Wednesday 29 June, 2016 13.00 EDT
20 August 2014
CMV co-infection linked to increased risk of heart and stroke problems
As mentioned in our previous CATIE News story, cytomegalovirus (CMV) is a member of the herpes family of viruses. CMV infection is relatively common among adults. For most people, CMV does not cause serious obvious disease. However, among people who have weakened immune systems—such as people who have untreated HIV infection or who use transplant medicines—CMV can cause serious complications.
In the time before potent combination anti-HIV therapy (commonly called ART or HAART), CMV infection of the light-sensitive portion of the eye (the retina) was a deeply feared AIDS-related complication, as it could lead to blindness.
However, in Canada and other high-income countries today, researchers have found that infectious complications from CMV among HIV-positive people taking ART are very rare. ART can greatly reduce production of HIV and allow the immune system to recover sufficiently such that serious AIDS-related infections become uncommon and survival can approach that seen in HIV-negative people.
Other effects from CMV
Observational studies of HIV-negative people suggest that CMV probably plays a role in accelerating the pace of cardiovascular disease. Some research also suggests that CMV can prematurely age the immune system.
Researchers in Rome have been monitoring the health of thousands of HIV-positive people living in Italy through a database called ICONA. The latest analysis from this database focused on HIV-positive people who were co-infected with CMV. The Italian researchers found that participants who had CMV co-infection were at heightened risk for developing severe complications that were not related to AIDS. In some cases, these complications led to death. CMV co-infection was particularly associated with an increased risk for complications from cardiovascular disease, including heart attack and stroke.
The ICONA database has been collecting health-related information from HIV-positive people since April 1997. Presently it holds data collected from more than 10,000 people across Italy.
Researchers analysed information collected up to October 2012 from participants with the following features when they entered the study:
- had antibodies to CMV
- were free from infectious complications arising from CMV (these can affect the eye, lungs, brain and gastrointestinal tract)
- did not have a heart attack or stroke or other major cardiovascular disease complications unrelated to AIDS
Researchers were able to analyse data from 6,111 HIV-positive participants—5,119 were co-infected with CMV and 992 were not.
The average profile of participants was as follows:
- age – between 32 and 42 years
- gender – 71% men and 29% women
- co-infected with hepatitis C virus – 34%
- co-infected with hepatitis B virus – 5%
- history of AIDS – 11%
- taking ART – 12%
- CD4+ count – 443 cells/mm3
- CD4/CD8 ratio – 0.46
- HIV viral load – 5,500 copies
Participants were monitored for between two and 10 years.
Over the course of the study, the following occurred:
- 413 people developed AIDS-related infections and/or cancers
- 77 people died from complications related to AIDS
Common AIDS-related infections included the following:
- severe yeast infections of the mouth and throat
- Pneumocystis jirovecii pneumonia (this pneumonia was originally called PCP [Pneumocystis carinii pneumonia] and was renamed after genetic analysis revealed that this germ needed to be reclassified; pneumonia caused by PJP is sometimes called Pneumocystis pneumonia)
- tuberculosis (TB)
- Kaposi’s sarcoma (KS)
There was no significant difference in the distribution of AIDS-related events or deaths between people who were co-infected with CMV and those who were not co-infected.
Results—Serious outcomes unrelated to AIDS
Over the course of the study, the following occurred:
- 326 people developed serious complications unrelated to AIDS
- 12 people died from complications unrelated to AIDS
Researchers estimated that over a decade the proportion of participants who would develop either of the above outcomes was distributed as follows:
- HIV positive and CMV negative – 6%
- HIV positive and CMV positive – 9%
This difference was statistically significant; that is, not likely due to chance alone.
Overall, CMV co-infection was associated with about a 50% increased risk for developing serious complications and dying from causes unrelated to AIDS.
Ruling out other factors
When researchers took into account other potential factors that could have had an impact on the study, such as the use of ART, HIV viral load, smoking tobacco and CD4+ cell counts, being CMV positive was still a significant factor for serious outcomes.
Further analyses took into account co-infection with hepatitis-causing viruses. In these analyses, participants with CMV who did not have hepatitis B or C viruses also had a significantly increased risk for serious illness and death unrelated to AIDS. Specifically in participants who were not co-infected with hepatitis-causing viruses, being CMV positive was associated with a two-fold increased risk for serious outcomes unrelated to AIDS.
Below are some of the severe illnesses and complications that people co-infected with HIV and CMV developed.
Cardiovascular, cardio-pulmonary and cerebrovascular complications:
- heart attack, heart failure, weakened and swollen hearts
- elevated blood pressure affecting the arteries of the lungs
- build-up of fluid in the lungs
- injured blood vessels
- Hodgkin’s lymphoma
- lung cancer
- head and neck cancer
- bladder cancer
Neurologic conditions unrelated to cardiovascular disease also occurred, including the following:
- injured nerves in the hands and feet (peripheral neuropathy)
What is new about this research?
Although another study with HIV-positive participants has found a link between CMV infection and increased risk for cardiovascular disease (as assessed by lab tests), the Italian study is the first to link CMV co-infection in HIV-positive people to clinical outcomes—illness and death—that are not related to AIDS.
Bear in mind that researchers are not certain exactly how CMV infection might cause cardiovascular complications, but several theories exist, some featuring CMV-related inflammation.
Advice from researchers
The study team encourages doctors and nurses caring for HIV-positive people to engage in close monitoring of their patients who are also CMV positive. In this way, they hope that serious complications associated with cardiovascular disease and related deaths can be prevented. The researchers also advise that healthcare professionals help their patients to reduce their overall risk for cardiovascular disease.
The findings from the ICONA study should be confirmed in other large data sets. It adds to the growing body of evidence that CMV may play a role in the health of HIV-positive people. As a result of the ICONA and other studies, there is growing interest in finding new, safer treatments for CMV. Our next CATIE News story explores current and emerging therapies for CMV infection.
HIV and cardiovascular disease – CATIE fact sheet
—Sean R. Hosein
- Lichtner M, Cicconi P, Vita S, et al. CMV co-infection is associated with increased risk of severe non-AIDS events in a large cohort of HIV-infected patients. Journal of Infectious Diseases. 2014; in press.
- Emery VC. Re-stimulating interest in cytomegalovirus as a cofactor for HIV infection. Journal of Infectious Diseases. 2014; in press.
- Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS Reviews. 2012 Jul-Sep;14(3):159-67.
- Barrett L, Stapleton SN, Fudge NJ and Grant M. Immune resilience in HIV-infected individuals seronegative for cytomegalovirus. AIDS. 2014; in press.
- Barrett L, Walmsley S. CMV retinopathy in the antiretroviral therapy era: prevention, diagnosis, and management. Current Infectious Diseases Reports. 2012 Aug;14(4):435-44.
- Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS. 2006 Nov 28;20(18):2275-83.
- Savva GM, Pachnio A, Kaul B, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell. 2013 Jun;12(3):381-7.
- Terrazzini N, Bajwa M, Vita S, et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. Journal of Infectious Diseases. 2014 May 1;209(9):1382-92.
- Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus infection and risk of Alzheimer’s disease in older blacks and whites. Journal of Infectious Diseases. 2014; in press.
- Potena L, Holweg CT, Chin C, et al. Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection. Transplantation. 2006 Aug 15;82(3):398-405.
- Wall NA, Chue CD, Edwards NC, et al. Cytomegalovirus seropositivity is associated with increased arterial stiffness in patients with chronic kidney disease. PLoS One. 2013;8(2):e55686.
- Gkrania-Klotsas E, Langenberg C, Sharp SJ, et al. Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population-based European prospective investigation of Cancer-Norfolk cohort. Clinical Infectious Diseases. 2013 May;56(10):1421-7.
- Sacre K, Hunt PW, Hsue PY, et al. A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis. AIDS. 2012 Apr 24;26(7):805-14.
- Haarala A, Kähönen M, Lehtimäki T, et al. Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study. Clinical & Experimental Immunology. 2012 Feb;167(2):309-16.
- Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathogens. 2014 May 15;10(5):e1004078.
- Appay V, Fastenackels S, Katlama C, et al. Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS. 2011 Sep 24;25(15):1813-22.