Inflammation and Immune Activation Linked to Increased Mortality Risk in People with HIV

		SUMMARY: Inflammation and excessive CD8 T-cell immune activation were independent predictors of increased risk of death both in a U.S. study and among HIV patients starting antiretroviral therapy (ART) in Uganda, according to 2 reports presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. While lower CD4 cell count may explain part of the association, inflammation itself was an independent predictor of mortality.

By Liz Highleyman

Researchers showed early in the epidemic that increased immune activation predicted progression of HIV/AIDS and, more recently, a growing body of evidence has accumulated suggesting that inflammation and immune activation contribute to elevated rates of non-AIDS conditions such as cardiovascular disease in people with HIV.

FRAM Study

Phyllis Tien and fellow investigators with the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study looked at the relationship between mortality and blood levels of the inflammation biomarker C-reactive protein (CRP) and the coagulation biomarker fibrinogen among 922 American FRAM participants over 5 years.

Both CRP and fibrinogen are released as part of the inflammatory and clotting cascades that occur with development of atherosclerosis, a build-up of cholesterol, immune cells, scar tissue, and other material in the arteries. When blood flow through the narrowed arteries becomes too restricted, this can cause a heart attack or stroke.

A majority of participants (about 70%) were men, the median age was about 42 years, and 40% were current smokers. About 90% had used ART, about 80% had undetectable viral load, and the average CD4 count was around 350 cells/mm3.

Results

	Participants with the highest tertile (third) of baseline fibrinogen levels were older, more likely to be African-American, had lower HDL "good" cholesterol, and had higher HIV viral loads and lower CD4 counts.
	Higher baseline fibrinogen levels were significantly associated with higher CRP levels.
	After adjusting for HIV status and traditional cardiovascular risk factors, baseline levels of both CRP and fibrinogen were strongly associated with death during follow-up.
	People in the highest tertile of fibrinogen levels had more than 3 times the risk of death as those in the lowest tertile.
	Patients in the highest tertile of CRP levels had nearly 3 times the risk of death as those in the lowest tertile.
	The correlation between biomarkers and mortality was significant at all CD4 cell levels.
	Even among participants with >500 cells/mm3, every additional 100 mg/dL of fibrinogen increased the risk of death by almost 50%, while every doubling of CRP increased mortality risk by 30%.

Based on these findings, the researchers concluded, "Elevated levels of fibrinogen and CRP were strong and independent predictors of 5-year mortality risk. Fibrinogen and CRP remained independently associated with higher odds of death regardless of the degree of immunosuppression."

These findings suggest "an important role for inflammation in mortality beyond demographic, cardiovascular, and HIV-related factors," they continued, and "inflammation remains an important factor even in those with relatively preserved CD4 cells."

Uganda Study

Turning to a resource-limited setting, Peter Hunt from the University of California at San Francisco and colleagues assessed the effect of immune activation among 500 people starting ART in the Uganda AIDS Rural Treatment Outcomes (UARTO) study.

In contrast with FRAM participants, this group had an average age of 34 years, about 70% were women, and the median CD4 count was much lower at 133 cells/mm3. Results were compared with those from an ongoing San Francisco cohort, but the 2 groups were not well matched with regard to either demographics or HIV disease status.

Results

	Overall, Ugandan participants had a higher level of CD8 T-cell activation, as indicated by CD38+HLA-DR+ markers, than the San Francisco cohort.
	CD8 cell activation declined after starting ART, but remained elevated relative to the San Francisco group, even after adjusting for CD4 count.
	Greater immune activation at baseline was associated with slower CD4 cell recovery after starting ART, despite good viral suppression.
	Individuals with greater CD8 T-cell activation before starting treatment had a significantly shorter average duration of survival.

"HIV positive Ugandans have higher CD8 activation levels that HIV positive San Franciscans both before and during suppressive ART," the researchers stated, adding that it was unclear whether the difference could be explained by genetic factors, viral factors, or concurrent infections.

"High pre-therapy CD8 activation predicts poor CD4 recovery during suppressive ART in HIV positive Ugandans," they continued, demonstrating that immune activation is "an important determinant of CD4 recovery even in resource-limited settings with prevalent coinfections."

Finally, they concluded, "Persistently high CD8 activation during ART-mediated viral suppression predicts earlier mortality, independent of CD4 count."

Related Research

In 2 other studies presented at the conference, researchers also reported links between inflammation or immune activation and mortality. Investigators with the INSIGHT collaboration found that participants in the FIRST study who had elevated baseline levels of CRP and the fibrosis biomarker hyaluronic acid were more likely to progress to AIDS, develop immune reconstitution inflammatory syndrome, or die within the first month after starting ART.

In the large SMART treatment interruption trial, elevated levels of the pro-inflammatory cytokine interleukin 6 (IL-6) and the coagulation biomarker D-dimer predicted a higher risk of non-AIDS death among HIV/HCV coinfected patients with impaired liver function, as indicated by elevated hyaluronic acid.

Taken together, these findings add to the evidence that inflammation and excess immune activation increase the risk of adverse outcomes among people with HIV despite suppressive ART, underlining the need for anti-inflammatory therapies.

FRAM Study: University of California, San Francisco, CA; San Francisco Veterans Affairs Medical Center, San Francisco, CA; Stanford University, Stanford, CA; University of California, San Diego, CA.

Uganda Study: Univ of California, San Francisco, CA; Joint Clinical Research Center, Kampala, Uganda; Massachusetts General Hosp, Harvard University, Boston, MA; Mbarara Univ of Sci and Tech, Uganda; California Dept of Public Health, Richmond, CA.

3/16/10

References

P Tien, A Choi, A Zolopa, and others. Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 725.

P Hunt, J Martin, I Ssewanyana, and others. Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating ART. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 306).