Can Immune Markers Predict Subsequent Discordance Between Immunologic and Virologic Responses to Antiretroviral Therapy?

Effective antiretroviral therapy rapidly lowers plasma HIV-1 RNA concentrations, increases the number of circulating CD4⁺ T cells, and reduces morbidity and mortality among persons with advanced HIV disease.

The CD4⁺ T cell response to therapy is biphasic, with the initial increase largely reflecting redistribution of lymphocytes from tissues into blood, and with subsequent increases reflecting overall increased CD4⁺ T cell numbers.

The strength of the inverse correlation between the decrease in the HIV-1 RNA level and the increase in the CD4⁺ T cell count is only moderate. Some patients with incomplete virologic suppression experience sustained CD4⁺ cell lymphocyte increases.

Conversely, suppression of plasma viremia does not assure immune restoration. Such discordant responses suggest that factors in addition to the decrease in the plasma HIV-1 RNA level influence CD4⁺ lymphocyte recovery.

The current study examined whether selected immune markers could help predict discordance between virologic and immunologic responses at 24 weeks of antiretroviral therapy.

Ten diverse, prospective antiretroviral studies with 1007 evaluable subjects were included. Subsets of subjects at increased risk for discordance were identified by recursive partitioning.

The strongest predictor of more-favorable immunologic than virologic responses was a lower baseline CD4⁺ lymphocyte count.

Weaker predictors in small subsets of subjects were fewer activated CD4⁺ lymphocytes and fewer CD8⁺ lymphocytes.

Conversely, the strongest predictors of more favorable-virologic than immunologic responses were higher baseline CD4⁺ lymphocyte count and percentage. Additional predictors in some analyses were higher CD8⁺ lymphocyte count or percentage and lower HIV-1 RNA concentrations.

Baseline markers of immune activation and naive/memory lymphocyte subsets had limited ability to predict subsequent discordance.

Discussion

In the present exploratory study, the strongest and most consistent baseline predictors of subsequent discordance were absolute CD4⁺ T cell counts and percentages. In some analyses, absolute CD8⁺ T cell counts and percentages, numbers of activated CD4⁺ T cells, and HIV-1 RNA concentrations also identified small subgroups of subjects most likely to experience subsequent discordance.

In contrast, serum neopterin and beta-2 microglobulin concentrations at baseline did not help to predict discordance.

The predictive value of HIV-1 RNA level at baseline at least in part reflects the discordance definitions that were used. Achieving plasma HIV-1 RNA levels less than the limits of quantification at the end of an evaluation interval was a major indicator of virologic success, although the magnitude of HIV-1 RNA change was incorporated into most discordance definitions. Therefore, subjects with low but detectable HIV-1 RNA levels at the start of an evaluation interval were most likely to achieve virologic success.

Previous studies have described immunologic changes that occur during the response to antiretroviral therapy, and some have examined the ability of laboratory values other than HIV-1 RNA and CD4 cell values to predict subsequent events. Such factors have included soluble and cellular markers of immune activation. Better definitions of whether such markers predict clinically relevant laboratory and/or clinical parameters may ultimately influence patient care.

Some subjects receiving potent antiretroviral therapy control HIV-1 replication but experience limited CD4⁺ T cell increases, whereas others maintain higher CD4⁺ T cell counts despite having ongoing viremia. Predicting the trajectory of decreases in the CD4⁺ T cell count or the likelihood of HIV-related complications could influence management decisions, in both treatment-naive and -experienced patients.

09/10/03

Reference
John Spritzler and others (for the Adult AIDS Clinical Trials Group). Can Immune Markers Predict Subsequent Discordance between Immunologic and Virologic Responses to Antiretroviral Therapy? Adult AIDS Clinical Trials Group. Clinical Infectious Diseases 37:551-558. August 15, 2003.