Inflammation Markers Linked to Liver Disease, Death in HIV/HBV and HIV/HCV Coinfection

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International AIDS Society Conference

July 17-20, 2011 - Rome, Italy

IAS 2011: Inflammation Markers Linked to Liver Disease, Death in HIV/HBV and

HIV/HCV Coinfection

Details Category: IAS 2011 Published on Friday, 05 August 2011 00:00 Written by

Liz Highleyman

Various blood biomarkers associated with immune activation and inflammation

predicted liver flares, fibrosis progression, and death among HIV positive

people coinfected with hepatitis B or C, according to 2 studies presented last

month at the 6th International AIDS Society Conference on HIV Pathogenesis,

Treatment and Prevention (IAS 2011) in Rome.

It is estimated that approximately one-third of people with HIV also have

hepatitis B virus (HBV) or hepatitis C virus (HCV). Several studies have shown

that HIV/HBV and HIV/HCV coinfected individuals experience more rapid liver

disease progression, have higher mortality, and respond less well to

interferon-based therapy than people with viral hepatitis alone, but the reasons

for this are not fully understood.

Liver Flares

Irini Sereti from the U.S. National Institutes of Health and an international

team of colleagues retrospectively measured various biomarkers in blood samples

from participants in a large clinical trial conducted by CPCRA (Community

Program For Clinical Research on AIDS) and analyzed their correlation with liver

flares with 4 months of starting antiretroviral therapy (ART) and death with 4

years of starting treatment.

Liver flares, or sudden liver enzyme elevations, frequently occur among

coinfected people starting ART, the researchers noted as background. Knowing

more about predictors of liver flares and death may guide monitoring and

elucidate pathogenic mechanisms, they added.

The analysis included 333 participants (out of a study population of 1397) who

initiated ART in the CPCRA FIRST trial: 253 with HIV/HCV, 70 with HIV/HBV, and

10 with all 3 viruses. Most (about 80%) were men, about 60% were black, the

median age was 41 years, and half had a history of injection drug use. The

median CD4 T-cell count was quite low at 150 cells/mm3 and 43% had an AIDS

diagnosis.

A liver flare was defined as alanine aminotransferase (ALT) > 100 IU/mL at month

1 or 4 and an ALT increase > 50 IU/mL from pre-ART level. Measured biomarkers

included C-reactive protein (CRP); pro- and anti-inflammatory cytokines and

chemokines (chemical messengers produced by immune cells) including interleukin

7 (IL-7), IL-10, and IL-13; the coagulation marker D-dimer; and the fibrosis

marker hyaluronic acid (HA).

Results

The researchers found evidence of 53 liver flares: 22 at 1 month after starting

ART;

38 at 4 months;

7 at both time points.

52 people died (7 who died also had flares).

The overall mortality rate was 15.6%, significantly higher than that of

non-coinfected people in the study population (9.4%).

Women, older patients, and people with prior AIDS were more likely to die.

The most common causes of death were bacterial infections (15 deaths) and AIDS

(10 deaths), with just 4 deaths due to liver failure.

Baseline ALT levels were higher among people who experienced flares.

People with HBV were significantly more likely to experience flares than those

with HCV (24.3% vs 12.3%), and the rate was highest among those with detectable

HBV DNA viral load.

Liver flares were not, however, associated with a higher risk of death.

In a multivariate analysis, higher levels of HA (adjusted odds ratio [aOR]

2.01), IL-10 (aOR 1.71), and IL-13 (aOR 1.66) were significantly higher among

people who experienced liver flares.

Levels of IL-6 (aOR 2.15), IL-8 (aOR 1.69), D-dimer (aOR 1.57), and TNF-alfa

(aOR 1.45) were significantly higher among people who died compared with

survivors.

Additional markers were also significant predictors of death when looking at

people with HBV and HCV separately.

The researchers concluded that liver flares are common among coinfected

individuals, " mostly driven by HBV. " High HBV viral load and elevated IL-10 and

IL-13 were associated with flares, which Sereti suggested was likely due to

immune restoration.

" Biomarkers of inflammation, fibrosis, and coagulation pre-ART are associated

with mortality in this patient population, " they continued, adding that

measuring these markers before starting treatment could help determine which

patients could benefit from more intensive monitoring.

Microbial Translocation

In the second study, investigators with the Women’s Interagency HIV Study (WIHS)

looked at how gut microbial translocation -- leakage of bacteria due to

HIV-related damage to the intestinal lining -- and its inflammatory consequences

contribute to liver disease progression.

The analysis included 44 HIV/HCV coinfected women. The median age was about 40

years and the median CD4 count was relatively high, just over 400 cells/mm3.

Liver disease non-progression was defined as no change in liver biopsy or

fibrosis markers between 2 time points a median of 5 years apart; 21 were

progressors and 23 were non-progressors.

The researchers measured biomarkers of microbial translocation including

bacterial lipopolysaccharide (LPS) and endotoxin, as well as macrophage

activation and pro- and anti-inflammatory cytokines.

Results

LPS, endotoxin, IL-10, and TNF-alfa levels did not differ in quantity or slope

(rate of change) over time between progressors and non-progressors.

However, levels of the indirect markers IL-6 (inflammation) and sCD14

(macrophage activation) were significantly higher among progressors, and the

IL-6 slope was greater.

Based on these findings, the researchers concluded, " Markers of macrophage

activation and inflammation were higher in HIV/HCV coinfected women during

periods when liver disease progression occurred, however LPS did not differ

between progressors and non-progressors. "

Taken together, these findings support other recent research indicating that

several non-AIDS conditions seen more frequently in people with HIV are related

to persistent immune activation and inflammation, even when HIV viral load is

suppressed on ART.

Investigator affiliations:

Abstract WELBX01: INSIGHT; NIH/NIAID/LPD, Bethesda, MD; University of Minnesota,

Minneapolis, MN; SAIC Frederick, National Cancer Institute, Frederick, MD;

University of Western Australia, Perth, Australia; Chulalongkorn University,

Bangkok, Thailand; Hospital La Paz, Madrd, Spain; MRC Clinical Trials Unit,

London, UK; Hospital III, Madrd, Spain; The Alfred Hospital, Melbourne,

Australia; Monash University, Melbourne, Australia.

Abstract TUPE102: CORE Center/Stroger (Cook County) Hospital, Rush University

Medical Center,Northwestern University Feinberg School of Medicine, Chicago IL;

University of California, San Francisco, CA.

8/5/11

References

B Andrade, K Huppler Hullsiek, D Boulware, et al. Biomarkers of inflammation,

coagulation and liver fibrosis are associated with hepatic flares and death in

HIV hepatitis co-infected persons. 6th International AIDS Society Conference on

HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011.

Abstract WELBX01.

A French, D Agniel, C , et al (Women’s Interagency HIV Study). Microbial

Translocation and Hepatitis C Disease Progression among HIV-infected Women. 6th

International AIDS Society Conference on HIV Pathogenesis, Treatment and

Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract TUPE102.