Background:  Following the initiation of hepatitis B virus (HBV) -active HAART in HIV/HBV-co-infected individuals, hepatic flare or worsening alanine aminotransferase (ALT) is a major clinical problem. We hypothesized that in this setting, hepatic flare is a form of immune restoration disease (IRD) and is a consequence of enhanced activated T cell recruitment to the liver in the setting of high HBV viral load.

Methods:  TICO is a prospective randomized (1:1:1) trial of tenofovir (TDF) vs lamivudine (LMV) vs TDF/LMV within an efavirenz (EFV) -based HAART regimen initiated in 36 HIV/HBV-co-infected antiretroviral-naïve patients in Thailand. Hepatic flare was defined as an alanine aminotransferase (ALT) >5 X upper limit of normal or >200 IU/mL above baseline, within 12 weeks of HAART initiation. Quantification of immune mediators (interleukin [IL] -18, -2, -6, -8, -10; soluble[s] CD26, sCD30, IP-10, macrophage chemotactic protein [MCP] -1, tumor necrosis factor [TNF] -a, interferon [IFN] -g and -a) in baseline, week 4, 8, and 12 sera was performed by enzyme-linked immunosorbent assay (ELISA), antigen capture bioassay, or cytometric bead array. We compared cases (hepatic flare, n = 8) with controls (n = 28), using either a Kruskal-Wallis with Dunn's multiple comparison post test (non-parametric) or repeated measures ANOVA with post-hoc analysis (parametric) based on the distributions of the log transformed data. In addition, immune mediator levels were correlated with ALT, HBV viral load, HIV viral load, and CD4 count at each time-point (Spearman's test).

Results: Cases had significantly higher HBV viral loads (p = 0.011) and ALT (p = 0.008) than controls prior to initiation of HAART. Following initiation of HAART, IP-10 significantly decreased by weeks 8 and 12 in controls (p <0.05, Kruskal-Wallis), while in cases there was no significant decrease in IP-10 over time. In cases, sCD30 and ALT levels peaked at week 8 (p <0.05, ANOVA) while there was no significant change in controls. Significant positive correlations were found between ALT and IP-10 (p = 0.005, r = 0.46), sCD30 (p = 0.006, r = 0.46), MCP-1 (p = 0.032, r = 0.36), and IL-18 (p = 0.009, r = 0.44) at week 8. There was a significant increase in sCD26 over time in both cases and controls (p <0.05, ANOVA). IL-2,-6, -8, and -10 and TNF-a and IFN-g and -a were not detectable in the majority of case and control sera.

Conclusions: IP-10 (an activated T cell and natural killer cell chemokine) and sCD30 (a T cell activation marker) play an important role in the pathogenesis of hepatic flare following initiation of HBV-active HAART in HIV/HBV-co-infected patients. Also implicated are markers of IFN-g induction (IL-18) and activity (MCP-1). These data support our hypothesis that hepatic flare is a consequence of IRD.