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Slight Advantage Possible With Switch to Truvada vs Kivexa
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4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
Mark Mascolini
Failure rates proved moderately higher in virologically suppressed people switching the nucleoside component of their regimen to Kivexa (3TC plus abacavir) than in those switching to Truvada (tenofovir plus emtricitabine), according to 48-week results of the BICOMBO trial [1].
Drug switches in the Kivexa arm because of presumed hypersensitivity reaction to abacavir at least partly explained the higher failure rate with Kivexa, because switching drugs counted as failure in this open-label trial. But not everyone diagnosed with abacavir hypersensitivity may have had that problem, because two thirds of them did not have a positive test for the HLA B*5701 genotype, which predicts hypersensitivity [2]. (note from Jules: misdiagnosed abacavir hypersensitivity occurs; the study was performed without the benefit of using the genetic blood test for abacavir hypersensitivity).
BICOMBO randomized 333 people with a viral load below 200 copies for at least 6 months to swap their nucleosides for Truvada or Kivexa. All study participants were taking a 3TC-containing regimen, and median CD4 counts stood above 500 in both study arms. The two treatment groups also matched closely in age, gender, HIV transmission group, liver enzymes, fasting lipids, creatinine, and glomerular filtration rate.
Before the trial statisticians determined that Kivexa would be noninferior to Truvada if the upper limit a 95% confidence interval around the 48-week difference between study arms lay within 12.5%. After 48 weeks the switch-equals-failure analysis determined that therapy failed in 22 of 166 people taking Truvada (13.3%) and in 32 of 167 taking Kivexa (19.2%). The 95% confidence interval of that 5.9% difference ranged from -2% to 14%, so the upper bound fell above 12.5%.
No one assigned to Truvada had an outright virologic failure (viral load above 200 copies), while 4 randomized to Kivexa (2.4%) had a virologic failure. The 95% confidence interval around that 2.4% difference ranged from 0.05% to 6%, within the 12.5% limit. In other words, Kivexa was noninferior to Truvada on strictly virologic grounds, but Kivexa was inferior to Truvada for overall efficacy, which included dropouts for side effects.
While 29 people (17%) discontinued treatment in the Kivexa arm, 22 (13%) stopped their regimen in the Truvada group. Adverse events accounted for 17 discontinuations in the Kivexa group versus 9 in the Truvada group. And 9 of the Kivexa arm "events" were suspected abacavir hypersensitivity reactions. Of these 9 people with suspected abacavir reactions, only 3 turned out to have a positive test for HLA-B*5701, the genetic marker for hypersensitivity [2]. So it seems likely that the 6 people with a negative B*5701 test actually were not hypersensitive to abacavir and could have continued the drug safely. The investigators did not offer a separate switch-equals-failure analysis that excluded those potentially unnecessary switchers.
People in the Kivexa group gained an average 44 CD4 cells through 48 weeks, while those taking Truvada lost an average 2.7 cells, a significant difference (P = 0.032). Principal investigator Jose Gatell did not speculate on what may explain this difference or whether it means anything in a study group switching nucleosides with more than 500 CD4s.
Changes in creatinine and glomerular filtration rate--markers of kidney problems seen with tenofovir--were not great and did not differ between the Truvada and Kivexa groups. People taking Truvada had significantly smaller changes in total cholesterol (P = 0.001), ominous low-density lipoprotein cholesterol (P < 0.001), and triglycerides (P = 0.01) than did people taking Kivexa. But the Truvada group also gained significantly less "good" high-density lipoprotein (HDL) cholesterol (P < 0.001). Gatell did not present a comparison of total-to-HDL cholesterol ratios.
A substudy showed that the two treatment groups gained statistically equivalent amounts of total and limb fat after the switch, and changes in bone mineral density were similar in the both groups.
References
1. Martinez E, Arranz JA, Podzamczer D, et al. Efficacy and safety of NRTIs switch to tenofovir plus emtricitabine (Truvada) vs. abacavir plus lamivudine (Kivexa) in patients with virologic suppression receiving a lamivudine containing HAART: the BICOMBO study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WESS102.
2. Mallal S, Phillips E, Carosi G, et al. PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WESS101.
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