In an early report from an ongoing, randomized clinical trial, researchers from the University of California, San Francisco have shown that the addition of the immune stimulator interleukin-2 (IL-2) to highly active antiretroviral therapy (HAART) improves immune function in patients who have been recently infected with HIV.
Results in 20 patients were reported today (July 12) by Frederick M. Hecht, MD, assistant clinical professor with the UCSF Positive Health Program at San Francisco General Hospital Medical Center. He presented the findings at the XIII International AIDS Conference in Durban, South Africa. "Adding IL-2 to HAART in this early period significantly improved CD4 cell counts" said Hecht.
Researchers are particularly interested in studying persons who start HAART within months of becoming HIV infected because these individuals may have better preserved immune responses to HIV -- responses that may be destroyed by the virus in the first year of infection. Researchers are trying to determine whether adding IL-2 to HAART in persons who begin treatment in this early phase of infection increases CD4 counts and bolsters immune responses to HIV. Participants were recruited by the UCSF Options Project, based at SFGHMC, which is conducting clinical, behavioral, epidemiological, and pathogenesis studies of the earliest stage of HIV infection, called primary infection. Study participants must begin antiretroviral therapy within 12 months of becoming infected, and most start therapy within 6 months of infection, said Hecht.
All patients received HAART with a combination of three drugs. Half of the patients were randomly assigned to supplement their medication with IL-2 early in the study. These patients began receiving IL-2 four weeks after HAART had suppressed the amount of virus in their blood to a specific point (less than 500 RNA copies/ml). The remaining patients were slated to begin IL-2 therapy later, 48 weeks after the amount of virus in their blood dropped below the designated point.
IL-2 is a powerful immune modulator, but it must be used with care in HIV patients because it has the potential to stimulate replication of HIV in infected cells, said Hecht. For this reason, the study was designed to ensure that patients did not take IL-2 until antiretroviral therapy was effectively blocking HIV replication.
Since the use of IL-2 was delayed in one group of patients, they were able to serve as a control group for those receiving IL-2 early in the study. Researchers were able to compare CD4 cell counts and other measures of immune function in the early IL-2 patients with those who initially received antiretroviral therapy alone.
"We divided the patients into early and late treatment groups in an effort to find out if use of IL-2 is helpful to patients with early HIV infection, and to see if results differ depending on how soon after infection IL-2 treatment is started," said Hecht.
Interleukin-2 was administered subcutaneously in what is considered a standard high-dose cycle (twice daily for five days every eight weeks for a total of six treatment cycles). At the Durban meeting, Hecht reported on results in 20 patients, 9 in the early IL-2 group and 11 in the deferred IL-2 treatment group. All the patients in the early IL-2 group experienced the side-effects common to treatment with this immune stimulator, including fever and chills.
After 48 weeks of antiretroviral treatment, the average CD4 cell count was 2,002 (up from 584) in the early IL-2 group and 706 (up from 451) in the delayed group, a statistically significant difference. In addition, the amount of virus in the blood had fallen to very low levels (less than 50 RNA copies/ml) in most patients in both treatment groups, providing a reassuring indication that the addition of IL-2 to HAART should not increase HIV replication, said Hecht.
"We will continue to follow these patients to see whether the immunological benefit that adding IL-2 to HAART appears to confer will improve the effectiveness of HAART over time, and whether there is other evidence of better immunologic control of HIV," said Hecht. The researchers will also look at whether persons who stop HAART treatment after receiving IL-2 maintain strong control of HIV replication.
Co-investigators included James O. Kahn, MD, UCSF Positive Health Program at SFGHMC; Margaret Chesney, PhD, UCSF Center for AIDS Prevention Studies; Robert Grant, MD, UCSF School of Medicine and the UCSF-affiliated Gladstone Institute of Immunology and Virology; Michael P. Busch, MD, PhD, UCSF Department of Laboratory Medicine and the Blood Centers of the Pacific; Jorge Oksenberg, MD, UCSF Department of Neurology; Michael McGrath, MD, PhD, UCSF School of Medicine and SFGHMC; Jay A. Levy, MD, UCSF School of Medicine and UCSF AIDS Research Institute; and Marcus Altfeld, MD, and Bruce Walker, MD, Massachusetts General Hospital and Harvard Medical School.