February 9, 2004
On the other hand, for patients failing an initial PI regimen, we have several treatment options, including the use of an NNRTI-based regimen, another PI-based regimen or potentially a combination of both.
This was the rationale behind the poster presented by Dr. Kostman from the University of Pennsylvania. This was a government-funded, open-label study (CPCRA 057) in which patients were randomized to receive one or two protease inhibitors in combination with an NNRTI and background therapy consisting of one or more nucleosides. The study was initially designed to enroll 400 patients, but due to slow accrual enrollment, the study was closed after 68 patients were randomized.
This study enrolled NNRTI-naive patients who were failing their first regimen with an unboosted PI: nelfinavir (NFV, Viracept), ritonavir (RTV, Norvir) or indinavir (IDV, Crixivan). Randomization was stratified by the PI in the failing regimen (nelfinavir, indinavir or ritonavir), baseline HIV RNA and whether the patient had previously achieved an undetectable HIV RNA (less than 500 copies/mL). The treatment arms included one new PI versus two new PIs, both in combination with an NNRTI and one or more nucleosides.
At 12 months, the percentage of patients achieving an undetectable viral load (<400 copies/mL) was significantly higher in the dual-PI group (61%) compared to the single-PI group (36%). The same trend was observed in the change in log HIV RNA, with a p-value of 0.05 at 12 months. The changes in CD4 counts were also higher in the dual-PI group. There were no significant differences between the treatment groups for HIV RNA greater than 10,000 copies/mL. Unfortunately, the study population is too small to draw any trends or conclusions regarding the stratification groups or the incidence of adverse events.
The investigators concluded that patients who experienced virologic failure on their first PI regimen may benefit from a combination of one NNRTI and two PIs. The suboptimal performance of the single-PI group may be due to the lack of pharmacological boosting or to pre-existing resistance.
It is very hard to draw a take-home message from this study. First, the study was too small and did not take into consideration the pharmacological boosting of the second PI. There is also no mention about the pharmacokinetic interactions of efavirenz (EFV, Sustiva) and PIs, and whether a dose adjustment was performed, for example, in patients taking efavirenz and amprenavir (APV, Agenerase) as part of their new regimen.
What is clear is that this study showed more evidence that using an unboosted PI for second-line therapy after failing a first PI is probably not adequate. But, with the availability of more antiretroviral agents in today's treatment paradigms and the widespread use of boosted regimens, most physicians will probably feel more comfortable using a boosted PI before selecting a dual-PI/NNRTI regimen after initial failure.
Abstract: A Randomized Trial of 1 or 2 Protease Inhibitors in Combination With a Non-Nucleoside Reverse Transcriptase Inhibitor and Background Therapy in Patients With Virologic Failure on an Initial Protease-Inhibitor Containing Regimen (Poster 548)
Authored by: J. Kostman, B. Grund, R. Leduc, J. Baxter, L. Crane, Terry Beirn Community Programs for Clinical Research on AIDS
Affiliations: Univ. of Pennsylvania Hlth. System, Philadelphia, PA; Univ. of Minnesota, Minneapolis, MN; Cooper Hosp.; Robert Wood Johnson Med. Sch., Camden, NJ; Wayne State Univ., Detroit, MI
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