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Integrase Inhibitors

Two New Drugs in this New Class of HIV Medication


Updated June 26, 2014

Currently there are four classes of HIV medications used in various combinations to control the replication of HIV. But in the HIV medication pipeline there is a fifth class of medication with two new drugs in clinical trials that have thus far shown promise in the battle against HIV replication. The new class, Integrase Inhibitors works by interfering with one of the three enzymes responsible for HIV replication, the enzyme integrase.

What are the Four Classes of HIV Drugs?

What is Intergrase?

Integrase is an enzyme that does what the name implies, it integrates HIV genetic material into the DNA of human CD4 cells making it possible for the infected cell to make new copies of HIV. By interfering with integrase, the integrase inhibitors prevent HIV genetic material from ingrating into the CD4 cell, thus stopping viral replication.

Understanding the HIV LIfe Cycle

See step-by-step the process of HIV replication

The First Two Integrase Inhibitors

The stage in which HIV genetic material is integrated into human DNA is not fully understood. For that reason, developing an integrase inhibitor that fits the bill and was effective has not been easy. Many have failed very early in clinical trials. However, there are two in the HIV medication pipeline currently that are showing great promise because they act in a different way than their failed predecessors. To explain, viral intergration takes place in three stages:
  • first integrase binds to the the cellular DNA;
  • next works on a specific area on the viral DNA, preparing it for integration;
  • finally, the process viral strand is transferred into the host cell.
Many of the first integrase inhibitors that failed worked on the first two stages of integration. The two new integrase inhibitors target the third stage when the viral strand is transferred to the host cell.

Isentress Fact Sheet

The Phases of Clinical Trials

Ten Questions to Ask Before Entering Clinical Trials

MK-0518 and GS-9137 - The Two New Integrase Inhibitors

So after several trials and many failures, two new integrase inhibitors have emerged and are showing promise. If they prove successful in trials, they represent the first in a brand new class of HIV medication, which represents new hope for those who have exhausted all conventional combinations.
  • MK-0518
    Merck, maker of the protease inhibitor Crixivan currently has the first integrase inhibitor to enter Phase II trials, MK-0518. There have been two studies of note:

    • In the first study people taking only the experimental drug for 10 days saw a 98% reduction in their viral load after that 10 days. The participants tolerated the drug very well with minor complaints of headache and dizziness with some fatigue.

    • In a larger study that tested several different doses of the drug in patients with HIV resistance, it was found that over 80% of patients saw a significant decline in their viral loads with the lowest dose. Ironically the study also suggested that lower doses of the drug actually was more effective in controlling the viral load when compared to higher doses. As in the previous study, the drug was well tolerated among the participants of the study.

    • Recent study results released by Roche AG, showed that 95% of patients taking MK-0518 along with Roche's drug Fuzeon achieved an undetectable HIV viral load compared to only 60-70% of patients taking MK-0518 without Fuzeon. This study makes it clear that not only is MK-0518 safe to take along with other HIV medications, it is effective as well.

    Additional trials have shown that unlike many HIV medications, MK-0518 does not appear to elevate cholesterol and triglycerides. So it is obvious that these two early trials show that unlike a number of its predecessors, this integrase inhibitor is well tolerated and is effective in the treatment of HIV.

  • GS-9137
    The second intergrase inhibitor is manufactured by Gilead, makers of the HIV medication Viread. GS-9137 has been proven safe, effective, and well tolerated in two Phase I/II studies.

    • In one study, 99% of those taking the drug as monotherapy showed a significant decrease in viral load. What's more encouraging is tha the drug has proven to be effective in once daily dosing, a fact that will make adhering to the therapy much easier than other multi-dose per day therapies.

    • Another study showed the drug to be very effective when boosted with the protease inhibitor Norvir. In fact, Norvir produced a 20-fold increase in the amount of GS-9137 in the blood compared to taking the drug without Norvir. Additionally, the drug has been found to be significantly more effective when taking with food.

    Drug Side Effects & Solutions

What Next?

The studies described in this article represent the beginning of the journey for these two medications. Further Phase II and Phase III studies are needed to assure that the drugs are effective and safe. But the promising results of these early studies gives hope to those waiting for their next regimen.

Source: "HIV Drug Watch"; BETA Magazine; Vol. 18, No4; Summer 2006, pps 13-16.

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