HCV-related Disease Research Articles

Renal Manifestations of Chronic Hepatitis C: A Review.

Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes.

Cosa deve sapere oggi il pediatra del trattamento dell’epatite C nell’era dei nuovi farmaci antivirali?

The treatment of hepatitis C virus (HCV) infection with the new directacting antivirals (DAAs) has dramatically modified the natural history of the HCV-related disease, eradicating the virus in over 90% of treated patients, with negligible collateral effects. The high costs of treatment, however, represent a factor that limits patients’ access to therapy and burdens the countries’ healthcare systems. In Italy the estimated cost of treatment for a naïve patient (8/12 weeks) amounts to approximately €5,500 (VAT excluded). HCV liver disease especially affects adults, in Italy the average prevalence of hepatitis C ranges between 2.4% and 3.3% in the general population. The prevalence of hepatitis C in children is significantly lower (0.15%) and the liver disease is rarely progressive in the paediatric age; however, there are not tools capable of interrupting the main route of infection, namely the vertical transmission from the infected mother. The effectiveness and great manageability of these new direct antivirals have also allowed their use in paediatrics starting from three years of age.

Hepatitis B and C in Europe: an update from the Global Burden of Disease Study 2019

In 2016, the World Health Assembly adopted the resolution to eliminate viral hepatitis by 2030. This study aims to provide an overview of the burdens of hepatitis B virus (HBV) and hepatitis C virus (HCV) in Europe and their changes from 2010 to 2019 using estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. We used GBD 2019 estimates of the burden associated with HBV-related and HCV-related diseases: acute hepatitis, cirrhosis and other chronic liver diseases, and liver cancer. We report total numbers and age-standardised rates per 100 000 for mortality, prevalence, incidence, and disability-adjusted life-years (DALYs) from 2010 to 2019. For each HBV-related and HCV-related disease and each measure, we analysed temporal changes and percentage changes for the 2010-19 period. In 2019, across all age groups, there were an estimated 2·08 million (95% uncertainty interval [UI] 1·66 to 2·54) incident cases of acute hepatitis B and 0·49 million (0·42 to 0·57) of hepatitis C in Europe. There were an estimated 8·24 million (7·56 to 8·88) prevalent cases of HBV-related cirrhosis and 11·87 million (9·77 to 14·41) of HCV-related cirrhosis, with 24·92 thousand (19·86 to 31·03) deaths due to HBV-related cirrhosis and 36·89 thousand (29·94 to 45·56) deaths due to HCV-related cirrhosis. Deaths were estimated at 9·00 thousand (6·88 to 11·62) due to HBV-related liver cancer and 23·07 thousand (18·95 to 27·31) due to HCV-related liver cancer. Between 2010 and 2019, the age-standardised incidence rate of acute hepatitis B decreased (-22·14% [95% UI -35·44 to -5·98]) as did its age-standardised mortality rate (-33·27% [-43·03 to -25·49]); the age-standardised prevalence rate (-20·60% [-22·09 to -19·10]) and mortality rate (-33·19% [-37·82 to -28·13]) of HBV-related cirrhosis also decreased in this time period. The age-standardised incidence rate of acute hepatitis C decreased by 3·24% (1·17 to 5·02) and its age-standardised mortality rate decreased by 35·73% (23·48 to 47·75) between 2010 and 2019; the age-standardised prevalence rate (-6·37% [-8·11 to -4·32]), incidence rate (-5·87% [-11·24 to -1·01]), and mortality rate (-11·11% [-16·54 to -5·53]) of HCV-related cirrhosis also decreased. No significant changes were observed in age-standardised rates of HBV-related and HCV-related liver cancer, although we observed a significant increase in numbers of cases of HCV-related liver cancer across all ages between 2010 and 2019 (16·41% [2·81 to 30·91] increase in prevalent cases). Substantial reductions in DALYs since 2010 were estimated for acute hepatitis B (-27·82% [-36·92 to -20·24]), acute hepatitis C (-27·07% [-15·97 to -39·34]), and HBV-related cirrhosis (-30·70% [-35·75 to -25·03]). A moderate reduction in DALYs was estimated for HCV-related cirrhosis (-6·19% [-0·19 to -12·57]). Only HCV-related liver cancer showed a significant increase in DALYs (10·37% [4·81-16·63]). Changes in age-standardised DALY rates closely resembled those observed for overall DALY counts, except for HCV-liver related cancer (-2·84% [-7·75 to 2·63]). Although decreases in some HBV-related and HCV-related diseases were estimated between 2010 and 2019, HBV-related and HCV-related diseases are still associated with a high burden, highlighting the need for more intensive and coordinated interventions within European countries to reach the goal of elimination by 2030. Bill & Melinda Gates Foundation.

Study of MicroRNA 203 and Its Target Genes (Survivin, Cyclin-D) in Circulating Liver Cancer Stem Cells in Patients with Chronic Hepatitis C with and without HCC

Abstract Background Hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality, infecting more than 180 million people worldwide. Chronic viral infection is one of the most common causes of hepatic fibrosis, distortion of the hepatic architecture, and ultimate progression to cirrhosis of the liver. HCV infection inflames the liver which, if unmanaged, will inevitably result in fibrosis and then progress to cirrhosis which has many co-morbid complications such as hepatocellular carcinoma (HCC). HCC is an aggressive tumor usually involving late stage liver cancers when diagnosed. Although significant progress regarding the treatment options for HCC has been made in recent years, poor prognosis remains a problem because of late diagnosis and drug resistance, making recurrence almost inevitable. Objective to compare level of miRNA 203 and its target genes (Survivin, Cyclin-D) in circulating liver cancer stem cells in patients with chronic hepatitis C with and without H.C.C. Patients and Methods This study was conducted in co-operation between Gastroenterology and Hepatology Department, Ain-Shams University and the Gastroenterology and Hepatology Department, Theodor Bilharz Research Institute “between” April 2021 to October 2021.It included total participants of 80 divided to 4 GrousGroup A (HCV group): twenty patients infected with HCV without liver cirrhosis.Group B (LC group): twenty patients infected with HCV with liver cirrhosis.Group C (HCC group): twenty patients infected with HCV with HCC.Control group: twenty normal populations. Results our study demonstrated that the level of miRNA 203 showed statistically significant difference between all study groups with lowest level was found in HCC group and highest level was in control group with statistically significant decrease in HCC group than LC and other groups. The study also demonstrated that circulating level of Survivn shows significant increase in HCC group than other study groups. With no significant changes in its level between non HCC groups (Control, HCV and LC groups).The circulating Cyclin D level showed significant increase in HCC group than other study groups, With statistically significant increase in its level in LC group than control and non-cirrhotic HCV group. The study markers (miRNA 203, Survivn and Cyclin D) showed no significant relation between their levels in HCC patients and AFP level. Also, no significant relation was established between (miRNA 203, Survivn and Cyclin D) and PVT, number of focal lesions, largest diameter of the lesion or BCLC. Conclusion miRNA 203 level in circulating CSCs showed significant changes according to the stage of HCV related disease with lowest level is seen in HCC patients.Survivin level in circulating CSCs showed significant increase in HCC patients with no significant difference between other groups, and this indicates that changes in its level is highly specific for malignant transformation.Cyclin D level in circulating CSCs showed significant increase in HCC patiens than other study groups, with increase in its level in LC patients than control and non-cirrhotic HCV patients, and this indicates that the changes in its level start with cirrhosis process. No relation was established between (circulating miRNA 203, Survivn and Cyclin D) and AFP, PVT, number of focal lesions, largest diameter of the lesion or BCLC.

Geographical variation in hepatitis C-related severe liver disease and patient risk factors: a multicentre cross-sectional study.

Despite promising steps towards the elimination of hepatitis C virus (HCV) in the UK, several indicators provide a cause for concern for future disease burden. We aimed to improve understanding of geographical variation in HCV-related severe liver disease and historic risk factor prevalence among clinic attendees in England and Scotland. We used metadata from 3829 HCV-positive patients consecutively enrolled into HCV Research UK from 48 hospital centres in England and Scotland during 2012-2014. Employing mixed-effects statistical modelling, several independent risk factors were identified: age 46-59 y (ORadj 3.06) and ≥60 y (ORadj 5.64) relative to <46 y, male relative to female sex (ORadj 1.58), high BMI (ORadj 1.73) and obesity (ORadj 2.81) relative to normal BMI, diabetes relative to no diabetes (ORadj 2.75), infection with HCV genotype (GT)-3 relative to GT-1 (ORadj 1.75), route of infection through blood products relative to injecting drug use (ORadj 1.40), and lower odds were associated with black ethnicity (ORadj 0.31) relative to white ethnicity. A small proportion of unexplained variation was attributed to differences between hospital centres and local health authorities. Our study provides a baseline measure of historic risk factor prevalence and potential geographical variation in healthcare provision, to support ongoing monitoring of HCV-related disease burden and the design of risk prevention measures.

Prevalence and risk factors of hepatitis C virus infection in Armenia, 2021

Abstract Background Liver damage caused by hepatitis C virus (HCV) is common, especially in low- and middle-income countries. Chronic HCV infection is among the leading causes of chronic liver disease, cirrhosis and hepatocellular carcinoma. Data on prevalence and risk factors of HCV infection are important for planning effective interventions to fight the virus. This study investigated the prevalence of HCV, its genotypes and factors associated with chronic HCV infection in Armenia. Methods The study included 3838 individuals 18 years and older selected via stratified two-stage cluster sampling from all regions of Armenia. Anti-HCV antibodies were detected using a third generation immunoassay. Those testing positive were further tested by Polymerase Chain Reaction and genotyping. Shortly after testing, the participants underwent a telephone survey. Logistic regression model was fitted to identify factors associated with chronic HCV infection. Results The participants mean age was 49.5 years, 70.0% were female. The prevalence of HCV antibodies weighted by age and sex was 1.9% (95% CI 1.5, 2.3), and chronic HCV infection - 0.7% (95% CI 0.4, 0.9), with genotype 3 being the most common (41.7%), followed by genotypes 2 (37.5%) and 1 (20.8%). The prevalence of both antibodies and chronic infection were higher among 50-69 years old (3.4% and 1.3%, respectively). In weighted analysis, the risk factors for chronic HCV infection included male sex (95% CI 1.23, 11.59), having tattoos (95% CI 1.10, 7.80), and reporting liver disease (95% CI 1.24, 14.61). Being employed was protective (95% CI 0.14, 0.93). Conclusions This study was the first attempt to measure the prevalence of HCV infection among the general population of Armenia, creating prerequisites for estimating the HCV-related disease burden and developing strategies to cope with it. The identified risk factors demonstrate that there is still room for strengthening safety measures to prevent the transmission of HCV in Armenia. Key messages • The prevalence of HCV antibodies is 1.9% among adult population of Armenia, increasing with age. Over one-third of seropositive cases have chronic infection caused by HCV genotypes 3, 2 or 1. • Having tattoos is associated with higher risk of being infected with HCV, demonstrating the need for strengthening safety measures during similar procedures to prevent viral transmission.

Direct-acting antivirals used in HCV-related liver disease do not affect thyroid function and autoimmunity

PurposeIt is well known that interferon-α (IFN-α), used for long time as the main therapy for HCV-related disease, induces thyroid alterations, but the impact of the new direct-acting antivirals (DAAs) on thyroid is not established. Aim of this prospective study was to evaluate if DAAs therapy may induce thyroid alterations.MethodsA total of 113 HCV patients, subdivided at the time of the enrollment in naïve group (n = 64) and in IFN-α group (n = 49) previously treated with pegylated interferon-α and ribavirin, were evaluated for thyroid function and autoimmunity before and after 20–32 weeks of DAAs.ResultsBefore starting DAAs, a total of 8/113 (7.1%) patients showed Hashimoto's thyroiditis (HT) all belonging to IFN-α group (8/49, 16.3%), while no HT cases were found in the naïve group. Overall, 7/113 (6.2%) patients were hypothyroid: 3/64 (4.7%) belonging to naïve group and 4/49 (8.2%) to IFN-α group. Furthermore, a total of 8/113 patients (7.1%) showed subclinical hyperthyroidism: 2/64 (3.1%) were from naïve group and 6/49 (12.2%) from IFN-α group. Interestingly, after DAAs therapy, no new cases of HT, hypothyroidism and hyperthyroidism was found in all series, while 6/11 (54.5%) patients with non-autoimmune subclinical thyroid dysfunction became euthyroid. Finally, the only association between viral genotypes and thyroid alterations was genotype 1 and hypothyroidism.ConclusionsThis study supports evidence that DAAs have a limited or missing influence on thyroid in patients with HCV-related diseases. Moreover, it provides preliminary evidence that subclinical non-autoimmune thyroid dysfunction may improve after HCV infection resolution obtained by DAAs.

413.5: HCV-Viremic Donor Allograft Consideration by Organ Type And Year, Among Adult and Pediatric Solid Organ Transplant Candidates

Introduction: Use of HCV-viremic donor organs (D+) for transplant into HCV-seronegative recipients (R-) has been shown to be safe and equally effective as using HCV-seronegative donor organs since 2016. Therefore, we sought to evaluate changes in frequency of transplant candidates being listed as willing to consider offers of HCV-viremic donor organs (“HCV offer interest”) from 2015-2021 as a measure of greater openness to HCV D+/R- transplants among transplant candidates and centers. Methods: We identified all waitlist candidates 2015-2021 listed for kidney, liver, heart, or lung transplantation in the United States using the Scientific Registry of Transplant Recipients. Waitlist candidate HCV serostatus was not available, but the proportion of waitlist additions for HCV-related disease in the United States is declining. We compared patient and center characteristics using Chi-square and McNemar tests, by HCV offer interest, for pediatric (<18 years old) and adult transplant candidates. Results: We identified 392,515 waitlist candidates (269,770 kidney, 69,728 liver, 32,418 heart, 20,599 lung), including 377,375 adult and 15,140 pediatric candidates. Overall, 33.8% of adult and 4.1% of pediatric candidates were recorded as interested in HCV D+ organ offers (p<0.001, Table 1). HCV offer interest varied by organ type among both adult (30.3% kidney vs. 42.3% liver vs. 45.0% heart vs. 35.3% lung, p<0.001) and pediatric candidates (2.0% kidney vs. 3.0% liver vs. 7.3% heart vs. 12.9% lung, p<0.001). All organ types showed increased HCV offer interest over time (Figure 2). The percentage of transplant centers who had at least one pediatric candidate listed as interested in HCV D+ offers had a trend toward an increased from 2015 to 2021 for kidney (4.5% vs. 12.1%, p=0.07), liver (3.6% vs. 9.4%, p=0.06), heart (7.1% vs. 16.1%, p=0.1), and lung candidates (12.0% vs. 33.3%, p=0.5). The percentage of transplant centers who had at least one adult candidate listed as interested in HCV D+ organ offers remained stable from 2015 to 2021 for kidney (74.2% vs. 77.4%, p=0.8) and liver (92.4% vs. 93.4%, p>0.9) candidates and increased for heart (48.6% vs. 72.1%, p<0.001) and lung (31.8% vs. 58.9%, p<0.001) candidates. Conclusion: Willingness to consider HCV-viremic donor organs has increased since 2015 at the patient and center levels among pediatric and adult candidates, especially pediatric lung transplant candidates. This reflects the increasing recognition of the safety and efficacy of HCV-viremic organ transplants into HCV-seronegative recipients. However, a substantial percentage of transplant centers still have no candidates listed as willing to consider HCV-viremic donor offers, possibly indicating a lack of comfort with HCV D+/R- transplants. We must address this discomfort with educational initiatives to ensure this valuable organ pool is available to as many waitlist candidates as possible. F32 AG067642-01A1 (National Institutes of Aging).

Outcomes in Hepatitis C Positive Liver Transplantation: Timing of Direct-Acting Antiviral Treatment and Impact on Graft Fibrosis

Liver transplantation for hepatitis C virus (HCV)-related disease has the lowest five-year graft survival among all liver transplant recipients. Graft failure due to accelerated fibrosis from unrestrained HCV replication is common. Optimal timing of HCV treatment with direct-acting antiviral agents remains unknown. We compared HCV liver transplant recipients successfully treated for HCV before transplant to those treated within 1 year of transplant to determine if graft fibrosis, measured by Fib-4 scores, differs with timing of treatment. Fib-4 scores less than or equal to 1.45 defined minimal fibrosis and greater than 1.45 defined greater than minimal fibrosis. We identified 117 liver transplant recipients: 52 treated before transplantation and 65 treated within 1 year of transplantation. Overall, 34% of recipients had minimal fibrosis, and the likelihood of having minimal fibrosis following treatment and liver transplantation did not differ by timing of treatment. The odds ratio of having greater than minimal fibrosis was 0.65 (95% CI 0.30, 1.42) among those treated within 1 year after transplantation compared to those treated before transplantation (p-value 0.28). Importantly, nearly 2/3 of these patients had evidence of fibrosis progression one year after sustained virologic response, supporting recommendations for early antiviral-based treatment to prevent accumulation of HCV-related disease.

Abstract 836: Immunologic markers and the progression of liver disease in HCV-positive individuals

Abstract Background: Host immune response and chronic inflammation associated with chronic hepatitis C virus (HCV) infection play a key role in the progression of liver disease from cirrhosis to hepatocellular carcinoma (HCC). We evaluated a large panel of circulating immunologic markers to better understand the natural history of HCV-related liver disease. Methods: We sampled 94 HCC, 68 cirrhotic and 100 non-cirrhotic controls from a Taiwanese prospective cohort study of chronically HCV-infected individuals. Multivariable polytomous logistic regression and canonical discriminant analysis (CDA) were used to compare baseline plasma levels for 102 markers in individuals who developed cirrhosis as compared to controls and those who developed HCC. P-values for individual markers were corrected for multiple testing using a false discovery rate of 10%; a p-value&amp;lt;0.05 was used to determine significance in CDA. Receiver operating characteristic curves were used to compare the predictive ability of marker groups from both analyses. Results: After adjusting for age, sex, years of follow-up, serum alanine aminotransferase level, alcohol and smoking, DEFA-1 (p-trend: &amp;lt;0.0001), ITGAM (p-trend: &amp;lt;0.0001), CCL18 (p-trend: 0.002) and ARTN (p-trend: 0.003) were all found to be positively associated with the development of cirrhosis when compared to non-cirrhotic controls; the same four markers were shown to be associated with HCC when compared to cirrhotic participants. Taken together, these four markers predicted cirrhosis and HCC development with 79% and 88% accuracy, respectively in adjusted models. CDA models isolated a twelve-marker signature that included DEFA1, CCL18, and ARTN, improving predictability of cirrhosis development to 91% accuracy in adjusted models. Using the same methods, a fourteen-marker signature that included DEFA-1, ITGAM, CCL18 and ARTN was found to predict HCC development with 97% accuracy when compared to cirrhotic individuals in adjusted models. Conclusion: To our knowledge, this is the first prospective study to assess immunologic markers in relation to liver disease progression in individuals chronically infected with HCV. While further validation is required, these findings highlight the importance of immunologic processes in HCV-related disease. Citation Format: Ilona Argirion, Ruth M. Pfeiffer, Zhiwei Liu, Allan Hildesheim, Ligia Pinto, Katherine A. McGlynn, Jessica L. Petrick, Tram Kim Lam, Thomas R. O'Brien, Kelly Yu, Chien-jen Chen, Hwai-I Yang, Mei-Hsuan Lee, Jill Koshiol. Immunologic markers and the progression of liver disease in HCV-positive individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 836.

Comorbidities impact and de-prescribing in elderly with HCV-related liver disease: analysis of a prospective cohort

Management for HCV has undergone a notable change using direct-acting antiviral drugs (DAAs), which are safe and effective even in elderly. Here, we define impact of comorbidities, concomitant medication and drug–drug interactions in elder patients with HCV related disease before starting DAAs regimen. We analyzed data of 814 patients prospectively enrolled at our Unit within the web based model HCV Sicily Network. Out of 814, 590 were treated with DAAs and 414 of them were older than 65 years. We divided those 414 in two groups, one including 215 patients, aged between 65 and 74 years, and another with 199 patients, aged of 75 years and over. Charlson Comorbidity Index (CCI) was assessed for each patient; drug–drug interactions (DDI) and de-prescribing process were carried out appropriately. Within 414 patients included, percentage rates of women treated was higher than males, BMI was lower and cirrhosis was frequently reported in patients older than 75 years. Hypertension, diabetes mellitus, dyslipidemia (p < 0.0001), prostatic pathologies, kidney disease, gastrointestinal disease (p < 0.0001), osteoporosis (p < 0.01) and depression were most common co-morbidities. CCI showed lower scores in the first group as compared with the second one (p < 0.0001). Among drugs, statins were frequently suspended and anti-hypertensive often replaced. DAAs are useful and effective regardless of disease severity, comorbidities, medications and age. De-prescribing allows a stable reduction of number of medications taken with real improvement of quality of life.

Epidemiology and Risk Factors for Hepatitis C Infection in Malaysia: A Narrative Review

Hepatitis C infection is a growing public health issue in Malaysia. A large number of people living with hepatitis C virus (HCV) are unaware of the infection. The treatment complexity warrants a comprehensive understanding of this infectious disease to support planning for strategies to reduce the burden of disease associated with hepatitis C. This study aimed to summarise the epidemiology and risk factors attributable to hepatitis C acquisition in Malaysia based on local published articles. Published articles related to epidemiology and risk factors for hepatitis C infection in Malaysia between 2005 and 2017 were searched through several online databases. Related information from the Ministry of Health official website was also compiled. An increasing trend in the incidence and mortality rate of hepatitis C infection is noted over the last decades. In 2009, the national prevalence of people infected with HCV was approximately 2.5%, with the prevalence rate varying according to different high-risk groups. The most common genotypes reported are genotypes 3 and 1. Frequently reported risk factor for HCV acquisition is injection drug use. Other identified risk factors are being a blood product recipient, haemodialysis patient or participant in high-risk sexual activity. Nevertheless, a considerable number of patients had no known risk factors. The prevalence and burden of HCV-related disease are substantial and can be attributed to many factors. High-quality design studies are needed to provide stronger evidence of the risk factors for hepatitis C infection in local populations for future public health planning.

HCV cirrhotic patients treated with direct-acting antivirals: Detection of tubular dysfunction and resolution after viral clearance.

Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients. One hundred and thirty-five consecutive Child-Pugh A cirrhotic patients were evaluated before antiviral treatment and 6months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1-microglobulin to creatinine ratio (α1-MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR). Almost all the patients (93.3%) showed a normal or mildly decreased e-GFR (KDIGO-G1/G2-categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co-occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1-MCR levels (21.0 vs 10.5μg/mg, P=.009) and tubular dysfunction resolved in 57.1% of subjects. Tubular dysfunction is an unrecognized feature of HCV-related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e-GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long-term impact on kidney function.

Direct-Acting Antiviral Agents for HCV-Associated Glomerular Disease and the Current Evidence.

Glomerular disease is an extra-hepatic manifestation of hepatitis C virus infection (HCV) and membranoproliferative glomerulonephritis is the most frequent glomerular disease associated with HCV. It occurs commonly in patients with HCV-related mixed cryoglobulinemia syndrome. Patients with HCV-related glomerular disease have been historically a difficult-to-treat group. The therapeutic armamentarium for HCV-related glomerular disease now includes antiviral regimens, selective or non-specific immunosuppressive drugs, immunomodulators, and symptomatic agents. The treatment of HCV-associated glomerular disease is dependent on the clinical presentation of the patient. The recent introduction of all-oral, interferon (IFN)-free/ribavirin (RBV)-free regimens is dramatically changing the course of HCV in the general population, and some regimens have been approved for HCV even in patients with advanced chronic kidney disease. According to a systematic review of the medical literature, the evidence concerning the efficacy/safety of direct-acting antiviral agents (DAAs) of HCV-induced glomerular disease is limited. The frequency of sustained virological response was 92.5% (62/67). Full or partial clinical remission was demonstrated in many patients (n = 46, 68.5%) after DAAs. There were no reports of deterioration of kidney function in patients on DAAs. Many patients (n = 29, 43%) underwent immunosuppression while on DAAs. A few cases of new onset or relapsing glomerular disease in patients with HCV successfully treated with DAAs have been observed. In summary, DAA-based combinations are making easier the management of HCV. However, patients with HCV-induced glomerular disease are still a difficult-to-treat group even at the time of DAAs.

Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma.

Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases.Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD).Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely.Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.

The associations between Toll-like receptor 4 gene polymorphisms and hepatitis C virus infection: a systematic review and meta-analysis.

Background and objective: The hepatitis C virus (HCV) is able to cause a life-threatening disease relating to lethal hepatocellular carcinoma. Previous, Toll-like receptor polymorphisms were proposed as promising biomarker for HCV-related hepatocellular carcinoma and disease progression. This study aimed to summarize the association of TLR4 polymorphisms and HCV infection through meta-analysis.Methods: We applied a systematic review and meta-analysis performed by using PubMed, EMBASE and Web of Science searches. The Modified Newcastle-Ottawa scale was used for quality assessment. The odd-ratio (OR) and 95% confidence interval (CI) were calculated to assess the association. In silico analysis was applied for proposing the function as microRNA (miRNA) of non-coding polymorphism. Finally, the miRNA target was predicted and annotated to suggest the possible relationship between polymorphism and HCV infection.Results: Our meta-analysis incorporated seven studies involving rs4986791, rs4986790 and rs2149356. No association exists between rs4986791 and HCV infection. However, the heterozygous model (AG vs GG) of rs4986790 significantly associates with HCV infection (OR = 0.33, 95% CI = 0.21–0.49, P<0.0001). Moreover, the rs2149356 TG genotype also associates with HCV infection in the over-dominant model (TG vs TT+TG: OR = 0.54, 95% CI = 0.40–0.75). In silico analysis of rs2149356G allele showed that this mutation is siRNA, which targets the set of genes, especially in the autophagy pathway.Conclusion: We demonstrated that rs4986790 and rs2149356 are associated with HCV infection.

Improved liver transplant waitlist mortality and lower risk of disease progression among chronic hepatitis C patients awaiting liver transplantation after the introduction of direct-acting antiviral therapies in the United States.

Direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV-related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on US liver transplant (LT) waitlist outcomes. We retrospectively evaluated US adults (age ≥18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6-month period after approval (Era 1: 1/1/2002-5/31/2014 vs Era 2: 6/1/2014-12/31/2016) using the United Network for Organ Sharing registry. Overall, LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002 to 2016, 158045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R2 : 0.99, P<0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non-HCV patients, those listed in Era 2 had lower likelihood of LT (HR: 0.91, P<0.001), more pronounced in the HCV cohort (HR: 0.83, P<0.001) compared to the non-HCV cohort (HR: 0.93, P<0.001). Compared to non-HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR: 1.08, P<0.001) but not in Era 2 (HR: 1.02, P=0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post-DAA era, HCV patients on the LT waitlist had improved waitlist mortality.

Hierarchical assessment of host factors influencing the spontaneous resolution of hepatitis C infection.

Hepatitis C virus (HCV) infection is associated with chronic liver disease, resulting in cirrhosis and hepatocellular carcinoma. Approximately 20% of HCV infections are spontaneously resolved. Here, we assessed the hierarchical relevance of host factors contributing to viral clearance. DNA samples from 40 resolved infections and 40 chronic HCV patients paired by age were analyzed. Bivariate analysis was performed to rank the importance of each contributing factor in spontaneous HCV clearance. Interestingly, 63.6% of patients with resolved infections exhibited the protective genotype CC for SNP rs12979860. Additionally, 59.3% of patients with resolved infections displayed the protective genotype TT/TT for SNP ss469415590. Moreover, a ranking of clearance factors was estimated. In order of importance, the IL28B CC genotype (OR 0.197, 95% CI 0.072-0.541) followed by the INFL4 TT/TT genotype (OR 0.237, 95% CI 0.083-0.679), and female gender (OR 0.394, 95% CI 0.159-0.977) were the main predictors for clearance of HCV infection. HCV clearance is multifactorial and the contributing factors display a hierarchical order. Identifying all elements playing role in HCV clearance is of the most importance for HCV-related disease management. Dissecting the relevance of each contributing factor will certainly improve our understanding of the pathogenesis of HCV infection.

Direct-acting antiviral agents and risk of hepatocellular carcinoma: is it still a clinical dilemma?

Direct-acting antivirals (DAAs) revolutionised the treatment of chronic HCV-related disease achieving high rates of sustained virological response (SVR), also in more advanced patients, with a good safety profile and a proven positive effect on the reduction of risk of HCC occurrence. Nevertheless, patients with an history of successfully treated early HCC were initially excluded from pivotal trials. Although some initial retrospective studies, affected by several methodological issues, raised concerns regarding a possible harmful effect on the risk of HCC recurrence after antiviral therapy, more recent prospective studies and meta-analyses provided evidence that risk of HCC recurrence after DAA therapy is similar, or even lower, than that observed in patients treated with interferon or in DAA-untreated controls. In the future, a meta-analyses of individual patient data would be necessary to definitively close this clinical debate, as well as prospective studies assessing ‘true endpoints’, such as overall survival.

Sofosobuvir (SOF) and Daclatasvir (DCV) Bypassing Genotypic Investigation of Chronic Hepatitis-C Infection

BACKGROUND & AIMS: The goal of chronic hepatitis C (CHC) treatment is to remove the virus to avoid progression of HCV-related disease, and to achieve end of treatment response (ETR) (12 week therapy) & sustained virological response (SVR-12), defined as undetectable HCV RNA at 12 weeks after end of therapy (ETR). Sustained virologic response (SVR) is the most widely used efficacy endpoint in clinical studies of hepatitis C, and represents the eradication of HCV from the body. In the compassionate use programme in Europe (CUP), Sofosbuvir (SOF) and Daclatasvir (DCV) was used in all genotypes and achieved SVR-12. We tried to compare patients who could not afford for investigating of HCV-Genotype price to those in whom genotype was done. METHOD: All the patients were given SOF DCV for 12 weeks and the endpoint of therapy was marked by undetectable HCV-RNA in blood by a lower limit of detection <15 IU/ml at the end of treatment (ETR-12), 12 weeks after end of treatment (SVR 12) and 24 weeks after end of treatment (SVR-24). RESULT: Group 1 include 10 patients, given SOF DCV without genotype and group 2 include 9 patients, given SOF DCV with genotype. All the patients completed the 12 weeks treatment with 12 and 24 weeks follow up. HCV RNA was undetectable in all the patients in both groups at the end of treatment and 12 and 24 weeks follow-up after completion of treatment i.e. 100% ETR-12, SVR12 and SVR-24 in both groups CONCLUSION: If patients do not investigate for genotype and use the SOF DCV in HCV infected patients, there is no effect on outcome end of treatment response. Funding: None Declaration of Interest: All authors: No reported conflicts. “The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.” Ethical Approval: A favorable ethical opinion was obtained from the King George’s Medical University ethical committee for the study.