Long-term benefit of cyclosporin A coupled with highly active antiretroviral therapy  in primary HIV-1 infection.

Pierre-Alexandre BART, Alexandre HARARI, Donatella CIUFFREDA (to 2007), Mona KHONKARLY (to October 2005)
and Giuseppe PANTALEO

Massive immune activation is a major feature of primary HIV-1 infection, and is a chief mechanism of HIV-1 infection-associated disease. In order to limit this activation, we designed a pilot protocol coupling cyclosporin A (CsA) with HAART during primary HIV-1 infection (PHI). Preliminary results were published in 2002 in JCI (see in references, Rizzardi et al.). These data suggest that reducing immune activation may be beneficial for immunologic measures.

The rationale of the study, i.e., to rapidly shut down immune activation, particularly during primary infection, is supported by a series of observations: (a) primary HIV infection is characterized by a heightened state of cellular activation; (b) initiation of HAART is accompanied by an increase in the relative proportion of CD4⁺ T cells that proliferate and/or are activated; (c) massive productive HIV-1 infection and virus spreading require proliferating and/or activated target cells; and (d) massive immune activation may lead to exhaustion and rapid elimination of HIV-specific CD8⁺ and CD4⁺ T cells.

This open-label prospective, controlled trial is carried in Lausanne, Switzerland, and at the San Raffaele Scientific Institute in Milan, Italy. 77 adults with confirmed diagnosis of primary HIV-1 infection have been consecutively treated with PI-containing HAART, either alone (n=43, control group) or coupled with CsA (n = 34, CsA group). All patients started therapy within 72 hours of screening. HAART contained 2 NRTI along with either 2 PI or 1 RTV-boosted PI, equally distributed between treatment groups. CsA was administered throughout the first 8 weeks of therapy, at a dose achieving CsA blood levels stably >100 ng/mL. After 8 weeks, CsA was discontinued and HAART was continued alone.

Immunologic and virologic measures were compared over 120 weeks in the 2 groups, both with a median follow-up of 28 months (range 3 to 36). Plasma viral load was measured with Amplicor assay (LOD 50 copies/mL).

During the first 56 days of CsA therapy, the net increase over baseline values in both CD4⁺ T cell percentage and cell counts was significantly greater in patients receiving CsA in combination with HAART than in those receiving HAART alone (Figure 1). The increase in CD4⁺ T cells was paralleled by a decrease in CD8⁺ T cell percentage and counts (data not shown), inducing a more rapid normalization of the CD4/CD8 ratio in patients receiving CsA + HAART than in those taking HAART alone.

It is worth noting that levels of plasma HIV-1 RNA measured at baseline significantly predicted changes from baseline in CD4⁺ T cell counts after 2 weeks of therapy, indicating that, in patients receiving CsA in addition to HAART, higher levels of plasma HIV-1 RNA at baseline are associated with greater increases in CD4⁺ T cell counts after 2 weeks of therapy.

Decreasing immune activation in the very early phases of HIV-1 infection has a beneficial impact on the long-term course of the disease, contributing to the establishment, following primary HIV-1 infection, of a more favorable immunologic set-point that affects the ultimate pattern and rate of disease progression.

The benefits achieved with HAART during primary HIV-1 infection may be extended via the use of an immune-modulating strategy interfering with early pathogenic events.

Figure 1

Dernière modification le 16.09.2008 - Impressum - Informations juridiques