First Integrase Inhibitor a Potent New Option

By Daniel M. Keller, PhD

See also "Drug Update" in this issue.

CHICAGO—The new oral integrase inhibitor raltegravir (Isentress) provides sustained viral suppression when given in combination with optimal background antiviral therapy, investigators reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy annual meeting.

In this 48-week double-blind trial, 178 treatment-experienced patients (median age, 43-44 years; 84%-91% men) were randomized in equal numbers to raltegravir 200, 400, or 600 mg twice daily or to placebo on top of optimal background antiretroviral therapy. Patients with virologic failure after at least 16 weeks could begin taking open-label raltegravir 400 mg twice daily plus background therapy, as could patients who completed 24 weeks of the study.

The patients had been taking antiretroviral therapy for a median of 9 to 11 years; all had virus resistant to ≥1 drugs in each of the 3 current antiretroviral classes. Patients' baseline HIV loads were ≥5000 copies/mL, and CD4⁺ counts were >50 cells/mm³.

Viral load reductions with raltegravir seen at 24 weeks were sustained at week 48. At that time, HIV RNA loads were <400 copies/mL in 64% to 71% of the patients and <50 copies/mL in 46% to 64% of the patients.

In the placebo plus background therapy group, <20% of the patients reached either of these viral loads at 24 weeks.

Coinvestigator Joseph Eron, MD, professor of medicine at the University of North Carolina in Chapel Hill, said that the proportion of patients achieving these levels of viral load reduction was "very substantial...in these highly treatment-experienced patients." These 48-week results are the longest-duration data so far for any trial of raltegravir.

In the raltegravir arms, "CD4 counts rose nicely," Dr Eron said. "It depended on the treatment arm, but approximately a 100-cell increase over the 48-week period." At 24 weeks, the CD4⁺ counts of patients receiving placebo plus background therapy were no different from study entry.

By week 48, 29% of the patients experienced virologic failure. "Even though the majority of patients suppressed below 50 copies, those patients who don't suppress or who rebound are likely to develop resistance," Dr Eron said.

Of the 38 viral failures in the study, 35 had some evidence of viral resistance. Overall, raltegravir was well tolerated, with 4 patients dropping out of the trial because of serious adverse effects&#8212;2 were taking raltegravir, and 2 were taking placebo. Whether these were related to raltegravir or to the background therapy drugs was not clear. The adverse effects were similar in the raltegravir and placebo groups.

Dr Eron concluded, "I think initially where it will fit in will be in our most highly treatment-experienced patients, because that's where the greatest need is." He foresees that "over time, patients who have less-advanced disease in terms of treatment will probably benefit from raltegravir."

A second integrase inhibitor, elvitegravir (Gilead Sciences), is in phase 2 clinical trials. Edwin DeJesus, MD, FACP, of the Orlando Immunology Center, Fla, and colleagues presented study results at the International AIDS Society annual meeting, which suggested that cross-resistance may occur between elvitegravir and raltegravir.