Surrogate markers for assessing treatment response in HIV disease.

OBJECTIVE

To provide an awareness of the issues surrounding the selection and utility of surrogate markers to evaluate treatment response for new antiretroviral therapies for HIV infection.

DATA SOURCES

A MEDLINE search of applicable articles published between 1987 to the present, including clinical trials, commentaries, and editorials, was performed.

DATA SYNTHESIS

Surrogate markers are proximal indicators that are predictive of rare or distant outcomes and can be used in clinical trials to decrease sample size and study duration. Characteristics of potential surrogate endpoints include relevance to disease state, face validity, ability to be detected in the majority of patients, and correlation between treatment-induced changes and terminal endpoints. Potential surrogate markers for assessing treatment response in HIV infection can be categorized as either virologic (p24 antigen, plasma viremia, proviral DNA) or immunologic (CD4+ lymphocytes, neopterin, beta 2-microglobulin, soluble interleukin-2 receptors, immunoglobulin A [IgA]). The CD4+ lymphocyte count and the p24 antigen have been evaluated in most of the clinical trials examining antiretroviral agents and have the greatest documentation supporting their use. Neopterin and beta 2-microglobulin are nonspecific markers, but may improve the predictive value of the CD4+ count when used in combination. Other markers (i.e., soluble interleukin-2 receptors, IgA) remain relatively unstudied at this point.

CONCLUSIONS

There is no current consensus regarding the selection of surrogate markers for HIV disease. On the basis of the present literature, the CD4+ lymphocyte count has the greatest endorsement: however, combination with several surrogate markers may prove to be useful in clinical trials. Studies are needed to verify the reliability of surrogate markers used alone and in combination to predict therapeutic response from antiretroviral therapy.