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New NRTI Apricitabine Versus 3TC in 3TC-Experienced Patients: 24-Week Results
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
Apricitabine, an experimental nucleoside with activity against nucleoside-resistant HIV, showed durable activity through 24 weeks in a double-blind trial comparing the new agent with 3TC (lamivudine) in treatment-experience people [1]. An earlier report on this phase 2b trial documented significantly greater viral load drops with apricitabine (-0.90 log with 600 mg twice daily, P = 0.006 versus 3TC; -0.71 log with 800 mg twice daily, P = 0.0506 versus placebo) than with 3TC (-0.03 log with 150 mg twice daily) after 21 days in which patients continued their baseline regimen [2].
Argentine researchers from several centers randomized people taking a stable 3TC- or FTC-containing combination to 600 mg of apricitabine twice daily, 800 mg of apricitabine twice daily, or 150 mg of 3TC twice daily for 21 days while continuing other drugs in their regimen. At day 21 clinicians could change other antiretrovirals based on resistance test results. After day 21 physicians could modify the regimen again or start open-label 800-mg apricitabine if the viral load had dropped less than a half log or rose 1 log from its lowest point.
Pedro Cahn (Fundacion Huesped, Buenos Aires) and coworkers enrolled 51 people with a viral load of 2000 copies or more while taking the same regimen for at least 2 months. Everyone had tried at least two antiretroviral classes for at least 2 months, had a CD4 count at or above 250, and had the M184V mutation conferred by 3TC or FTC.
At randomization 7 of 17 people (41%) in the 600-mg apricitabine arm, 5 of 18 (28%) in the 800-mg arm, and 5 of 16 (31%) in the 3TC arm had a viral load below 10,000 copies. Respective proportions with a load above 100,000 copies were 6%, 6%, and 12.5%. While 47% taking 600 mg of apricitabine had AIDS, 72% taking 800 mg and 69% taking 3TC had AIDS.
Baseline regimens included a nonnucleoside in 55% and a protease inhibitor (PI) in 43%. After the drug changes allowed at day 21, 86% were taking a PI and 10% were taking a nonnucleoside. While 3 people randomized to 3TC started enfuvirtide at day 21, 1 in each of the apricitabine groups started enfuvirtide. Two people randomized to 600 mg of apricitabine, one randomized to 800 mg, and 4 randomized to 3TC had to refine their background regimen again after day 21. One person in each group added enfuvirtide, and 5 people started open-label 800-mg apricitabine.
After day 21 viral loads continued to fall through week 24 in the apricitabine group and began to fall among people taking 3TC. Although average viral load declines with 3TC never caught up with apricitabine-induced drops, the difference between apricitabine and 3TC lacked statistical significance after day 21. That result is no surprise, Cahn and colleagues noted, because the study had statistical power to show significant differences only through day 21.
After 24 weeks 80% or more in the apricitabine groups had a viral load below 400 copies, compared with about 67% in the 3TC group. At that point slightly more than 70% taking apricitabine and just under 60% taking 3TC had fewer than 50 copies. None of these differences reached statistical significance. Cahn and colleagues appropriately note the difficulty in figuring how much apricitabine contributed to viral control after day 21 because so many people in whom a first-line nonnucleoside failed switched to a PI--a sure recipe for renewed viral suppression.
Average CD4 gains at week 24 were highest in the 800-mg apricitabine groun (+211.5), and lower with 600 mg (+145.5) and 3TC (+113.6).
Among people with three or more AZT or d4T mutations when the study began, viral load drops averaged 2.16 log with 800 mg of apricitabine and 1.71 log with 600 mg. But that difference lacked statistical significance. The investigators did not report viral load changes in those randomized to 3TC with AZT or d4T mutations. Two people taking each of the apricitabine doses and 4 taking 3TC had genotyping at week 24. One in each of the apricitabine arms and all four in the 3TC group had detectable M184V at that point. Mutations at reverse transcriptase positions 65, 74, 75, and 115 did not emerge by week 24.
Rates of serious adverse events were higher with 3TC than with 800 or 600 mg of apricitabine (31% versus 0% in the apricitabine groups), as were rates of severe adverse events (75% with 3TC, 39% with 800 mg of apricitabine, and 29% with 600 mg). But rates of side effects blamed on drugs in the reigmens were similar with 3TC (31%) and 800 mg of apricitabine (28%), though lower with 600 mg of apricitabine (18%).
References
1. Cahn P, Altclas J, Martins M, et al. 24-Week data from Study AVX-201: a prospective, randomized, double-blind, dose-ranging phase IIb study of apricitabine in treatment-experienced patients with M184Vand NRTI resistance. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 793.
2. Cahn P, Altclas J, Martins M, et al. Superior activity of apricitabine compared to 3TC over 21 days in treatment experienced HIV-1 infected patients failing therapy with M184V and NRTI resistance. 4th IAS Conference on HIV Pathogenesis and Treatment and Prevention. July 22-25, 2007. Sydney. Abstract WESS203.
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