Antiretroviral therapy of HIV-1 infection currently depends on combination therapies including NRTI. The virologic efficacy of antiretroviral treatment is measured by suppression of plasma HIV-1 RNA, which is associated with a reduction in clinical progression and disease, although this has yet to be demonstrated in early infection. However, in the development of ongoing treatment strategies, durable suppression of plasma HIV-1 RNA to below the limits of detection of sensitive assays for more than 48 weeks is accepted as evidence for the sustained activity of antiretroviral drug regimens. To achieve and sustain virologic suppression, current recommendations for the treatment of NRTI-experienced HIV-1 infected individuals include the use of three drugs: new RTI combinations and a potent PI or NNRTI. The combined use of all three classes of antiretroviral drugs has the potential advantage of increased activity and potency although may be accompanied by greater risk for drug toxicity compared to three-drug options. On the other hand, strategies which use only two classes of drug may spare toxicity and preserve future therapeutic options.

In patients with complex antiretroviral drug histories and detectable virus load, the approach to "highly active" therapy is complicated by the reduced activity of drugs in second- and third-line regimens. In many cases, this can be explained by antiretroviral drug resistance, although the capacity to assess and act on the information provided by drug resistance assays is limited. Empirically, what are the factors that might encourage or discourage the use of a three-drug vs a four-drug approach in antiretroviral experienced patients? Certainly a high virus load, a history of multiple drug failure, and a low CD4 cell count are often cited as risks for the failure of three-drug regimens. However, the use of four drugs from all three classes (two NRTI, a PI, and an NNRTI) may be daunting because of pill burden, toxicities, drug-drug interactions and finally, because of the risk that failure will be associated with multidrug resistance.

A recently completed study, ACTG 364, provides new data on the comparative activity of efavirenz, nelfinavir or both in the setting of one or two new NRTI. ACTG 364 is a moderate-sized study which has followed 196 HIV infected individuals with HIV RNA levels < 500 copies/mL at enrolment who had a well-documented history of treatment with two or three NRTI for more than five years. Subjects entering ACTG 364 were assigned at least one new NRTI (27%) or two new NRTI (73%) and were randomized to receive a potent NNRTI (efavirenz, EFZ), a protease inhibitor (nelfinavir, NFV) or both.

The main results of the study, presented by protocol chair Mary Albrecht at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago were surprising [1]. Although the primary endpoint of the study, suppression of HIV RNA to undetectable levels at 16 weeks, did not demonstrate a significant difference between the treatment regimens, at 40-48 weeks there was a significant advantage to EFZ and EFZ + NFV treatment compared to NFV plus two NRTI with respect to virologic efficacy. Using the most stringent analysis (intent to treat, loss to follow-up counts as failure), the percentage of patients with HIV RNA levels below 500 copies/mL at 40 and 48 weeks was 35% among NFV recipients, 60% among EFZ recipients and 74% among patients who received NFV + EFZ. The virologic results of this study at 48 weeks may be explained in several ways. First, it is clear that patients with higher virus load were at greater risk for failure. Second, the subjects treated with only one new NRTI were particularly vulnerable. Among those who received two new NRTI, 3TC was an important component of successful virologic suppression. Importantly, over the 48 weeks of the study there was no evidence for increased toxicity of NFV + EFZ and two NRTI.

This is one of the first head-to-head comparisons of EFZ and NFV demonstrating that among nucleoside-experienced individuals, EFZ and two NRTI has more potent activity than NFV + two NRTI. The long-term results suggest that in highly nucleoside-experienced individuals who are naïve to both PI and NNRTI, two new nucleosides + EFZ and NFV was a safe, effective regimen that minimized virologic failure. While not significantly more effective than two NRTI and EFZ, the four drug combination offers increased potency without added toxicity.