The association between surrogate marker response measures and the development of opportunistic illnesses in HIV-infected persons enrolled in a large randomized clinical trial.

Abstract

Introduction. Surrogate marker responses are imperfect indicators of response to antiretroviral therapy in HIV. It is proposed that the area under the curve of surrogate marker response will be superior to peak response, or to that measured after a period of therapy. Methods. The database from a study of ritonavir in advanced HIV was used. Using logistic regression, the specificity of the surrogate marker level at baseline, change between baseline and at time points to week 16, peak response, and area under the curve of the response to week 16 and week 40 were determined. The predictive values, likelihood ratios and receiver operating characteristic curves were determined for those of highest specificity. Results. Specificities increased from baseline to week 16. Peak responses were inferior to time period surrogate marker changes, whereas the areas under the curve were comparable or better than the time period surrogate marker changes. The highest specificity at any time point was for the CD4 change at week 8 (55.90%), whereas the highest overall specificity was for the 16 week AUC for the CD4% (69.63%). However, the PPV, NPV, likelihood ratios and ROC curves demonstrated poor performance overall for these surrogate markers. Too few subjects had viral load testing for this marker to be assessed. Discussion. Within the limits of this study, it was demonstrated that the CD4 and CD4% were the surrogate markers most associated with clinical outcome, with the CD4% AUC to 16 weeks having the highest overall specificity and the week 8 CD4 having the greatest specificity for clinical use. However, all surrogate markers had specificities below 70%.