MK-0518 Integrase Inhibitor Is Active Against HIV through 24 Weeks

By Liz Highleyman

The experimental integrase inhibitor MK-0518, being developed by Merck & Co., has generated considerable interest since data were presented at the Retrovirus conference this past February showing it was effective in treatment-experienced patients with drug-resistant virus.

Integrase inhibitors represent a new class of antiretroviral agents that target the integration step, in which a strand of HIV genetic material is incorporated into the host cell's DNA.

At the XVI International AIDS Conference, held last week in Toronto, Martin Markowitz, MD, presented late-breaking 24-week data from a dose-ranging study of MK-0518 in patients being treated for the first time.

In this double-blind, multicenter Phase II trial, 198 treatment-naïve patients with viral loads of at least 5000 copies/mL and CD4 cell counts of at least 100 cells/mm3 were randomly assigned to receive one of four doses of MK-0518 (100, 200, 400, or 600 mg twice daily) or else efavirenz (Sustiva; 600 mg once daily); all participants also took tenofovir (Viread) and 3TC (lamivudine, Epivir). Some patients continued on from an earlier 10-day monotherapy stage of the study, while others were newly enrolled.

Results

Study participants had a mean age of 36 years, about 80% were male, about 70% were non-white, and more than 30% had a previous AIDS diagnosis; these baseline characteristic were similar across all arms.

In all MK-0518 dose arms, HIV RNA decreased by more than 2 logs.

Viral load initially dropped rapidly -- within two weeks - in the MK-0518 arms, then leveled off.

A similar proportion of patients achieved viral load reductions below 50 copies/mL in the MK-0158 arms (85%-95%) and the efavirenz arm (92%).

While patients achieved undetectable HIV RNA sooner in the MK-0518 arms compared with the efavirenz arm, most participants in all arms had viral load below 50 copies/mL by week 4.

At 16 weeks (as presented in the published abstract), the proportions of patients achieving HIV RNA below 400 and below 50 copies/mL were as follows:

At 24 weeks, reductions in viral load remained stable, and were similar across all arms.

Increases in CD4 cell count were similar in the various arms, ranging from about 75-135 cells/mm3.

MK-0518 was generally well tolerated; drug-related adverse events were similar in the MK-0518 and placebo arms, with the most common side effects being nausea, headache, dizziness, diarrhea, and insomnia.

Laboratory abnormalities were common, and were mostly mild-to-moderate.

A total of 8 severe adverse events were reported (4% in the MK-0518 groups and 3% in the efavirenz group), none of which were considered drug-related.

One patient discontinued MK-0518 due to elevated aspartate aminotransferase (AST) in the highest-dose MK-0518 arm; this patient was taking isoniazid, which is known to cause liver toxicity.

Conclusion

On the basis of this preliminary data, the authors concluded that MK-0518, used in combination with tenofovir/3TC, "at all doses studied had potent antiretroviral activity and was generally well-tolerated" in antiretroviral-naïve patients.

The current study will continue through 96 weeks, and a Phase III 48-week combination therapy trial is currently enrolling patients.

In related news, Merck announced on August 17 that it will offer MK-0518 in an expanded access program for patients who are ineligible for clinical trials. Expanded access is intended for individuals with life-threatening illness who lack other viable treatment options. Enrollment in the program is expected to begin in the next few months.

8/22/06

Reference
M Markowitz, B-Y Nguyen, F Gotuzzo, and others. Potent antiviral effect of MK-0518, novel HIV-1 integrase inhibitor, as part of combination ART in treatment -naïve HIV-1 infected patients. XVI International AIDS Conference. Toronto, August 13-18, 2006. Abstract THLB0214.