IL-2 provides quick ‘AIDS rescue’, but effect does not always last

Using the immune-stimulating drug interleukin-2 (IL-2) alongside conventional antiretroviral therapy (ART) can produce a more rapid CD4 increase than usual in people who are diagnosed with very low CD4 counts, and may help to prevent AIDS-related illnesses in the first few months, an Italian study has found.

IL-2 is a naturally-occurring cytokine (immune-modulating protein) that can also be made artificially. It produces significant rises in CD4 counts in the majority of people who take it by lengthening the lives of CD4 cells. It has been the subject of two long-running drug trials in people with HIV, ESPRIT and SILCAAT, which are expected to report in 2009.

These trials were initiated at a time when IL-2 was envisaged as a possible alternative to ART, or at least a way of delaying its initiation. However IL-2 produced unpleasant (and unpopular) flu-like side-effects in many trial subjects, and with the improvement in tolerability of antiretrovirals, enthusiasm for it as a long-term alternative to ART has waned.

However it could be used in other ways, including as a short-term emergency CD4 booster for people with very low CD4 counts, in order to reduce the risk of opportunistic infections until antiretroviral therapy has boosted the immune system enough for the risk to have passed. This is the strategy Camilla Tincati and colleagues from two HIV clinics in Milan decided to try.

Tincati started 73 recently diagnosed patients on ART, then after two weeks randomised patients either to continue on ART as normal (40 patients) or to receive IL-2 as well (33 patients). The IL-2 patients received three ‘cycles’ of IL-2; these consisted of ten average-size doses of IL-2 given as a subcutaneous injection once daily, spread over two weeks with a weekend break. This was repeated three times in the first three months on therapy.

Patients’ progress was followed for 18 months after the first three-month cycle of IL-2 treatment. Those failing to show a recovery of more than 30% in CD4 count from baseline after six months received three more IL-2 cycles in months 6 to 9.

The patients had low CD4 counts at baseline, with an average count of 48 cells/mm³ in the ART patients and 61 cells/mm³ in the IL-2 patients. Twenty-seven (67.5%) of the ART patients and 15 (45.5%) of the IL-2 patients had AIDS-defining illnesses at the start of the study. All patients responded to ART with declining viral loads.

Interleukin-2 therapy provided a significant degree of what Tincati and colleagues called ‘CD4 rescue’. At the end of three months, and three cycles of IL-2 in the patients who took it, the average CD4 count increase in patients on ART alone was 20 cells/mm³, and their CD4 counts now averaged 68 cells/mm³; in patients taking IL-2 it was 145 cells/mm³, and the average count was now 206 cells/mm³.

However, the CD4 count increases did not last. By the end of six months, the average CD4 count increase was identical in patients whether or not they received IL-2: 59 cells/mm³. In other words while the patients on ART experienced a slow increase to an average of 107 cells/mm³, the IL-2 patients actually experienced a considerable CD4 decline in the second three months and the average CD4 cell count in the IL-2 group now stood at 120 cells/mm³.

By the end of 18 months, ART patients had an average CD4 count of 145 cells/mm³ (up 97) and the IL-2 patients had an average count of 168 cells/mm³ (up 107) – not a significant difference.

Response to IL-2, however, varied considerably between patients. Tincati and colleagues divided the patient group into 23 (70%) IL-2 ‘responders’ and ten (30%) ‘non-responders’. Both responders and non-responders had an initial CD4 boost in response to the first cycle: a 161 cells/mm³ increase in responders and a 95 cells/mm³ increase in non-responders, meaning that non-responders still had an initial increase far in excess of that seen in patients on ART alone.

However although the CD4 count rises were quite well sustained in responders (up 61 cells/mm³ at six months and up 135 cells/mm³ at 18 months from baseline), they were not sustained in non-responders (up only 28 cells/mm³ at six months, and 74 cells/mm³ at 18 months, meaning they ended up with slightly lower CD4 counts than patients on ART alone). Further cycles of IL-2 did not produce any more significant CD4 rises in non-responders.

Nonetheless, the IL-2 therapy did appear to reduce considerably the danger of new AIDS-defining illnesses in the first few months on therapy. While new AIDS illnesses were diagnosed in six (15%) patients on ART, only one was diagnosed in a patient receiving IL-2 (3%). Although this difference just escaped statistical significance (p = 0.06), the researchers commented that “the finding of a reduced prevalence of patients developing AIDS-defining conditions suggests a possible efficacy” in the strategy of boosting with IL-2, “which may translate into earlier clinical benefit.”