Coinfection

IDWeek 2013: Liver Fibrosis Linked to Immune Activation in HIV/HCV Coinfected Women

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CD4 and CD8 T-cell activation were found to be associated with biomarkers of liver fibrosis among HIV/HCV coinfected women, suggesting that immune activation related to persistent HIV infection may play a role in liver disease progression, researchers reported at the Second IDWeek conference this week in San Francisco.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to serious liver disease including advanced fibrosis, cirrhosis, or hepatocellular carcinoma. Liver disease is now a leading cause of death among people with HIV. Research has shown that HIV/HCV coinfected individuals experience more rapid liver disease progression and do not respond as well to interferon as people with HCV alone, but the reasons for this are not fully understood.

Eva Operskalski and Andrea Kovacs from the University of Southern California in Los Angeles and colleagues conducted a study looking at associations between HIV and hepatitis C status, liver fibrosis biomarkers, and immune activation. 

Lower CD4 counts have been associated with worse liver fibrosis in coinfected people, and some studies have shown that markers of macrophage activation -- including soluble CD14 (sCD14) and interleukin 6 (IL-6) -- are related to liver disease, the researchers noted as background. However, the impact of HIV-associated T-cell activation on liver disease in coinfected people remains unclear.

This study looked at participants in the Women’s Interagency HIV Study (WIHS), a prospective multicenter cohort of women living with and at risk for HIV in the U.S. The full cohort includes nearly 3000 HIV positive and nearly 1000 at-risk HIV negative women in 6 cities.

This retrospective analysis included 351 HIV/HCV coinfected and 269 HIV monoinfected women followed from 1994 to 2002. People who also had hepatitis B were excluded.

About 60% were African-American, about 24% were Hispanic, and about 15% were white. The coinfected women were significantly older than the HIV monoinfected group (27% vs 60% under age 35; 17% vs 7% age 45 or older). Coinfected women were much more likely to have a history of injection drug use (60% former, 27% current) than the monoinfected women (1% for each) and they were more likely to report moderate or heavy alcohol consumption.

Looking at HIV status, in both groups approximately 20% had CD4 counts <200 cells/mm3, half had 20-500 cells/mm3, and nearly one-third had >500 cells/mm3 at baseline. Given the time period, few women were on effective antiretroviral therapy (ART) at study entry. Over the course of follow-up 40% of coinfected women and 75% of monoinfected women started potent combination regimens classified as "HAART."

The researchers measured T-cell activation markers and liver fibrosis markers at semi-annual study visits, with a median of 2 visits per woman. They looked at percentages of CD4 and CD8 T-cells expressing a pair of cell-surface markers, CD38 and HLA-DR, which indicate cell activation. Absence of these markers indicates resting cells.

To assess fibrosis, they used 2 non-invasive biomarker indices, APRI (aspartate aminotransferase/platelet ratio index) and FIB-4 (incorporating age, aspartate and alanine aminotransferase, and platelet count). For each index, women were divided into 3 categories of fibrosis severity (APRI: <0.5 normal or no significant fibrosis; 0.5-1.5 moderate fibrosis; >1.5 significant fibrosis).

Although a majority of women in both groups had no significant fibrosis according to APRI, coinfected women, as expected, were more likely to have advanced fibrosis. More than 80% of all tests showing moderate fibrosis and more than 90% showing significant fibrosis were from coinfected participants.

Results

  • For both HIV/HCV coinfected and HIV monoinfected women, higher plasma HIV RNA and lower CD4 count were significantly associated with worse liver fibrosis according to APRI scores; use of ART, however, did not have a significant effect.
  • Older age and higher baseline HCV RNA were also significant predictors for the coinfected group.
  • Among coinfected women, having a higher percentage of activated CD4 cells -- but not activated CD8 cells -- was significantly associated with higher APRI scores after adjusting for demographic variables and HIV and HCV viral load.
  • Conversely, having more resting CD4 and CD8 cells predicted less fibrosis.
  • In contrast, among HIV monoinfected women, links between CD4 or CD8 activation and APRI scores did not reach statistical significance.
  • Similar patterns were observed for FIB-4 scores.

"CD4 activation is associated with markers of liver fibrosis in HIV/HCV co-infected women, independent of HIV RNA level," the researchers concluded.

Based on these findings, they suggested that "T-cell activation may play a role in the pathogenesis of liver fibrosis," and recommended that "targeted treatments to reduce T-cell activation should be evaluated to reduce incidence of liver fibrosis in HIV/HCV coinfected patients."

A limitation of this study is that most participants were either not on ART or were taking less effective and more toxic older antiretroviral regimens, so further study is needed on the effects of long-term immune activation on liver disease and liver-related mortality in the modern ART era.

This analysis also did not look at hepatitis C treatment. Sustained virological response to interferon-based therapy has been shown to slow or halt fibrosis progression and reduce liver-related mortality, and the benefits are likely to be even greater with more effective direct-acting antiviral agents. 

10/4/13

Reference

E Operskalski, R Karim, S Christensen, A Kovacs, et al. Association of T cell activation with a non-invasive marker of liver fibrosis in HIV-infected women with and without hepatitis C co-infection. 2nd ID Week Conference (IDWeek 2013). San Francisco. October 2-6, 2013. Abstract 74.