Background and Aim The causes of chronic liver disease (CLD) among adults have changed. Data are lacking on trends among youth. We determined the trends and changes in the global burden of CLD among adolescents and young adults using Global Burden of Disease (GBD) data (2009–2019). Approach and Results The GBD study estimation methods were used to assess CLD prevalence, incidence, and deaths (21 GBD regions). Annual percent change (APC) calculation by joinpoint regression modeling. Age groups were 15–19, 20–24, and 25–29 years old. Globally in 2019, the 15–29 group accounted for 17.2% (0.29 billion) of CLD prevalent cases, 11.2% (n = 232,072) CLD incident cases, and 3.8% (n = 55,515) CLD deaths. Between 2009 and 2019, CLD prevalence rate increased annually among 25–29 (APC = +0.41%, p < 0.001); remained stable among 20–24 (APC = +0.02%, p = 0.582); and decreased among 15–19 (APC = −2.13%, p < 0.001). CLD prevalence increases were driven by the proportion with NAFLD (15–19: 40.8% to 52.9%, p < 0.001); 20–24: 57.6% to 62.7%, p < 0.001); and 25–29: 66.9% to 70.1%, p < 0.001); the proportion with HBV decreased across all age groups. NAFLD prevalence worsening trend (APC ≥ 0%) was global. Overall CLD death rate decreased annually in all age groups, driven by the decrease in the proportion with HBV [aged 15–19 (from 5.90% to 5.20%, p < 0.001); aged 20–24 (from 18.62% to 16.37%, p < 0.001); and aged 25–29 (from 28.69% to 25.28%, p < 0.001)]; from 2015 to 2019, CLD death rate for HCV (APC = +1.46%) and NAFLD (APC = +2.26%) increased. Conclusions Over the past decade, the causes of CLD among 15–29‐year‐olds have shifted: viral hepatitis remains the most common cause of CLD deaths, but the global burden of HBV incidence is decreasing, whereas NAFLD is the main driver for increased CLD incidence.

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8+ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8 + T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT ( -) virus: (1) LAT ( + ) virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT ( + ) virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-a; and (3) DCs infected in vitro with LAT ( + ) virus had significantly reduced the ability to stimulate HSV-specific CD8 + T cells. While a similar number of DCs was found in LAT ( + ) and LAT ( -) latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT ( + ) virus. Consistent with these findings, HSV-specific cytotoxic CD8 + T cells in the TG of mice latently-infected with LAT ( + ) virus produced less IFN-c and TNF-a than those from TG of LAT ( -) infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSVspecific CD8 + T cells in the TG of mice latently infected with LAT ( + ) virus.

Considering the limited success of the recent herpes clinical vaccine trial, new vaccine strategies are needed. Infections with HSV-1 and HSV-2 in the majority of men and women are usually asymptomatic and result in lifelong viral latency in neurons of sensory ganglia. However, in a minority of men and women, spontaneous HSV reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e., those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 and HSV-2 epitopes that induce strong in vitro CD4 and CD8 T-cell responses from peripheral blood mononuclear cells derived from asymptomatic men and women (designated here as ‘asymptomatic’ protective epitopes) could boost local and systemic ‘natural’ protective immunity, induced by natural infection. Here we highlight the rationale and the future of our emerging asymptomatic T-cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease.

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