Nucleoside-sparing regimens consisting of a protease inhibitor (PI) plus a non-nucleoside reverse transcriptase inhibitor have been studied since the original DuPont 006 study,¹ which included a treatment arm of indinavir (IDV, Crixivan) + efavirenz (EFV, Sustiva, Stocrin). While this 2-drug regimen did not perform as well as zidovudine (AZT, Retrovir) + lamivudine (3TC, Epivir) + efavirenz, interest in such regimens has persisted. This is largely due to the potential for the adverse effects of nucleoside analogs, in particular the problem of lipoatrophy.

In AIDS Clinical Trials Group (ACTG) Study A5116 presented here, a maintenance regimen of lopinavir/ritonavir (LPV/r, Kaletra) + efavirenz was compared to a standard dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) + efavirenz regimen for patients with virologic suppression.

Study subjects could enter either while continuing with successful therapy from ACTG 388² (a prior clinical trial for treatment-naive patients with a CD4+ cell count below or equal to 200), or with virologic suppression outside the study, but with similar baseline characteristics.

Participants received efavirenz + lopinavir/ritonavir at the increased dose of 4 capsules (533/133) twice daily to counter the induction of metabolism by efavirenz, or a dual-NRTI regimen of choice plus efavirenz at standard doses. Most of the patients received zidovudine/lamivudine as their NRTI backbone. A total of 236 patients enrolled, with a baseline CD4+ cell count in the high 400s.

At the end of a median follow-up of 110 weeks, 74% of the group on dual NRTI + efavirenz maintained virologic suppression, versus 66% of those who had been randomized to lopinavir/ritonavir + efavirenz. The lopinavir/ritonavir regimen was also associated with significantly higher elevations in total cholesterol, low-density lipoprotein cholesterol and triglycerides.

For the combined endpoint of time to virologic failure or time to treatment limiting toxicity, the results favored the standard dual NRTI + efavirenz strategy; for time to virologic failure alone, there was a trend favoring this arm as well, although it did not meet statistical significance.

In results of a metabolic analysis presented elsewhere at this conference (ACTG 5125), the patients randomized to the nucleoside-sparing arm showed a greater increase in limb fat, suggesting a reversal of lipoatrophy.

The results of the study overall favor the use of a dual NRTI + efavirenz regimen over the boosted PI + efavirenz approach for maintaining virologic suppression. It is likely that the significantly lower pill burden of the NRTI regimen, as well as the requirement for increasing the dose of lopinavir/ritonavir with efavirenz contributed to the higher rate of tolerability endpoints.

In addition, both lopinavir/ritonavir and efavirenz are known to individually influence lipid metabolism unfavorably, a result clearly seen in this study. The efficacy and tolerability of this same lopinavir/ritonavir + efavirenz arm in treatment-naive patients is currently being studied in ACTG 5142, a randomized clinical trial from which we hopefully will have some results in the coming year.

Footnotes

1. Tashima K, Staszewski S, Nelson M, et al. Durable viral suppression on EFV-based HAART: 168 weeks of follow-up. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4547.

2. Fischl M, Ribaudo H, Collier AC, et al, for the AIDS Clinical Trials Group 388 Team. A randomized trial comparing 2 4-drug antiretroviral regimens with a 3-drug regimen in advanced HIV disease. In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Wash. Abstract 41.