HIV, cardiovascular disease, anti-retroviral resistance: the issue with protease inhibitors and a need for alternatives
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Today, it is estimated that 35 million people are living with human immunodeficiency virus (HIV). Since its initial discovery in 1981, researchers and medical providers have worked endless hours to understand the pathology, transmission, and medical management of HIV. In the early days of HIV, life expectancy after diagnosis was 10 years. However, after the development of zidovudine (AZT) in 1987, life expectancy of HIV patients began to slowly increase, albeit still lower than that of the general population. The development of AZT opened the door for more antiretroviral drugs and more drug classes. Now, patients undergo a triple drug regimen to manage HIV. These patients are able to maintain viral suppression and are no longer experiencing opportunistic infection or other AIDS-related conditions. While HIV is medically managed, this is a chronic condition and to-date, not cured. As opposed to opportunistic infections and other AIDS-related conditions, patients are succumbing to non-AIDs related conditions such as renal, neurological, bone disorders, and liver complications. The leading non-AIDs related condition is cardiovascular disease (CVD). Even with viral suppression, HIV infection itself contributes to the pathology and development of atherosclerosis and CVD. It is clear that chronic immune activation, HIV proteins, and dyslipidemia appear to be key factors in CVD development. Since the life expectancy of HIV patients has increased, physicians are now seeing an older generation of HIV patients. Medical providers are shifting focus toward understanding the long-term effects of not just HIV, but antiretroviral therapy (ART) as well. It appears that drug interactions and long-term toxicity augment CVD development. Protease inhibitors (PIs), compared to other ART drug classes, appear to increase the risk of atherosclerosis, especially through dyslipidemia. Due to management of HIV being life-long, compliance is difficult because of high pill burden, drug-drug interactions, and drug side effects. This can result in drug failure leading HIV patients to switch to second-line ART regimens. PIs are a common component of second-line ART regimens. Compared to other ART drugs, PIs have a high genetic barrier to resistance. However, PIs have a low bioavailability requiring high dosage and/or boosting with ritonavir (RTV). Lopinavir (LPV) boosted with RTV (LPV/r) is a favorable PI as it is used in a combination pill and is the most cost effective. However, multiple studies have shown LPV/r correlates more to CVD compared to other PIs. Patients on LPV/r exhibit an increased intima-medial thickening, a hallmark characteristic of atherosclerosis and an increased risk for myocardial infarction. Unfortunately, researchers are greatly conflicted as to why this is and in general why PIs increase the risk of CVD. Future medical treatment for HIV is complex and requires long-term medical management. In recent years, integrase inhibitors (IIs) have exhibited promise to provide better lipid profiles while maintaining viral suppression. However, as this drug class is relatively new and expensive, the financial burden on HIV patients is high. The next step toward addressing the global health issue of HIV is understanding the exact mechanism of how PIs contribute to CVD. This will not only increase the life expectancy of HIV patients, but reduce drug toxicity, non-AIDS related conditions, and increase adherence and viral suppression. It is clear that future research must be focused on understanding the role PIs have in CVD development. Physicians are seeing an older generation of HIV patients, and a vast majority are on second-line regimens. By understanding this relationship, researchers could design alternative drugs to manage CVD risk, by modifying current PIs or designing entirely new drugs.
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