HIV and Inflammation
Consequences of Inflammation
Changes in biomarker levels reflect physiological processes that can ultimately lead to serious clinical consequences. Not long after the advent of effective combination ART, researchers began to notice that as HIV-positive people lived longer, they were at higher risk for chronic progressive conditions such as cardiovascular disease, kidney disease, bone loss, neurocognitive impairment, and certain non-AIDS-related cancers. Numerous studies have shown that these age-related conditions are associated with elevated levels of inflammation biomarkers. HIV infection has been shown to promote immunosenescence and many people with HIV and their doctors have noted that the virus seems to accelerate aging in general. HIV-positive individuals tend to develop these progressive conditions sooner than their HIV-negative counterparts. For example, people with long-term HIV infection have brain function similar to that of HIV-negative people 15-20 years older, on average, while blood vessel function resembles that of people 10 years older.
Large general population studies have shown that blood levels of inflammatory chemicals involved in atherosclerosis, or "hardening of the arteries," can predict future cardiovascular events. Not coincidentally, these are the same biomarkers linked to cardiovascular events and death in SMART and other studies of people with HIV.
Observational studies since the advent of ART in the mid-1990s have seen higher rates of cardiovascular disease among people with HIV. This may be attributable to the virus itself, antiretroviral drugs, greater frequency of risk factors such as smoking, or some combination of factors, with inflammation playing a key role.
As described at CROI 2010, Priscilla Hsue and her team at UCSF found that HIV-positive people experienced faster atherosclerosis progression, as measured by intima-media thickness, or thickness of blood vessel walls, than HIV-negative individual over two years. This was the case for people with undetectable viral load on ART and even for elite controllers. People with HIV also had impaired ability of arteries to respond to changes in blood flow. Both measures were associated with inflammation, as indicated by elevated CRP levels.
At the same meeting, Robert Kaplan and colleagues reported that increased carotid artery intima-media thickness and reduced distensibility (ability of blood vessels to expand) were linked to greater CD4 and CD8 cell activation and T-cell senescence in HIV-positive women.
Looking at actual clinical events among patients at Massachusetts General Hospital and Brigham and Women's Hospital in Boston, Triant et al. found that HIV-positive people with high CRP had four times greater risk of myocardial infarction than HIV-negative people with normal CRP. More recently, Phyllis Tien and fellow investigators with the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study reported that HIV-positive people with elevated CRP and fibrinogen had a significantly higher risk of death over five years.
While the detrimental effects of inflammation have been most clearly demonstrated for cardiovascular disease, similar associations are seen for cognitive impairment, non-AIDS-related cancer, and other progressive age-related conditions.
The initial goal of HIV medicine was simply to keep people alive by managing opportunistic illnesses, and over time shifted to viral load suppression and managing ART side effects and complications. Today, the focus is on improving overall health and enabling HIV-positive people to live as long as their HIV-negative counterparts.
A number of different strategies have been proposed for managing inflammation in people with HIV. As noted, optimizing ART to keep viral load as low as possible for as long as possible, as well as treatment of coinfections, are the most reliable current approaches. Numerous studies have shown that suppressing HIV decreases T-cell activation and reduces inflammation biomarkers, while stopping ART worsens inflammation. Managing inflammation is a major rationale for the current trend toward earlier treatment.
Researchers have looked at a wide variety of anti-inflammatory and immune-suppressing agents for managing inflammation in HIV-positive people. Many of these work by altering production or activity of cytokines. Some researchers are particularly interested in CCR5 antagonists, drugs that prevent HIV from using the CCR5 co-receptor to enter cells. CCR5's role in immune response is not fully understood, but drugs like maraviroc (Selzentry) appear to have anti-inflammatory as well as antiretroviral properties. Some clinical trials of maraviroc have shown that even though it does not suppress HIV better than other antiretroviral classes, it appears to produce larger CD4 cell gains, reduce T-cell activation, and decrease inflammatory biomarkers.
At CROI 2010 and at the XVIII International AIDS Conference this past July, researchers presented data on a novel experimental drug, TBR-652, that blocks both CCR5 and CCR2 cell surface receptors. Early studies suggest it has anti-inflammatory as well as antiretroviral activity.
But interfering with immune response can be dangerous in people who have HIV, which already suppresses immune function. Furthermore, there is potential for unintended consequences when altering cytokine activity and other cell-signaling pathways that are not fully understood.
A safer approach involves lifestyle changes to reduce inflammation, including smoking cessation, weight loss, diet modification, exercise, adequate sleep, and stress management.
Over the past few years, researchers have learned a great deal about inflammation and its relationship to HIV. Today, studies routinely collect data about biomarkers and other indicators of inflammation and immune activation, and clinicians are starting to think about how such measures could be applied in real-world patient care.
Inflammation may ultimately prove to be the key that unlocks some of the mysteries of HIV disease. In turn, advances in HIV medicine may contribute to the development of anti-inflammatory approaches that will also benefit people with other diseases.
Liz Highleyman is a freelance medical writer specializing in HIV and hepatitis.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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