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raltegravir safety
Jul 1, 2007

I am 56 yo male, have been + for over 26 years, never sick from HIV. I have had 2 angioplastys and stents due to the enormous rise in choleterol and tryglycerid levels plus my genetics. To resolve this ongoing problem, my doctor wants me to take Raltegravir in place of norvir(I've been accepted to the early access program by merck). I'm currently taking norvir, prezista, rescriptor, epzicom, viread, and a host of cholesterol/blood pressure/blood thinning meds. Is switching the norvir for the raltegravir a good idea? i have not yet built up resistance to the norvir, so my doctor says can go back to it if the raltegravir doesnt work. My cardiologist is concerned about my triglyceride levels being around mid 300s; cholesterol is low at 130-140, but the hdl:ldl ratio is not optimal. What's your knowledge of the safety and efficacy of this new drug?

Response from Dr. Frascino

Hi,

As you realize, Merck's integrase inhibitor, raltegravir (Isentress), is an investigational drug not yet approved by the FDA for use outside of clinical trials and the early-access program; consequently, our experience is still somewhat limited. Considering your cardiac risk profile, hypertriglyceridemia and lipid HDL:LDL ratio, I agree a trial of raltegravir may well be warranted. Regarding safety and efficacy, see below for what we know so far.

Good luck!

Dr. Bob

Isentress (raltegravir, RGV, or MK-0518)

(AIDSmeds.com)

What is Isentress? Isentress is an experimental integrase inhibitor being developed by Merck & Company. The U.S. Food and Drug Administration (FDA) is now reviewing the safety and effectiveness of Isentress. It is expected to be approved by the FDA by mid-October 2007.

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 Isentress, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.

Isentress 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.

Merck has announced that it has initiated an expanded access program (EAP), called EARMRK, for Isentress. The program provides the drug, free of charge, to HIV-positive people with limited treatment options. This is defined as people who: 1) have HIV resistance to at least one drug in all three classes of oral HIV drugs, 2) are failing their current regimens, and 3) require a new drug to which their HIV may not be resistant. For more information on the EARMRK program, call 1-877-EARMRK1 or review Merck's EARMRK website.

What is already known about Isentress? The Isentress dose being studied in phase III clinical trials is 400mg taken by mouth twice a day.

Isentress 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.

Isentress holds promise for HIV-positive patients who have taken other anti-HIV drugs in the past. Because Isentress 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 Isentress.

What do we know about Isentress 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 Isentress twice a day (100mg, 200mg, 400mg, or 600mg) or placebo without any other anti-HIV medications. After ten days of treatment, viral loads were reduced in all patients receiving Isentress 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 Isentress 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 Isentress 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 178 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 Isentress (200, 400, or 600mg twice daily), or placebo, in combination with a regimen of currently approved anti-HIV drugs. After 24 weeks of treatment, up to 67% of the patients receiving Isentress (most notably those receiving 600mg twice daily) had viral loads below 50, compared to 14% of the patients who took placebo.

Preliminary results from two Phase III studies of Isentress have been reported. The studies, BENCHMRK-1 and BENCHMRK-2, are randomized evaluations of Isentress (400mg twice daily) compared to placebo, both combined with an optimized background regimen (OBR), in patients with multiple-drug-resistant HIV and a history of treatment failure (including the regimens they were taking prior to enrollment). After 16 weeks of treatment in BENCHMRK-1, 61% of patients in the Isentress group had viral loads below 50, compared to 33%% of patients in the placebo group. Sixteen-week results from BENCHMRK-2 were similar to those of BENCHMRK-1: viral loads were below 50 in 62% of the Isentress recipients and 36% of those receiving placebo. Treatment results were best among those who started therapy with Fuzeon® (enfuvirtide) and/or Prezista® (darunavir) for the first time as components of their OBRs. Additional Phase III studies of Isentress are being conducted. An expanded access program (EAP) was initiated in September (see above and below).

What is known about side effects? In the two phase III studies reported to date, side effects were similar between the Isentress groups and the placebo groups. Approximately 83% of the patients, regardless of which treatment they received, experienced at least one mild side effect. Serious side effects were also similar between the groups, documented in approximately 12% of patients. The most common side effects were diarrhea, injection site reactions (among those receiving Fuzeon), and headaches.

Additional data from studies evaluating the safety of Isentress are needed.

Who should not take Isentress? It is not known whether Isentress 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 Isentress passes into breast milk and what effect 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.

Where can I learn more about clinical trials of Isentress? The manufacturer has developed a website called benchmrk.com to help HIV-positive people with limited treatment options find out if they are potential candidates for a new clinical trial studying Isentress, and to locate the nearest participating clinic.

Information about the Isentress expanded access program (EAP) can be found on a website called earmrk.com.

Other sources of clinical trial information include an interactive web site run by ACRIA, the AIDS Community Research Initiative of America, and AIDSinfo.nih.gov, a site run by the U.S. National Institutes of Health (NIH). The NIH also have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).


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