Extrahepatic Manifestations Of Hepatitis C Virus Research Articles

Коморбидные состояния как внепеченочные проявления хронической HCV-инфекции

Chronic hepatitis C virus (HCV) infection is a serious public health problem. In 2022, more than 33.8 thousand cases of chronic hepatitis C virus (HCV) were registered in the Russian Federation, with a total economic burden of RUB 60.9 billion. In addition to liver damage, a significant number of patients with CHC have various comorbid conditions, the development of which may be due to extrahepatic replication of HCV. In clinical practice, it is difficult to prove the association of comorbid pathology with extrahepatic manifestations of HCV. This literature review presents the results of meta-analyses and systematic studies that demonstrate the development of extrahepatic manifestations in chronic HCV infection. The data on cardiovascular and endocrine system damage, development of mixed cryoglobulinemia, neurological disorders are discussed. The analysis of scientific studies on the influence of HCV therapy with direct antiviral drugs on the course of comorbid pathology is carried out, personalized approaches to antiviral therapy for HCV patients with comorbid pathology and the prospects of clinical research to study this problem are substantiated. Key words: chronic HCV infection, chronic hepatitis C, extrahepatic manifestations, comorbid conditions, direct antiviral drugs

Liver Transplantation Using Hepatitis C Virus-Viremic Donors Into Hepatitis C Virus-Aviremic Recipients as Standard of Care.

Liver transplantation (LT) using allografts from hepatitis C virus (HCV)‐viremic/nucleic acid testing–positive donors’ (DNAT+) organs into HCV‐aviremic recipients (rHCV−) has been limited owing to nearly universal HCV transmission and concerns regarding availability, safety, and efficacy post‐LT with direct‐acting antiviral (DAA) therapy. We report our experience of LT using DNAT+ organs into rHCV− as a routine standard of care. Following verification of DAA access, absence of critical drug‐drug interactions (DDIs) with DAAs, and informed consent, allocated DNAT+ organs were offered to patients on the waiting list for LT irrespective of recipient HCV status. Between June 2018 and December 2019, 292/339 rHCV− received an LT. Forty‐seven patients were excluded from analysis because of recipient HCV viremia, refusal to receive DNAT+ organs, or inability to receive DAA therapy post‐LT. Of these 292 patients, 61 rHCV− received DNAT+ livers (study group), and 231 rHCV− received DNAT− (aviremic donors [nuclear acid test‐negative donors]) livers (control group). Recipient and donor characteristics as well as 1‐year post‐LT patient and graft survival were similar between groups. In the study group, 4 patients died, and 1 patient required retransplantation within the first year post‐LT (all unrelated to HCV); 56 patients received DAA therapy, with a median time from LT to the start of DAA treatment of 66.9days (interquartile range [IQR], 36‐68.5), and 51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR‐12) (1 patient required retreatment owing to relapse following initial DAA therapy). No patients had evidence of fibrosing cholestatic hepatitis or extrahepatic manifestations of HCV. This report indicates that transplantation of DNAT+ livers into rHCV− and subsequent DAA therapy is associated with clinical outcomes comparable to those achieved with DNAT− allografts.

Remission of long-term hepatic and renal disease induced by HCV after direct-acting antivirals therapy.

In addition to liver disease, the hepatitis C virus (HCV) has been associated with autoimmune phenomena, such as mixed cryoglobulin and glomerulonephritis (GN). Until recently, both chronic hepatitis and HCV extra-hepatic manifestations were treated with peg-interferon plus ribavirin, however these drugs presented low efficacy and induced severe side effects. Nowadays, the HCV chronic hepatitis has been treated with direct acting antivirals (DAA), but studies on the DAA therapy for HCV-associated glomerulonephritis are scarce. Here, we describe two cases of HCV-associated glomerulonephritis that were treated with DAAs. In these two cases, previously experienced to peg-interferon plus ribavirin, the sofosbuvir plus simeprevir therapy was effective, without significant side effects, and interrupted the evolution of at least 20 years of both hepatic and renal diseases. These cases join the seven previously described cases that were treated with this DAAs association.

The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection.

Direct-acting anti-viral (DAA) therapy may have a beneficial role in extrahepatic manifestations of hepatitis C virus (HCV) infection. However, the available data are limited. To examine the effects of DAA treatment on the risk of several extrahepatic manifestations of HCV. We conducted a retrospective cohort study of patients from the US Department of Veterans Affairs Corporate Data Warehouse who had a positive HCV RNA test and received first course of DAAs between 2012 and 2016. We calculated incidence rates by sustained virological response (SVR) status for six extrahepatic manifestations, and effect of SVR on these conditions was evaluated in adjusted Cox regression models. Of the 45260 patients treated with DAA with mean follow-up of 2.01years, 41711 (92.2%) experienced SVR. Incidence rates ranged from 0.17/1000 PY for porphyria cutanea tarda to 21.04/1000 PY for diabetes in the SVR group and 0.51/1000 PY for porphyria cutanea tarda to 23.11/1000 PY for diabetes in the no SVR group. The risk was reduced with SVR for mixed cryoglobulinaemia (adjusted HR (aHR)=0.23; 95% CI 0.10-0.56), glomerulonephritis (aHR=0.61; 95% CI 0.41-0.90) and lichen planus (aHR=0.46; 95% CI 0.30-0.70), but not for non-Hodgkin's lymphoma (aHR=0.86; 95% CI 0.52-1.43) or diabetes (aHR=0.98; 95% CI 0.81-1.19). Non significant risk reduction was seen for porphyria cutanea tarda (aHR=0.33; 95% CI 0.11-1.03). Successful DAA treatment resulting in SVR was associated with significant reductions in the risk of mixed cryoglobulinaemia, glomerulonephritis, lichen planus and possibly porphyria cutanea tarda, but not non-Hodgkin's lymphoma or diabetes.

Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe.

Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta-analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (€). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (€), with a per-HCV-patient cost ranging from €899 to €1647 annually. DAA treatment was projected to result in cost savings of €316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs.

Chronic kidney disease in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection affects many organs in the body, including the liver, kidneys, skin, joints and others. Although the hepatic manifestation of HCV has been widely studied, the extrahepatic manifestations of HCV have not been fully appreciated. Studies have shown that patients with HCV have a higher risk of chronic kidney disease and end-stage renal disease, as well as poorer outcomes after kidney transplantation. Given these findings, it is important to screen HCV patients for presence of renal impairment in a timely manner. Current guidelines recommend screening for kidney disease at the time of HCV diagnosis, along with annual urinalysis and creatinine checks. It is important to note that chronic HCV infection has been associated with a number of renal disorders, including cryoglobulinemic glomerulonephritis, membranoproliferative glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathies, and hepatorenal syndrome. Of these, while HRS can be reversible post-transplantation, cryoglobulinemic glomerulonephritis is common and is primarily caused by mixed cryoglobulinemia. These patients may be asymptomatic or may present with hematuria, proteinuria, nephrotic syndrome, or impaired renal function only detected by laboratory data. In this review, we will provide an up-to-date assessment of these renal complications in patients with HCV infection.

Hepatitis C virus infections: is it only e liver disease?

Hepatitis C virus (HCV) infection is widely diffused in general population, and the likelihood that an infected individual is affected by other disesases is high. A lot of epidemiological and explicative studies, even if with different levels of evidence, reported a potential effect of HCV infection -by direct and indirect mechanisms- on the pathogenesis of extrahepatic comorbidities related to dysregulation of the immune system, or cardiometabolic comorbidities like diabetes, neuropsychiatric disorders, chronic kidney disease, cardiovascular alterations, etc. Along this line, some studies observed a positive effect of viral eradication on extrahepatic diseases. However, these data are some time affected by selection bias and by the fact that they are mostly focuded on populations underwent interferon-based therapies. Until now only few data are available on the impact of viral eradication by direct antiviral agents on extrahepatic manifestations of HCV. Consistently, to draw conclusions, further validation studies are needed also stratifying the effect of viral eradication according to lenght and severity of both hepatic and extrahepatic damage.

Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCV Extrahepatic Manifestations.

Cytokines and chemokines, hepatitis C virus (HCV) infection-induced, participate in viral control and liver damage. The complex cytokine network, operating during initial infection allows a coordinated and effective development of innate and adaptive immune responses. "HCV interferes with cytokines at various levels and escapes immune response by inducing a T helper (Th)2/T cytotoxic 2 cytokine profile". A predominance of the Th1 immune response (and related cytokines) has been evidenced in chronic hepatitis C infection and in extrahepatic manifestations. Interferon (IFN)-γ and IFN-γ-inducible chemokine (C-X-C motif) ligand (CXCL)9, -10 and -11 recruit inflammatory infiltrates into the liver parenchyma due to the incapability to control the infection process, resulting in extensive liver damage and liver cirrhosis. "The most important systemic HCV-related extrahepatic diseases - mixed cryoglobulinemia, lymphoproliferative disorders, diabetes and autoimmune thyroid disorders - are associated with a complex dysregulation of the cytokine/chemokine network and involve pro-inflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-α may result in viral clearance during persistent infection and reverts this process" reducing circulating CXCL10 levels. "Several studies have reported interleukin (IL)-28B polymorphisms, and circulating CXCL10, may be prognostic markers for HCV treatment efficacy in HCV infection". Other studies have also shown that HCV clearance by directly acting antiviral agents therapy decreases circulating CXCL10 levels. "Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy", simultaneously reducing inflammatory immune cell activation.

A pleasant dilemma to have: to treat the HCV patient on the waiting list or to treat post-liver transplantation?

New and relatively well-tolerated medications to treat hepatitis C virus (HCV) infection have presented an opportunity for hepatologists to eliminate HCV in liver transplant (LT) candidates prior to transplantation. While concern for causing decompensated liver disease in the sickest subset of pre-transplant patients makes some clinicians reluctant to offer treatment, we believe that several advantages of early HCV eradication appear to shift the debate in favor of using anti-HCV agents before LT. There are encouraging safety data for new HCV medications in cirrhotic patients, and given the limited supply of donor livers available, delaying or possibly preventing the need for LT by treating HCV can offer significant benefit. Post-LT, making immunosuppression management easier as well as avoiding both extrahepatic manifestations of HCV (e.g., diabetes mellitus and kidney disease) and the dilemma of distinguishing post-transplant viral recurrence from allograft rejection makes earlier treatment of HCV especially appealing to clinicians. Furthermore, retrospective data have demonstrated a mortality benefit among HCV patients who are free of the virus at the time of LT. This article explores arguments for and against treating HCV in patients on the transplant list.

Extrahepatic Nasal Manifestations of Hepatitis C Virus

©2015. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. The nose is a competent immunological organ that reflects many of the cellular and molecular events seen in mucosal immunity. Viruses are major causative agents for respiratory tract infections in children and adults. Viruses induced rhinitis is usually of acute nature resulting in the common cold symptoms; rhinorrhea, nasal obstruction, malaise and exacerbation of already existing airways disease. Among the viruses frequently infecting the human nose are the RNA virus such as coronavirus, rhinovirus, and the influ enza/parainfluenza virus and the double-stranded DNA adenovirus. These viruses induce rhinitis (common cold and flu) by attaching themselves to the lining of the nose and paranasal sinuses. Other chronic blood borne viruses may produce rhinopathy. Examples of such viruses are the human acquired immune deficien cy virus (HIV) and hepatitis C virus (HCV). While the rhinosinusitis seen in HIV population is due to superinfection with other pathogens due to the general weak immunological system caused by HIV, the rhinosinusitis seen in HCV could be due to specific nasal immunological response. HCV which belongs to lenti viruses is known to be associated with head and neck diseases. Thyroid disease is commonly seen in people with HCV. Correlation between HCV and lymphocytic sialoadenitis, similar to sialoadenitis associated with idiopathic Sjogren syndrome has been also described [1], but nasal extrahepatic manifestations of HCV is poorly defined except for HCV

Clinical Evaluation of Chronic Hepatitis C and Indications for HCV Treatment

Hepatitis C virus (HCV) is the most common cause of liver cirrhosis in the United States. If untreated, HCV can lead to death from complications of liver failure or hepatocellular carcinoma, making screening imperative in high-risk patients. Established risk factors for HCV infection include injection drug use, receipt of blood transfusion or organ transplantation prior to 1992, and hemodialysis. Recent evidence has demonstrated that those born between 1945-1965 are additionally at high risk for HCV acquisition and should undergo one time screening. Once diagnosed, consideration for treatment should be based on patient motivation, concurrent medical co-morbidities, degree of liver injury, and risk of progression to cirrhosis. Therapy may also be indicated in patients with extra-hepatic manifestations of HCV.

Commentary on: The optimal Dose of Ribavirin for Chronic Hepatitis C: From Literature Evidence to Clinical Practice

Commentary on: The optimal Dose of Ribavirin for Chronic Hepatitis C: From Literature Evidence to Clinical Practice

Immunological alterations in hepatitis C virus infection

A higher prevalence of immunological processes has recently been reported in patients with hepatitis C virus (HCV) infection, focusing the attention of physicians and researchers on the close association between HCV and immune disorders. HCV lymphotropism represents the most important step in the pathogenesis of virus-related immunological diseases and experimental, virologic, and clinical evidence has demonstrated a trigger role for HCV both in systemic autoimmune diseases, such as rheumatoid arthritis, Sjögren syndrome, hemolytic anemia and severe thrombocytopenia, and in organ-specific autoimmune diseases, such as autoimmune hepatitis, thyroid disorders and diabetes. This review will outline the principal aspects of such HCV-induced immunological alterations, focusing on the prevalence of these less characterized HCV extrahepatic manifestations.

Hepatitis C and Metabolic Disorders: Genetics, Mechanism, and Therapies (Clinical and Experimental)

Hepatitis C and Metabolic Disorders: Genetics, Mechanism, and Therapies (Clinical and Experimental)

HCV Eradication: Implications for Disease Resolution

Hepatitis C virus (HCV) is a leading cause of liver-related death worldwide. The evolution of hepatitis C therapy has made serologic eradication of HCV RNA a reality for many patients. Although it is debated whether undetectable virus in the serum represents a cure with complete clearance of viral RNA from the host, improved clinical outcomes have been shown after successful treatment in patients who achieve a sustained virologic response (SVR). Specifically, patients with SVR have longer survival, reduced progression and, in some cases, regression of fibrosis, decreased likelihood of developing hepatocellular carcinoma, and improvement of many extrahepatic manifestations of HCV. This review discusses viral kinetics on therapy leading to eradication, identification, and clinical significance of occult HCV infection and clinical outcomes after successful treatment.

Extrahepatic Manifestations of Hepatitis C Virus Infection: Mixed Cryoglobulinemia and Beyond

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States and is a leading cause of chronic liver disease worldwide. Extrahepatic manifestations of HCV infection occur frequently and are important to recognize as well as understand if they improve with antiviral therapy. This review summarizes the extrahepatic manifestations of HCV with particular emphasis on their degree of association and available treatment options.

Hepatitis C virus infection and lymphoproliferative diseases in France: a national study. The GERMIVIC Group.

The putative role of hepatitis C virus (HCV) infection in the pathophysiology of lymphoproliferative diseases (LPD) is supported by North American and southern European studies reporting high HCV seroprevalence in patients with B-cell-non-Hodgkin lymphoma (NHL). In order to evaluate the situation in France, we conducted a retrospective national study about the association of chronic HCV infection and LPD. 72 Internal Medicine and Infectious Diseases departments were contacted. Response rate was 51.4%. We recorded 43 LPD (19 males, 24 females): 31 B-cell-NHL, 4 Waldenström's macroglobulinemia, 3 chronic lymphocytic leukemia, 2 multiple myeloma, 2 lymphomas of the mucosa-associated lymphoid tissue, and 1 Hodgkin's disease. Mean age at HCV diagnosis was 62 years (range 33-84). In 16 cases, LPD occurred in patients known to be HCV-infected. For 11 patients, LPD diagnosis preceded the diagnosis of HCV infection, whereas diagnosis was done simultaneously in 11 patients. For those with accurate infection date, mean interval between both events was 15.2 years. Fourteen patients had HCV extrahepatic manifestations: 9 mixed cryoglobulinemia, including 7 with NHL, 5 sicca syndrome (5 NHL), and both in one patient. Cohort of HCV-infected patients could be accurately determined for 16 departments, totaling 1,485 patients and 37 cases. Thus, from our data the frequency of LPD among HCV-infected patients approximates 2. 49%. Despite possible bias inherent to this retrospective study, our data support the hypothesis of HCV-associated LPD and particularly B-cell-NHL. In France, this association is much lower than in Italy. Further studies are needed to assess the precise role of HCV in the multistep process leading to monoclonal proliferation.

Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to anti-phospholipid syndrome.

Chronic infection with hepatitis C virus (HCV) has been found to be associated with various diseases known as extra-hepatic manifestations of HCV. Recently, HCV has been implicated as a cause of the antiphospholipid syndrome (APLS). We conducted a study in a well-characterized area for epidemiological and prospective studies in the north-western part of Greece in order to address whether an aetiopathogenesis exists between HCV and APLS. Seventy-five patients with chronic hepatitis C were investigated for the presence of anti-cardiolipin antibodies (anti-CL) and for a past medical history supportive to the diagnosis of APLS. In addition, 24 patients with well-defined APLS (primary or secondary) and 12 patients with systemic lupus erythematosus (SLE) were tested for the presence of markers of HCV infection (anti-HCV and HCV RNA). The SLE patients were anti-CL-positive but none of them had developed any of the known clinical features of APLS. In addition, 267 healthy subjects were investigated for the presence of anti-CL. IgG and IgM anti-CL were determined by a quantitative isotype-specific solid phase enzyme-linked immunosorbent assay set up in our laboratory. Anti-HCV was determined using a third-generation enzyme immunoassay and a confirmatory third-generation recombinant immunoblot assay. Active virus replication was defined by the detection of HCV RNA using a combination assay based on a reverse transcriptase polymerase chain reaction and a DNA enzyme immunoassay. Of the HCV patients, 37.3% had IgG and/or IgM anti-CL (P<0.00005 compared to healthy controls (2.25%)). However, the mean titres of each specific isotype were significantly lower in HCV patients compared with those found in the APLS patients (P<0.05 for IgM and P<0.001 for IgG isotypes). The mean titres of IgG anti-CL were also significantly lower in HCV patients compared with those found in the SLE patients (P<0.01). All patients with APLS or SLE (n = 36) tested negative for HCV infection markers. In addition, neither thrombotic events nor thrombocytopenia were associated with a positive anti-CL test in HCV patients. A significant proportion of HCV patients (37.3%) had detectable anti-CL of low titre. However, this finding was not associated with the development of APLS. On the other hand, none of the APLS patients was positive for HCV. Taken together, our data rather failed to reveal an aetiopathogenetic link between HCV and APLS. For this reason, testing for HCV in patients with APLS or follow-up for the possibility of the development of APLS in HCV patients cannot be suggested, at least in Greek patients. More prospective studies of longer duration are required in order to address whether HCV is involved or not in the aetiopathogenesis of APLS.