Blood biomarkers of expressed and inducible HIV-1.

OBJECTIVE: To define the relationships between molecular measures of viral persistence in blood (i.e., plasma viremia, cellular HIV-1 DNA, and mRNA) and expressed or inducible virus from resting CD4 T cells of individuals on suppressive antiretroviral therapy. DESIGN: We compared molecular measurements of HIV-1 in plasma and in uncultured peripheral blood mononuclear cells (PBMCs) to the levels of virions produced by either unstimulated or phorbol myristate acetate and ionomycin (PMA/iono)-stimulated PBMC or resting CD4 T cells from 21 donors on suppressive antiretroviral therapy. RESULTS: We found that unstimulated virion release from cultured resting CD4 T cells was positively correlated with the levels of plasma viremia in vivo (Spearman rho = 0.67, P = 0.0017). We also found that levels of both cellular HIV-1 DNA and unspliced HIV-1 mRNA per million uncultured PBMC were positively correlated with the levels of inducible virion release from both PMA/iono-stimulated PBMC (total HIV-1 DNA: rho = 0.64, P = 0.0017; unspliced HIV-1 RNA: rho = 0.77, P < 0.001) and PMA/iono-stimulated resting CD4 T cells (total HIV-1 DNA: rho = 0.75, P < 0.001; unspliced HIV-1 RNA: rho = 0.75, P < 0.001). CONCLUSION: These results show for the first time that there are strong associations between in-vivo measures of HIV-1 persistence and ex-vivo measures of spontaneous and inducible virus production from cultured PBMC and resting CD4 T cells. Findings from this study provide insight into the biology of HIV-1 persistence and suggest methods to guide the evaluation of clinical strategies to reduce the size of the viral reservoir.

Cost-effectiveness of tissue-type plasminogen activator in the 3- to 4.5-hour time window for acute ischemic stroke.

BACKGROUND AND PURPOSE: The aim of this study was to determine the cost-effectiveness of tissue-type plasminogen activator (tPA) treatment in the 3- to 4.5-hour time window after ischemic stroke. METHODS: Decision-analytic and Markov state-transition models were created to determine the cost-effectiveness of treatment of ischemic stroke patients with intravenous tPA administered in the 3- to 4.5-hour time window compared with medical therapy without tPA. Health benefits were measured in quality-adjusted life-years (QALYs). The economic outcome measure of the model was the difference in estimated healthcare costs between the 2 treatment alternatives. The incremental cost-effectiveness ratio was calculated by dividing the cost difference by the difference in QALYs. One-way sensitivity and probabilistic analyses were performed to test the robustness of the model. RESULTS: The administration of tPA compared with standard medical therapy resulted in a lifetime gain of 0.28 QALYs for an additional cost of $6050, yielding an incremental cost-effectiveness ratio of $21 978 per QALY. One-way sensitivity analyses demonstrated that the incremental cost-effectiveness ratio was most sensitive to the cost of hospitalization for patients who received tPA. Based on probabilistic analysis, there is an 88% probability that tPA is the preferred treatment at a willingness-to-pay threshold of $50 000 per QALY. CONCLUSIONS: The balance of costs and benefits favors treatment with intravenous tPA in the 3- to 4.5-hour time window. This supports, from a societal perspective, the use of tPA therapy in this treatment time window for acute ischemic stroke.