October 27, 2008 (Washington, DC) – Raltegravir (RAL; Isentress, Merck & Co), the first-in-class integrase inhibitor, continues to impress with its safety and efficacy, this time with 48-week data from treatment-naïve patients. Data from the STARTMRK trial were presented here at the 48th Annual ICAAC/IDSA 46th Annual Meeting, a joint meeting of the American Society for Microbiology and the Infectious Diseases Society of America.

Treatment-naïve patients were screened for resistance to tenofovir or emtricitabine, and the 563 patients who showed no resistance were enrolled in the randomized blinded trial to add either RAL (400 mg twice daily) or efavirenz (600 mg every day at bedtime) to the regimen. At baseline, the patients reflected the naïve population, a significant portion of which has advanced human immunodeficiency virus (HIV) disease: 53% had more than 105 HIV RNA copies/mL, and 47% had a CD4 T-cell count of 200 or less cells/mm3.

The primary end point was suppression to less than 50 HIV RNA copies/mL, said Jeffrey Lennox, MD, a professor at Emory University in Atlanta, Georgia, who presented the study findings.

Using an intent-to-treat analysis, where dropouts for any reason were counted as failures, 86.1% of the RAL and 81.9% of the efavirenz groups achieved the primary end point of less than 50 HIV RNA copies/mL. The difference did not reach statistical significance, but the study easily achieved its goal of "demonstrating that RAL is noninferior to efavirenz" (P < .001), Dr. Lennox said.

There was faster initial suppression of viremia in the RAL group, but the 2 groups converged over time. The increase in CD4 cells from baseline was 26 cells/mm3 higher in the RAL group (189 cells/mm3 vs 163 cells/mm3), which did reach statistical significance. However, there is no consensus that either of these differences is clinically significant.

Adverse effects were common in both groups (44% vs 77%), with RAL maintaining its more favorable profile for moderate to severe events (16% vs 32%).

One of the greatest drawbacks to efavirenz is that a portion of patients experience central nervous system (CNS) problems, some to the point of discontinuing its use. Dr. Lennox explained that accumulated CNS adverse events to week 8 favored RAL (10.3% vs 17.4%). Depression occurred in ~5% of patients in both groups to week 48.

"There was 1 malignancy in the RAL arm and 9 malignancies in the efavirenz arm, most of which were Kaposi's sarcoma," he said. "The lipid changes in this study were relatively mild.... There was very little change [in total cholesterol] in either arm of the study."

The findings mirror what was seen earlier in the continuation of a smaller dose-ranging study in treatment-naïve patients who used lamivudine in their regimen because emtricitabine was not yet available. That study, reported by Medscape HIV/AIDS at the time, was presented in August at the XVII International AIDS Conference, in Mexico City.

"This is a very nice presentation that confirms the data we have seen previously," commented Mark Wainberg, PhD, during the question period. The researcher from McGill University in Montreal, Quebec, suggested that the initial rate of decline in viremia might be explained by "the very slow off rate of raltegravir from the integration complex." Dr. Lennox agreed that this is probably the case.

Daniel Kuritzkes, MD, a conference organizer and clinician at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape HIV/AIDS that this continues the trend of newer therapies providing similar or greater efficacy and fewer adverse effects. The fact that there are fewer adverse effects contributes to better adherence and, combined, these advantages make it less likely that resistance to thevirus will emerge. He believes that raltegravir will play an increasingly important role in the early initiation of therapy.

Merck funded this multicenter international trial. Dr. Lennox is an academic researcher with financial ties to Merck, Bristol-Myers Squibb, and Gilead Sciences. Neither Drs. Wainberg nor Kuritzkes have disclosed any relevant financial relationships.

48th Annual ICAAC/IDSA 46th Annual Meeting: A Joint Meeting of the American Society for Microbiology and the Infectious Diseases Society of America: Abstract H-896a. Presented October 26, 2008.

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