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There's nothing more frustrating for Philippe Chiliade, MD, than watching his HIV-positive patients develop resistance to their anti-HIV drug regimens. Despite relying on an arsenal of 16 unique antiretroviral HIV medications and two multidrug combination pills, the medical director at Washington, D.C.'s Whitman-Walker Clinic has seen more and more of his patients lose ground in their battle with AIDS. "We know that with time, most HIV-positive people will develop drug resistance," he notes. "Until we find a way to cure or eliminate the virus, we have to count on new drugs and new drug targets to help keep people alive."

Currently available anti-HIV drugs target only two of the enzymes that HIV uses to infect immune system T cells: reverse transcriptase and protease. But for the first time in the 20-year history of AIDS, medications that interfere with other stages of the infection process are advancing through clinical trials. This ongoing research could open up entirely new treatment avenues--necessary advances if HIV is to be managed as a chronic, long-term condition, says Kenneth Mayer, MD, medical research director at Boston's Fenway Community Health Center.

Closest to Food and Drug Administration approval are drugs in the entry inhibitor class. Also known as fusion inhibitors or attachment inhibitors, the drugs thwart HIV's attempt to latch on to immune system cells. "These work at the beachhead, before the cell even becomes infected, by cutting HIV off at the pass," explains Candace Pert, a research professor at Georgetown University and co-inventor of the experimental entry inhibitor Peptide-T. "By disabling HIV's ability to attach to the cells, you can prevent cellular infection."

The entry inhibitor nearest to market is T-20 (enfuvirtide). It's currently in two Phase III human studies, the final series of clinical trials before the FDA can review and approve a drug for general use. Manufactured by Trimeris Inc. and Hoffman-LaRoche Inc., T-20 works by blocking an HIV protein called gp41, one part of the viral harpoon that hooks onto human T cells.

"Our data show that T-20 is a powerful inhibitor of infection," says Trimeris CEO and chief scientific officer Dani Bolognesi. A study of 71 patients who had failed, on average, about 10 other antiretroviral HIV medications showed that T-20, used in combination with other anti-HIV drugs, significantly reduced the amount of virus in their blood. Bolognesi says the company plans to file for FDA approval of T-20 in the second half of 2002 and adds, "Assuming that everything goes well, we'll launch the drug in early 2003."

Trimeris also has a second-generation entry inhibitor in early clinical trials. The drug, called T-1249, binds more tightly to HIV proteins and to a slightly different viral region than T-20, Bolognesi says. The compound also stays in the body longer, which may make once-a-day dosing possible.

Studies of T-20 and T-1249 to date show that the compounds are well-tolerated, says Chiliade--a potential boon for HIV patients who suffer from side effects and toxicity on current anti-HIV drugs. Because entry inhibitors work outside of the cells, there's no threat of intracellular damage, a danger with some other anti-HIV drugs.

Peptide-T, an entry inhibitor first discovered in the 1980s but not studied as an anti-HIV drug until the late '90s, is also so well tolerated that codeveloper Pert says one possible use for the drug would be for patients on so-called drug holidays--periods when they stop taking anti-HIV drugs in order to reduce toxic side effects. "It also can be used with any drug combination as an added weapon," Pert says. The compound works by blocking a receptor on the surface of T cells and thus preventing HIV from attaching to the cells. Peptide-T is currently in a Phase II clinical trial at San Francisco's St. Francis Memorial Hospital, which puts it at least several years away from FDA approval.

Other experimental entry inhibitors work by jamming a different T-cell receptor that HIV also uses to latch on to immune system cells. Companies researching these drugs include Schering-Plough, Progenics, and Bristol-Myers Squibb.

One benefit may be less extensive drug resistance, Chiliade explains. Although all entry inhibitors work in similar ways, they target different parts of HIV or T cells. That means that resistance to one of these drugs is not likely to lead to resistance to others, he says.

The downside to the entry inhibitors will be that the drugs, in their current form, must be injected rather than taken as pills. While this means such common antiretroviral-related side effects as nausea and chronic diarrhea will be avoided, it also means the medications are likely to be more expensive than current anti-HIV drugs. What's more, the prospect of regular injections may also discourage many patients from using entry inhibitors, says Steven Deeks, MD, an associate professor at the University of California, San Francisco. Patients prefer pills to shots and tend to adhere to injection regimens less faithfully.

Farther back in the research pipeline are integrase inhibitors, drugs that interfere with an enzyme that HIV uses during one stage of viral replication. New Jersey--based drugmaker Merck and the Japanese firm Shionogi & Co. Ltd. are among those developing integrase inhibitors; Shionogi has one drug in early human trials.

Meanwhile, Belgian pharmaceutical company Hubriphar S.A. is developing the experimental "zinc-finger" inhibitor azodicarbonamide. Known as ADA, the drug is designed to disable a part of HIV known as its zinc fingers--chains of amino acids involved in viral replication. Inhibiting the zinc fingers causes the creation of faulty copies of the virus, which are unable to infect new cells. ADA is also in early clinical trials.

While these experimental drugs may ultimately serve as powerful weapons against HIV, researchers have not abandoned tried-and-true anti-HIV medication classes. New reverse transcriptase inhibitors are in the works, with names like DAPD and Coviracil (FTC), both from Triangle Pharmaceuticals; calanolide A, from Sarawak MediChem; capravirine, from Agouron; DPC 083 and DPC 961, from DuPont; and TMC 125 and TMC 120, from Tibotec-Virco. The new protease inhibitors tipranavir from Boehringer Ingelheim and atazanavir from Bristol-Myers Squibb may also provide fresh options for standard cocktail therapy.

Refinements to existing medications--including Videx (ddI), Zerit (d4T), and Sustiva--have resulted in once-a-day versions; Viread and Epivir also come in daily formulations [see sidebar, "Cocktail menu"]. One-time-daily drug therapy is the holy grail of HIV treatment, says Gary R. Cohan, MD, vice president and managing director of Beverly Hills--based Pacific Oaks Medical Group. "It is well established that when adherence rates fall below 95%, treatments tend to fail. If we can't design simpler, more forgiving regimens that will be easier to take and not fail the patient if the patient misses a dose, then we will ultimately fail in our effort to prevent resistance and treat HIV effectively."

A summary of current anti-HIV medications and how they are combined

In AIDS treatment the term cocktail refers to a combination of three or more medications that work synergistically to keep HIV replication in check. "It's like a one-two-three punch approach," explains Candace Pert, a research professor at the Georgetown University School of Medicine in Washington, D.C. A typical anti-HIV cocktail consists of one protease inhibitor, such as Kaletra or Viracept, and two nucleoside reverse transcriptase inhibitors, such as Zerit, Retrovir, and Videx. Sustiva--now available in a one-pill-a-day form--may be used in place of the protease inhibitor.

It's also possible to craft a potent regimen by combining three or more drugs from the NRTI class, says Philippe Chiliade, MD, medical director at Washington, D.C.'s Whitman-Walker clinic. There's no hard and fast rule for what drugs should be used at a particular time, he says. "The combination totally depends on what a patient can tolerate," he explains. "Each regimen has its own advantages and some disadvantages."

Cocktail menu

Currently available anti-HIV drugs

Strongly recommended combinations

Based on guidelines from the U.S. Department of Health and Human Services. One choice from Column A and one from Column B. Drugs are listed in alphabetical order.

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