rilpivirine versus 12% efavirenz
Psychiatric side effects proved less frequent with rilpivirine than efavirenz in every age group except 30- to 39-year-olds, and rates did not vary greatly with age. The highest rates were 9.7% in 40-to-49-year-olds taking efavirenz and 14.0% in people 50 and over taking efavirenz. Depression and insomnia affected only 1% to 2% in all age groups with both drugs, except for people 50 and older taking efavirenz (7.0% for both depression and insomnia).
Skin and subcutaneous tissue problems affected lower proportions taking rilpivirine than efavirenz in every age group. In people 40 to 49 incidence was 1.6% with rilpivirine and 7.3% with efavirenz. In people 50 and older incidence was 1.4% with rilpivirine and 15.8% with efavirenz. Rash also affected lower proportions with rilpivirine than efavirenz in every age group. In the efavirenz group, rash incidence was higher in the 50-and-older group (8.8%) than in the 40-to-49 group (4.9%) or the 30-to-39 group (5.2%).
Total and "bad" LDL cholesterol changes were more favorable with rilpivirine than with efavirenz in every age group. Median changes in triglycerides for rilpivirine versus efavirenz through 96 weeks were -8.9 versus +8.9 mg/dL in people under 30, -7.1 versus +6.2 mg/dL in the 30-to-39 group, -2.7 versus 0 mg/dL in the 40-to-49 group, and -12.8 versus +2.7 mg/dL in the 50-and-older group. In every age group people randomized to efavirenz gained more "good" HDL cholesterol.
Median DEXA-measured bone mineral density declined slightly through 96 weeks (about 0.015 g/cm2) in the first three age groups, and declines were similar with rilpivirine and efavirenz. In the 50-and-older group, the 14 people taking rilpivirine had a median bone mineral density drop of 0.035 g/cm2 and the 16 people taking efavirenz had a median drop of 0.049 g/cm2.
These CD4 and side effect findings differ from those reported at 48 weeks in trials of elvitegravir-containing QUAD versus efavirenz or atazanavir/ritonavir (reviewed separately by NATAP) [4]. In the QUAD trials CD4 gains were slower in people over 50 than in younger participants in every treatment arm. And in that comparison adverse events leading to discontinuation were more frequent in the 50-and-older group.
ICAAC: Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Demonstrates Comparable Efficacy and Favorable Tolerability to Efavirenz/Emtricitabine/Tenofovir DF and to Ritonavir-boosted Atazanavir plus Emtricitabine/Tenofovir DF in Patients ≥50 Years - (09/11/12)
References
1. 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.
2. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378:238-246.
3. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-237.
4. 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.
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