Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis

Abstract

Objective: HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4 T-cell counts (HIV controllers).

Methods and results: Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4 T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness.

Conclusions: Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation - which is higher in controllers than in HIV-uninfected persons - may account for early atherosclerosis in these patients.

Figure 1. Comparison of Carotid IMT in HIV-infected and uninfected individuals

Antiretroviral-untreated patients with undetectable viral loads (HIV controllers) had a higher median carotid IMT than the HIV-seronegative persons, even after controlling for traditional risk factors. Carotid IMT was comparable in the HIV controllers and untreated HIV non-controllers.

Figure 2. IMT in HIV Controllers and HIV-seronegatives stratified by potential confounders

Carotid IMT was higher in HIV controllers than HIV-seronegative persons when stratified by age (Panel A), the presence or absence of hypertension (Panel B), and a history of tobacco smoking (Panel C). Carotid IMT was also higher among the controllers than HIV-seronegatives even after restricting the analysis to those with CD4+ T cell counts above 500 cells/mm³ (Panel D).

Figure 3. Effect of HAART on carotid IMT

Carotid IMT was higher in patients who were receiving highly active antiretroviral therapy (HAART) than in either antiretroviral untreated patients or HIV-seronegative persons. The effect of HAART remained significant after controlling for traditional risk factors.