Raltegravir Provides Durable Virologic Suppression in Treatment-Naive Patients with HIV at 96 Weeks

Bob Roehr

August 07, 2008

August 7, 2008 (Mexico City) — Raltegravir (RAL), the first-in-class integrase inhibitor, continues to provide durable virologic suppression in treatment-naive patients with HIV at 96 weeks when used in combination therapy. The results are similar to what was seen at 48 weeks, according to the latest data presented here at the XVII International AIDS Conference.

The trial randomly assigned 160 treatment-naive patients to either a regimen containing RAL plus tenofovir and lamivudine (RAL + TDF + 3TC) or a comparison group of 38 patients receiving a combination based on efavirenz (EFV + TDC + 3TC) in a trial designed to demonstrate equivalency.

Patients received doses of 100, 200, 400, or 600 mg RAL twice a day for the first 48 weeks in the dose-ranging portion of the study. All participants were switched to RAL 400 mg twice a day after week 48 for continuation of the trial. The principal endpoint was HIV RNA levels of lower than 50 copies/mL.

Investigator Martin Markowitz, MD, from the Aaron Diamond AIDS Research Center in New York City, said that at 96 weeks, 83% of the patients receiving RAL and 84% of the patients receiving EFV maintained HIV RNA levels of lower than 50 copies/mL in an intent-to-treat analysis. Using observed failure analysis, the responses were 92% and 91%, respectively, for the 2 drugs.

The change in baseline CD4 cell counts also was similar for the 2 groups, with increases of 221 and 232 cells/µL, respectively, "demonstrating that with virologic control, in both arms there is concomitant improvement in immunological status," Dr. Markowitz said.

One patient from each group experienced virologic failure, as defined by an initial decline below HIV RNA levels of 400 copies/mL and then a rebound of a least 1 log above that threshold, during the period from week 48 to week 96. Dr. Markowitz said that analysis of the patient in the RAL group failed to detect any of the known mutations associated with resistance to that drug.

Dr. Markowitz next turned to the adverse event profiles. Total drug-related clinical adverse events favored RAL (51% vs 74%). Neuropsychiatric symptoms were most likely to occur in both groups by week 48 (13% vs 29%), with little increase through week 96 (16% vs 32%). The rates of malignancies were similar (3/160 vs 1/38), and grade 3/4 laboratory abnormalities were uncommon.

"[RAL] had a neutral effect on serum lipid profiles," Dr. Markowitz said. The changes in cholesterol, [low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol] are statistically significantly different when compared with the [EFV] arm," at week 96. Triglycerides in the RAL group showed a decline of 10.8 mg/dL from baseline by week 96, whereas the EFV group showed a slight increase.

Dr. Markowitz said the combination containing RAL proved itself equal to that containing EFV in this international study.

During the discussion, panel cochair Sharon Walmsley, MD, from the University of Toronto in Canada, asked whether the more rapid initial virologic suppression seen in trials of RAL has any lasting clinical significance.

"We still don't know what the clinical significances of those differences are," said Dr. Markowitz. It may be a product of the different mechanisms of action of the drugs.

He added that the 400-mg dose was settled on because pharmacokinetic data showed "a huge amount of variability within the same person and from person to person. The 400-mg dose ensured the best exposure and coverage of the drug. It also provides a safety margin for coadministration with drugs such as rifampin that reduce exposure to [RAL]."

He reminded the audience that RAL was initially developed for the treatment-experienced patient and that perhaps it would make sense to study the efficacy of lower doses in a naive population at some later time.

Roy Gulick, MD, MPH, a professor of medicine at the Weill Cornell Medical College in New York City, told Medscape HIV/AIDS, "It's nice to see durable activity with a new agent in treatment-naive patients."

The study was sponsored by Merck. Dr. Walmsley and Dr. Gulick have disclosed no relevant financial relationships.

XVII International AIDS Conference: Abstract TUAB0102. Presented August 5, 2008.


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