Protease inhibitors (PIs) occupy an ambiguous position in contemporary HIV care. On the one hand they are perceived as potent agents, particularly when boosted by ritonavir (RTV, Norvir), and are rightly credited with launching the highly active antiretroviral therapy (HAART) revolution. But many PIs are also viewed with some unease because of their propensity to cause dysmetabolic side effects that include insulin resistance and hyperlipidemia. It is this concern regarding hyperlipidemia that has been the chief motive behind many of the PI switch studies to date, and this trial is no different in this regard.

Study

This was a prospective, multi-center study that enrolled people who were receiving a PI-based regimen and had undetectable plasma HIV RNA. The trial participants were randomized to switch to either the triple nucleoside zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen consisting of nevirapine (NVP, Viramune) and zidovudine/lamivudine (AZT/3TC, Combivir).

The primary endpoint of the study was the percentage of participants who maintained plasma HIV RNA suppression 48 weeks after the switch in therapy. Sixty-eight subjects were randomized to zidovudine/lamivudine/abacavir (group 1) and 66 to the zidovudine/lamivudine and nevirapine (group 2).

Overall, there were no differences in the primary endpoint between the 2 groups by intent-to-treat analysis, with 71% and 73% of trial participants maintaining undetectable viral loads at 48 weeks in groups 1 and 2, respectively. Using on-treatment analysis, 98.6% of participants in group 1 had undetectable viral loads and 98.5% in group 2. There were also no significant differences in CD4+ cell count changes between the 2 groups.

Fourteen subjects in both groups had adverse events that led to discontinuation of therapy. This included 5 participants in the zidovudine/lamivudine/abacavir group who stopped because of rash and suspected abacavir hypersensitivity reaction. Seven subjects in the nevirapine group halted treatment due to hepatotoxicity.

As expected, lipid parameters improved in both groups. In the zidovudine/lamivudine/abacavir group, the percentage of participants with abnormally high cholesterol (>5.2 mmol/L, >200 mg/dL) changed from 55% to 30% after the switch at week 48 (P = .019). In the nevirapine group, 69% of the participants had high cholesterol at baseline versus 42% at week 48 (P = .019)

Comment

This trial demonstrates similar outcomes in the participants who switched to zidovudine/lamivudine/abacavir as compared with those who switched to the zidovudine/lamivudine and nevirapine combination. These results are consistent with prior switch studies that have evaluated replacement of PIs with either nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) or NNRTI-based combinations in subjects with controlled viral replication.¹

Of course, as can be seen by the 14 participants who discontinued therapy because of adverse effects, switching therapy is not without risks -- particularly for side effects related to the new regimen. But the fact remains that a PI-switch strategy is a viable option for patients experiencing metabolic side effects, and it often results in significant improvements in lipid levels.

Footnote

1. Drechsler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis. November 15, 2002;35(10):1219-1230.