key: cord-0798854-jgq62vke
authors: Shirley, Kate; Loftis, Jennifer M.
title: A spotlight on HCV and SARS-CoV-2 co-infection and brain function
date: 2022-05-10
journal: Pharmacol Biochem Behav
DOI: 10.1016/j.pbb.2022.173403
sha: 22b25498f4e5a80de05c204f5212df74f7c32bf0
doc_id: 798854
cord_uid: jgq62vke

nan

Co-infection with pathogenic RNA viruses, including hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), can affect disease severity and clinical outcomes (Devi et al., 2021) . There are limited data on the effects of HCV infection on outcomes in individuals with coronavirus disease 2019 , and no data on outcomes in individuals with long-term symptoms associated with COVID-19 (long COVID syndrome; postacute sequelae of SARS CoV-2 infection [PASC] ). Liver injury has been reported in association with SARS-CoV-2 infection (e.g., Weber et al., 2021) , but evidence is lacking regarding the impact of pre-existing HCV infection on COVID-19 outcomes. Cognitive impairment and neuropsychiatric dysfunction are documented sequelae of both HCV (Adinolfi et al., 2015; Hilsabeck et al., 2002 , Huckans et al., 2009 Yarlott et al., 2017) and long COVID syndrome (Frontera et al., 2021; Graham et al., 2021) , but little is known about the consequences of coinfection on central nervous system (CNS) and related neuropsychiatric outcomes. Since coinfection may alter both treatment and prognosis, attention to the neurological and neuropsychiatric manifestations of HCV and SARS-CoV-2 co-infection is critical in disease surveillance and development of evidence-based strategies that optimize treatment.

show dysregulation during co-infection, which enhances disease severity such as liver fibrosis and hepatocyte inflammation (Roe & Hall, 2008; Zignego et al., 2012) ; the progression of HIV which can be positive or negative (McArdle et al., 2018; Li et al., 2021) . Positive interactions occur when pathogens act synergistically and lead to worsening of disease symptoms, severity, and outcomes (Kehe et al., 2021) . Negative interactions occur when one pathogen hinders the growth of another pathogen through competition, parasitism, or interference (e.g., Hoffman et al., 2006) . Negative interactions can result in short-lived protective effects, as has been observed between influenza A virus (IAV) and rhinoviruses (RV). This is known as viral interference and leads to early clearance of one infection and persistence of the other one (Kumar et al., 2018) . In addition to interactions between co-infecting pathogens, host response also plays a key role in determining the outcome of co-infections. The host response depends on multiple factors, including demographic (e.g., age), psychological (e.g., stress), genetic, environmental, and other factors.

Importantly, for HCV and SARS-CoV-2, the degree and nature of their interactions and the underlying mechanisms remain largely unexplored, although the potential for disease modulating effects of HCV infection on COVID-19 outcomes, including long COVID symptoms, is highlighted by evidence discussed in recent reviews (Devi et al., 2021; da Mata et al., 2021) . For example, one study suggests that among patients with HCV and hepatocellular carcinoma, those with undetectable HCV infection may be at a lower risk of fatality than those with active HCV infection, when diagnosed with SARS-CoV-2 infection (Guler-Margaritis et al., 2021) . In a large, retrospective study of individuals with COVID-19 (n = 1,193), co-infection with HCV added a cumulative increased risk of mortality to clinical and laboratory predictors of J o u r n a l P r e -p r o o f Journal Pre-proof mortality risk, and HCV infection was the only strong predictor of mortality after matching individuals with and without HCV for baseline confounding clinical and laboratory predictors of mortality (Ronderos et al., 2021) . It was concluded that the pathological effects of SARS-CoV-2 infection are worsened in individuals with HCV compared to those without HCV, regardless of age, sex, baseline clinical status (e.g., medical comorbidities [respiratory disease, hypertension]), or admission laboratory parameters (i.e., test results typically associated with greater rates of inhospital mortality). No significant increased risk of contracting COVID-19 has been observed in people with HCV (Kovalic et al., 2020) , although this population is at increased risk of developing severe illness from COVID-19, especially if compounded by other risk factors such as older age, hypertension, and obesity (Ronderos et al., 2021; Xie et al., 2020) . Research suggests that HCV can exacerbate COVID-19-related disease severity and mortality, but the role of co-infecting pathogens and host response on disease pathogenesis remains unclear.

Co-infection can modulate oxidative stress, immune response, and disease severity. with HCV and SARS-CoV-2 co-infection (Ronderos et al., 2021)  Transmembrane protease serine 2 (TMPRSS2) expression. TMPRSS2 can potentiate SARS-CoV-2 viral entry (Hoffmann et al., 2020) .TMPRSS2 is over-expressed in patients with HCV (Esumi et al., 2015) , which may lead to exaggerated SARS-CoV-2 infection in these individuals.

 Circulating immune complexes and immune-mediated cellular toxicity. HCV is a systemic disease associated with extrahepatic morbidity, which can occur independently of liver injury (Gill et al., 2016) . The induction of circulating immune complexes and immune-mediated cellular toxicity that also occurs in SARS-CoV-2 may be related to the potentiated effects on the virus in individuals with HCV.

 Immune response overlap. In chronic HCV infection there are correlations between the production of pro-inflammatory cytokines, such as IFN-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and the degree of liver injury and extrahepatic effects (e.g., depressive symptoms) (Rehermann, 2009; Loftis et al., 2008) . These pro-inflammatory cytokines are also elevated in SARS-CoV-2 and associated with worse clinical outcomes. For example, a recent study showed that higher levels of IFN-γ are associated with elevated mortality in patients with COVID-19 (Gadotti et al., 2020) . These findings and others suggest that baseline inflammatory status in individuals with HCV could be related to the higher morbidity in those patients when contracting COVID-19, as well as the potential for the development of long COVID symptoms.

 Vascular endothelial dysfunction. HCV and SARS-CoV-2 both induce endothelial dysfunction, which causes vascular leakage and immune activation. The integrity of the endothelial function and immune system is important for a regulated immune response in order to help control viral spread (Perico et al., 2021) . Consequently, it is hypothesized that direct endothelial cell infection in individuals with COVID-19 may be exacerbated by the baseline endothelial dysfunction reported to occur in individuals with HCV infection.

19, 51% reported at least one new symptom that did not exist before COVID-19 infection: 31%

fatigue, 21% cognitive symptoms, and 16% new-onset dyspnea (Writing Committee for COMEBAC, 2021)-symptoms likely resulting directly or indirectly from COVID-19's effects on the brain. There appears to be significant overlap in pathological cell states, particularly within astrocytes and microglia, in the brains of individuals with COVID-19 compared to individuals with depression, schizophrenia, cognitive impairment, and other neuropsychiatric disorders (Tang et al., 2021; Vargas et al., 2020; Yang et al., 2021) . However, the effects of coinfection with HCV on the brain are unknown.

Since the introduction of direct acting antiviral (DAA) therapy for HCV, there has been an increase in awareness and treatment rates. Importantly, DAA therapy can improve brain function. A study of 135 patients with HCV who achieved virological response found decreases in the prevalence of cognitive impairment and improvements in health-related quality of life (Ibáñez-Samaniego et al., 2021) . It is yet to be determined how co-infection with SARS-CoV-2 and the development of COVID-19 impact the mental and physical health improvements that accompany HCV clearance. Further, the COVID-19 pandemic has placed a number of challenges on hepatitis programs and interventions (screening, diagnosis, and treatment). One study examined the percent change in DAA therapy units dispensed (from March to August 2019 to the same period of time in 2020) across 54 countries and found significant declines in DAA therapy utilization (p < 0.01) for a number of countries, including the U.S. (Shakeri et al., 2021) .

Another study used microsimulation methods to estimate the 10-year impact of COVID-19 disruptions in healthcare delivery on HCV outcomes including identified infections, linkage to care, treatment initiation and completion, cirrhosis, and liver-related death. Compared to the 'no pandemic' scenario, in the scenario in which there was no return to pre-pandemic levels of HCV J o u r n a l P r e -p r o o f Journal Pre-proof care delivery, it was estimated that there would be 1,060 fewer identified cases, 21 additional cases of cirrhosis, and 16 additional liver-related deaths per 100,000 people. Only 3% of identified cases initiate treatment and <1% achieve sustained virologic response (Barocas et al., 2021) . Thus, a recommitment to the HCV epidemic, which involves additional resources and increased efforts to screen, identify, and treat people with HCV may be needed to overcome the COVID-19-related disruptions.

The clinical consequences of COVID-19 and HCV co-infection require further attention, particularly concerning the impact of co-infection on neurologic and neuropsychiatric function.

Research suggests that HCV can affect the progression of COVID-19, including disease severity and mortality (Devi et al., 2021) , which may be related to extrahepatic effects of HCV leading to enhanced ACE-2/TMPRSS mechanisms of SARS-CoV-2 viral entry, baseline cytokine-mediated pro-inflammation, and endothelial dysfunction/impact on BBB. Further study of these extrahepatic effects will aid in identifying the various neurologic and neuropsychiatric symptoms, long-lasting effects, and appropriate methods of treatment to improve viral clearance and mental health outcomes in individuals with HCV and COVID-19.

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This material is the result of work supported, in part, by the United States Department of