As the onslaught of HIV wipes out CD4 sentinels in infected patients,the fewer and weaker become the T cell defenders against infectionand malignancy, until eventually death ensues, marking AIDS' finalconquest.

To stem this progression, HIV-infected patients and their physiciansattempt to strike back at the fast-multiplying viral invader with potentnucleoside analogues to thwart or slow retroviral replication.Recently, protease inhibitors have been added to disrupt the viralvirions.

Now researchers have added recombinant interleukin-2 to the arsenalto bolster and replenish the perishing population of defensive Tlymphocytes. While new antiviral drugs attack AIDS viruses head on,IL-2 gives a drooping immune system a wake-up call.

A 14-month-long controlled Phase II clinical trial showed that IL-2produced significant and sustained increases of CD4 cells.

Immunologist H. Clifford Lane, who directed the study, reported:"Among individuals randomized only to standard anti-retroviraltherapy, five people developed AIDS-related conditions or died, ascompared to two in the group randomized to receive IL-2 in additionto that therapy."

Lane is clinical director of the National Institute of Allergy andInfectious Diseases (NIAID), which conducted the 60-patient trial.He is senior author of a final account of the study in today's NewEngland Journal of Medicine (NEJM). Its title: "Controlled trial ofinterleukin-2 infusions in patients infected with the humanimmunodeficiency virus."

The trial enrolled 60 HIV-infected volunteers between April andDecember 1993.

The 30 members of that 60-person cohort who received intermittentintravenous infusions of IL-2 experienced an average doubling oftheir CD4-positive T-cell counts during the 14 months of the protocol_ up from 428 cells per cubic centimeter of blood to 916. Bycontrast, in the 29 control individuals, who got only the antiviraldrugs, those average T-cell numbers dropped rather than rose _ from406 to 349.

"Normal, healthy people have CD4 T-cell counts in the general rangeof 600 to 1,200," said infectious disease specialist Joseph Kovacs,first author of today's NEJM paper. He is a senior investigator in theCritical Care Medicine department of the National Institutes ofHealth (NIH) Clinical Center in Bethesda, Md., where the trial tookplace.

"Each patient in the IL-2 arm of the study," Kovacs told BioWorldToday, "was hospitalized every two months for five days, to receive around-the-clock infusion of the cytokine. And once the 14-monthformal phase of the protocol ended, we made IL-2 availableindefinitely to everybody in the study, including the control group."

In the trial, IL-2 did its therapeutic job with tough love. All of the 30persons in the IL-2 arm of the study felt the cytokine's side effects,some of which were "dose-limiting" or "intolerable" _ mainlyfatigue, malaise, headache, abdominal pain. Downsizing of the IL-2dosage usually relieved these toxic symptoms, but five patients quittaking it because of them.

However, one-third of the controls, on antiviral drugs only,experienced comparable toxic side effects.

"IL-2 dosage levels," Kovacs said, "were tailored to each participantindividually, in terms of side effects they sustained. And we're nowlooking at inhibitors of tumor necrosis factor [TNF] to see if theydecrease some of the side effects of IL-2."

He and his co-authors now "have some other studies ongoing,looking at combinations of IL-2 with more potent antivirals,specifically with protease inhibitors, which weren't available whenwe started this trial in 1993. And we're collaborating with Chiron onmany of these studies."

Chiron Corp., Emeryville, Calif., supplied the IL-2 (trade-namedProleukin) for the trial without cost. The company's director ofclinical development, Gwendolyn Fyfe, is a co-author of the NEJMarticle.

Her company is negotiating with the NIH for a license to U.S. patentNo. 5,419,900, dated May 30, 1995, and titled "Immunologicenhancement with intermittent interleukin-2 therapy." Assigned toNIH, its principal inventors are Lane and Kovacs. (See BioWorldToday, Aug. 13, 1995, p. 4.)

"From Chiron's historical perspective," Fyfe told BioWorld Today,NIH initiated that Phase II clinical trial within a year of IL-2 beingapproved by the FDA for treatment of metastatic renal-cellcarcinoma. "This followed clinical trials of the cytokine for thatparticular cancer.

"We've always provided the recombinant IL-2," Fyfe observed, "butI think that was the first time we became actively involved asparticipants in design and execution of trials."

Chiron, she added, intends to file a new drug application with theFDA approving use of the drug for metastatic melanoma, for whichphysicians already are prescribing it.

Fyfe said that for its use in treating the renal cancer, IL-2 costs "about$5,000 for a course of treatment. For HIV," she added, "the costwould be in the $4,000-to-$6,000 range per year."

Now, she noted, a larger, international Phase III trial of IL-2supplementation is in the works, to confirm the treatment's clinicalbenefits in HIV therapy. "Chiron," she said, "is working closely withCliff Lane at the NIH and David Cooper in Australia to try to set upthe Phase III's international component." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.