New Experimental Drug Integrase Inhibitor (MK-0518)

For the last six years, treatment has driven the AIDS agenda. Just this past summer, the Food and Drug Administration (FDA) approved Prezista, a new Protease Inhibitor, as well as Atripla, the first once-daily single tablet regiment for adults with HIV infections. And while treatment remains an essential part of the battle against AIDS, the agenda driving the 16th International AIDS Conference in Toronto, Canada, moved away from treatment and toward prevention. I personally feel in order to keep the pandemic/epidemic at bay, we need a triple combination of Prevention-Intervention-Treatment, and boosted with a lot of Advocacy.

There was some treatment information during the conference that got my attention, one being MK-0518 an integrase inhibitor. Although just a year ago entry inhibitors that aim to prevent HIV from latching onto CCR5 receptors on the surface of the immune-system cells seemed to be the next big development for treatment, setbacks in clinical trials of the drugs dampened that enthusiasm. In this article I'll focus on MK-0518.

What Is MK-0518?

MK-0518 is an experimental integrase inhibitor being developed by Merck & Company. After HIV's genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIV's DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as MK-0518, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.

MK-0518 will need to be used in combination with other drugs. Clinical trials will evaluate its effect in combination with other drugs, including those currently approved for the treatment of HIV.

What Is Already Known About MK-0518?

The MK-0518 dose being studied in phase III clinical trials is 400 mg taken by mouth twice a day. It might interact with other medications, including those used to treat HIV. It is important that your personal physician and/or the research nurse or study investigator be aware of all drugs you are taking, including those you buy without a prescription.

This new drug holds promise for HIV-positive patients who have taken other anti-HIV drugs in the past. Because MK-0518 targets HIV differently than currently available drugs, chances are that most people living with the virus -- regardless of their treatment history -- will likely benefit from using it.

What Do We Know About MK-0518 From Clinical Trials?

Results of a two-part Phase II study have been presented. The first part of the study enrolled 35 HIV-infected patients who had not received other anti-HIV medications in the past. The patients received one of four doses of MK-0518 twice a day (100 mg, 200 mg, 400 mg, or 600 mg) or placebo without any other anti-HIV medications. After ten days of treatment, viral loads were reduced in all patients receiving MK-0518 by 1.7 to 2.2 log (approximately 98%).

The second part of the study enrolled 198 HIV-positive people, including 30 participants enrolled in part one of the study. The patients were to take one of the four doses of MK-0518 or Sustiva® (efavirenz). All patients in the study also received Viread® (tenofovir) and Epivir® (lamivudine). After 24 weeks of therapy, 85% to 95% of patients taking the MK-0518 regimen saw their viral loads reduced to less than 50, regardless of which dosing group they were in. In the Sustiva group, approximately 92% of patients experienced viral load reductions to less than 50 CD4 cell counts increased in all patients after 24 weeks or treatment. This study will follow patients for a total of 48 weeks.

A phase IIb study enrolled 167 HIV-positive participants, most of whom had evidence of resistance to drugs in three available classes (NRTIs, NNRTIs, and PIs). Patients were randomly assigned to one of three doses of MK-0518 (200, 400, or 600 mg twice daily), or placebo, in combination with a regimen of currently approved anti-HIV drugs. After 16 weeks of treatment, up to 72% of the patients receiving MK-0518 (most notably those receiving 600 mg twice daily) had viral loads below 50, compared to 16% of the patients who took placebo.

Phase III studies of MK-0518 have been started. An expanded access program (EAP) was initiated in September.

What Is Known About Side Effects?

In the two phase II studies reported to date, MK-0518 therapy was generally well tolerated. The most common side effects included diarrhea, nausea, vomiting, fatigue, dizziness, headache, flushing, itching, and injection-site reactions (among patients taking Fuzeon®). However, these side effects were also seen in patients receiving placebo. The only possible treatment-related toxicity of concern was a patient in the two-part phase II study taking 600 mg MK-0518 group. He was required to discontinue therapy due to significantly increased liver enzymes.

Who Should Not Take MK-0518?

It is not known whether MK-0518 will harm an unborn baby. It is very important to treat HIV/AIDS during pregnancy to reduce the risk of infecting your baby. Talk to your doctor about your treatment options. It is not known whether MK-0518 passes into breast milk and what affect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.

Who Can Qualify for Expanded Access?

The Expanded Access Program (EAP) for the experimental HIV integrase inhibitor MK-0518 (EARMRK) from Merck opened on Monday, September 11 in the US. EAPs provide experimental therapies without charge to patients with serious illnesses who have exhausted the benefits of available therapies. Following is the text of the EAP announcement on MK-0518 from Merck:

To qualify for the MK-0518 integrase inhibitor program, patients must have documented resistance or intolerance to at least one drug in each of the three major classes of anti-HIV medications - nucleoside analogues (NRTIs), non nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs).

Patients who qualify must not be adequately suppressing viral load on their current anti-HIV regimen and be at risk of clinical or immunologic progression. Their physician must determine that they need such an investigational medication to construct a potentially viable regimen.

To be eligible, patients must be at least 16 years old.

The safety and efficacy of MK-0518 has not been established. To increase the likelihood that patients will respond to this new experimental treatment, patients are encouraged to optimize their current regimen when beginning therapy with MK-0518. To do this, it is recommended that patients failing their current regimen receive at least two new antiretroviral medications to which their virus is still sensitive.

Eligible patients will be able to use MK-0518 with any available antiretroviral medications, including other medications available through expanded access research programs sponsored by other manufacturers after review and approval by the sponsor. Patients are ineligible if they are currently or were previously participating in a clinical trial with MK-0518. They also are ineligible if they are taking any medications prohibited by the study protocol, including Phenobarbital, phenytoin, and rifampin.

Until there is a cure KEEP SAFE!!

George Burgess is the Early Intervention Service Assistant of AIDS Survival Project.