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Efficacy and Safety of Abacavir/Lamivudine Compared to Tenofovir/Emtricitabine in Combination with Once-Daily Lopinavir/Ritonavir through 48 Weeks in the HEAT Study
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Reported by Jules Levin
CROI 2008, Boston
Kimberly Y. Smith1, Derek Fine2, Parul Patel3, Nicholaos C. Bellos4, Louis Sloan5, Phillip Lackey6, Denise H. Sutherland-Phillips3, Cindy Vavro3, Qiming Liao3, and Mark S. Shaefer3
1Rush University Medical Center, Chicago, IL, US; 2Johns Hopkins University School of Medicine, Baltimore, MD, US; 3GlaxoSmithKline, RTP, NC, US; 4Southwest Infectious Disease Associates, Dallas, TX, US; 5North Texas Infectious Disease Consultants, Dallas, TX, US; 6ID Consultants, Charlotte, NC, US
INTRODUCTION
Limited direct comparative data exist between the recommended dual NRTI fixed dose combinations, ABC/3TC and TDF/FTC.
The HEAT study is the first head-to-head trial to evaluate the efficacy and safety of these dual NRTI backbones with a boosted PI as part of recommended first-line treatments in HIV-1 infected subjects.
STUDY OBJECTIVES
To establish that ABC/3TC is virologically noninferior to TDF/FTC when administered in combination with LPV/r over 48 weeks.
To compare the safety and tolerability of ABC/3TC versus TDF/FTC over 96 weeks.
AUTHOR CONCLUSION
ABC/3TC is comparable to TDF/FTC in virologic efficacy when combined with LPV/r through 48 weeks.
Both treatment regimens were well tolerated with few discontinuations due to adverse events in either arm.
AUTHOR DISCSSION
ABC/3TC was virologically non-inferior to TDF/FTC through 48 weeks when each was combined with LPV/r.
--68% vs. 67% of subjects (ABC/3TC vs. TDF/FTC) achieved an HIV-1 RNA <50 c/mL at Week 48 (ITT-E, M=F, switch included).
--75% vs. 71% of subjects (ABC/3TC vs. TDF/FTC) achieved an HIV-1 RNA <400 c/mL at Week 48 (ITT-E, M=F, switch included).
Efficacy results were consistent and robust to multiple analyses including when switches were counted as failures.
Median CD4+ cell responses differed between arms at Week 48 (429 cells/mm3 for ABC/3TC and 370 cells/mm3 for TDF/FTC).
A conservative definition of virologic failure resulted in a somewhat elevated failure rate in both arms. Twice as many subjects receiving TDF/FTC failed therapy with an M184V or mixture which was a finding not previously reported.
No new safety findings were observed for either NRTI backbone.
--Rate of ABC HSR was 4% with ABC/3TC and 1% with TDF/FTC.
(HLA-B*5701 screening was not performed in this study)
--PRTD occurred in 0% with ABC/3TC and 1% with TDF/FTC.
--Lipids elevations were observed in both arms, however TC:HDL ratio remained below 5 for each.
A blinded analysis of the data was performed at Week 48 to protect the integrity of this 96 week study.
PROTOCOL DESIGNED STUDY FAILURE
Failure to achieve HIV-1 RNA <200 c/mL or confirmed rebound to ≥ 200 c/mL after confirmed reduction to <50 c/mL by Week 24.
Confirmed HIV-1 RNA ≥ 200 c/mL after Week 24.
Statistical Analysis
Non-inferiority of ABC/3TC compared to TDF/FTC would be established if the lower bound of the two-sided 95% CI on the difference in proportions achieving an HIV-1 RNA <50 c/mL at Week 48 was -0.12 or greater [ITT-E, missing=failure, switch included].
For stratified analyses by baseline HIV-1 RNA (< or ≥100,000 c/mL), the Cochran-Mantel-Haenszel method was used to compare virologic response between treatment groups.
Results
Table 1. Baseline Demographics and Characteristics
![SubDisp-1.gif](../images/020508/SubDisp-1.gif)
Other included pregnancy (1), site closure (2), and incarceration (3) in the ABC/3TC arm and site closure (1), death (1), incarceration (2) and relocation (2) in the TDF/FTC arm.
Protocol-Allowable Toxicity Switches
NRTI switches included suspected ABC HSR [14 (4%) ABC/3TC; 3 (1%) TDF/FTC] and Proximal Renal Tubule Dysfunction (PRTD) [0 ABC/3TC;
3 (1%) TDF/FTC].
-- PRTD definition: serum creatinine rise of ≥0.5 mg/dL from BL and serum phosphate < 2mg/dL or either of the former plus any 2 of the following: proteinuria ≥100 mg/dL, glycosuria ≥250 g/dL, low serum potassium <3 meQ/L, or low serum bicarbonate <19 meQ/L.
For PI-induced GI intolerability, LPV/r was permitted to be dosed twice daily. For treatment-limiting PI toxicity, LPV/r could be switched to FPV.
All subjects switched from LPV/r soft gel capsules (SGC) to LPV/r tablets at Week 48 to maintain formulation consistency during the study.
![RNA-2.gif](../images/020508/RNA-2.gif)
The lower bound of the 95% CI was greater than -0.12, thus establishing non-inferiority of ABC/3TC to TDF/FTC, (ITT-E, M=F, 95% CI (ABC/3TCTDF/ FTC) [-6.63,7.40]).
Consistent results were observed regardless of analysis method used including when switches were counted as failures (MD=F analysis).
In stratified analyses (ABC/3TC vs. TDF/FTC), 71% vs. 69% of subjects in the <100K viral strata achieved an HIV-1 RNA <50 c/mL; 63% vs. 65% of subjects in the ≥100K viral strata achieved this same endpoint at Week 48 (ITT -E, M=F).
![Change-3.gif](../images/020508/Change-3.gif)
Rate of virologic failure was similar in both groups.
The slightly higher rate of protocol-defined virologic failure may be attributed to the use of a more stringent criteria to determine success (HIV-1 RNA <200 c/mL).
![AE-4.gif](../images/020508/AE-4.gif)
![Medain-5.gif](../images/020508/Medain-5.gif)
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