International AIDS Society Conference

July 17-20, 2011 - Rome, Italy

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

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


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).


  • 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.


  • 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 Carlos 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.



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 Evans, 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.