Friday, October 26, 2007

Integrase Inhibitor Isentress Provides a New Way to Treat AIDS Patients

Welcome to this installment of The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I’m Mike Neri.

In this podcast, I will talk about the optimism surrounding the recently FDA approved AIDS drug Isentress, including how it works, what step in the HIV replication cycle it affects, and what preliminary data show about the drug’s effectiveness and side effects. Ever since the discovery of HIV as the causative agent of AIDS, scientists have searched for weaknesses in its life cycle that they can exploit. As early as 1990, scientists had identified 13 pathways in the life cycle of HIV where the virus was susceptible to treatment. Unfortunately, due to the years of trial and error necessary to produce safe and effective drugs, new AIDS medications are developed slowly, and often have many side effects.

But optimism is high after the new drug Isentress showed very promising results when acting on a novel pathway to inhibit HIV replication. Isentress, also called Raltegravir, was developed by the Merck Corporation. It’s the first drug in a new line of AIDS medications called integrase inhibitors. As the name suggests, these drugs target an enzyme called integrase that the virus brings with it into an infected cell. Integrase, along with two other enzymes called reverse transcriptase and protease, is essential for HIV’s replication within the host. Therefore, scientists believe that if they can find a compound that stops integrase, they may be able to stop HIV from replicating.

After HIV has entered the cell by fusing with the membrane of its target cell, the virus dumps its genetic material and enzymes inside. It then makes copies of its own genetic material and uses integrase to insert them into the DNA of its host. This allows the virus to replicate its genome using the host’s machinery, and essentially take over the infected cell for its own reproductive purposes. The goal of integrase inhibitors is to prevent integrase from working correctly, therefore keeping the HIV genetic material out of the host’s genome and hindering viral replication. Previously, there had been only four pathways that drugs target in the HIV life cycle, and none of them had targeted integrase. However, integrase is an attractive target molecule for drug development for a number of reasons. First of all, integrase does not resemble any known human proteins, meaning the chances of side effects are reduced. In addition, by going after a new viral pathway for infection, doctors can combine integrase inhibitors with drugs targeting different pathways, which prevent the virus from becoming resistant to an entire class of drugs.

Scientists have long wanted to develop an integrase inhibitor, but the road to creating an effective drug and gaining FDA approval for it is a long one. According to Merck’s website, research into integrase inhibitors began in 1993 and eventually resulted in the identification of a class of compounds that could impede the function of the enzyme. These compounds work by binding to the active site of the integrase, thus preventing it from binding and cutting the host DNA, which prevents the viral genome from being inserted. After this discovery, researchers worked with these compounds in the lab to create the best integrase inhibitor, and tested it in virus cultures and animals. The use of animals allowed them to get an idea of the severity of the side effects and an approximate idea of the appropriate drug dosage. The final product of this drug testing was named Isentress. After emerging from the laboratory phase, Isentress was put through three phases of clinical studies involving groups of healthy and sick people. Results from the studies of Isentress given with a combination of other AIDS drugs were compared to a placebo given with the same drugs. From these data, researchers were able to get an idea of the effectiveness of the drug in treating the virus and fine-tune dosage information, all while closely monitoring side effects. At the end of this process, Merck submitted the data from all of the tests and clinical studies to the FDA for it to decide whether the drug was safe to be offered on the market. And on October 12, 2007, Isentress was officially approved by the FDA for treatment in AIDS patients, specifically those with HIV strains resistant to all other drugs. Most of the optimism surrounding the approval and release of the drug comes from the data obtained in the clinical studies. In the later phases of these trials, Isentress and a standard combination of other drugs were given to the most drug-resistant patients and compared to a placebo group. After 16 weeks, the Isentress treatment reduced the viral load to almost undetectable amounts in nearly 80% of patients, compared to only 43% in the placebo group.

While questions concerning Isentress still remain, such as whether the drug will work over longer periods of time and what the long term side effects might be, the preliminary results suggest that Isentress will have a significant impact on the treatment of AIDS immediately. As mentioned before, Isentress is initially expected to be used in patients who have exhausted all other drug treatment options. However, the overwhelming success of the drug so far has medical professionals wondering whether it can eventually be used as a front-line treatment against HIV. The true impact of Isentress cannot be known until it has been used by all types of AIDS patients over long periods of time. Nevertheless, the approval of Isentress is a sure sign for optimism in the AIDS community and a great success for the drug and pharmaceutical companies that have spent years producing and testing it.

I’m Mike Neri, and thanks for listening.

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