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The Body Covers: The 46th Interscience Conference on Antimicrobial Agents and Chemotherapy

COOL Study: The Ultimate Misnomer?

Coverage provided by Graeme Moyle, M.D.

September 29, 2006

There is considerable interest in improving convenience of administration, reducing toxicity and reducing pill burden for HIV-infected people. Some ideas, like getting antiretroviral manufacturers to cooperate and produce combination tablets based on well-studied, effective combinations, have led to valuable refinements in therapy. However, other so-called "simplification" ideas, such as protease inhibitor (PI) monotherapy or regimens consisting of three nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), have proven disappointing. These ideas have led to the development of HIV drug resistance and unnecessary loss of treatment options in some people.

Simplification thus actually led to complications. With initial therapy that has been based around NRTIs, several things have been consistently observed. Firstly, that two NRTIs plus a third agent from an additional class provides the best backbone for therapy. Secondly, that a TC drug (i.e., either emtricitabine [FTC, Emtriva] or lamivudine [3TC, Epivir]) is a key component of such NRTI pairs, adding efficacy without added toxicity or substantial pill burden.

It is therefore intriguing that a study would be conceived with the goal of discontinuing the TC component from a successful treatment regimen. Why discontinue the least toxic, most evidenced-based component of a regimen that adds little to pill burden, or cost? The irony of the study was to give it the name COOL.1

The study included 143 individuals with suppressed (below 50 copies/mL) HIV-1 RNA who were on a range of treatment regimens, but who had never failed therapy. They were randomized to switch to two possible arms: tenofovir (TDF, Viread) + lamivudine + efavirenz (EFV, Sustiva, Stocrin) (n=72) or a "lamivudine-sparing" regimen of dual therapy with tenofovir + efavirenz (n=71).


% of Patients With Viral Load < 50 c/mL (ITT/AT Populations)
Click to enlarge
Slide by Pierre-Marie Girard, M.D.; reprinted with permission of Gilead Sciences. Click here to download the complete presentation.


For those who remember the de-intensification studies of the late 1990s, such as AIDS Clinical Trials Group (ACTG) 343,2 Trilège3 and ADAM, the results of this study come as no surprise. Higher rates of virological rebound were observed in the two-drug arm, with the emergence of efavirenz resistance and the loss of the non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class (at least for now). By intent-to-treat (ITT) analysis, the proportion of individuals whose HIV-RNA remained below 50 copies/mL was 97% with triple-drug therapy versus 82% with dual-drug therapy.


Biological Parameters: W48 Change From Baseline
Click to enlarge
Slide by Pierre-Marie Girard, M.D.; reprinted with permission of Gilead Sciences. Click here to download the complete presentation.


Furthermore, changes in CD4+ cell count (+35 versus +14) and hemoglobin (+0.8 versus +0.45) tended to favor the triple-therapy arm. Indeed, no differences in a range of laboratory parameters, including lipids, or clinical adverse event parameters were seen between the groups, underlining that there is no added toxicity with the addition of lamivudine to treatment.

The poet and philosopher George Santayana is quoted as saying, "Those who cannot remember the past are condemned to repeat it." This certainly holds resonance for those considering "strategies" around treatment de-intensification.

Footnotes

  1. Girard PM, Cabié A, Michelet C, et al. TenofovirDF + efavirenz (TDF+EFV) vs tenofovirDF+ efavirenz + lamivudine (TDF+EFV+3TC) maintenance regimen in virologically controlled patients (pts): COOL Trial. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1383.
    View slides: Download PowerPoint

  2. Havlir DV, Marschner IC, Hirsch MS, et al, for The AIDS Clinical Trials Group Study 343 Team. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med. October 29, 1998;339(18):1261-1268.

  3. Pialoux G, Raffi F, Brun-Vezinet F, et al, for The Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. N Engl J Med. October 29, 1998;339(18):1269-1276.


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