Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection
Xiaoming Cheng, … , Kazuaki Chayama, T. Jake Liang
Xiaoming Cheng, … , Kazuaki Chayama, T. Jake Liang
Published March 12, 2020
Citation Information: J Clin Invest. 2020;130(6):3205-3220. https://doi.org/10.1172/JCI135616.
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Research Article Hepatology Virology

Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection

Abstract

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV–coinfected persons.

Authors

Xiaoming Cheng, Takuro Uchida, Yuchen Xia, Regina Umarova, Chun-Jen Liu, Pei-Jer Chen, Anuj Gaggar, Vithika Suri, Marcus M. Mücke, Johannes Vermehren, Stefan Zeuzem, Yuji Teraoka, Mitsutaka Osawa, Hiroshi Aikata, Keiji Tsuji, Nami Mori, Shuhei Hige, Yoshiyasu Karino, Michio Imamura, Kazuaki Chayama, T. Jake Liang

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Figure 7

Baseline and longitudinal changes of ALT and immune cytokines in coinfected patients undergoing DAA regimen.

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Baseline and longitudinal changes of ALT and immune cytokines in coinfec...
A pilot cohort of 35 coinfected patients were randomly selected for circulating cytokine measurement by multiplex cytokine ELISA. (A) Serum ALT level (upper) and plasma CXCL10 (lower) at indicated times are shown. Sample numbers for CXCL10 measurement are below the x axis. Means ± SEM are shown. Unpaired t test was used. *P < 0.05; **P < 0.01. (B) Dynamic fold-changes of cytokines during the early course of treatment were calculated by comparing to baseline levels. The available sample numbers are given in the upper-left corner of each spider plot. Means are shown. For CXCL10, week 1 P = 0.0007, week 2 P = 0.0036, week 4 P = 0.0012. For CCL5, week 1 P = 0.034. After Bonferroni’s correction for multiple comparisons (5 cytokines), the P values for CXCL10 are still significant (*P < 0.05; **P < 0.01) but not those for CCL5. (C) Performance of ROC curves of CCL5 fold-change (FC-CCL5) (black dotted line; AUC, 0.63; 95% CI, 0.50–0.75), baseline ALT (red dotted line; AUC, 0.68; 95% CI, 0.56–0.80), FC-CXCL10 (green dotted line; AUC = 0.81, 95% CI, 0.71–0.90), baseline ALT × FC-CXCL10 (blue solid line; AUC, 0.81; 95% CI, 0.71–0.90), and combined baseline ALT × FC-CXCL10 with FC-CCL5 (red solid line; AUC, 0.82; 95% CI, 0.73–0.90) for predicting coinfected patients with HBV reactivation. Interactions are denoted by ×. (D) Blood CXCL10 and CCL5 of an independent coinfected-patient cohort were measured. Fold-change of CXCL10 was calculated by comparing the earliest on-treatment level available (10 patients from week 1; 2 patients from week 2; 1 patient from week 3, 4, and 12) to baseline level. Fold-change of CCL5 was calculated by comparing week 1 to baseline level (10 patients have available samples). The final data were grouped based on HBV outcome following the same reactivation criteria. Means ± SEM are shown. Unpaired t test was used. **P < 0.01.