ESS30009 is a 48-week study comparing the safety and efficacy of 2 once-daily, low pill burden highly active antiretroviral therapy regimens in antiretroviral-naive patients.

One of the arms was the fixed-dose combination abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) + efavirenz (EFV, Sustiva, Stocrin). The other arm was the fixed-dose combination abacavir/lamivudine + tenofovir (TDF, Viread).

The triple-nucleoside arm of abacavir/lamivudine + tenofovir had to be closed early due to excess risk of virologic failure. We still do not completely understand why almost 50% of the patients in this arm did not respond to this combination. Joel Gallant from Johns Hopkins University did the original presentation of this study 18 months ago at ICAAC 2003.¹

Ninety-eight percent of the patients who had failed virologically in ESS30009 had the M184V mutation and a significant proportion (54%) of these patients also had the K65R mutation. The purpose of this study was to see if the participants who showed no evidence of K65R using the population genotypic testing actually did have the mutation when a more sensitive "clonal" analysis was employed. The researchers only did this extremely labor-intensive analysis in 4 of the patients who did not have the K65R mutation and had failed by week 12 of the study. In all 4 cases the presence of this mutation was identified with the more sensitive analysis.

The small size of the study (only 4 patients) is its main limitation. The take-home message from this study is that the current population genotypic techniques miss a lot of resistance that is present at a lower level. However, I do not think it explains why this triple-nucleoside combination never worked very well in the first place.

ESS30009 was a clear example of a study that went wrong. Fortunately, the inferior arm was shut down immediately and we learned that abacavir/lamivudine + tenofovir should never be used as a triple-antiretroviral therapy.

However, not all triple-nucleoside combinations are created equal and there are still some that deserve investigation. There were a couple of presentations during the meeting about the positive results of combining zidovudine/lamivudine (AZT/3TC, Combivir) + tenofovir. The use of these triple-nuke combinations is particularly important in Africa since they can be used in patients with concomitant tuberculosis that requires treatment with drugs that could potentially interfere with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Footnote

1. Gallant JE, Rodriguez AE, Weinberg W, et al. Early non-response to tenofovir DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) + ABC and 3TC: ESS30009 unplanned interim analysis. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract H-1722a.