AIDS 2010: NRTI-sparing Regimen of Lopinavir/ritonavir plus Raltegravir Works as Well as Traditional 3-drug HAART

An antiretroviral therapy (ART) regimen consisting of the protease inhibitor lopinavir/ritonavir (Kaletra) plus the integrase inhibitor raltegravir (Isentress) suppressed HIV viral load as well as a traditional 3-drug highly active ART (HAART) combination, while avoiding potential adverse side effects of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), according to study findings reported this week at the XVIII International AIDS Conference (AIDS 2010) in Vienna.

HAART regimens to date have typically included a protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) plus a "backbone" of 2 NRTIs. Development of new drug classes -- including integrase inhibitors that prevent HIV from inserting its genetic material into host cells -- offers new options for constructing potent combination regimens.

Jacques Reynes and fellow investigators with the PROGRESS (PROtease/InteGRasE Simplification Study [aka M10-336]) team designed this open-label Phase 3 trial to compare a traditional 3-drug HAART regimen and a 2-drug NRTI-sparing combination.

A total of 206 treatment-naive participants were randomly assigned (1:1) to receive 400/100 mg twice-daily lopinavir/ritonavir combined with either 400 mg twice-daily raltegravir -- but no NRTIs -- or else once-daily tenofovir/emtricitabine (Truvada).

Most participants (about 85%) were men, 75% were white, 21% were black, and the average age was 49 years. All had plasma viral load > 1000 copies/mL -- with a mean of about 20,000 -- and the average CD4 count was nearly 300 cells/mm3.

The primary endpoint of undetectable viral load  (< 40 copies/mL) at 48 weeks was reported at AIDS 2010, but follow-up is continuing through 96 weeks.

Results

• In a 48-week intent-to-treat TLOVR analysis, 83.2% of participants in the raltegravir group and 84.8% in the tenofovir/emtricitabine group achieved undetectable viral load.
• This difference of -1.6% easily fell within the predefined non-inferiority thresholds of 20% and 12%, allowing investigators to conclude that the NRTI-sparing combination was non-inferior to the traditional HAART regimen.
• Raltegravir suppressed viral load in more patients during the early treatment period -- with significant differences at weeks 2, 4, 8, and 16 -- but tenofovir/emtricitabine caught up by week 24.
• CD4 cell counts rose by statistically similar amounts at all time points, ending with gains of 215 cells/mm3 in the raltegravir group and 245 cells/mm3 in the tenofovir/emtricitabine group.
• Both study regimens were generally well-tolerated.
• 8% of participants in the raltegravir arm and 11% in the tenofovir/emtricitabine arm discontinued the study for any reason, not a significant difference.
• 2 patients in both groups quit due to adverse events; 1 in the raltegravir group and 2 in the tenofovir/emtricitabine group did so due to virological failure.
• The most common side effects, occurring at similar rates in the raltegravir and tenofovir/emtricitabine arms, were diarrhea (8% vs 13%, respectively) and elevated cholesterol (8% vs 5%, respectively).
• Total cholesterol, HDL "good" cholesterol, and triglyceride levels increased by a larger average amount, and in more patients, in the raltegravir arm.
• 1 person in each arm had evidence of drug resistance mutations, but there were no new protease resistance mutations.

Based on these findings, the PROGRESS investigators concluded that lopinavir/ritonavir plus raltegravir "resulted in non-inferior efficacy and similar tolerability as a traditional 3-drug antiviral regimen."

"The 48-week PROGRESS study results, while not definitive, suggest that the nucleoside-sparing HIV regimen of Kaletra and Isentress may be an alternative treatment option for patients new to HIV therapy, when compared to a standard HIV regimen." Reynes said in a press release issue by Abbott, the maker of lopinavir/ritonavir.

Investigator affiliations: Hôpital Gui de Chauliac, Montpellier, France; Abbott, Abbott Park, IL; Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain; Innovative Care PSC, Bayamon, Puerto Rico; Therapeutic Concepts, Houston, TX.

7/23/10

Reference

J Reynes, A Lawal, F Pulido, and others. Lopinavir/ritonavir combined with raltegravir demonstrated similar antiviral efficacy and safety as lopinavir/ritonavir combined with tenofovir disoproxil fumarate/emtricitabine in treatment-naive HIV-1 infected subjects: PROGRESS 48 week results. XVIII International AIDS Conference. Vienna, July 18-23, 2010. Abstract MOAB0101.

Other Source

Abbott. Abbott's PROGRESS Study of Kaletra and Isentress Compared with a Standard HIV Regimen Meets the Pre-Specified Primary Efficacy Endpoint. Press release. July 19, 2010.