Amongst individuals with a discordant CD4 and viral load response to HAART, host factors appear to be just as important as virological factors in explaining why some maintain a good immunological response to treatment despite a lack of viral load suppression, according to findings from a study of 30 North Carolina patients published in the April 1 edition of the Journal of Infectious Diseases.
The researchers at Duke University and University of North Carolina at Chapel Hill recruited three groups of patients receiving current PI-based therapy who had a CD4 cell count below 50 cells/mm3 and/or viral load above 50,000 copies/ml prior to commencing HAART. Non-adherent individuals and those receiving immunomodulators such as hydroxyurea were excluded from the study.
Participants were divided into three groups: treatment success group (VL 200 cells/mm3 for at least two years); discordant response group (VL between 500 and 5,000 copies/ml and CD4 count >200 cells/mm3 with stable or increasing trend for at least two years); and treatment failure group (viral load > 400 copies/ml and increasing after initial reduction of at least 3 log, and CD4 cell count declining). Ten patients were enrolled to each group.
Patient characteristics, including gender, race, age, HLA type and treatment regimen did not differ significantly between the groups, except for a trend towards a larger number of patients taking nelfinavir in the discordant response group.
However, patients with a discordant response to treatment had significantly greater CD8+ and CD4+ cell responses to HIV’s gag region (P=0.03), indicating a stronger HIV-specific immune response among this group. Patients in the discordant group were also more likely to have non-cytoloytic CD8 cell-mediated suppressive activity targeted at CXCR4-tropic virus, although this difference was not statistically significant.
Patients in the discordant group also had higher levels of immune activation as measured by circulating CD4 and CD8 cells (p=0.005 and 0.001 respectively) than individuals with virologic suppression.
The authors believe that viral activity alone may not explain the higher levels of HIV-specific immune activity, since non-cytolytic responses that may be less dependent on viral stimulation were more similar to those of treatment success patients than treatment failure patients.
The authors suggest that it may be the case that “the presence of strong CD4+ cell help or other unknown immunologic factors, and not viral replication, stimulates and maintains this response.”
They also note that cellular activation as measured by CD38 ABC expression on CD8+ cells was lower in discordant individuals than individuals experiencing treatment failure, suggesting that CD4+ cells are being spared due to a lower level of activation-induced apoptosis.
Replication capacity was measured with an assay developed by ViroLogic, and was found to be lower in patients with discordant responses. Lower replication capacity was not associated with any specific resistance mutations in this small sample, although there was a trend towards a higher prevalence of D30N (nelfinavir) in the discordant group compared to the treatment failure group, as would be expected given that twice as many patients in the discordant group were taking nelfinavir.
Sufka SA et al. Prolonged CD4+ cell/virus load discordance during treatment with protease inhibitor-based highly active antiretroviral therapy: immune response and viral control. Journal of Infectious Diseases 187: 1027-37, 2003.