Publications

OBJECTIVES

Evidence from the current era of combination antiretroviral therapy supports an association between HIV and cerebrovascular disease. In addition to traditional vascular risk factors, HIV-specific factors including immunodeficiency and viral replication may also predict stroke risk. The aim of this study was to determine the relationship between CD4(+) cell count, viral suppression and validated ischemic stroke outcomes.

DESIGN

A single-centre, case-control study.

METHODS

We identified ischemic stroke cases in HIV-infected adults from an HIV clinic using International Classification of Diseases codes for cerebrovascular disease followed by validation of each case. Controls from the same HIV clinic were selected by incidence density sampling. Demographic and clinical data, including the most recent CD4(+) cell count and plasma HIV RNA concentration, were abstracted from hospital and HIV clinic electronic medical records. Matched conditional logistic regression models were used to evaluate the association between CD4(+) cell count, viral suppression and ischemic stroke.

RESULTS

In an adjusted model, viral suppression decreased the odds of ischemic stroke by a factor of 0.16 [95% confidence interval (95% CI) 0.05-0.50, P = 0.002]. This association, although attenuated [odds ratio (OR) 0.31, 95% CI 0.09-1.06, P = 0.062], remained after restricting the analysis to ischemic strokes due to true atherosclerotic mechanisms (i.e. excluding infection and malignancy-related strokes).

CONCLUSION

Achieving viral suppression may reduce ischemic stroke risk, including risk of atherosclerotic strokes, in HIV-infected individuals.

UNLABELLED

Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.

TRIAL REGISTRATION

ClinicalTrials.gov NCT01365065.