Primary source: Interscience Conference on Antimicrobial Agents and Chemotherapy

Source reference:
Severe P et al. “A Randomized Clinical Trial of EarlyVersus Standard Antiretroviral Therapy for HIV-Infected Patients with a CD4 T Cell Count of 200 - 350 Cells/ml (CIPRAHT001)” ICAAC 2009; Abstract H-1230c.

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• IAS: Earlier HIV Therapy Would Save Lives, Model Shows

• Explain to interested patients that this study showed that adding interleukin-2 to standard HIV therapy increased CD4 cells counts, but had no effect on outcomes.

Adding the signaling molecule interleukin-2 to standard HIV therapy has no effect on the risk of death or opportunistic disease, two major clinical trials have concluded.

The addition of interleukin-2 was intended to — and did — increase the CD4-positive T cell count, according to James Neaton, PhD, of the University of Minnesota in Minneapolis, and colleagues.

But the increase did not translate into better clinical outcomes, the researchers said in the Oct. 15 issue of the New England Journal of Medicine.

The findings reinforce the need for clinical trials when novel interventions aimed at so-called surrogate markers are proposed, the researchers said.

As in this case, “surrogate markers often do not accurately predict the clinical effects of a treatment,” they said.

Results of the parallel trials were discussed at a meeting last year and appear to have ruled out a role for interleukin-2 in the treatment of HIV, many observers said. (See CROI: IL-2 Benefit in HIV Ruled Out)

The two trials — dubbed SILCAAT and ESPRIT — were undertaken in patients with fewer than 300 CD4 cells per cubic millimeter of blood in the case of SILCAAT and at least 300 in ESPRIT.

In SILCAAT, 849 patients got interleukin-2 plus anti-retroviral therapy and 846 got anti-retroviral medications alone. Median CD4 cell count was 202 cells per cubic millimeter.

In ESPRIT, 2,071 got the cytokine plus HIV therapy and 2,040 got HIV treatment alone. Median CD4 cell count was 457 cells per cubic millimeter.

The interleukin-2 regimen consisted of five-day cycles, administered every eight weeks. In SILCAAT, patients got six cycles at 4.5 million IU of interleukin-2 twice a day; in ESPRIT they got three cycles at 7.5 million IU twice daily.

The researchers used a combined primary endpoint of opportunistic disease or death from any cause, and secondary endpoints of death from any cause by itself or Grade 4 adverse events, defined as potentially life-threatening events requiring medical intervention.

Over a median follow-up period of seven to eight years, they found:

• The CD4 cell count was higher in the interleukin-2 group by 53 cells per cubic millimeter, on average, in SILCAAT and and 159 in ESPRIT.
• The hazard ratio for opportunistic disease or death from any cause with interleukin-2 plus anti-retroviral therapy was 0.91 in SILCAAT and 0.94 in ESPRIT, but neither was significantly different from anti-retroviral treatment alone. The 95% confidence intervals were 0.70 to 1.18 and 0.75 to 1.16, with P=0.47 and P=0.55, respectively.
• The hazard ratio for death from any cause was 1.06 in SILCAAT, non-significant at P=0.73, and 0.90 in ESPIRIT, also not significant at P=0.42.
• For Grade 4 clinical events, the hazard ratios were 1.10 in SILCAAT and 1.23 in ESPRIT. The first was not significant at P=0.35, while the second reached significance at P=0.003.

The researchers said there might be two possible explanations for the result.

First, the CD4 cells generated by the cytokine may not play any role in host defenses.

Second, such cells might be protective but their benefit might be overwhelmed by negative effects of the interleukin-2.