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Independent Analysis Suggests TDF/FTC Outdoes ABC/3TC With First-Line PIs
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48th ICAAC
October 25-28, 2008
Washington, DC
Mark Mascolini
This year's ICAAC turned up the heat under the controversy over first-line abacavir/lamivudine (ABC/3TC) versus tenofovir/emtricitabine (TDF/FTC). In a study analyzed separately by NATAP, ARIES trial investigators reported that ABC/3TC plus atazanavir/ritonavir yielded an 80% sub-50-copy response rate at study week 36 [1]. By some measures, but not by others, virologic response appeared to be equivalent in people who began treatment with a viral load above 100,000 copies and in those who started with a lower load. Earlier this year ACTG A5202 investigators charted a faster time to virologic failure with ABC/3TC than with TDF/FTC (plus atazanavir/ritonavir or efavirenz) if pretreatment load stood above 100,000 [2].
An earlier six-study analysis by GlaxoSmithKline, makers of ABC and 3TC, found no profound response deficit in people starting those antiretrovirals with more than 100,000 HIV RNA copies [3]. But a 12-study meta-analysis by independent investigators at this ICAAC produced evidence supporting TDF/FTC as a stronger option than ABC/3TC with certain first-line ritonavir-boosted protease inhibitors (PIs), regardless of pretreatment viral load [4].
Andrew Hill of Liverpool University and Will Sawyer of SEARCH, in Bangkok, scoured the medical literature and found 12 clinical trials in which 3340 previously untreated people started TDF/FTC and another 1556 naive people started ABC/3TC with ritonavir-boosted atazanavir, darunavir, fosamprenavir, lopinavir, or saquinavir [4]. Hill and Sawyer used the FDA-favored time-to-loss-of-virologic-response (TLOVR) yardstick--or the nearest equivalent endpoint--to combine under-50-copy response rates for each PI at 48 weeks.
Median pretreatment CD4 count did not differ significantly between people starting TDF/FTC (204) and ABC/3TC (195). Nor did median pretreatment viral load differ much between the two groups (4.9 log with TDF/FTC and 5.0 log with ABC/3TC, or about 80,000 and 100,000 copies).
In the identified trials, investigators evaluated TDF/FTC, but not ABC/3TC, with saquinavir/ritonavir and darunavir/ritonavir. Sub-50 response rates at 48 weeks measured 65% in 166 people taking saquinavir/ritonavir and 84% in 343 people taking darunavir/ritonavir with TDF/FTC. For the other three boosted PIs, 48-week sub-50-copy TLOVR rates proved consistently higher with TDF/FTC than with ABC/3TC:
· Lopinavir/ritonavir: 74% with TDF/FTC (n = 2285) versus 66% with ABC/3TC (n = 722)
· Fosamprenavir/ritonavir: 75% with TDF/FTC (n = 53) versus 67% with ABC/3TC (n = 722)
· Atazanavir/ritonavir: 79% with TDF/FTC (n = 493) versus 77% with ABC/3TC (n = 112)
It should be re-emphasized that these cumulative PI-by-PI comparisons of TDF/FTC versus ABC/3TC are not the results of head-to-head trials but of combined data from several trials, only two of which (ACTG 5202 and HEAT) directly compared TDF/FTC with ABC/3TC.
Hill and Sawyer also compared 48-week sub-50-copy results in trials that tested TDF or ABC with various boosted PIs and stratified outcomes by pretreatment viral load. The four boosted PIs assessed in these studies were lopinavir, atazanavir, fosamprenavir, and darunavir. In the combined results, 48-week responses with ABC/3TC significantly lagged those with TDF/FTC in people starting treatment with fewer than 100,000 copies after adjusting for the PI used (69.5% versus 79.1%, P = 0.0001). Combined results in people beginning therapy with more than 100,000 copies also disclosed an inferior 48-week sub-50 response rate with ABC/3TC, 65.9% versus 70.6% with TDF/FTC, but that difference fell short of statistical significance (P = 0.0995).
Three trials that directly compared TDF/FTC with ABC/3TC in people taking a boosted PI yielded discordant results. ACTG 5202 findings, which so far involve only people with a pretreatment load above 100,000, show a significant primary virologic endpoint advantage with TDF/FTC over ABC/3TC combined with either atazanavir/ritonavir or efavirenz (93.5% versus 86% , P = 0.0003). The BICOMBO trial comparing these two backbones in people who already had a load below 50 copies charted a trend to a better 48-week sub-200 response with TDF/FTC (87% versus 81%, P = 0.12). The HEAT trial found no 48-week sub-50 response difference between TDF/FTC and ABC/3TC taken with lopinavir/ritonavir (67% versus 68%).
The investigators cautioned that a study like this cannot provide a definitive conclusion on whether TDF/FTC is a stronger first-line option than ABC/3TC with the partner PIs. But Hill and Sawyer noted that a similar meta-analysis favored TDF/FTC over ABC/3TC when combined with efavirenz [5]. They also stressed that most failures in a TLOVR analysis are discontinuations for nonvirologic responses. "Therefore," they advised, "apparent differences in treatment efficacy between trials might be influenced by differences in trial procedures to manage adverse events, or maintain adherence."
References
1. Squires K, Young B, DeJesus E, et al. Atazanavir/ritonavir + abacavir/lamivudine in antiretroviral-naive HIV-1 infected HLA-B*5701 negative subjects demonstrates efficacy and safety: the ARIES trial. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-1250a.
2. Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure (VF) with ABC/3TC than TDF/FTC in treatment-naive subjects with HIV RNA >100,000. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0303.
3. Pappa K, Hernandez J, Ha B, et al. ABC/3TC shows robust virologic responses in ART-naïve patients for baseline (BL) viral loads of >100,000c/mL and <100,000c/mL by endpoint used in ACTG5202. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0304.
4. Hill AM, Sawyer WS. Effects of NRTI backbone on efficacy of first-line boosted PI-based HAART--meta-analysis of 12 clinical trials in 4896 patients. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-1254.
5. Bartlett JA, Chen SS, Quinn JB , Wulfsohn M. Overview of time to loss of virologic response (TLOVR) outcomes between efavirenz-based regimens in ART-naive HIV-1-infected adults. XVI International AIDS Conference. 2006. Toronto. Abstract THPE0111.
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