IL-2 Increases CD4 Counts in Early HIV

April 1, 1995

BETHESDA, Md--Intermittent infusions of interleukin-2 (IL-2, aldesleukin) have led to significant increases in CD4+ T cell counts in HIV-infected patients with early disease, a study from the National Institute of Allergy and Infectious Diseases (NIAID) has found.

BETHESDA, Md--Intermittent infusions of interleukin-2 (IL-2, aldesleukin)have led to significant increases in CD4+ T cell counts in HIV-infectedpatients with early disease, a study from the National Instituteof Allergy and Infectious Diseases (NIAID) has found.

"This study provides the strongest evidence so far that itmay be possible to rebuild and maintain the damaged immune systemsof HIV-infected individuals," said H. Clifford Lane, MD,NIAID clinical director. Dr. Lane was the lead investigator alongwith Dr. Joseph A. Kovacs of the NIH Clinical Center's CriticalCare Medicine Department.

Whether the increases in CD4 counts will translate into clinicalbenefits will be determined by ongoing trials, Dr. Lane told OncologyNews International in an interview.

The study included 25 patients, 10 with baseline CD4 counts greaterthan 200/mm³ (early disease) and 15 with baseline CD4 countsless than 200/mm³ (advanced disease). Patients received IL-2intravenously for 5 consecutive days every 2 months. All participantsalso took at least one approved antiretroviral drug such as zidovudine(AZT, Retrovir) or didanosine (ddI, Videx) during the study.

In six of 10 patients with early disease, CD4 counts rose by morethan 50% after 12 months. In several of these patients, the risewas dramatic, from 554 to 1,998 in one individual. The remainingfour patients had stable counts or a slight decline. Follow-upof several of these patients has shown that CD4 increases havepersisted for more than 2 years (N Engl J Med 332:567-575, 1995).

Dr. Lane pointed out that as a patient's CD4 counts improve withuse of IL-2, infusions can be spaced out longer. One of the bestresponders in the study received six 5-day infusions over thecourse of a year. "When we stopped the infusions, his countwas around 2,000; then over 8 months, it came down to around 1,000at which time he got a single IL-2 infusion, and the count wentback up," he said.

Thus, the increases in CD4 counts seen with IL-2 therapy appearto be a "reproducible phenomenon," he said, noting thatunlike the antiviral drugs, resistance to IL-2 should not be asignificant issue.

The therapy was far less successful in the patients with moreadvanced disease. Only 2 of the 15 patients with counts below200 showed a 50% increase, while the remaining 13 had no significantincreases. In addition, side effects were considerably more severethan in the patients with early disease.

The lack of efficacy in the advanced patients may be related tothe transient bursts of viral replication associated with IL-2therapy. "When we push T cell activation with IL-2, we alsopush viral replication," Dr. Lane said. In patients witha lower viral burden, the viral burst goes up and comes back downpretty quickly. But for patients with more advanced disease, "theviral burst goes up and may just keep rising," he said.

Thus, in these patients, T cell stimulation occurs in a settingof massive viral expansion, making it difficult to achieve a meaningfulimmune system response. "We're not giving up on these patients,"Dr. Lane said, noting that new research will focus on strategiesto improve results in patients with advanced disease.

'Like the Worst Flu Ever'

Side effects to IL-2 therapy were common and severe, includingstomatitis, rash, fever, fatigue, nausea, flu-like symptoms, diarrhea,and laboratory abnormalities such as reduced calcium, albumin,and magnesium.

Although none of the side effects were life-threatening, Dr. Lanestressed their severity. Many patients have told him that theside effects of their IL-2 treatments were the worst they hadever experienced, worse than their "worst ever" boutwith the flu.

"Side effects peak around day 4 or 5 of the infusion, butonce the drug is stopped, patients start to feel better withina couple of hours and that's a great psychological boost,"Dr. Lane said. "However, it usually takes a couple of weeksor even a month before they get back to feeling normal."

During the therapy, eight of the 10 patients with early diseaserequired dose reductions, and two chose to discontinue treatment.Dr. Lane said that the NIAID will continue to search for the lowesteffective dose of IL-2 in an attempt to reduce side effects. "Ithink we can probably get to lower doses and less frequent dosingthan 5 days every 8 weeks," he said.

NIAID investigators are currently recruiting patients for a newseries of studies that will link the timing of IL-2 infusionsto changes in CD4 counts; examine the safety and potential effectivenessof subcutaneous IL-2 therapy; and assess whether blockage of tumornecrosis factor will diminish the side effects and/or viral replicationburst associated with IL-2 infusion.

Although IL-2 is currently FDA approved for metastatic renal cellcancer, Dr. Lane stressed that the agent is not licensed for thetreatment of HIV infection, and HIV-infected patients should receivethe agent only in the context of an approved clinical trial .