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Investigative Antiviral Agent Aplaviroc Lowers Viral Load Without Inducing Global Immune Changes: Presented at ICAAC

By Paula Moyer

WASHINGTON, DC -- December 22, 2005 -- The investigative antiviral agent aplaviroc lowers RNA levels in patients with HIV-1 without causing changes in plasma levels of chemokines and cytokines, investigators reported here at the 45^th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

This finding implies that aplaviroc, which targets the cellular chemokine receptor 5 (CCR5), can treat HIV-1 without harming the immune system function, said principal investigator Kathryn Kitrinos, PhD, clinical researcher, clinical virology department, GlaxoSmithKline, Research Triangle Park, North Carolina. GlaxoSmithKline funded the study.

"Short-term administration of aplaviroc did not induce global changes in immune activation," she said during her presentation on December 17^th.

Although macrophage inflammatory protein-1 bet (MIP-1 beta) increased 1.5- to 2.5-fold temporarily after subjects received aplaviroc, levels remained the same in healthy volunteers. In HIV-positive subjects, the MIP-1 beta increase correlated with the nadir of HIV-1 RNA. After 48 hours, the levels returned to their predosing levels, she said.

Earlier research showed promising safety results with aplaviroc. Therefore, Dr. Kitrinos and colleagues conducted their study to analyzed the potential immunological impact of the drug by assessing the levels of several chemokines and cytokines in 30 HIV-negative subjects and 40 HIV-positive subjects.

HIV-negative subjects received either placebo or 1 of 3 doses of aplaviroc twice daily for 7 days with a 7-day follow-up period. The dose groups for these subjects were 200 mg, 600 mg, or 800 mg.

HIV-positive subjects received either placebo or 1 of 4 dosing regiments: 200 mg 2 times daily, 200 mg twice daily, 400 mg 4 times daily, or 600 mg twice daily. These patients were treated for 10 days and followed for 14 days posttreatment.

The investigators assessed patients' plasma chemokine and cytokine levels at baseline, steady-state, and follow-up.

In both groups, 10 of the 11 chemokines and cytokines showed no consistent change with short-term exposure to aplaviroc when compared with placebo. The chemokines assessed included regulated on activation normal T cell expressed and secreted (RANTES), MIP-1 alpha MIP-1 beta, interleukin-8 (IL-8), membrane cofactor protein-1 (MCP-1), and T helper 1 (TH 1) and T helper 2. The cytokines consisted of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and IL-2, IL-4, IL-5, and IL-10.

MIP-1 beta levels increased transiently, and began to return to baseline levels during the follow-up period. Dr. Kitrinos noted that despite the increase, the MIP-1 beta levels remained within the range observed in normal plasma samples.

The findings are promising because of the lack of impact or minimal impact on plasma chemokine and TH1 and TH2 cytokine levels, she said.

"These data suggest that aplaviroc does not induce global changes in immune activation following short-term administration," she concluded.


[Presentation title: Minimal to No Changes in Plasma Chemokine/Cytokine Levels in HIV-Negative and HIV-Positive Subjects Following Short Term Administration of 873140. Abstract H-1097]

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