Findings from ANRS 119, the Interstart trial, show that it may be possible to defer antiretroviral treatment for nearly two years by using a limited number of short courses of interleukin-2 to keep CD4 cell counts above the recommended threshold for antiretroviral treatment initiation, Jean-Michel Molina of the University of Paris reported at the XVII International AIDS Conference in Mexico City on Tuesday.
Interleukin-2 (IL-2) is a naturally-occurring chemical messenger (chemokine) that plays a key role in stimulating the human immune system to respond to infection. Manufactured versions of IL-2, given by injection, trigger the production of CD4 cells by mimicking the body's own inflammatory response. IL-2 can thus produce significant boosts in CD4 cell count levels, as demonstrated in many clinical trials, but it has yet to find a well-defined clinical use outside the experimental setting.
In this randomised open-label trial, 130 HIV-positive adults with CD4 cell counts between 300 and 500 cells/mm3 were assigned to IL-2 (n=66) or to no treatment (n=64). In the IL-2 group, patients received four cycles of IL-2 treatment during the first 24 weeks of the study.
Each cycle consisted of 4.5 MIU of IL-2, given by injection twice daily for five days every eight weeks (a relatively low dose compared to the IL-2 doses used in several other studies.) After the first year, one or two optional cycles per year thereafter were allowed at the discretion of the patient and investigator, if the CD4 count fell to less than 1.2 times baseline; very few patients actually underwent these additional cycles.
At baseline, median age of the 130 participants was 36 years, median CD4 cell count was 383 cells/mm3, and median viral load was 4.36 log10 copies/ml. All participants were either treatment-naïve or had previously been on antiretroviral treatment for no more than three months.
The primary endpoint, assessed at week 96, was defined as any one of the following: a CD4 cell count that had fallen below 300 cells/mm3, the initiation of antiretroviral treatment, or the occurrence of an AIDS-defining event or death. Follow-up was extended to 150 weeks and multivariate analyses were performed to identify which baseline characteristics predicted progression.
Through week 96, 35% and 59% in the IL-2 and control arm, respectively, progressed to the primary endpoint (p=0.008). CD4 cell count rose by a median of 51 cells/mm3 in the treatment arm, and fell by 64 cells/mm3 in the control arm (p10 copies/ml respectively (p = 0.93).
The best outcomes were seen in participants with lower viral loads (less than 4.5 log10 copies/ml). After nearly three years (study week 150), among patients with viral load less than 4.5 log10 copies/ml, 66% percent of the IL-2 arm had not progressed to any of the study endpoints – i.e., had remained free of AIDS-defining events, off antiretroviral treatment, and with CD4 cell counts above 300 cells/mm3 – versus only 10% in the control arm (p
Dr. Molina concluded that, "IL-2 therapy in asymptomatic HIV-infected patients, notably those with low plasma viral load, increased CD4 cell counts and allowed to safely defer the initiation of HAART." IL-2 benefit extended well beyond the 48-week treatment period, with no or very few additional treatment cycles.
IL-2 treatment is frequently accompanied by lesser-grade adverse events, notably flu-like symptoms including fever, fatigue and malaise, that can have significant impact on quality of life. Asked about such adverse events, Molina stated that – possibly due to the lower doses of IL-2 used in this study - discontinuation rates were very small, and a patient quality of life assessment at two years showed no significant difference between the study arms.
Reference:
Molina J-M et al. Interleukin-2 (IL-2) therapy to prevent CD4 T-cell loss and defer HAART in antiretroviral naive HIV-1 infected patients - Interstart ANRS 119 trial. Seventeenth International AIDS Conference, Mexico City, abstract TUPDA105, 2008.