The lowest ever CD4 count, not the pre-treatment CD4 count, appears to predict the best response to treatment with the immune modulating therapy, interleukin-2 (IL-2), according to a US study due to appear in the October 15th edition of Clinical Infectious Diseases (now available online).
IL-2 is a cytokine (a chemical messenger) secreted by immune cells which co-ordinates and controls the intricate workings of the immune system. People treated with IL-2 plus HAART experience a significant, sustained improvement in their CD4 counts compared to people who receive anti-HIV therapy alone, although it is not clear whether this signifies improvement in CD4 function, or how this affects the long-term risk of disease and death. Since IL-2’s side-effects can be extremely unpleasant - often described as similar to a bout of flu - identifying who might best respond to IL-2 therapy is critical. Previously it was thought that CD4 baseline was the best marker of response, which also appeared to be dose-dependent.
However, this large multicentre, randomised, open-label trial, by the Community Program for Clinical Research on AIDS (CPCRA 059) found that three cycles of either 7.5 MIU or 4.5 MIU IL-2 twice a day for five days, every eight weeks, produced a similar response in those with a CD4 nadir higher than 300 cells/mm3. Over the three cycles, those on 4.5 MIU received an average of 95% of the total possible dose, whereas those on 7.5 MIU received an average of 90%. The higher frequency of missed or reduced doses in the higher IL-2 arm may have contributed to the lack of difference seen between the two arms.
Between September 1998 and July 1999, 511 adults with baseline CD4 counts of 300 cells/mm3 or more, receiving HAART (59% had a viral load below 50 copies/mL), were randomised to receive either 4.5 MIU of IL-2 (n=130), 7.5 MIU of IL-2 (n=126) or no IL-2 (n=255). Those included in the analysis completed at least three cycles of IL-2, which was just under 77% of those assigned to the 4.5 MIU arm and just over 75% of those assigned to the 7.5 MIU arm.
CD4 nadir emerged as the strongest predictor of CD4 response to IL-2: every 100 cell increase in the CD4 nadir accounted for a 67 cell rise in IL-2 response, on average (95% CI 20.9-113.6 cells/mm3; p = 0.005). IL-2 dose only made a significant difference in those with a CD4 nadir of 200 cells or less. After three cycles, those in the 4.5 MIU arm had a mean increase of 240 cells/mm3, whereas those in the 7.5 MIU arm had a mean increase of 463 cells/mm3 (95% CI for the difference, 121-323 cells/mm3; p = 0.006). No differences were seen between those with viral load below 50 copies/mL at baseline and those above 50 copies/mL, although the power to detect such differences was limited.
Response to the first cycle of IL-2 also predicted response by the third cycle: those who achieved an increase of 50 cells or more after the first cycle were 8.9 times more likely than those who did not to achieve an increase of over 200 cells after three cycles (p = 0.0001).
Nevertheless, everyone who completed three cycles of IL-2 achieved a significant rise in CD4 cells compared to those receiving HAART alone. One year after the study began, the mean difference between those who received IL-2 and those who did not was 251 cells/mm3 (p
One surprising finding never seen before was that non-white men experienced a mean CD4 cell increase 178 cells greater than seen for white men (95% CI 21.8-334.2 cells/mm3; p = 0.027). Just over 27% of those receiving IL-2 were non-white, and just over 10% of those receiving IL-2 were women, although numbers were too small to allow for comparisons between the genders and black, hispanic and ‘other’ races, individually.
The authors conclude that since IL-2 response appears to be related to CD4 nadir, “these findings strongly suggest that at least some aspects of the immune system are irreversibly changed by HIV infection.” They also suggest that higher doses of IL-2 may be needed in people with nadir CD4 counts below 200 cells/mm3, those with first-cycle responses below 50 cells/mm3, and those with a very large body surface area, although “the validity of this suggestion, as well as the roles of sex and race in dosage selection, requires further study.”
Further information on this website
Interleukin-2 and immune restoration - menu of information
Immune Therapies - factsheet (pdf)
Markowitz N et al. Nadir CD4+ T Cell Count Predicts Response to Subcutaneous Recombinant Interleukin-2. Clin Infect Dis 37, electronically published 24 September, 2003.