Anti-HDV IgM as a marker of disease activity in hepatitis delta

Abstract

Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.

Methods: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6-12).

Results: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).

Conclusions: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.

Figure 1. Anti-HDV IgM values in the two cohorts.

Grouping into different IgM categories was performed as descripted in materials and methods.

Figure 2. Distribution of ALT values according to Anti-HDV IgM categories in the HIDIT-2 cohort.

ALT values were significantly associated with the different anti-HDV IgM groups based on univariate ANOVA (p = 0.04) and univariate T- test in the HIDIT-2 cohort.

Figure 3. Distribution of ALT values according to Anti-HDV IgM categories in the MHH cohort (only significant p-values).

The association of anti-HDV IgM and ALT was confirmed in the MHH cohort with significance over all groups of 0.03.

Figure 4. Histological grading of the HIDIT-2 cohort.

Diagrammed% of patients with a HAI≥8 within the anti-HDV IgM groups.

Figure 5. Histological staging of the HIDIT-2 cohort.

Diagrammed% of patients with cirrhosis (based on the classification indicated in material and methods) within the anti-HDV IgM groups.

Figure 6. Distribution of HBV values according to Anti-HDV IgM categories in the HIDIT-2 cohort.

HBV-DNA (log) is clearly associated with anti-HDV IgM indicated by ANOVA (p<0.01) and by T-test during the different IgM groups.

Figure 7. Distribution of HBV values according to Anti-HDV IgM categories in the MHH cohort.

HBV-DNA levels were also lower in greater anti-HDV IgM groups in the MHH cohort although no differences could be observed within the anti-HDV IgM groups.

Figure 8. Factors associated with anti-HDV IgM based on univariate ANOVA testing in the HIDIT-2 cohort.

The dashed line indicated a p-value of 0.05. All parameters above the line were determined as significantly associated with the four anti-HDV IgM groups. Dots in blue indicate low levels of the value in greater anti-HDV IgM groups while orange dots represent parameters with high levels in a great anti-HDV IgM group shown at x axis.

Figure 9. Cumulative event free survival of patients with anti-HDV IgM positive and negative values.