Immunomodulatory effects of antiretroviral chemotherapy

Antiretroviral chemotherapeutic agents exhibit complex immunoregulatory changes in HIV-1 infected individuals that reflect the summation of the direct effects of the agents on the immune response and indirect effects through the amelioration of viral replication. Immunological parameters are useful in the context of clinical investigation and in the management of HIV-1 infected individuals in that they serve as prognostic indicators of disease, markers of biologic activity of antiretroviral drugs, and, to a lesser extent, predictors of clinical outcome. Many questions remain in the evaluation of these parameters in the context of clinical trials and in the management of individual patients. Although it is frequently tempting to measure all available parameters in any setting, it is important to be cognizant both of cost and of the fact that many of these parameters are codependent variables (29). Most evaluations that have been undertaken to date involve nucleoside analogs, either as single agents or in combination. It is clear that CD4 cells rise in association with the initiation of non-nucleoside reverse transcriptase inhibitors and HIV-1 protease inhibitors (30-32). It is not yet clear whether the CD4 cell changes observed with these classes of drugs exhibit the same relationships with other immunologic markers or with virologic or clinical parameters. Evidence has begun to emerge that CD4 cell changes in association with HIV-1 protease inhibitor therapy may be more durable than changes in viral load as assessed by plasma HIV-1 RNA. Given the more robust antiviral potency of HIV-1 protease inhibitors alone or in combination with nucleoside analogs, it is quite likely that many of the ambiguities with respect to prior studies of immunologic markers will be resolved in that the changes observed will likely be of a much greater magnitude and duration than those seen in association with nucleoside analog monotherapy. Finally, with the advent of more potent antiviral regimens, and with the more reproducible and sensitive techniques for measuring viral replication in vivo, the cogent investigation of immunologic parameters will provide important insights into the pathogenesis of HIV-1 infection (33, 34).