HIV-positive individuals have an increased risk of hardening of the arteries, or atherosclerosis, even when taking into account the possible effects of HIV treatment, continued HIV replication, and immune suppression, US investigators report in the June 1st edition of AIDS. They believe that chronic inflammation, caused by even very low levels of HIV replication, may be the cause.
Cardiovascular disease is an increasingly important cause of illness and death in people with HIV. There are a number of possible explanations for this. These include the side-effects of some anti-HIV drugs; and the inflammation that can accompany HIV replication and a weak immune system.
Chronic inflammation and immune activation have both been identified as risk factors for atherosclerosis (hardening of the arteries). Investigators wished to test the importance of HIV treatment, HIV replication, immune suppression, and chronic inflammation to hardening of the arteries in HIV-positive individuals.
To ensure that their cross-sectional research could examine each of these factors, their study population comprised a diverse sample of HIV-positive patients. This included 'elite' controllers (33 individuals), patients who maintained an undetectable viral load without the need for HIV treatment; untreated patients with a detectable viral load (96 individuals); and patients taking antiretroviral therapy some of whom had an undetectable viral load (180 patients), with others having a detectable viral load (92 individuals).
The researchers compared carotid intima-media thickness, an important measure of atherosclerosis, in the HIV-positive patients with 93 HIV-negative controls. They then undertook further analysis restricted to the patients with HIV to assess the importance of HIV-related factors to hardening of the arteries.
As expected, HIV-positive patients had significantly higher carotid intima-media thickness than the HIV-negative controls (median 0.91 vs 0.72 mm, p
Furthermore, the researchers found that carotid intima-media thickness was higher in HIV 'elite' controllers than HIV-negative controls (median 0.92 vs 0.72 mm. p 3 (p = 0.001). Further analysis that took into account independent risk factors for hardening of the arteries still showed that 'elite' controllers had significantly higher carotid intima-media thickness than HIV-negative controls (p = 0.031).
The investigators then compared carotid intima-media thickness between “elite” controllers and HIV-positive patients not taking antiretroviral drugs who had a detectable viral load. This comparison showed that controllers had slightly higher carotid intima-media thickness (0.91 vs 0.83 mm). The investigators write that this suggests “that high levels of HIV replication and/or immunodeficiency…are not a prerequisite for the development of atherosclerosis in the setting of untreated HIV infection.”
There was no evidence of a difference in carotid intima-media thickness between controllers and patients taking HIV treatment, irrespective of whether they had an undetectable viral load. Nor was CD4 cell count shown to be significant in any of the investigators’ analysis.
Patients taking antiretroviral therapy had higher carotid intima-media thickness than those not taking anti-HIV drugs (0.94 vs 0.85 mm, p = 0.006). Increased duration of treatment with anti-HIV drugs, therapy that included a protease inhibitor, and use of a nucleoside reverse transcriptase inhibitors were all significantly associated with increased carotid intima-media thickness (all p
The investigators also found that levels of C-reactive protein, a measure of inflammation, were higher in HIV-positive patients than controls (p = 0.03). There was no difference in C-reactive protein levels between controllers and other groups of HIV-positive patients.
“Compared to uninfected controls, carotid intima-media thickness was higher among all groups of HIV patients, irrespective of antiretroviral treatment or the level of viremia”, write the investigators. They add “these data argue for a possible role of persistent HIV-associated inflammation as a potential cause for accelerated atherosclerosis in HIV disease".
Even a very low level of HIV replication that is below the limit of detection may be contributing to inflammation and hardening of the arteries. The investigators therefore conclude “in the future, achieving and maintaining even lower viral loads than current therapies permit in individuals with HIV will need to be investigated both in terms of HIV disease and cardiovascular risk.”
Hsue PY et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 23: 1059-67, 2009.