Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review

Abstract

A substantial body of evidence indicates that CD4 cell count is an important independent prognostic indicator for progression of HIV disease. Consequently, in addition to plasma HIV RNA levels, CD4 cell count change is considered to be a key surrogate marker for disease progression in clinical practice and in clinical studies. Given the relationship between changes in CD4 count and disease progression, it is notable that protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) can rapidly increase CD4 cell count early in treatment in both therapy-naïve and -experienced patients, and can sustain clinically relevant levels beyond 24 weeks. A number of trials with a follow-up of more than 3 years allow us to conclude that the gains in CD4 counts are maintained in a durable manner. This review evaluated randomized studies of PI-based and PI-boosted HAART (published between January 1996 and February 2006) to determine the effect of PI-based therapy on CD4 cell count. Only studies that assessed CD4 response in the overall patient population were included. Four mechanisms have been proposed to account for the rapid increase in CD4 cell count that occurs with HAART: CD4 cell redistribution from lymphatic tissues, increased CD4 cell production, reduction of apoptotic CD4 cells and the recovery of hematopoietic activity in bone marrow. Further research is required to clarify the relative importance of these mechanisms and ways in which they might be enhanced.

Risk factors for loss of virological suppression in patients receiving lopinavir/ritonavir monotherapy for maintenance of HIV suppression

“…Interestingly, in the M03-613 trial, lower baseline CD4 + T-cell counts were significantly associated with a lower likelihood of maintaining suppression of viraemia for patints undergoing LPV/r monotherapy. As the M03-613 T-cell count might imply an irreversible impairment of the immune response against HIV-1 that impedes a profound and durable suppression of HIV-1 replication under any antiretroviral therapy [13,14] and, perhaps, a higher HIV-1 cellular reservoir. In addition, low CD4 + T-cell counts before treatment have been associated with relative higher levels of residual replication (between 0-50 copies/µl) after suppression with an antiretroviral regimen [15].…”

Reconstitution of the immunological defence and Candida albicans infection in oral mucosa of HIV+ patients under HAART

“…With HAART application, the immunological system of the HIV patient is partially and temporarily reconstituted 27 , due to the decrease of the viral load and the enhanced response of the defensive cells, in adults 19,83,9,332 and children 335 . More than the increase in number of the defensive cells, with increase of the hematopoietic activity 332 , there is a functional recovery of immunodepressed cells 232,332 .…”

Short Communication: Enhanced CD8+ T Cell Apoptosis in HIV-Infected Adolescents with Virologic Failure on Protease Inhibitor-Based Therapy

“…This finding was surprising, given the beneficial effects of PI on CD4 + T cell retention and reconstitution previously reported in some HIV + patients. [2][3][4] However, PI may exert differential cellular effects on different cell types, including proapoptotic effects in some cell types. 4 Moreover, there were earlier reports of unfavorable clinical outcomes in PI + ART compared to PI À ART.…”

“…1 Interestingly, numerous follow-up studies have provided evidence that protease inhibitors (PI) have effects on the maintenance or restoration of CD4 + T cell levels that appear to be independent of their antiviral effects. 2,3 A direct effect of PI on CD4 + T cells is to inhibit CD4 + T cell apoptosis, 4 a major cause of CD4 + T cell loss during chronic HIV infection. 5 In contrast, less is known about the immunomodulatory effects of PI on CD8 + T cells.…”