Publications

OBJECTIVE

Despite widespread HAART use, HIV disease remains associated with increased risk of kidney disease. Whether tenofovir use is associated with higher risk of kidney disease is controversial.

DESIGN

We evaluated the association of cumulative and ever exposure to tenofovir on kidney outcomes in 10,841 HIV-infected patients from the Veterans Health Administration who initiated antiretroviral therapy from 1997 to 2007.

METHODS

Cox proportional hazards and marginal structural models evaluated associations between tenofovir and time to first occurrence of proteinuria (two consecutive urine dipstick measurements ≥30 mg/dl), rapid decline in kidney function (≥3 ml/min per 1.73 m annual decline), and chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min per 1.73 m).

RESULTS

Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD), during which 3400 proteinuria, 3078 rapid decline, and 533 CKD events occurred. After multivariable adjustment, each year of exposure to tenofovir was associated with 34% increased risk of proteinuria [95% confidence interval (CI) 25-45, P < 0.0001], 11% increased risk of rapid decline (3-18, P = 0.0033), and 33% increased risk of CKD (18-51, P < 0.0001). Preexisting renal risk factors did not appear to worsen the effects of tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events. Among those who discontinued tenofovir use, risk of kidney disease events did not appear to decrease during follow-up.

CONCLUSION

Tenofovir exposure was independently associated with increased risk for three types of kidney disease events, and did not appear to be reversible. Because subtle kidney function decline affects long-term morbidity and mortality, the balance between efficacy and probable adverse effects requires further study.

BACKGROUND

Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.

METHODS AND RESULTS

We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.

CONCLUSIONS

Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)

CLINICAL TRIAL REGISTRATION

URL: http://clinicaltrials.gov. Unique identifier: NCT01519141.

OBJECTIVE

HIV-infected individuals are at increased risk for myocardial infarction. Given observations that cytomegalovirus (CMV) infection, CMV-specific T cells, and CX3CR1 have each been associated with atherosclerosis, we hypothesized that CMV-induced T-cell immunopathology could contribute to HIV-associated atherosclerosis.

METHODS

We measured the expression of CX3CR1 on peripheral blood mononuclear cells and its association with carotid artery intima-media thickness (IMT) in 29 HIV-infected individuals and 48 uninfected controls. We analyzed the phenotype and specificity of CX3CR1(+)CD4(+) T cells, the production of CX3CL1 (the ligand of CX3CR1) by CMV-infected endothelial cells in vitro, and the migration of CD4(+) T cells induced by CX3CL1.

RESULTS

The progression of atherosclerosis in HIV-infected individuals, as assessed by longitudinal measurements of carotid IMT, was associated with a high frequency of CD4(+) T cells that express the chemokine receptor CX3CR1. Such CD4(+)CX3CR1(+) T cells were antigen-primed, produced high levels of pro-inflammatory cytokines, and composed the majority of the CMV-specific CD4(+) T cells. CMV-stimulated CD4(+) T cells were also found to induce the production of CX3CL1 (the ligand for CX3CR1) by human arterial endothelial cells, driving the transendothelial migration of pro-inflammatory CD4(+) T cells. Finally, we observed that CD4(+)CX3CR1(+) T cells could be localized to the coronary arterial wall in HIV disease.

CONCLUSION

HIV-associated atherosclerosis may be driven by a positive feedback pathway in which a high frequency of antigen-stimulated, CMV-specific CD4(+)CX3CR1(+) T cells induce endothelial cells to secrete CX3CL1, which itself drives progressive infiltration of the arterial wall by pro-inflammatory cells.