What's in the Pipeline
Peering into the future, it can be hard to distinguish old-news drugs from those that may make headlines. Here's the lowdown on what's up-and coming, from second-generation protease inhibitors to novel therapies.

Name: Protease inhibitors (PIs)
Game: Reigning champ of current antiviral meds.
Selling Point: New additions to this established class actually seem to live up to their promises of simpler dosing and more potency and activity against drug-resistant virus. Some companies are looking at new PI duos that may keep higher levels of the drug in the blood for longer amounts of time. Abbott's ABT-378, for example, combines a new, more potent PI compound with small amounts of Norvir, another one of its drugs. Norvir seems to slow down the metabolic drain that funnels drugs through the liver and out of the body, allowing whatever it's paired with to remain in the blood.
Drawback: Upping the dosage may work in the short term to stymie viral replication, but it could have long-term effects on liver and other organ systems that will now be undergoing prolonged exposure to the drug. This is particularly worrisome for the estimated half of HIV-positive people in the United States who are coinfected with hepatitis B and C, which cripple the liver's ability to regenerate.
Ones to Watch: Tipranavir (Phase II) uses a flexible, nonpeptidic structure to grip the virus more tightly. It seems to work against drug-resistant virus but may have troubling GI side effects. Early trials required up to a whopping 30-pill-per-day dosing schedule! ABT-378 (Phase II), a much ballyhooed PI, packs a wallop some 10 times more potent than Norvir. It also seems to work against PI-resistant strains. BMS-232632 (Phase II) promises once-daily dosing but doesn't work well against Crixivan and Norvir-resistant HIV. Human trials of AG-1776 are pending. L-756,423, a chemical cousin to Crixivan, stays in the bloodstream longer, so less drug is required. The same is true of DMP-450 (Phase I), which can be taken in a single dose.

Name: Nucleoside Reverse Transcriptase Inhibitors (NRTIs/"Nukes")
Game: The original weapon against HIV, and still a valuable part of a two- or three-pronged attack on the viral life cycle. The potent anticancer drug hydroxyurea works best in combination with ddI, a nuke. Other synergystic combos may be out there waiting to be discovered.
Selling Point: Some of these drugs, like FTC, DAPD, and the approved 3TC, also work against hepatitis B.
Drawback: New findings link nukes to everything from lipodystrophy to genetic mutations. More studies are needed to determine the true extent of these toxicities.
Ones to Watch: FTC looks and acts like 3TC but with a better safety and efficacy profile. F-ddA (Phase II) has been around for 10 years and may have something new to offer but activists are debating its toxicity. In lab studies, dOTC (Phase I/II) is active against 3TC-, AZT-, and Norvir- and Crixivan-resistant viruses. PZT, DAPD (Phase I/II), work against AZT/3TC drug-resistant virus.

Name: Nonnucleoside reverse transcriptase inhibitors (NNRTIs/"Nonnukes")
Game: New drugs will act as salvage therapy to pick up where PIs have failed, or step up as first-line therapy that saves PIs for later.
Selling Point: Easier to formulate and easier to take than protease drugs.
Drawback: In a word, resistance. A single mutation called K103N creates nearly complete cross-resistance to all the drugs in the class.
Ones to Watch: AG 1549 (Phase I/II), looks like it works against cross-resistant virus. MKC-442 (Phase III) has more in common with existing drugs, and so may be less effective in people who've taken NNRTIs before. Calanolide A (Phase I) is an organic compound that crosses the blood-brain barrier. DMP 961 and DMP 963 (entering Phase I), souped-up versions of Sustiva that are up to eight times more potent than Sustiva in vitro and stay in the blood at such high concentrations that they may be active against K103N mutants. It takes at least two mutations before HIV stops responding to GW420867X (Phase I).

Name: Fusion inhibitors (FIs)
Game: Target proteins that HIV uses as landing gear to dock on cell surface.
Selling Point: A new class with a new target. That's good news for people with viruses resistant to nukes, nonnukes, or protease inhibitors.
Drawback: Because the drugs themselves are large proteins, they can't be taken in pill form. Instead, Trimeris is hoping to increase the half-life of its drugs T-20 and T-1249 enough so that one or two injections a day or maybe even a week will deliver the needed dosage.
Ones to Watch: T-1249 (Phase 1), T-20 (Phase II), FP-21399, PRO 542 (Phase I/II).

Name: Coreceptor blockers
Game: Get between the virus and the cellular sites it needs for entry.
Selling Point: This class goes after cellular targets without apparent serious side effects.
Drawback: The virus seems to be able to switch from one set of receptors to another. Will the blockers work or just inspire more evasive viral action?
Ones to Watch: AMD-3100 (Phase I), ALX 404C (Phase II), T-22, TAC 779, AOP Rantes.

-EB