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Abacavir/3TC vs TDF/FTC: The HEAT Study
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
Failure of tenofovir/emtricitabine (TDF/FTC, Truvada) resulted in more M184V resistance mutations than failure of abacavir/lamivudine (ABC/3TC, Epzicom) in previously untreated people after 48 weeks of the placebo-controlled HEAT trial [1] (from Jules: the significance of this resistance finding is unexpected and needs further investigation). The two once-daily fixed-dose nucleosides, each given with once-daily lopinavir/ritonavir, yielded similar virologic results.
This 15th Conference on Retroviruses turned up the heat under an already-bubbling fray between Epzicom and Truvada with this report and a separate D:A:D cohort study that tied abacavir and didanosine--but not zidovudine (AZT), 3TC, or stavudine--to a higher risk of myocardial infarction [2]. D:A:D investigators issued a statement advising people taking abacavir to discuss with their physician "whether a modification of their anti-HIV drug regimen is appropriate." (The D:A:D poster and a report are available on the NATAP site.) (from Jules: my evaluation of the DAD Study was it is a cohort of cohort studies and further prospective perhaps randomized studies are needed before much stock is put into the DAD Study finding).
Kimberly Smith (Rush University, Chicago) and US colleagues randomized 343 antiretroviral-naive people to Epzicom plus lopinavir/ritonavir and Truvada placebo and 345 enrollees to Truvada plus the same PIs and Epzicom placebo. Everyone had a viral load of at least 1000 copies, and no one got screened for the HLA-B*5701 genetic marker of abacavir hypersensitivity reaction.
The study group was about half white, one third African American, and 20% Hispanic. Median pretreatment viral load measured about 80,000 copies in the Truvada group and 70,000 copies in the Epzicom group, while respective median CD4 counts stood at 214 and 193. Fewer than 20% in either study arm had AIDS when the trial began.
People with suspected hypersensitivity reactions could swap abacavir for AZT, and people with kidney trouble could switch TDF for any nucleoside except abacavir. Everyone took the old capsule formulation of lopinavir/ritonavir.
Relatively high proportions dropped out of each study arm by week 48, 68 (20%) from the Epzicom group and 83 (24%) from the Truvada group. Loss to follow-up and "patient decision" accounted for most of these dropouts. Only 4 people in each arm left the trial because of virologic failure. While 13 people (4%) stopped Epzicom because of side effects, 20 (6%) stopped Truvada for that reason.
Four different 48-week analyses of sub-50-copy response found no difference between the regimens. In a missing-data-equal-failure analysis, 68% responded to Epzicom and 67% to Truvada. In an on-treatment analysis, 84% taking Epzicom and 87% taking Truvada had a 48-week viral load under 50 copies. In all these analyses, responses met criteria that established the noninferiority of Epzicom to Truvada. Median CD4 gains measured 201 cells with Epzicom and 173 cells with Truvada.
HEAT investigators defined virologic failure in three ways--failure to reach a viral load under 200 copies, confirmed rebound to 200 or more after a confirmed sub-50 load, and confirmed load of 200 or more after week 24. By those measures, the Epzicom regimen failed in 40 people (12%) and the Truvada regimen in 39 (11%). Among people with genotypic resistance data before treatment and at failure (35 patients on Epzicom and 32 on Truvada), more than half taking Truvada (53%) versus one third (34%) taking Epzicom had new mutations during treatment (table). The M184V mutation evoked by 3TC or FTC emerged in twice as many people taking Truvada (44% vs 20%). M184V or mixtures were found in 7 on Epzicom and 14 on Truvada; the K70K/R mutation was found in 1 patient on Epzicom and none on Truvada. The Y181Y/C NNRTI muation was found in 1 (3%) patient on Epzicom and none on Truvada. Minor PI mutations were reported in 6 (17%) patients on Epzicom and 6 (19%) on Truvada. Major PI mutations were not found in either study treatment arm.
Why M184V arose twice as often upon failure of Truvada remains unclear. Smith did not present adherence data to show whether people took the Truvada regimen as faithfully as they took the Epzicom combo. Rates of side effects that may cause poor adherence--such as diarrhea, nausea, and vomiting--were virtually equal in the two groups. Substantially more people randomized to Epzicom than Truvada had suspected abacavir hypersensitivity reaction--14 (3%) versus 3 (1%). Three people (1%) switched from Truvada because of proximal renal tubule dysfunction, while none switched from Epzicom for that reason.
Earlier studies did not find a higher M184V mutation risk with TDF/FTC than with 3TC-containing combinations. After 96 weeks in a trial comparing TDF/FTC (not as Truvada) with Combivir (AZT/3TC) plus efavirenz in previously untreated people, significantly more taking Combivir had M184V--9 versus 2 (P = 0.036) [3].
The Epzicom regimen took a harder hit at lipids than the Truvada regimen, resulting in greater gains in total cholesterol (+32 mg/dL vs +23 mg/dL), triglycerides (+64 mg/dL vs +38 mg/dL), and low-density lipoprotein cholesterol (+8 mg/dL vs -1 mg/dL). But lipids remained largely in the safety zone in both groups. The total-to-high-density lipoprotein cholesterol ratio fell from 4.4 to 4.2 in the Epzicom group and from 4.5 to 4 in the Truvada group.
The HEAT researchers did not present data on limb fat changes through 48 weeks. Analysis of 48-week results were blinded, and the trial will continue through week 96.
References
1. Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir) through 48 weeks in the HEAT study. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 774.
2. Sabin C, Worm S, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 957c.
3. Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients virologic, immunologic, and morphologic changes--a 96-week analysis. JAIDS. 2006;43:535-540.
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