CD4 and CD8 cell
activation were found to be associated with biomarkers of liver fibrosis among
HIV/HCV co-infected women, suggesting that immune activation related to
persistent HIV infection may play a role in liver disease progression,
researchers reported yesterday at the IDWeek 2013 conference in San
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 co-infected 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.
Andrea Kovacs from
the Keck School of Medicine in Los Angeles presented findings from an analysis
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 co-infected 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 co-infected people remains
This study looked at participants in the Women’s
Interagency HIV Study (WIHS), a prospective multicentre cohort of women living
with and at risk for HIV in the US. The full cohort includes nearly 3000
HIV-positive and nearly 1000 at-risk HIV-negative women in six cities.
This retrospective analysis included 351 HIV/HCV
co-infected and 269 HIV mono-infected women followed from 1994 to 2002. People
who also had hepatitis B were excluded.
About 60% of the participants were African-American, about 24% were
Hispanic and about 15% were white. The co-infected women were significantly
older than the HIV mono-infected group (27 vs 60% under age 35; 17 vs 7% age
45 or older). Co-infected women were much more likely to have a history of
injecting drug use (60% former, 27% current) than the mono-infected women (1%
for each) and were more likely to report moderate or heavy alcohol consumption.
Looking at HIV status, in both groups approximately
20% had CD4 counts under 200 cells/mm3, half had 200 to 500 cells/mm3
and nearly one-third had CD4 cell counts higher than 500 cells/mm3 at baseline. Given
the time period, few women were on effective antiretroviral therapy (ART) at
study entry. Over the course of the study, 40% of co-infected women and 75% of
mono-infected 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 two visits
per woman. They looked at percentages of CD4 and CD8 cells expressing two
cell-surface markers, CD38 and HLA-DR, which indicate cell activation. Absence
of these markers indicates resting cells.
To assess fibrosis, they used two 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 three 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, co-infected 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
For both HIV/HCV co-infected and HIV mono-infected
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 co-infected group.
Amongst co-infected 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, amongst HIV mono-infected women, links
between CD4 or CD8 activation and APRI scores did not reach statistical
significance. Similar patterns were seen 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 co-infected 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 effect of long-term
immune activation on liver disease and liver-related mortality in the modern
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