IL-2 and/or therapeutic vaccines for successful treatment interruptions?

A French therapeutic vaccine combination alongside three cycles of IL-2 therapy kept one in four HAART responders off therapy for an average of nine months, according to research presented Wednesday at a late-breaker session at the 2nd IAS Conference on HIV Pathogenesis and Treatment in Paris.

However, an American study found similar success with the immune-enhancing IL-2 alone, adding to the confusion and debate around the future prospect of therapeutic vaccines that was something of a leitmotif of the Paris conference.

Unlike preventative vaccines, the goal of therapeutic vaccines is to enable the immune system to continue to control the virus in the absence of antiretrovirals in people already infected with HIV.

IL-2 is not a therapeutic vaccine: it simply enhances production of CD4 cells. It is currently being studied in a large multinational trial (ESPRIT) to see if the increases in CD4 cells seen so far are clinically relevant over time. Very preliminary results presented in Paris eight months into the multi-year study revealed what we already know about IL-2: CD4 cell count response is associated with a higher CD4 nadir, higher baseline CD4 and younger age.

The French vaccine study reported a one year extended follow-up of 70 patients who started the trial with CD4 counts above 350 cells/mm³ and an HIV viral load under 50 copies/mL which was achieved on HAART for at least a year. Thirty-seven subjects (with a median CD4 nadir of 290 cells/mm³) were then randomised to continue HAART alone and 33 subjects (with a median CD4 nadir of 262 cells/mm³) continued on HAART as well as being given a combination vaccine consisting of ALVAC and Lipo-6T given four times over 12 weeks (at weeks 0,4,8,12). This was followed by three cycles of IL-2 (4.5 MIU, twice a day for five days) at weeks 16, 24 and 32.

The 63 subjects whose viral load was below 50 copies/mL at week 36 stopped HAART at week 40. They had to restart HAART if their viral load rebounded to above 10,000 copies/mL. By week 52, two (5%) of the controls and 8 (24%) of those vaccinated remained off HAART, which was statistically significant (p=0.027).

The time it took for subjects to reach a viral load of 10,000 copies/mL was delayed in the vaccinated arm compared to controls (p=0.02), which, the study’s presenter argued, showed that the vaccine had an effect on the viral set point.

The overall median time off therapy for the vaccinated subjects was 35 weeks (13-65), with three out of the eight still off therapy at 60-65 weeks. Unsurprisingly, given the use of IL-2, the median nadir CD4 cell count during interruption was 630 (range 332-1308) cells/mm³ compared to 493 (range 235 - 1056) in controls.

However, a poster presentation from researchers at the US National Institutes of Health showed that IL-2 alone can sustain CD4 counts above 500 cells/mm³ during structured treatment interruptions for six months in patients who had received three or more cycles prior to interruption. Since the French vaccine study did not include a vaccine-only or IL-2-only arm, it is impossible to say what role - if any - the vaccine played in keeping CD4 cell counts so high.

In the US IL-2 treatment interruption study, 17 patients who had previously received at least three IL-2 treatments alongside their HAART and had maintained a CD4 count above 500 cells/mm³ were given another five day cycle of IL-2 and then randomised to their stop therapy (n=11) or continue their HAART (n=6) for six months.

At baseline, patients in the interruption arm had a median of 902 CD4 cells/mm³ and 9/11 had viral load below 50 copies/mL. Those in the continuous arm had a median 1040 CD4 cells/mm³ and 4/6 had a viral load below 50 copies/mL.

After six months, the median CD4 count change was an increase of 10 cells/mm³ (ranging from a loss of 118 to a gain of 522) for the patients in the interruption arm and an increase of 377 cells/mm³ in the continuous arm (range 203–843, p=0.03).

Peak median viral load in the interruption arm was 95,200 copies/mL at a median of four months after interruption, and median viral at six months was 47,600 copies/ml. Only four of eleven patients in the interruption arm required one additional IL-2 cycle during the study duration and all eleven maintained CD4 counts above 500 cells/mm³at six months.