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Anti-HIV Pipeline: Spotlight on Integrase Inhibitors

July 2004


Current anti-HIV drugs work at three points in HIV's life cycle. Entry inhibitors, like enfuvirtide, keep HIV from entering cells. Reverse transcriptase inhibitors -- like AZT, tenofovir and efavirenz -- keep HIV from changing its genetic structure. Protease inhibitors, like atazanavir and Kaletra, ensure that newly made viral particles aren't assembled into infectious virus. (For a list of these drugs and their classes, see the Drug ID Chart.)

After many years of research, drugs are nearing development that block another part of the viral life cycle. These are called integrase inhibitors. This article highlights both the challenges and the promise of integrase inhibitor development.

What Are Integrase Inhibitors?

Viral integration is when newly made genetic material of the virus (called viral DNA) enters the nucleus of a cell and inserts itself into the cell's genetic material (DNA). Once this integration is complete, the cell is operating on the genetic instructions of the virus as opposed to the cell and the cell becomes a sort of HIV factory. Integrase inhibitors seek to block the integrase enzyme from allowing this integration process from happening.

Blocking integrase could offer much to the treatment of HIV disease. Because it would work at a different part in the viral life cycle than existing drugs, an integrase inhibitor would likely work against virus resistant to the current drugs. Also, the integrase enzyme doesn't occur naturally in the body, so blocking it might not cause some of the side effects common to the existing drugs.

Resistance to integrase inhibitors is likely to develop. However, researchers hope that integrase inhibitor resistant virus would be less able to infect other cells and make new virus. Such hopes have kept integrase inhibitor research alive despite the challenges involved in developing them.

Identifying and Developing Integrase Inhibitors

Chemists must comb through millions of potential compounds when searching for drugs that may be active against HIV. In order to narrow the search, they must create tests that determine which candidates are most likely to be active. Creating tests that accurately mimic the integrase enzyme has been one of the biggest challenges. However, a number of private and government researchers have now developed tests for integrase, and two integrase inhibitor candidates have gone into human testing in the past two years.

The first, L-870,810 by Merck, was last reported on in the spring of 2003. It performed well in test tubes and in animal studies. In both test tubes and monkeys, resistance to L-870,810 was slow to develop and when it did, the resistant virus was severely crippled in its ability to reproduce. Initial tests in HIV-negative volunteers found that the drug was well tolerated. A phase II study was planned for 2003. Merck has been undergoing significant restructuring, however, and their HIV research has been slowed down considerably for the past year. They've stated recently that they are still committed to integrase research and we hope to hear more in the coming year.

The second integrase inhibitor candidate, S-1360, is a joint venture between Shionogi Pharmaceuticals and GlaxoSmithKline. S-1360 showed anti-HIV activity in test tubes and safety in animals. In phase I studies, volunteers maintained adequate levels of S-1360 in blood. This had been a concern before the study started, because the drug binds easily with blood proteins, keeping much of it from entering the cells where it needs to go. Side effects were minimal in the study and development moved forward.

A phase II study of S-1360 was conducted in early 2003 in HIV-positive people. Unfortunately, S-1360 did not reduce HIV levels enough to warrant continued development. The companies have a back-up candidate, however, currently called RSC 1838. This compound is similar to S-1360 in its structure and function. RSC 1838 has not yet entered human testing and few details of studies in test tubes and animals are available.

While it has taken longer for integrase inhibitors to make it into human testing than the current classes of drugs, the failure and/or delay of these first two is no reason to write off the entire class. People living with HIV stand only to gain from having more options in treating the disease, and determined activism has helped a number of other drugs make it to the marketplace.

The Future of Integrase Inhibitors

Test tube studies of more than a dozen integrase inhibitor candidates have appeared in scientific journal articles over the past two years. Nearly all are the work of academic scientists in the United States and Europe. While it is too early to tell whether any of these will make it into development, it is imperative that activists work with researchers to help them overcome hurdles to drug development.

Several approved anti-HIV drugs originated from research started at universities. Drugs like enfuvirtide and tenofovir may never have made it through development without the assistance of community activists. Helping add integrase inhibitors to the list of approved drugs is merely one more challenge, and we are equal to the task.

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