What is an Integrase Inhibitor?

An integrase inhibitor is a new class of anti-HIV drugs that targets the enzyme integrase. As of early 2010, one member of this class has been approved for commercial use in the United States. Raltegravir, also known as Isentress®, has advanced the treatment of HIV infection, since it targets a step of the disease that was previously considered invulnerable. Another advantage is that it can be used with people who have developed resistance to other types of anti-HIV drugs. This drug was approved for use in the United States in October 2007.

Human immunodeficiency virus (HIV), the casual agent of acquired immune deficiency syndrome (AIDS), is a retrovirus. Its genetic material is in the form of RNA, not DNA. It uses an enzyme, a molecule that catalyzes reactions, called reverse transcriptase to copy the RNA into viral DNA. It inserts its DNA into the host’s DNA, where it is propagated as if it belonged to the human cells. It infects the cells that function to warn the immune system of foreign invaders, so the body does not mount an effective response to the virus.

Without treatment, the virus proliferates in the absence of a functional immune system. It used to be that HIV almost always progressed to AIDS, generally leading to fatalities. Drugs used to treat retrovirus infections are known as antiretroviral drugs, and their development has been a revolution in the treatment of HIV. The mortality rate of individuals infected with this virus has been greatly reduced since these drugs have been in use. One problem with this treatment, however, has been the development of virus resistance to multiple antiretroviral drugs.

These types of drugs affect different steps in the virus’s life cycle, particularly several enzymes that are involved in the process of an HIV molecule infecting its human cell host. The previous enzymes targeted for treatment have been reverse transcriptase and a protease, which cleaves proteins. Resistance has developed to both of these mechanisms. Thus, the development of an integrase inhibitor has been of great importance for HIV treatment, since it targets an entirely different step.

It is the step of insertion into the host’s DNA that is targeted by an integrase inhibitor. There are three phases of integrase activity. First, the integrase binds the cell’s DNA. Next, it prepares the viral DNA for integration by slighting altering its DNA to prepare it for insertion. Then the processed DNA is inserted into the host cell, which is now altered to make virus particles.

The original research on developing integrase inhibitors was not successful, but it primarily targeted the first two steps. Raltegravir targets the third step. With integration into the host cell blocked, the virus cannot spread. This gives the patient's immune system a chance to recover.

The standard treatment when using an antiretroviral drug to treat HIV infection is to use multiple drugs. At least three drugs are generally used simultaneously. The United States Food and Drug Administration (FDA) has approved raltegravir for use by people who already take other anti-HIV medications. It has been shown to work well with other drugs, and for people who have developed resistance to other treatments. Raltegravir is not approved for people who are newly infected with HIV.

This integrase inhibitor is taken as a pill, generally twice daily. Common side effects are nausea, diarrhea, fever, and headache. There is another drug in advanced clinical trials in the United States known as elvitegravir. It is possible that there will soon be another integrase inhibitor available for HIV treatment.