Hepatitis B virus and hepatitis C virus dual infection

Hepatitis B virus(HBV)and hepatitis C virus(HCV)share common mode of transmission and both are able to induce a chronic infection.Dual HBV/HCV chronic coinfection is a fairly frequent occurrence,especially in high endemic areas and among individuals at high risk of parenterally transmitted infections.The intracellular interplay between HBV and HCV has not yet been sufficiently clarified,also due to the lack of a proper in vitro cellular model.Longitudinal evaluation of serum HBV DNA and HCV RNA amounts has revealed that complex virological profiles may be present in coinfected patients.Dual HBV/HCV infection has been associated to a severe course of the liver disease and to a high risk of developing hepatocellular carcinoma.Despite the clinical importance,solid evidence and clear guidelines for treatment of this special population are still lacking.This review summarizes the available data on the virological and clinical features as well as the therapeutic options of the dual HBV/HCV infection,and highlights the aspects that need to be better clarified.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Direct antiviral agents in hepatitis C virus related liver disease:Don’t count the chickens before they’re hatched

Since molecules with direct-acting antiviral(DAA)became available,the landscape of the treatment of hepatitis C virus(HCV)infection has completely changed.The new drugs are extremely effective in eradicating infection,and treatment is very well tolerated with a duration of 8-12 wk.This review aims to report the outstanding clinical benefits of DAA and to highlight their critical disadvantages,identifying some clinically relevant hot topics.First,do the rates of virological response remain as high when patients with more advanced cirrhosis are considered?Large studies have shown slightly lower but still satisfactory rates of response in these patients.Nevertheless,modified schedules with an extended treatment duration and use of ribavirin may be necessary.Second,does the treatment of HCV infection affect the risk of occurrence and recurrence of liver cancer?Incidence is reduced after viral eradication but remains high enough to warrant periodic surveillance for an early diagnosis.In contrast,the risk of recurrence seems to be unaffected by viral clearance;however,DAA treatment improves survival because of the reduced risk of progression of liver disease.Third,can HCV treatment also have favorable effects on major comorbidities?HCV eradication is associated with a reduced incidence of diabetes,an improvement in glycemic control and a decreased risk of cardiovascular events;nevertheless,a risk of hypoglycemia during DAA treatment has been reported.Finally,is it safe to treat patients with HCV/hepatitis B virus(HBV)coinfection?In this setting,HCV is usually the main driver of viral activity,while HBV replication is suppressed.Because various studies have described HBV reactivation after HCV clearance,a baseline evaluation for HBV coinfection and a specific follow-up is mandatory.

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings

The global burden of hepatitis B virus(HBV)and hepatitis C virus(HCV)infections and coinfection represents a major public health concern,particularly in resource-limited settings.Elimination of HCV by 2030 has become foreseeable,with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries(LMICs).However,access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices.Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal.Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection,and with improved access to medications,the most significant barrier remains access to affordable diagnostics and preventive strategies.The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs,albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage.This review underpins the HBV and HCV management challenges in resource-limited settings,highlighting the current status and suggested future elimination strategies in some of these countries.Global efforts should continue to improve awareness and political commitment.Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.

Impact of comorbidities on the severity of chronic hepatitis B at presentation

AIM:To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.METHODS:Out of 1366 hepatitis B surface antigen(HBsAg) positive subjects consecutively observed in 79 Italian hospitals,53(4.3%) showed as the only cofactor hepatitis D virus(HDV) infection [hepatitis B virus(HBV)/HDV group],130(9.5%) hepatitis C virus(HCV)(group HBV/HCV),6(0.4%) human immunodeficiencyvirus(HIV)(group HBV/HIV),138(10.2%) alcohol abuse(group HBV/alcohol);109(8.0%) subjects had at least two cofactors and 924 were in the cofactor-free(CF) group.RESULTS:Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis(P < 0.001),those in group HBV/HDV were younger(P < 0.001),more frequently resided in the south of the country and had cirrhosis(P <0.001),those in group HBV/HCV were older(P < 0.001) and more frequently had cirrhosis(P < 0.001).These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients.Multivariate analysis showed that an older age [odds ratio(OR) 1.06,95% CI:1.05-1.08],alcohol abuse with more than 8 drinks daily(OR 2.89,95% CI:1.81-4.62) and anti-HDV positivity(OR 3.48,95% CI:2.16-5.58) are all independently associated with liver cirrhosis.This association was found also for anti-HCV positivity in univariate analysis,but it was no longer associated(OR 1.23,95% CI:0.84-1.80) at multivariate analysis.CONCLUSION:Older age,HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection,while HCV replication plays a lesser role in the severity of hepatic damage.

Theoretical basis of a beneficial role for vitamin D in viral hepatitis

Abnormal bone metabolism and dysfunction of the calcium-parathyroid hormone-vitamin D axis have been reported in patients with viral hepatitis. Some studies suggested a relationship between vitamin D and viral hepatitis. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to the pathology of viral hepatitis (i.e., the major histocompatibility complex class Ⅱ molecules, the vitamin D receptor, cytochrome P 450 , the renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, and the proteins regulated by the Sp1 promoter gene). Vitamin D also exerts its effects on viral hepatitis via non-genomic factors, i.e., matrix metalloproteinase, endothelial vascular growth factor, prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D could have a beneficial role in viral hepatitis. Calcitriol is best used for viral hepatitis because it is the active form of the vitamin D 3 metabolite.

Effect of soy protein supplementation in patients with chronic hepatitis C:A randomized clinical trial

AIM:To evaluate the effects of soy supplementation on insulin resistance,fatty liver and alanine aminotransferase(ALT) levels in non-diabetic patients with chronic hepatitis C(CHC).METHODS:In a prospective,randomized and singleblinded clinical trial,we compared patients with CHC who had casein as a supplement(n = 80)(control group),with patients who consumed a soy supplement diet(n = 80) [intervention group(IG)].Both groups received 32 g/d of protein for 12 wk.RESULTS:Patients' baseline features showed that 48.1% were overweight,43.7% had abdominal fat accumulation,34.7% had hepatic steatosis and 36.3% had an homeostasis model assessment index of insulin resistance(HOMA-IR) ≥ 3.0.Descriptive analysis showed that protein supplementation diet reduced hepatic steatosis in both groups;however,significant reductions in ALT levels occurred in the soy group.Multiple regression modeling indicated that in the presence of severe fibrosis(F3/F4),g glutamyl transferase elevation and high density lipoprotein(HDL) reduction,the intervention group had 75% less chance of developing hepatic steatosis(OR= 0.25;95% CI:0.06-0.82) and 55% less chance of presenting with an ALT level ≥ 1.5 × the upper limit of normal(ULN)(OR = 0.45,95% CI:0.22-0.89).Soy treatment did not have any effect on insulin resistance(OR = 1.92;95% CI:0.80-4.83),which might be attributed to the fact that the HOMAIR values at baseline in most of our patients were in the normal range.Advanced hepatic fibrosis,an ALT level > 1.5 × ULN and visceral fat were predictors of an HOMA-IR ≥ 3.The IG group had a reduced risk of an ALT level > 1.5 × ULN.An HOMA-IR ≥ 3.0 and HDL < 35 mg/dL were also risk factors for increased ALT.CONCLUSION:Soy supplementation decreased ALT levels and thus may improve liver inflammation in hepatitis C virus(HCV) patients;it also reduced hepatic steatosis in a subgroup of patients but did not change insulin resistance.It should be considered in the nutritional care of HCV patients.

NKT cells in liver diseases

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CDld-expressing cells or bystander cells.