Landmark study shows why AZT/3TC/efavirenz now preferred as first-line HIV treatment

The combination of AZT, 3TC and efavirenz proved more durable than two initial HAART combinations composed of four drugs, and outclassed all combinations based on either d4T/ddI or nelfinavir, according to final results from the ACTG 384 study published in the December 11^th edition of the New England Journal of Medicine. Interim findings from this study were presented to the International AIDS Conference in Barcelona in 2002, and a regimen of AZT, 3TC and efavirenz is one of the initial regimens of choice recommended in the latest US treatment HIV guidelines.

A total of 620 antiretroviral treatment naïve individuals were recruited to a multicentre trial, designed to compare the safety and efficacy of either AZT, 3TC and efavirenz, or ddI, d4T and nelfinavir as an initial HAART regimen. The primary end point of the study was the time taken to the failure of the second HAART regimen.

Individuals were followed for a median of two and a quarter years. Investigators discovered that patients who started with a HAART regimen consisting of AZT, 3TC and efavirenz (but not ddI, d4T and efavirenz) delayed the failure of their second regimen compared to a nelfinavir-containing regimen, and significantly reduced the risk of first regimen failure (hazard ratio 0.39) and first virologic failure (HR 0.34).

The investigators also established the superiority of the AZT, 3TC, efavirenz (but not AZT, 3TC and nelfinavir) regimen over a HAART combination of ddI, d4T and nelfinavir. Again, patients taking the efavirenz-containing regimen delayed the time to second treatment failure (HR 0.68), and the times to first and second virologic failure (HR 0.39 and 0.49 respectively).

Investigators from the ACTG 384 study also compared three and four drug initial HAART regimens. A total of 980 patients were enrolled to the study and followed for a median of two and a quarter years. There was no significant difference in the occurrence of second regimen failures between the four drug regimen, when patients took drugs from each of the three main classes of anti-HIV drugs, including ddI, d4T, nelfinavir and efavirenz, and either of two three drug regimens (ddI, d4T and efavirenz, or ddI, d4T and nelfinavir). Nor was there any significant difference between patients receiving the four-drug regimen of AZT, 3TC, nelfinavir and efavirenz, compared to the three-drug combination of AZT, 3TC and efavirenz.

However, patients taking a four drug regimen had a longer duration until first treatment failure than individuals taking all three drug regimens except AZT/3TC/efavirenz.

An editorial accompanying these studies notes that these studies confirm "that the combination of stavudine (d4T) and didanosine (ddI) should not be used for the initial treatment of HIV infection". However, the author cautions that the findings of the ACTG 384 study should not be taken to mean that a combination of AZT, 3TC and a non-nucleoide analogue is superior to one including a protease inhibitor. The use of more potent boosted protease inhibitors "may well constitute important options for initial treatment in combination with other agents."

Although the ACTG 384 study failed to find any advantage from taking four drugs as opposed to three, it did reveal what the editorial author describes as “provocative” resistance data. These show that that the four-drug combination resulted in fewer circulating mutations. They note "since, for patients in whom initial therapy fails, drug resistance is often the primary difficulty in devising subsequent drug regimens, this advantage may be an important one."

Further information on this website

US HIV guidelines: choose either lopinavir or efavirenz in first-line treatment - news story

ACTG 384: Major HAART strategy trial a closing day highlight in Barcelona - news story