When Ron Travelletti, 46, began HIV treatment last spring, it wasn’tbecause he had to: Diagnosed in 1985, this long-term non-progressor hada respectable 330 CD4s and a tame viral load of 19,000. Rather, anHIVer friend had told him about a short-term study in which GSK-873,140(or GSK-140 for short), an experimental GlaxoSmithKline drug, would betested on HIVers for the first time. Travelletti signed up for the sakeof science—and the $1,000 fee: “My partner and I are on disability,” hesays, “and it’s pretty tight.” After the requisite 10 days ofswallowing the drug, he learned that it had squashed his viral load toa mere 160.

Someday, Travelletti may be able to say he was among the first HIVerguinea pigs for a revolutionary wave of HIV medicines called entryinhibitors (EIs). Essentially, EIs stop HIV before it can get insidethe immune system’s CD4 cells, which the virus uses as factories formaking more HIV. One EI—the pioneering Fuzeon (T-20)—has been availablesince 2003, but use has been limited to HIVers who badly need newoptions and can stand its pain-in-the-ass (sometimes literally)twice-daily needlestick routine.

Happily, most of the coming EIs are plain old pills. And drugcompanies are hustling to roll them out. “The EI race is on,” says BobHuff, editor of Gay Men’s Health Crisis’ Treatment Issues, whoforecasts that EIs will hit the market in 2007 or 2008. Leading thepack is Pfizer’s UK-427,857 (or just UK-427), which, taken alone in astudy of about 80 HIVers, reduced viral load up to 1.6 log (say, from100,000 to about 4,000) after 10 days. Pfizer will test UK-427 inhundreds of HIVers worldwide late this year. Also impressive in asimilar trial was Schering-Plough’s SCH-690, which is already enrollingU.S. HIVers on HAART in a phase II, or midsize safety, trial.

Meanwhile, says Glaxo’s Steve Piscitelli, PharmD, “We’ve beenquietly sneaking up behind Pfizer” with GSK-140. Pending data from thestudy Travelletti joined, GSK will begin larger trials by year’s end.Also in the mix are Bristol-Myers Squibb’s BMS-488043, Tanox’s TNX-355and Progenics’ PRO-542. “We may be in a whole new world,” says Huff—onewith new options for HIVers with multidrug resistance and without theside effects linked to our current meds. But EIs bring new challenges,too.

Point of Entry

To understand the buzz, here’s a brief HIV refresher course.Normally, the virus hijacks CD4 cells in a three-step, SpaceInvaders–like process. First, a protein on HIV’s surface called gp120hooks to a pronglike receptor on the CD4 cell. (See “1, 2, 3...Entry!”)Then gp120 hooks to one of two other receptors on a CD4 cell’s surface,called CCR5 or CXCR4. With countless molecular gears and leverswhirring, HIV and the CD4 cell move closer, fusing their slipperysurfaces until an ever-expanding pore opens up—and HIV slips inside theCD4 cell.

That’s when HIV’s real dirty work begins—and when most HAART drugsstart fighting the virus. But by working inside CD4 cells, our currentmeds also muck up the cells’ energy centers, called mitochondria. Andthat, many experts believe, is why some current HIV meds can cause orcontribute to awful side effects like lipodystrophy and neuropathy.EIs, on the other hand, keep HIV from ever getting inside human cells.BMS-488043, for example, stops HIV’s gp120 from attaching to the CD4receptor. The Pfizer, GSK and Schering EIs, called CCR5 antagonists,block the CD4 cell’s CCR5 receptor. Yet another candidate, Anormed’sAMD070, blocks the CXCR4 receptor. Fuzeon foils entry’s final step,when HIV and the CD4 cell fuse.

Sparing us side effects is only one of the big hopes for EIs. (Wewon’t know how often EIs cause more mundane woes like nausea anddiarrhea—or even all-new side effects—until they’ve been tested over along period of time). Since different EIs hit the entry process atdifferent stages, researchers believe that they could be taken as acombo and create a whole new anti-HIV strategy outside the cell. Huffexplains: “If you can slow down [entry steps 1 or 2], it may notcompletely block HIV, but it opens up a bigger window for drugsdownstream like Fuzeon to work.” Says the AIDS Treatment ActivistsCoalition’s Nelson Vergel, “I can see humongous synergy among thesecompounds.”

Until we have enough EIs for a combo, we can likely combine EIs withcurrent meds for a broader treatment palette (that’s how they’ll betested in phase II and III trials). Gegeny imagines a day when everyonestarts treatment on EIs alone and uses “protease inhibitors and nukes[NRTIs]”—with their infamous side effects—only “down the road ifresistance develops.”

Wait a minute! Resistance to EIs? Sorry to say, the class isvulnerable, due mainly to mutations in HIV’s gp120. (It’s alreadyhappened with Fuzeon.) Then there’s…

The 64,000 Question

Pfizer’s, GSK’s and Schering’s EIs are CCR5 antagonists—a promisinggroup. CCR5 receptors aren’t essential to CD4 cells, so drugs blockingthem are a seemingly safe bet. But there’s a catch. In early infection,the virus prefers attaching to CCR5 receptors. However, in roughly halfof HIVers, as HIV progresses over the years, it is increasingly able toattach to CXCR4 receptors. What isn’t known is whether advanced diseasecauses the CXCR4 switch or vice versa. The big fear—what Piscitellicalls “the $64,000 question”—is that blocking the CCR5 receptor willdrive HIV toward the CXCR4 receptor and hasten disease progression.

The makers of the CCR5 antagonists haven’t spotted such a switch inthe test tube or, for the most part, in their early trials. But eventhough all 66 HIVers on Pfizer’s UK-427 had been screened to ensurethat they had only CCR5-using virus, CXCR4-using virus emerged in twoof them. They stopped taking the drug: One patient’s virus went back tousing CCR5 only, but the other’s virus has continued to use both CCR5and CXCR4 for nearly a year. Howard Mayer, MD, a Pfizer scientist atthe fore of the UK-427 research, says both patients still responded toUK-427 and that the one with the CXCR4-using virus has shown no diseaseprogression. But experts acknowledge that the screening test, whichMayer says is 97 percent sensitive, may miss “lurking” CXCR4, and theyworry what that could mean once more HIVers go on the drugs in largertrials.

The drugmakers say that trials will separately track HIVers with theCCR5-using, CXCR4-using and mixed-use virus and watch for treatmentfailure. Participants will also take standard HIV meds for backup,which the Food and Drug Administration requires. “We’re hopeful [theCCR5 drugs] will also be useful in people with resistance [to currentmeds],” explains the FDA’s Jeff Murray, who works with drug companieson HIV trials. Yet he worries that up to half of the very folks whomost need the CCR5 antagonists—longtime HIVers with heavy drugresistance—may benefit least because their advanced virus now grabsmainly CXCR4 receptors.

Room for All?

These HIV veterans may benefit nonetheless. All three CCR5candidates target HIV in entirely new places, so trials won’t rejectanyone because of heavy resistance to current drugs. Better still:HIVers coinfected with hepatitis B or C won’t be excluded unless theyhave skyrocketing liver enzymes. Coinfected patients constitute atleast one third of all HIVers; their response to new drugs is“something we want to know right away,” says Piscitelli.

The biggest EI-testing debate concerns how soon drugmakers will lettheir separate agents be combined in multidrug-resistant HIVers, whogenerally need more than one new med at a time. Makers of CCR5antagonists say they likely won’t pair up their drugs before theirexpanded-access programs, which usually don’t launch until well intophase III (final, large-scale) trials. “You don’t study twoinvestigational drugs in early development because you need to learnabout your one compound,” says Piscitelli, insisting, “It’s not thatwe’re not going to share.”

But Vergel says that for emergency cases, he and other


Is one right for you? Is there a trial site nearby? Search the candidates named in this story at www.clinicaltrials.gov or call 800.HIV.0440 and ask about them.

activists want action early in phase III. Huff says,pharmaceutical companies are “afraid that if something goes wrong, theFDA will stop all trials until they figure out [which drug] caused theproblem.” Theoretically, earlier collaborative studies may happen, saysthe FDA’s Murray, adding that the agency is “not opposed at all” to theidea. Vergel stresses that for those who need new options most, “Wecan’t go on with this stupid sequential monotherapy”—giving people onenew drug at a time.

Hype and Hope

Poised for major investigation, EIs are at a crossroads betweenpromise and reality. When it comes to large-scale data, “nothing hasblown me away yet,” says Gegeny. “My fingers are crossed.”

Meanwhile, Ron Travelletti got an unexpected EI bonus. On a visit tothe trial site to take his GSK-140, he saw that the receptionist wasabsent. “I asked if they were looking for someone,” he says. “I didn’twant to sit around on disability.”

Five months later, Travelletti reports, “I’ve never been happier with a job.”