ICAAC 2006; San Francisco, Calif.; September 27-30, 2006

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The Body PRO Covers: The 46th Interscience Conference on Antimicrobial Agents and Chemotherapy

The Integrase Inhibitor MK-0518 Demonstrates a Favorable Lipid Profile

September 27, 2006

New data on HIV integrase inhibitors have garnered a lot of backroom discussion at recent international conferences. Integrase, one of the essential HIV enzymes, has long been a target for drug developers, but, until very lately, all attempts to effectively block the protein in patients had failed. Finding a compound that inhibits integrase would be very valuable, especially for patients whose HIV had become resistant to most, if not all, existing HIV medications.

Hence, the excitement when initial monotherapy clinical studies of Merck's integrase inhibitor MK-0518 showed dramatic reductions in HIV viral loads.1 More recently, excellent antiviral activity in HIV-infected patients has been demonstrated by MK-0518 in combination therapy. Preliminary data from the phase 2, dose-ranging Protocol 004 study2 showed that in combination with tenofovir (TDF, Viread) and lamivudine (3TC, Epivir) in treatment-naive persons, MK-0518 compares well to the benchmark drug efavirenz (EFV, Sustiva, Stocrin), with similar numbers of persons with undetectable HIV viral loads after 24 weeks. In addition, a surprisingly greater percentage of MK-0518 trial participants were undetectable at earlier timepoints, suggestive of even greater antiviral potency than efavirenz. Furthermore, the tolerability of the drug in this group of patients was excellent, with side effect profiles that were also similar to that of efavirenz, but lacked the well-characterized and, sometimes difficult to manage, neuropsychological effects of efavirenz.

Today's late breaker presentation3 by H. Teppler and colleagues from Merck examines the effect of MK-0518 and efavirenz on the fasting serum cholesterol and triglyceride levels observed in Protocol 004. In this study, 38 people received efavirenz and 40 people received one of four different doses of MK-0518.

The average age of the participants was about 36 years, with about 66% non-white. At week 24, serum total cholesterol had increased 19 mg/dL in patients who were taking efavirenz, but decreased from -2 to -7 mg/dL among the MK-0518 groups. The low-density lipoprotein (LDL) cholesterol decreased significantly among all MK-0518 groups; modest high-density lipoprotein (HDL) cholesterol increases were seen in all participants -- there was no significant difference between those receiving efavirenz and those receiving MK-0518.

Among patients receiving efavirenz, fasting triglycerides increased 47 mg/dL and changed from +2 to -43 mg/dL in the MK-0158 groups. The differences between efavirenz and all four MK-0518 groups were strongly statistically significant. The authors correctly conclude that MK-0518 is not associated with increases in cholesterol or triglycerides and is significantly different from efavirenz with respect to those changes associated with treatment.

As with all data on experimental drugs, these data should have little immediate impact on today's treatment decision making. Nevertheless, an expanded access program for MK-0518 has been announced and patients soon will have access to this drug in the United States; this study will have clinical relevancy for those patients.

Current drug therapies for HIV have come a long way -- this study compares a benchmark, well-tolerated drug regimen to a newcomer. Efavirenz is recommended by treatment guidelines the world over and is supported by excellent results in study after study. That the integrase inhibitor MK-0518 has been able to positively distinguish itself from efavirenz comes as a surprise to this writer. The favorable lipid profile of MK-0518 in this interim, 24-week report is an additional desirable attribute.

Taken together, the current set of presentations suggest a challenger to the throne that has similar (or perhaps, better) viral suppression and similar (or perhaps, better) tolerability. Future analyses will be anticipated with great interest.


  1. Morales-Ramirez JO, Teppler H, Kovacs C, et al, and the Protocol 004 Team. Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naive HIV-1 infected patients. In: Program and abstracts of the 10th European AIDS Conference; November 17-20, 2005; Dublin, Ireland. Abstract LBPS1/6.

  2. Markowitz M, Nguyen BY, Gotuzzo F, et al, and the Protocol 004 Part II Study Team. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214.
    View slides: Download PowerPoint

  3. Teppler H, Azrolan N, Chen J, Nguyen BY, for the Protocol 004 Study Group. Differential effect of MK-0518 and efavirenz on serum lipids and lipoproteins in antiretroviral therapy (ART)-naive patients. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-0256a.
    View poster: Download PDF

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