July 27, 2005
It's the million dollar question that still remains unanswered: Which nucleoside/tide reverse transcriptase inhibitor (NRTI) combination is more powerful and, more importantly for patients, has fewer side effects? Study 934, which is the first trial to compare the older twice-daily fixed-dose combination of zidovudine/lamivudine (AZT/3TC, Combivir) to the newer once-daily combination of tenofovir (TDF, Viread) + emtricitabine (FTC, Emtriva), is an ongoing, randomized, open-label, non-inferiority study. This multicenter, international trial is led by Anton Pozniak, of London's Chelsea and Westminster Hospital, and colleagues and is supported by Gilead, the maker of tenofovir and emtricitabine. Enrolled are treatment-naive patients with any CD4+ cell count and an HIV plasma viral load more than 10,000 copies/mL.
A total of 509 patients were randomized to receive efavirenz (EFV, Sustiva, Stocrin) with either tenofovir + emtricitabine (n = 255, group 1) or zidovudine/lamivudine (n = 254, group 2).
Median baseline values were generally similar, as noted in the chart below.
|Median Baseline Value||Group 1 (TDF + FTC)||Group 2 (AZT/3TC)|
|CD4+ cell count||233 cells/mm3||241 cells/mm3|
|HIV plasma viral load||5.0 log10 copies/mL||5.0 log10 copies/mL|
|Patients with CD4+ cell count <200 cells/mm3||41%||41%|
|Patients with HIV plasma viral load >100,000 copies/mL||52%||50%|
Week-48 data was presented at this conference. The primary endpoint was virologic suppression to less than 400 copies/mL, but data on suppression to less than 50 copies/mL was obtained as well. In both cases, suppression rates were higher in the tenofovir + emtricitabine group (P = .005), as was the increase in CD4+ cell count from baseline (P = .002):
|Group 1 (TDF + FTC)||Group 2 (AZT/3TC)|
|Viral load <400 copies/mL||81%||70% (P = .005)|
|Viral load <50 copies/mL||77%||68% (P = .034)|
|CD4+ cell count increase from baseline||189 cells/mm3||158 cells/mm3|
Each of these figures of virologic suppression increases by 2% to 3% if the 22 subjects with baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, whom regulatory authorities asked be removed from the analysis, are added back to the cohort. Thus, baseline NNRTI resistance would not affect the relative results in any way.
It is interesting to note that true virologic failure was present in only 2% of the patients receiving tenofovir + emtricitabine and 4% of the patients receiving zidovudine/lamivudine. The real difference in this study (accounting for the differences in the proportion of patients achieving virologic suppression in an intent-to-treat analysis) was not a difference in efficacy, but a difference in tolerability, with discontinuation due to toxicity being more frequent in the zidovudine/lamivudine group (23% versus 14%). Severe zidovudine-associated anemia (6%) and nausea, vomiting or fatigue (4%) were the primary observed toxicities associated with zidovudine/lamivudine use.
There were no cases of significant renal dysfunction in patients on the tenofovir + emtricitabine regimen, although a non-significant decrease in glomerular filtration rate (-1.2 versus +6.2 mL/min) was observed in the tenofovir + emtricitabine group. Patients on zidovudine/lamivudine experienced a more significant increase in triglycerides (31 mg/dL, versus 3 mg/dL in the tenofovir + emtricitabine arm) and cholesterol (35 mg/dL, versus 21 mg/dL in the tenofovir + emtricitabine arm). There may also have been more loss of limb fat in the zidovudine/lamivudine group.
So, what does all this mean? In the battle of the NRTI combinations, tenofovir + emtricitabine beats zidovudine/lamivudine, the latter being hampered not by a lack of efficacy (note the vanishingly low rate of virologic failure), but by zidovudine-associated toxicities. In this era in which we have multiple effective regimens, this type of difference is enough to give one an advantage over the other, especially since tenofovir + emtricitabine can be given once a day, while zidovudine/lamivudine is a twice-daily drug.
An issue that this study does not address is whether a combination such as abacavir/lamivudine (ABC/3TC, Epzicom), which can also be given once a day and which will not be hampered by issues of zidovudine toxicity, would perform as well as tenofovir + emtricitabine. I feel it might be important to evaluate this, as it would be nice to have a simple alternative to tenofovir + emtricitabine for drug-naive patients, should the use of tenofovir be inappropriate in an individual patient. The U.S. AIDS Clinical Trials Group is planning a large study to compare these single-pill NRTI combinations and the results of such a study will be eagerly awaited.
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