Implementation of a Hepatocellular Carcinoma Surveillance Program in a Community-Based Integrated Health System in Patients With Hepatitis C Cirrhosis.

INTRODUCTION: Underutilization of hepatocellular cancer (HCC) surveillance has been reported, although data evaluating interventions to improve surveillance are sparse. We assessed the effect of a population-based HCC surveillance program on HCC surveillance utilization and outcomes. METHODS: In this retrospective cohort study, we assessed preinclusion and postinclusion HCC surveillance patterns among 597 patients with hepatitis C virus cirrhosis enrolled in a program at an integrated health system between 2013 and 2020. Adequate surveillance was defined as at least 5 surveillance studies within 36 months pre-enrollment and postenrollment; a secondary outcome was proportion of time covered by surveillance over 36 months. Tumor size, stage, and receipt of curative therapy were compared between HCC detected on the first imaging examination (prevalent HCC) and surveillance-detected HCC (incident HCC). We performed Kaplan-Meier analysis and multivariable competing risk analysis to characterize the association between surveillance and mortality. RESULTS: The surveillance program significantly improved surveillance completion (77.6% vs 5.0%, P < 0.001) and proportion time covered (80.9% vs 15.8%, P < 0.001). Compared with prevalent HCC, surveillance-detected cases were more likely unifocal (77.8% vs 44.8%, P < 0.001), early-stage (85.2% vs 44.8%, P < 0.001), with smaller maximum diameter (median 2.3 vs 3.2 cm), and more likely to undergo curative therapy (92.5% vs 72.4% P = 0.010). Survival was improved compared with prevalent cases hazard ratio (HR) 0.23 (0.11-0.51) after adjusting for age and Model for End Stage Liver Disease score. DISCUSSION: Implementation of a population-based program resulted in significant improvement in HCC surveillance use and clinical outcomes among patients with hepatitis C virus cirrhosis. These findings may inform similar interventions by other healthcare systems.

ASSOCIATION BETWEEN SERUM ZINC, COPPER AND SELENIUM LEVELS AND THE DEGREE OF LIVER DAMAGE IN PATIENTS WITH CHRONIC HEPATITIS C.

OBJECTIVE: The aim: To evaluate the content of trace elements Zn, Cu and Se in blood serum and their relationship with viral load and the degree of liver fibrosis according to the results of the FibroMax test in patients with CHC. PATIENTS AND METHODS: Materials and methods: 62 outpatients with a verified diagnosis of CHC were under observation, in which serum Zn, Cu and Se levels, viral load and degree of liver fibrosis were determined according to the FibroMax test. RESULTS: Results: HCV 1b genotype was detected in all patients. The proportion of patients with a high viral load was 32%, with a low viral load - 68%. In 19% of patients, the level of Zn was below normal, and the levels of Cu and Se were within the reference values. The proportion of patients without fibrosis was 32%, 16% had minimal fibrosis, 40% had moderate fibrosis, 8% had progressive fibrosis, and 3% had severe fibrosis. 68% of patients had active inflammation of various degrees, liver steatosis - 65%, non-alcoholic steatohepatitis - 48%, inflammation caused by alcohol consumption was absent. No statistically significant difference was found in serum trace element levels and viral load (p>0.05). A weak negative correlation between the level of Zn and the degree of fibrosis (ρ=-0.340, p=0.007) and a negligible negative correlation between the level of Zn and inflammation activity (ρ=-0.286, p=0.024) were revealed. Patients with fibrosis grade ≥F2 had lower Zn levels compared to patients with fibrosis ≤F1 (0.607 (0.540, 0.691) mg/l vs. 0.716 (0.593, 0.875) mg/l, p=0.01), and when comparing there was no difference in Cu and Se levels (р>0.05). CONCLUSION: Conclusions: Thus, there is a relationship between the level of Zn in blood serum and the degree of liver damage in patients with CHC, which indicates the prospects for further research.

Clinical and economic impact of an alert system in primary care for the detection of patients with chronic hepatitis C.

INTRODUCTION: Prevalence of chronic hepatitis C (CHC) is higher in patients born between 1955-1975. The aim was to perform an economic evaluation of an age-based electronic health record (EHR) alert in primary care to detect patients with undiagnosed CHC and its treatment in comparison with non-use of the alert system, in Valencian Community, Spain. MATERIALS AND METHODS: Decision trees and Markov model were used to evaluate the diagnosis and progression of the disease, respectively. CHC was diagnosed by serology and viral load in seropositive subjects. Epidemiological data and diagnostic costs were extracted from public sources of the Valencian Community. Probabilities, utilities and costs of model states were obtained from the literature. The impact on mortality and hepatic complications avoided by the implementation of the alert were estimated, and efficiency was measured as an incremental cost-utility ratio (ICUR) based on quality-adjusted life years (QALYs) and the costs of both alternatives. RESULTS: The EHR alert detected 269,548 patients, of whom 1,331 had CHC (vs. 23 patients with non-alert). Over the patients' lifetime, the alert would prevent 93% of decompensated cirrhosis cases, 87% of hepatocellular carcinomas, 90% of liver transplants, and 89% of liver related deaths compared to non-use of the alert system. In addition, it would obtain an additional 3.3 QALY per patient, with an incremental cost of €10,880 and an ICUR of €3,321. CONCLUSIONS: The implementation of an age-based EHR alert in primary care to detect patients with CHC reduces hepatic complications and mortality and is an efficient strategy.

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

BACKGROUND: The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID. METHODS AND FINDINGS: INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment. CONCLUSIONS: Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov.no NCT03155906.

Single center analysis of therapy and outcomes of hepatocellular carcinoma in Sub-Saharan Africa.

PURPOSE: To evaluate the characteristics and response to therapy for HCC in sub-Saharan Africa. PATIENTS AND METHODS: We retrospectively evaluated demographic, clinical and outcome variables of HCC in a referral clinic in Ethiopia from 2016 to 2018. Survival assessment was performed using the Mann-Whitney test. Associations between categorical variables was assessed using Pearson Chi-square test. RESULTS: We report 46 HCC cases with a median age of 54 years (IQR 45-62) and 50% female. Viral hepatitis was the most common underlying etiology, with 41% of subjects infected with hepatitis B virus (HBV) and 45% with hepatitis C. The median MELD was 12 (IQR 8-17), we found no association between survival and a MELD score 15, regardless of underlying disease (pr=0.61, p>0.05). 31% of individuals underwent supportive treatment with a median survival of 27 days (IQR 19-181), 18% used Sorafenib (median survival of 94 days, IQR 24-121), and trans-arterial chemoembolization (TACE) was utilized in 16% (median survival of 352 days, IQR 30-436). HBV cases were diagnosed younger (31% before the age of 40) and those on Tenofovir had a longer median survival than those off Tenofovir (121 vs 34 days). CONCLUSION: Our study found that antiviral treatment of HBV infection was associated with longer survival in HCC. Furthermore, Sorafenib seemed beneficial in patients that used this modality and NLR was a good prognostic factor.

Laparoscopic Microwave Thermal Ablation for the Treatment of Hepatocellular Carcinoma in Chronic Hepatic Patients.

Background: Laparoscopic microwave thermal ablation (LMWTA) is a well-established alternative treatment to liver resection for treatment of liver tumors. The aim of this study was to describe our experience in LMWTA for hepatocellular carcinoma (HCC) in chronic hepatic patients. Materials and Methods: A study group of 61 consecutive HCC patients treated with LMWTA from January, 2013 to May, 2020 were considered for this study. Patient characteristics, liver function test, operational characteristics, and complications were recorded. Results: Of the 61 patients who underwent LMWTA, median age was 64 (interquartile range [IQR]: 58-71) years, mean body mass index was 26.2 (IQR: 23.2-29.4); 44 patients (72%) presented with an hepatitis C virus etiology, 46 (75%) were Child-Pugh Class A, median model for end-stage liver disease (MELD) score was 8.0 (IQR: 7.0-9.4). Viral infection was confirmed to be the most important risk factor in determining progressive cirrhotic evolution with HCC expression. Conclusions: LMWTA is a safe alternative treatment to traditional surgery, and can be combined with surgery.

Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected anti-retroviral naïve persons with alcohol use in Russia.

BACKGROUND AND AIMS: Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. METHODS: This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. RESULTS: The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses. CONCLUSIONS: In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis.

Cerebral patterns of neuropsychological disturbances in hepatitis C patients.

Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.

Liver stiffness measurement changes following hepatocellular carcinoma treatment with percutaneous microwave ablation or transarterial chemoembolization: a cohort study.

BACKGROUND: Liver stiffness increases after the development of hepatocellular carcinoma (HCC). Transient elastography for liver stiffness measurement (LSM) using fibroscan is a simple noninvasive method of proven efficacy. This study aims to assess the changes in LSM following HCC treatment. PATIENTS AND METHODS: This study included 150 patients with hepatitis C virus related HCC attending the multidisciplinary HCC clinic, Kasr Al-Ainy Hospital between March 2014 and October 2015 who underwent either transarterial chemoembolization (TACE) or microwave ablation (MWA). Baseline LSM was carried out 3 and 6 months after treatment. The response rate was calculated according to the modified Response Evaluation Criteria in Solid Tumors criteria; overall survival and LSM changes were then compared between the two procedures. RESULTS: MWA showed higher rates of complete ablation (77.4%) than did TACE (31.7%) (P=0.004). Increase in LSM 3 and 6 months after treatment was statistically significant in the TACE group (P<0.001) but not in the MWA group (P=0.4). Patients who showed complete ablation had statistically significant lower baseline LSM than those with incomplete ablation, and their 6 months increase in LSM was also significantly lower. Logistic regression revealed that with each unit increase in baseline stiffness, 3% reduction in the odds of complete ablation is expected, and this did not change after controlling for the type of treatment. Child-Pugh class, number, and size of HCCs were our independent prognostic factors by Cox proportional analysis. CONCLUSION: The increase in LSM is significant after TACE than after MWA. Moreover, lower pre-ablation LSM is a predictor of complete ablation.

Randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis.

BACKGROUND AND AIM: Anticoagulation therapy is the main line of treatment for acute portal vein thrombosis (PVT) in the absence of cirrhosis. However, the use of this therapy in cirrhotic PVT is still with doubtful evidence. We aimed to evaluate the efficacy and safety of rivaroxaban compared to warfarin for the management of acute non-neoplastic PVT in Hepatitis C virus (HCV)-related compensated cirrhosis. METHODS: Out of 578 patients with chronic HCV infection, 80 patients with acute PVT who had undergone splenectomy due to hypersplenism and 4 patients with acute PVT due to portal pyemia were selected. The patients were randomly assigned (1:1) to the study group (n = 40), in which the patients received rivaroxaban 10 mg/12 h, or the control group (n = 40), in which the patients received warfarin. RESULTS: In the rivaroxaban group, the resolution of PVT was achieved in 34 patients (85%) within 2.6 ±â€¯0.4 months and delayed, partial recanalization after 6.7 ±â€¯1.2 months (n = 6.15%). Complications such as major bleeding, abnormal liver functions, death, or recurrence did not occur during treatment, and patients in this group showed improved short-term survival rate (20.4 ±â€¯2.2 months) compared to the survival rate in the control group (10.6 ±â€¯1.8 months) in which warfarin achieved complete resolution in 45% of patients. Complications such as severe upper GI tract bleeding (43.3%), hepatic decompensation (22.5%), progression to mesenteric ischemia (12.5%), recurrence (10%), and death (20%) were observed in the control group. The duration until complete resolution of thrombus correlated with age, the extent of the thrombus, creatinine level, and MELD score. The recurrence after complete resolution of thrombus correlated with age, the extent of the thrombus, thrombogenic gene polymorphism, and the use of warfarin. CONCLUSION: Rivaroxaban was effective and safe in acute HCV-related non-neoplastic PVT with improved short-term survival rate; ClinicalTrials.gov Identifier: NCT03201367.

Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature.

Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.

Hepatitis C virus infection in chronic kidney disease: paradigm shift in management.

Hepatitis C virus (HCV) infection in chronic kidney disease (CKD) is associated with increased liver-related morbidity and mortality rates, accelerated progression to end-stage renal disease, and risk of cardiovascular events. CKD patients with HCV infection require antiviral therapy. Pegylated interferon (peg-IFN) plus ribavirin was the standard of care for HCV-infected CKD patients before the introduction of first-generation direct-acting antiviral (DAA) oral anti-HCV agents. Peg-IFN-based treatment has a low virologic response rate and poor compliance, resulting in a high dropout rate. Recently, several clinical trials of all-DAA combination regimens have reported excellent antiviral efficacy and few adverse drug reactions in HCV-infected patients with CKD. These positive results have revolutionized the treatment of chronic HCV infection in this population. In this review, we address the impact of chronic HCV infection in CKD patients, and discuss their management using next-generation DAAs.

Impact of Alcohol and Coffee Intake on the Risk of Advanced Liver Fibrosis: A Longitudinal Analysis in HIV-HCV Coinfected Patients (ANRS HEPAVIH CO-13 Cohort).

BACKGROUND: Coffee intake has been shown to modulate both the effect of ethanol on serum GGT activities in some alcohol consumers and the risk of alcoholic cirrhosis in some patients with chronic diseases. This study aimed to analyze the impact of coffee intake and alcohol consumption on advanced liver fibrosis (ALF) in HIV-HCV co-infected patients. METHODS: ANRS CO13-HEPAVIH is a French, nationwide, multicenter cohort of HIV-HCV-co-infected patients. Sociodemographic, behavioral, and clinical data including alcohol and coffee consumption were prospectively collected using annual self-administered questionnaires during five years of follow-up. Mixed logistic regression models were performed, relating coffee intake and alcohol consumption to ALF. RESULTS: 1019 patients were included. At the last available visit, 5.8% reported high-risk alcohol consumption, 27.4% reported high coffee intake and 14.5% had ALF. Compared with patients with low coffee intake and high-risk alcohol consumption, patients with low coffee intake and low-risk alcohol consumption had a lower risk of ALF (aOR (95% CI) 0.24 (0.12­0.50)). In addition, patients with high coffee intake had a lower risk of ALF than the reference group (0.14 (0.03­0.64) in high-risk alcohol drinkers and 0.11 (0.05­0.25) in low-risk alcohol drinkers). CONCLUSIONS: High coffee intake was associated with a low risk of liver fibrosis even in HIV-HCV co-infected patients with high-risk alcohol consumption.

Determinants of survival following hepatocellular carcinoma in Egyptian patients with untreated chronic HCV infection in the pre-DAA era.

BACKGROUND AND STUDY AIMS: In this study we assessed rates and determinants of survival in people with untreated chronic HCV infection and hepatocellular carcinoma (HCC) in an Egyptian liver clinic setting. PATIENTS AND METHODS: This is a prospective cohort study of patients diagnosed with HCV-related HCC and undergoing HCC management at a national liver centre in Egypt in 2013-2014 and with a follow-up through 2016. RESULTS: A total of 345 patients diagnosed with HCV-related liver cirrhosis complicated by HCC were included. Median age at diagnosis was 57 years (IQR = 52, 62), the majority were male (78%) and Child-Turcotte-Pugh (CTP) class A (64%). At diagnosis Barcelona Clinic Liver Cancer staging (BCLC) was 0 (8%), A (48%), B (20%), C (17%), and D (7%). Most common HCC management modalities were transarterial chemoembolization (TACE) (42%), and radiofrequency ablation (RFA) (21%). Median survival following HCC was 22.8 months. Factors associated with poorer survival in adjusted analyses were INR (HR = 1.81, p = 0.01), alpha-foeto protein (AFP) ≥200 (HR = 1.41, p = 0.02), higher CTP score (HR = 2.48, p < 0.01), and advanced BCLC stage (HR = 1.85, p < 0.01). One year survival in patients with CTP A, B, and C was 85%, 71% and 32%, respectively. One year survival following RFA, TACE, combination RFA/TACE, and sorafenib was 93%, 79%, 80% and 60%, respectively. CONCLUSION: Survival following HCV-HCC in Egyptian patients undergoing HCC management in a specialised clinic setting is poor, although similar to high income country settings. CTP score is a key determinant of survival, even following adjustment for BCLC stage and HCC management.

Vitamin D supplementation for chronic liver diseases in adults.

BACKGROUND: Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017. SELECTION CRITERIA: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE. MAIN RESULTS: We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. AUTHORS' CONCLUSIONS: We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.

Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies.

Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon-free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct-acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow-up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.

Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study.

Hepatic fibrosis is the net accumulation of matrix tissue components which controlled by pro-fibrolytic enzymes, matrix metalloproteinases (MMPs), and pro-fibrotic cytokine, TGF-ß1, and enzymes, tissue inhibitors of MMPs (TIMPs). Vitamin D (VD) supplementation has been shown to reverse these processes in vitro and in vivo. This study sought to determine the effect of VD supplementation on serum fibrotic markers in chronic hepatitis C (CHC) patients. Fifty-four CHC patients with VD deficiency were randomized into two groups, a VD group (n = 29) and a placebo group (n = 29). The serum levels of 25-hydroxy VD, TGF-ß1, TIMP-1, MMP2 and MMP9 were measured at baseline and at the end of the 6-week study period. Upon correction of VD levels, TGF-ß1 and TIMP-1 levels were decreased, and the MMP2 and MMP9 levels were significantly increased in the VD group. A comparison of the mean changes (delta) in the markers between groups showed that TGF-ß1 and TIMP-1 levels were significantly decreased and the MMP2 and MMP9 were significantly higher in the VD group than in the placebo group. By using CHC patients as a model, this study provides additional evidence that VD plays an important role in the reversal of hepatic fibrogenesis.

Correction of vitamin D deficiency facilitated suppression of IP-10 and DPP IV levels in patients with chronic hepatitis C: A randomised double-blinded, placebo-control trial.

Vitamin D deficiency was common among patients with chronic hepatitis C (CHC) and had negative influence on treatment outcome. Correction of vitamin D deficiency improved treatment response. Interferon gamma-induced protein 10 (IP-10) and enzyme dipeptidyl peptidase-4 (DPP IV) involved in inflammatory responses in CHC. Their higher levels at pretreatment of CHC could predict poorer responses. Vitamin D suppressed expression of IP-10 from monocytes in vitro. In CHC patients, DPP IV involved in IP-10 regulation. We hypothesized that correction of vitamin D insufficiency or deficiency in CHC patients might restore immune dysregulation through a pathway linked to the TH1/Th2 cytokines, IP-10 or DPP IV. We conducted a double-blind, placebo-controlled trial. 80 CHC patients with vitamin D levels less than 30 ng/mL were assigned to receive vitamin D (40) or placebo (40) supplements for 6 weeks. The levels of 25-hydroxyvitamin D [25(OH)D], Th1/Th2 cytokines, IP-10 and DPP IV were measured at baseline and at the 6th week. At the end of study, the mean 25(OH)D level in vitamin D group was significantly increased and normalised. There were no changes in the level of Th1/Th2 cytokines. Our important finding revealed that upon correction of vitamin D insufficiency or deficiency, the serum IP-10 and DPP IV levels were decreased significantly as compare to the placebo group (delta changes; 83.27 vs -133.80; 95% CI [-326.910, -40.758], p = 0.0125, and 271.04 vs -518.69; 95% CI [-1179,15, -59.781], p = 0.0305, respectively. As previous evidences suggested that each factor individually influenced and predicted outcome of CHC treatment. Our results offer a new insight and help to piece the puzzle of vitamin D deficiency, IP-10 and DPP IV together in CHC. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20160429001.