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Treatmentupdate 223 Vol TreatmentUpdate 223 Vol. 29, No. 5 · December 2017 Available online at www.catie.ca/en/treatmentupdate Contents G. Canakinumab’s anti-cancer potential 10 I INFLAMMATION AND HIV H. Issues to consider with canakinumab 12 A. Exploring HIV and inflammation 2 I. Canakinumab in HIV reduces B. Inflammation in arteries vs. inflammation 13 lymph nodes 5 J. The potential of Ixolaris 15 C. Pitavastatin found to reduce levels of bad cholesterol and inflammation 6 K. Clinical trials in Canada to explore reducing inflammation in HIV 16 D. Inflammation-related illness among HIV-positive people 7 L. suPAR—an early warning signal 16 E. Why is there renewed interest in the antibody canakinumab? 8 F. Canakinumab—effect on reducing inflammation and heart attacks in the Cantos study 9 produced by 555 Richmond Street West, Suite 505 Box 1104 Toronto, Ontario M5V 3B1 Canada phone: 416.203.7122 toll-free: 1.800.263.1638 fax: 416.203.8284 www.catie.ca charitable registration number: 13225 8740 RR Page 2 TreatmentUpdate 223 — Vol. 29 No. 5 __________________________________________________________ I INFLAMMATION AND HIV Why is persistent immune activation and inflammation important? A. Exploring HIV and inflammation The activation of the immune system and inflammation are important responses used by Chronic HIV infection is associated with relatively the immune system to help control infections and high levels of inflammation and a growing body tumours. However, researchers are concerned that of evidence suggests that inflammation may prolonged immune activation and inflammation increase the risk for a range of health problems. could slowly degrade vital organ-systems in the body. Before delving into potential approaches to reduce Research suggests that persistent inflammation inflammation, it is important to understand why (and likely immune activation) probably plays inflammation occurs and persists. some role in the following conditions: • cardiovascular disease What usually happens with a • degenerative conditions of the brain (such as viral infection Alzheimer’s and Parkinson’s diseases) • type 2 diabetes In the case of ordinary viral infections, such as a • inflammatory diseases of the digestive tract cold or flu, cells of the immune system capture the (such as Crohn’s disease) invading virus and take it to nearby lymph nodes. • arthritis Inside the lymph nodes, which house many other • psoriasis cells of the immune system, the captured germ is presented or shown to cells as something that they It is also possible that persistent chronic immune need to recognize and attack. B-cells and T-cells in activation and inflammation could gradually the lymph nodes that have been educated about weaken and age the immune system. Therefore, the virus become activated and release chemical research teams in North America and Western signals (cytokines) that cause inflammation and Europe are studying the issue of HIV-related help mobilize the immune system. B-cells produce inflammation and immune activation and antibodies, and T-cells can attack the virus directly conducting clinical trials to try to dampen it. as well as virus-infected cells. Both activated B- and T-cells are stimulated to clone themselves and are sent from lymph nodes to the rest of the body to Why do persistent immune activation fight the infection. Eventually the tide turns against and inflammation occur in chronic the infection and virus-infected cells decrease. Once HIV infection? the infection has been vanquished, cells of the immune system release further chemical signals There are at least several possible explanations for that dampen inflammation and activation. this, including the following: HIV in the lymph nodes HIV and inflammation When taken as prescribed and directed, ART can In the case of HIV, the virus becomes a chronic drive down the production of HIV in the blood infection in people. In the early stages of infection, to very low levels (these low levels are commonly the activation of the immune system and its called “undetectable”). However, despite good attendant inflammation do not seem to control adherence to ART, some researchers have found this virus. Initiating HIV therapy (ART) greatly that HIV can still be infecting cells of the immune helps to lower levels of the virus and immune system in the lymph nodes and lymphatic tissues. activation and inflammation. However, the overall This occurs because ART does not penetrate levels of immune activation and inflammation are the lymph nodes and lymphatic tissues in high higher in ART users than in HIV-negative people. concentrations as it does in the blood. Unfriendly bacteria in the intestines There are many lymph nodes and small collections of lymphatic tissue around the intestines. HIV accumulates in those tissues because many cells of the immune system are there. As HIV attacks cells Page 2 TreatmentUpdate 223 — Vol. 29 No. 5 __________________________________________________________ __________________________________________________________ TreatmentUpdate 223 — Vol. 29 No. 5 Page 3 in those tissues, this causes inflammation, which AIDS-like condition over a period of months or also affects the intestines, weakening the barrier in years, depending on the virulence of the strain of the gut. This inflammation also likely plays a role in SIV used. the malabsorption that is a feature of untreated HIV infection. Due to HIV infection, certain bacteria These experiments have revealed that within 24 that are naturally present in the intestine in small hours of infection with SIV, the virus has spread proportions can grow as the balance of bacteria is relatively far, hitching a ride on infected cells of altered. These bacteria produce proteins that can the immune system and reaching the bone marrow incite and prolong inflammation. These proteins and spleen, major organs of the immune system. can cross a weakened gut barrier and become absorbed into the blood and spread throughout Researchers have found that within 72 hours after the body. The scientific term for the passage of high genital infection, SIV has spread even further in the levels of bacterial proteins across the gut to the body—to the thymus gland (another organ of the blood is called bacterial translocation. Researchers immune system), tonsils, and cells of the immune have found that over time ART can greatly reduce system that reside in the liver, lungs and brain. the passage of these bacteria across the gut to the blood. However, ART does not decrease the level Not only did SIV spread very quickly after of these bacterial proteins to very low levels seen initial exposure, in the same monkeys used in in healthy, HIV-negative people. the experiments above, it also quickly triggered activation and inflammation of the immune system. CMV co-infection There is a growing body of research suggesting that That SIV, a virus closely related to HIV, caused co-infection with the common sexually transmitted inflammation and activation of the immune cytomegalovirus (CMV, a member of the herpes system so early in the course of infection suggests family of viruses) plays a role in the aging of the that these are consequences that may be difficult to immune system and persistent immune activation fully suppress, as they appear to be key features of and inflammation. Researchers have conducted a viral infection with SIV and HIV. clinical trial with the anti-CMV drug valganciclovir (Valgan) in HIV-positive people who were taking ART. Valganciclovir did reduce inflammation What hasn’t worked but it was toxic to the bone marrow. A newer, These findings with SIV and HIV have stimulated safer anti-CMV drug, letermovir (Prevymis), has researchers to explore avenues that could be used been approved in the U.S. and will hopefully be to reduce immune activation and inflammation approved in Canada in the future. Lab experiments that persists despite the use of ART. Initial steps with CMV-infected cells suggest that letermovir to try to reduce HIV-related inflammation and has potential to reduce immune activation and immune activation have involved the use of inflammation. Researchers in the U.S. hope to test simple anti-inflammatory drugs. However, well- letermovir’s impact on immune activation and designed studies have found that these drugs do inflammation in HIV-positive people who are co- not significantly address the issue of inflammation. infected with CMV. These drugs have included the following: Aspirin (this drug is still useful for reducing Timing is everything • the risk of excessive blood clots) It is difficult to study the immunological events • sevelamer (Renagel) that occur very early (in the first 24 hours after • mesalamine (Mesasal) infection) in the course of HIV infection, as most people are not yet aware of their infection at that The antibiotic rifaximin (Zaxine) is a very poorly point because symptoms do not immediately absorbed drug. This property makes it useful for appear and, when they do, they can resemble treating infections of the intestine, as the antibiotic those of a cold or flu. To overcome this, researchers concentrates in that organ. In an attempt to reduce conducted experiments with monkeys susceptible the inflammation associated with bacteria in the to a virus called SIV (simian immunodeficiency gut in HIV-positive people, researchers conducted virus), which is closely related to HIV. Monkeys a clinical trial of this drug. Unfortunately, rifaximin that are susceptible to SIV eventually develop an did not significantly reduce levels of immune Page 4 TreatmentUpdate 223 — Vol. 29 No. 5 __________________________________________________________ activation and inflammation. However, clinical • engaging in doctor-approved exercise on a trials of friendly bacteria (probiotics) are planned regular basis (this can be something as simple or underway to see if this can help. as walking briskly) • getting advice from a registered dietitian about making helpful changes to the diet, New approaches—The Reprieve study such as eating more colourful fruits and Statins are a group of medicines used to help vegetables; using whole grains (rich in fibre) normalize cholesterol levels in the blood.
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