HIV Integrase Inhibitor MK-0518 Monotherapy Demonstrates Potent Anti-HIV Activity in 10-day Study

By Ronald Baker, PhD

MK-0518 from Merck is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 and excellent bioavailability. In the current study, researchers evaluated the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy.

The study group consisted of therapy-naïve patients with HIV-1 RNA levels of at least 5000 copies/mL and CD4+ T-cell counts of at least 100 cells/mm3.

This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy.

Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect.

Results

Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy;

The mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group.

On day 10, the mean decrease from baseline in the log10 HIV RNA level was -0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively.

All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo).

At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10.

Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated.

The most common adverse experiences were headache and dizziness; these were similar between active and control groups.

There were no discontinuations because of adverse experiences and no serious adverse experiences.

The authors conclude, "MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated."

Discussion

Certain properties of MK-0518 are important considerations for its clinical use. It is primarily metabolized by the liver and is neither an inducer nor an inhibitor of CYP3A4. According to the study authors, this characteristic of the drug should reduce potential drug interactions with other commonly used antiretroviral agents, especially the currently available protease inhibitors and non nucleoside reverse transcriptase inhibitors.

The authors emphasize that there is no potential or need for boosting with CYP3A4 inhibitors such as ritonavir. "Thus, use in salvage regimens, where the need is most acute, should be less complicated," they note.

In addition, the drug does not appear to affect changes in triglyceride or cholesterol levels, as is so often seen in the protease inhibitor drug class.

A more complete side effect profile of MK-0518 will emerge as the results of ongoing larger scale studies become available.

The authors regard MK-0518 as a "clinically relevant" HIV-1 integrase inhibitor that represents "a major advance in basic and clinical science." With this drug scientists have accomplished the important objective of successfully targeting all 3 enzymes required for viral replication.

The manner in which clinicians will incorporate this compound into the armamentarium of antiretroviral drugs remains to be seen.

Interim results are now available from Phase 2 trials of MK-0518 in treatment-naive and treatment-experienced patients with multidrug-resistant HIV in combination regimens and at doses similar to those used in the present study.

The results show that after 16 to 24 weeks, MK-0518 demonstrates sustained antiretroviral activity without significant toxicity.

Based on these findings, the authors conclude, "If this observation is confirmed in the phase 3 studies now underway, MK-0518 should clearly be a welcome addition to the existing treatment options for those persons infected with HIV-1."

12/08/06

Reference
M Markowitz, J O Morales-Ramirez, B-Y Nguyen, and others. Antiretroviral Activity, Pharmacokinetics, and Tolerability of MK-0518, a Novel Inhibitor of HIV-1 Integrase, Dosed As Monotherapy for 10 Days in Treatment-Naive HIV-1-Infected Individuals. Journal of Acquired Immune Deficiency Syndromes 43(5): 509-515. December 15, 2006.