Cardiovascular implications from untreated human immunodeficiency virus infection

Abstract

Atherosclerotic cardiovascular disease (CVD) has become an important cause of morbidity and mortality among individuals with human immunodeficiency virus (HIV) infection with access to antiretroviral medications, as the risk for AIDS has fallen and life expectancy improved. Traditional CVD risk factors are often more common among individuals with HIV infection, and traditional prevention strategies remain important. Recent data have revealed that untreated HIV infection itself amplifies additional pro-atherogenic mechanisms related to immune activation, inflammation, coagulation, and lipoprotein particle changes (e.g. high-density lipoprotein particles). Some of these mechanisms are attenuated, though incompletely, with antiretroviral therapy (ART)-related suppression of HIV replication. Exposure to ART is also associated with variable toxicity that may simultaneously decrease (via viral suppression) and increase CVD risk. Ultimately, additional adjunctive treatment will be needed to mitigate premature CVD risk among contemporary HIV-infected patients with access to ART.

Figure 1

Pro-atherogenic factors related to untreated human immunodeficiency virus (HIV) infection. Key pro-atherogenic factors amplified in the setting of untreated HIV infection are presented. HIV replication and activation of lymphocytes and monocytes is associated with release of inflammatory cytokines and early vessel dysfunction. Key candidate drivers of immune activation include, but may not be limited to, HIV persistence (including low-level viral replication below level of detection for clinical assays), permanent damage to mucosal lymphatic tissue with increased microbial translocation, and the presence of co-pathogens (e.g. cytomegalovirus). Subsequent coagulation and thrombotic activity, via cell damage and up-regulation of tissue factor pathways, platelet activation, or other mechanisms may contribute to premature atherosclerosis. Pro-atherogenic changes in lipids and lipoprotein metabolism are also consequences of both HIV infection and chronic inflammation. Some of these mechanisms are attenuated, though incompletely, with antiretroviral therapy and suppression of HIV replication.

Figure 2

Risk for cardiovascular disease (CVD) by interleukin (IL)-6 levels and total high-density lipoprotein particle (HDLp) concentration in SMART. Odds ratio (OR) for a cardiovascular disease event during follow-up in SMART when stratified by baseline ( ≥ or < median) interleukin-6 levels and total high-density lipoprotein particle concentration. Reference category has interleukin levels < median and total high-density lipoprotein particle concentration ≥ median values (white). Figure derived from published data and included here with permission.

Figure 3

Antiretroviral therapy has both positive and negative effects on cardiovascular risk. Progression of atherosclerosis is depicted in the setting of human immunodeficiency virus (HIV) infection. Antiretroviral therapy-related suppression of HIV replication may reduce HIV-related cardiovascular disease risk, but is also associated with variable toxicity that may, itself, increase cardiovascular disease risk. Antiretroviral therapy toxicity varies by the specific antiretroviral but, in part, may include adverse lipoprotein changes, insulin resistance, inflammation, platelet dysfunction, and vascular injury. Thus, compared with untreated HIV infection, the net effect of starting antiretroviral therapy on cardiovascular disease risk is unknown as it may increase or decrease risk overall. Traditional risk factors remain of high importance in this context, and should be targeted by prevention strategies.