The combined polymorphisms of interleukin-6-174GG genotype and interleukin-10 ATA haplotype are associated with a poor quality of life in patients with chronic hepatitis C.

PURPOSE: Chronic hepatitis C (CHC) is associated with a decreased health-related quality of life (HRQOL). More recent studies have pointed toward a genetic basis of patient-reported quality of life outcomes. Taking into account that the influence of single-nucleotide polymorphisms (SNPs) on the HRQOL of CHC patients has not been studied, we investigated the combined IL10-1082G/A, - 819C/T, and - 592C/A SNPs, and IL6-174G/C SNP. We also evaluated the association between demographic, clinical, psychiatric, virological, and genetic variables with domains and summaries of HRQOL in CHC patients. METHODS: 132 consecutive CHC patients and 98 controls underwent psychiatric evaluation by using the Mini International Neuropsychiatric Interview. HRQOL was assessed by a generic questionnaire, the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and by the specific Liver Disease Quality of Life Questionnaire (LDQOL). IL6 and IL10 polymorphisms were evaluated by Taqman SNP genotyping assay. Multivariate analysis was used to evaluate the associations. RESULTS: Major depressive disorder was associated with lower SF-36 and LDQOL scores in seven and ten domains, respectively. Diabetes and hypertension were also associated with reduced HRQOL. CHC patients carrying the combination of IL10 ATA haplotype/IL6-GG genotype had lower scores in the SF-36-physical functioning domain, and reduced scores in the LDQOL effects of liver disease on activities of daily living, quality of social interaction, and sexual function domains than the non-carriers of the combined haplotype/genotype. CONCLUSION: This is the first study to demonstrate that combined IL6 high-producer GG genotype and IL10 low-producer ATA haplotype is associated with poorer HRQOL in CHC patients.

Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals.

BACKGROUND: Immunosenescence is associated with several changes in adaptive and innate immune cells. Altered cytokine production is among the most prominent of these changes. The impact of age-related alterations on cytokine global profiles produced by distinct populations of leukocytes from healthy Brazilian individuals was studied. We analysed frequencies of cytokine-producing lymphocytes and innate immune cells from individuals at several ages spanning a lifetime period (0-85 years). RESULTS: Healthy adult individuals presented a balanced profile suggestive of a mature immune system with equal contributions of both innate and adaptive immunity and of both categories of cytokines (inflammatory and regulatory). In healthy newborns and elderly, innate immune cells, especially neutrophils and NK-cells, contributed the most to a balanced profile of cytokines. CONCLUSIONS: Our results support the hypothesis that ageing is not associated with a progressive pro-inflammatory cytokine production by all leukocytes but rather with distinct fluctuations in the frequency of cytokine-producing cells throughout life.

Phenotypic features of innate and adaptive immunity in patients with chronic hepatitis C and end-stage renal disease.

BACKGROUND: The knowledge of the immunological profile of patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) on haemodialysis (HD) is still limited. AIMS: This study investigated the immune response profile in HCV patients with concomitant ESRD focusing on the influence of the renal disease on the phenotypic profile of peripheral blood lymphocytes. METHODS: Immunophenotypic features of peripheral blood leucocytes were assessed by flow cytometry in two distinct groups: HCV patients with ESRD (CHC+ESRD, n = 16) and HCV patients with normal renal function (CHC, n = 20). Two control groups that were included were as follows: HCV negative blood donors (BD, n = 15) and HCV negative patients with ESRD (ESRD, n = 19). RESULTS: Higher frequency of macrophage-like and pro-inflammatory monocytes along with enhanced frequency of CD3(-) CD16(-) CD56(+) , mainly CD56(dim) NK-cells, were the hallmark of CHC+ESRD patients. Lower frequency of B cells with significant decreased of B1 and CD23(+) B-cells were associated with ESRD, regardless the HCV infection. Although higher rates of activated CD4(+) and CD8(+) T cells were observed in the CHC and CHC+ESRD groups, the chemotaxis of T-cell subsets, based on their chemokine receptor expression, was affected by ESRD. CONCLUSIONS: Chronic hepatitis C patients with ESRD on HD exhibit distinctive phenotypic profile of circulating leucocytes. It may be implicated in the natural history of HCV infection in this particular group of patients and warrants further investigation.

Correlation between salivary anti-HCV antibodies and HCV RNA in saliva and salivary glands of patients with chronic hepatitis C.

BACKGROUND: To investigate the correlation between anti-hepatitis C virus (HCV) antibodies in saliva and detection of HCV RNA in saliva and salivary glands of patients with chronic hepatitis C. METHODS: A total of 180 samples of saliva (131 non-stimulated and 49 stimulated) from 133 patients with chronic hepatitis C were tested by ELISA for presence of anti-HCV antibodies. Results were compared with the detection of HCV RNA in saliva and salivary glands samples. Pearson's chi-squared and Fisher's exact tests were performed for statistical analysis. RESULTS: Anti-HCV antibodies could be detected in 47/180 (26.1%) saliva samples. In 11/47 (23.5%) of these, HCV RNA was also detected. From the 133/180 (73.9%) saliva samples with undetectable anti-HCV antibodies, 49/133 (36.8%) were positive for HCV RNA at least in one saliva sample. From the 64 patients from whom salivary gland samples were available, 17/64 (26.6%) had detectable anti-HCV antibodies in saliva, from which 2/17 (11.8%) also had HCV RNA in the salivary gland. From the 47/64 (73.4%) cases negative for anti-HCV antibodies in saliva, 10/47 (21.3%) were positive for HCV RNA in salivary gland. CONCLUSIONS: Taken together, our results suggest that there is no correlation between the presence of anti-HCV antibodies in saliva and the detection of HCV RNA in saliva and salivary glands in patients with chronic hepatitis C. Nevertheless, as there was a statistically significant difference between detection of anti-HCV antibodies and HCV RNA in stimulated saliva, our study points toward the need for new research on mechanisms of HCV shedding in saliva.

Incidence and Risk Factors of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals.

BACKGROUND: Conflicting data regarding the incidence of hepatocellular carcinoma (HCC) after cure of HCV infection with direct-acting antivirals (DAAs) remains. We investigated the incidence and risk factors to HCC after treatment with DAAs followed up for five years. METHODS: A total of 1075 HCV patients ≥ 18 years were treated with DAAs from 2015 to 2019 and followed until 2022. Ultrasonography was performed before DAAs and each 6 months thereafter. RESULTS: Of the total, 51/1075 (4.7%) developed HCC in the median of 40 (IQR 25-58) months: 26/51 (51%) male, median age 60 (IQR 54-66) years, alpha-fetoprotein (AFP) 12.2 (IQR 6.1-18.8) ng/mL, 47/51 (92.1%) cirrhotic 78.7%, 8/51 (15.7%) without sustained virological response (SVR). Seventeen percent had non-characterized nodules before DAAs. Cumulative HCC incidence was 5.9% in 5 years. Overall incidence was 1.46/100 patient-years (PY) (95% CI = 1.09-1.91), being 2.31/100 PY (95% CI = 1.70-3.06), 0.45/100 PY (95% CI = 0.09-1.32) and 0.20/100 PY (95% CI 0.01-1.01) in METAVIR F4, F3 and F2, respectively, and the main risks to HCC were non-characterized nodule, cirrhosis, high AFP values and non-SVR. CONCLUSION: HCV cure reduced risk for HCC, but it still occurred particularly in cirrhotic patients. Some risk factors can be identified to predict early HCC diagnosis.

BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR SYSTEMIC TREATMENT OF HEPATOCELLULAR CARCINOMA.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Kinetics of hepatitis C virus load and hemodialysis: is there any influence of the reuse of dialysis membrane on HCV viremia?

BACKGROUND: Patients with chronic kidney disease (CKD) on regular hemodialysis are at increased risk of acquiring hepatitis C virus (HCV). Although controversial, a distinct dynamic of the HCV load has been reported in this group - a lower HCV viremia compared to non-uremic patients. The reasons for this remain unclear, but the host immune response related to the hemodialysis procedure and the reuse of dialysis membranes are the most investigated factors. METHODS: We analyzed the kinetics of HCV RNA viremia in 21 hemodialysis patients infected with genotype 1, through a highly sensitive quantitative method (real-time polymerase chain reaction), immediately before and at the end of the first use and the last reuse of the cellulose diacetate dialysis membrane. RESULTS: Initial HCV load did not correlate with demographic or biochemical parameters, but higher HCV viremia was associated with a longer time on hemodialysis (r = 0.44, p = 0.04). Although not significant, HCV RNA decreased in 11/21 (52.3%) patients after the first dialysis session (median 279,000 vs 176,000 IU/ml, p = 0.91). However, a significant increase in HCV RNA viremia was observed in 17/21 (80.9%) patients after the tenth session (median 187,000 vs 342,000 IU/ml, p = 0.009). CONCLUSIONS: Except for the first session of hemodialysis, we did not confirm a decrease in HCV viremia related to the time on hemodialysis or with the reuse of the dialysis membrane. Factors other than the reuse of the dialysis membrane might be involved in the multifaceted kinetics of HCV RNA in CKD patients on hemodialysis.

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

INTRODUCTION: A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. MATERIAL AND METHODS: Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). RESULTS: The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. CONCLUSION: Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

Metabolic-associated fatty liver disease is associated with low muscle mass and strength in patients with chronic hepatitis B.

BACKGROUND: Although the prognostic relevance of sarcopenia has been increasingly recognised in the context of liver disease, there is a paucity of data evaluating body composition in patients with chronic hepatitis B (CHB). Beyond virus-related factors, nutritional and metabolic aspects can be associated with skeletal muscle abnormalities in these patients and should not be disregarded. AIM: To evaluate the association between components of sarcopenia and demographic, clinical, lifestyle, nutritional, and biochemical variables in CHB patients. METHODS: Dual-energy X-ray absorptiometry (DXA) was used to assess muscle mass by quantifying appendicular lean mass (ALM) adjusted for body mass index (ALMBMI). Muscle function was evaluated by hand grip strength (HGS) and the timed up and go test. Metabolic-associated fatty liver disease (MAFLD) was defined according to the criteria proposed by an international expert panel. A body shape index and the International Physical Activity Questionnaire were used to assess central obesity and physical activity level, respectively. RESULTS: This cross-sectional study included 105 CHB outpatients followed at the tertiary care ambulatory centre (mean age, 48.5 ± 12.0 years; 58.1% males; 76.2% without cirrhosis; 23.8% with compensated cirrhosis). The DXA-derived fat mass percentage was inversely correlated with the ALMBMI (r = - 0.87) and HGS (r = - 0.63). In the multivariable analysis, MAFLD, sedentarism and central obesity were positively and independently associated with low ALMBMI. MAFLD and central obesity were independently associated with low HGS. CONCLUSION: MAFLD and central obesity were associated with low muscle mass and strength in patients with chronic hepatitis B, independent of the liver disease stage.

National Brazilian survey on the outcomes of hepatitis c retreatment in patients non-responders to direct antiviral agents.

BACKGROUND AND AIMS: Treatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. PATIENTS AND METHODS: Institutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. RESULTS: As previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. CONCLUSION: The retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.