Evaluation of different diagnostic modalities of minimal hepatic encephalopathy in cirrhotic patients: case-control study.

INTRODUCTION: Minimal hepatic encephalopathy (MHE) represents one of the most overlooked complications of liver cirrhosis. AIM OF THE STUDY: To compare the utility and efficacy of different MHE diagnostic modalities. MATERIAL AND METHODS: This case-control study was conducted on hepatitis C virus (HCV)-related compensated cirrhotic patients. The Psychometric Hepatic Encephalopathy Score (PHES) was used to assign patients to MHE and controls. All patients were subjected to plasma ammonia, serum 3-nitrotyrosine (3-NT), critical flicker frequency (CFF), and the modified inhibitory control test (ICT). RESULTS: CFF was significantly lower in the control group (38.5, 40 Hz, p = 0.003). The unweighted lures on ICT were 8.7, 4.9 in MHE and controls (p < 0.001). Moreover, ammonia was higher in the MHE group (89, 61.5 µmol/l, p < 0.001). 3-NT was also higher in the MHE group (31.5, 13.7 nmol/l, p < 0.001) respectively. CFF at cutoff < 39 Hz had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 57.5%, 77.5%, 71.9% and 64.6%, respectively; in modified ICT, at cutoff > 5 unweighted lures the values were 87.5%, 80%, 81.4% and 86.5%, respectively; in ammonia, at cutoff ≥ 76.45 µmol/l the values were 65%, 72.5%, 70.3% and 67.4%, respectively; for 3-NT at cutoff ≥ 14.15 nmol/l the values were 85%, 82.5%, 82.9% and 84.6%, respectively. The accuracy for MHE diagnosis was 67.5%, 83.3%, 68.8%, 83.8% relying on CFF, 3-NT, ammonia, and ICT respectively. On multivariate analysis, CFF < 39 Hz (OR = 10.2, p = 0.04), modified ICT > 5 unweighted lures (OR = 43.2, p = 0.002), and serum 3-NT levels ≥ 14.15 nmol/l (OR = 50.4, p < 0.001) were independent predictors of MHE. CONCLUSIONS: 3-NT and ICT are advantageous to reveal MHE in compensated liver cirrhosis, while CFF can be only used as adjuncts, with humble merits of ammonia.

Direct Relationship between Interleukin-10 Gene Polymorphism and Hepatocellular Carcinoma Complicated by Direct Acting Antiviral Treatment of Hepatitis C Virus.

OBJECTIVE: This study aimed to assess the correlation between the genotyping of interleukin-10 (IL-10 polymorphism rs 1800871) and the incidence hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) treated with direct acting antivirals (DAAs). METHOD: For 200 patients with HCV infection who completed DAA treatment and followed up for 1 year, IL-10 polymorphism SNP(-819) rs 1800871 analysis was conducted via real time polymerase chain reaction. During the follow-up period, 100 patients who developed HCC were selected and compared with 100 patients who did not develop any complications. RESULTS: The studied patients were divided into two groups according to the incidence of complications after completion of DAA treatments. During the follow-up, 100 patients with HCV infection who developed HCC were selected and compared with 100 patients with HCV infection who did not develop any complications (positive control group). For the HCC group (n = 100), the mean age was 58.1 ± 6.4 years, with 92.7% being male and 7.3% being female; 91% had cirrhosis, 10% had lymphadenitis, 75% had splenomegaly, and 17% had ascites. In the positive control group (n = 100), mean age was 46.3 ± 9.4 years, with 68% being male and 32% being female; 20% had cirrhosis, 12% had splenomegaly, and 4.2% had ascites. The results demonstrated that sofosbuvir (SOF) + daclatasvir + ribavirin regimen was the most prevalent drug treatment for patients with HCC (72%), while SOF + Simeprevir was the most safe treatment for HCV infection among patients with HCC (2%). CT genotype was the most common genotype in the HCC group (56%), among different drug regimen (67.8%). T allele was the most prevalent in HCC group (61%), while the C allele was the least prevalent (39%). CONCLUSION: IL-10 genotyping may help in selecting the safest and most accurate drug regimen according to the safest genotype response relationship and follow-up of genotype resistance.

HBVsvp-Pulsed Dendritic Cell Immunotherapy Induces Th1 Polarization and Hepatitis B Virus-Specific Cytotoxic T Lymphocytes Production.

BACKGROUND: In chronic hepatitis B virus (CHB) patients, both dendritic cells (DCs) and T cells are functionally impaired and consequently the HBV-specific cellular immune responses are downregulated. The present study aims to investigate whether monocyte-derived DC (MoDCs)-pulsed-HBV subviral particles (HBVsvp) can polarize Th1 cells to induce HBV-specific cytotoxic T-lymphocytes (CTL) responses in CHB patients. METHODS AND MATERIALS: To this end, the human hepatoma HepG2.2.15 cell line was used to produce HBVsvp as a culturing system, and HBVsvp were concentrated for highly virus titer using the polyethylene glycol protocol. Peripheral blood mononuclear cells (PBMCs), collected from CHB patients and healthy donors, were differentiated into MoDCs and T cells. PBMCs-derived MoDCs were first pulsed with HBVsvp and then cultured with PBMCs-derived T cells. MoDCs and/or T subsets cells were identified for phenotypic activation by FACS analysis. The cytokine secretion of IL-4, IL-12, and IFN-γ in the culture supernatants was detected. RESULTS: The MoDCs were restored for their activation upon pulsing with HBVsvp in vitro, as identified by significantly overexpression of both CD86 and HLA-DR, and overproduction of IL-4 and IL-12. Furthermore, MoDCs-pulsed-HBVsvp induced Th1 frequencies and activated HBV-specific CTL to produce significantly highest amount of IFN-γ. Enhanced HBV-specific CTL led to strong cytolytic capacity against HepG2.2.15. CONCLUSION: Overall, our data suggest that in vitro activation of MoDCs with HBVsvp overcomes the functionally impaired DCs and T cells in CHB patients offering a promising tool for therapeutic or vaccine-based approaches against HBV.

Value of IFNL3 genetic polymorphism in the prediction of HCV treatment response to direct-acting antiviral drugs versus interferon therapy.

Background: Despite the outstanding results of direct-acting antiviral therapies (DAAs) of Hepatitis C infection (HCV), non-responders had to be more defined. Aim: assess the outcome of DAAs in linkage with Interferon lambda 3 (IFNL3) in HCV patients. Methods: This case-control-study was conducted on 495 chronic-HCV (genotype-4a), previously treated Egyptians by either DAAs (responders 195, 120 relapsers) or interferon/ribavirin (IFN/RBV) (140 responders, 60 relapsers), and 98 healthy controls. IFNL3 distribution, clinical and laboratory data were assessed. Results: CT was the most predominant genotype in Egyptians (51%). All genotypes were sensitive to DAAs mainly CT genotype (60%), even TT genotype (resistant to IFN/RBV 40%) had 29.2% sensitivity. CT genotype was predominant in sofosbuvir/Daclatasvir responders (67.6%) (OR = 0.66), while non-CT prevailed in relapsers (56.7%). TT genotype may respond to SOF/Ledi better than other regimens (66.7%). In IFN/RBV relapsers; CT genotype was commoner (50%) than others, while CC genotype predominated in responders (54.3%). The c allele was the commonest in responders to IFN/RBV (71.4%), while the T allele was resistant to treatment (65% in relapsers). Addition of RBV to SOF/DCV reported higher resistance with CT genotype (42.2%-50%) and TT genotype (17.8%-27.8%). Conclusion: This study recommended IFNL3 genotyping to be a prerequisite before stratifying treatment for HCV-4a Egyptians.

Role of Ribavirin in the Era of Direct-Acting Antiviral Therapies of Chronic Hepatitis C.

BACKGROUND: The efficacy of adding ribavirin (RBV) to direct antivirals (DAAs) in HCV treatment is still debatable, with allegations of insecure profiles. OBJECTIVES: To evaluate safety and efficacy of RBV in the era of DAAs in chronic HCV Egyptian patients. METHODS: In this cohort retrospective study, data of 847 HCV patients treated with different regimens of DAAs with or without RBV were recruited between June 2017 and September 2018. Cases were categorized into five groups: non-cirrhotic (318), compensated (196), decompensated liver cirrhosis (53), post liver transplantation (30), and 250 treatment experienced patients. All patients' demographics and laboratory characteristics were evaluated at baseline, week4, 12, 24 of treatment. Ribavirin was prescribed or banned outside international guideline recommendations of HCV treatment in cases assembled from the private sector.Results: No statistically significant difference between RBV and non-RBV treated patients was documented regarding SVR12 (97.2%, 97.8%) respectively in the whole cohort (p 0.509). On grouping, adding RBV was only significant in the treatment experienced patients (96.8%, 85% in RBV and non-RBV regimens respectively) (p 0.001). Adding RBV to DAA regimens was generally associated with modest adverse events particularly anemia (8.5%), and hepatic decompensation (jaundice and ascites) (0.3%). Bilirubin, INR, and platelet counts all were found to be the most independent predictors of SVR achievement by multivariate analysis (p ≤ 0.05).Conclusion: RBV may still have an augmenting role in treatment experienced patients; permitting effectual shortening of therapy particularly in patients with cirrhosis, with modest side and adverse consequences.

Circulating microRNA-301 as a promising diagnostic biomarker of hepatitis C virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a serious consequence of persistent hepatitis C virus (HCV) infection and represents one of the most aggressive neoplasms globally. The implication of microRNA-301 (miR-301) in the initiation and progression of different types of cancers has been proved. We aimed to assess circulating microRNA-301 as possible biomarker for the early detection of HCC in patients with chronic HCV infection. miR-301 expression levels were estimated in plasma samples of 42 patients with newly diagnosed HCV-related HCC, 48 chronically HCV infected patients with liver cirrhosis and 40 healthy individuals by reverse transcription-quantitative polymerase chain reaction technique. In comparison with chronically HCV infected patients and healthy controls, miR-301 expression levels were significantly increased in HCC patients (P < 0.001). miR-301 levels distinguished HCC patients from chronic HCV patients, with area under the receiver-operating characteristic curve of 0.89 (95% CI 0.82-0.96), the sensitivity and the specificity were 78.57% and 89.58% respectively. Moreover, miR-301 levels were significantly linked with tumor size (P = 0.014), serum levels of alpha-fetoprotein (AFP) (P = 0.028) and Barcelona Clinic Liver Cancer (BCLC) score (P = 0.003). These results reveal that miR-301 can serve as a promising non-invasive biomarker for diagnosis of HCC in chronically HCV infected patients.

High efficacy of generic and brand direct acting antivirals in treatment of chronic hepatitis C.

BACKGROUND: Direct acting antivirals (DAAs) are highly effective for treatment of hepatitis C (HCV) but brand products are priced beyond the means of most low and middle income countries (LMICs). Although a few DAAs are offered at reduced prices in access programs, they are still beyond affordability in limited resource settings with a large HCV infected population. Cheap generics might fill this economic need, but studies comparing their clinical efficacy to that of original products are limited. AIM: To compare efficacy of brand and generic DAAs used in the national treatment program in Egypt. METHODS: HCV treatment eligible patients (n=971) were enrolled. They were treated with 12 weeks of either sofosbuvir-daclatasvir (SOF-DCV) or SOF-ledipasvir (SOF-LDV). Ribavirin (RBV) was added to patients with cirrhosis and to SOF experienced patients. Patients with cirrhosis who were RBV intolerant were treated for 24 weeks without RBV. RESULTS: Most patients were males (61.4%), treatment naïve (88.6%), without cirrhosis (61.7%), and the mean age was 51.3±11.31 years. Baseline characteristics were not different in patients treated with brand or generic medications regarding age, liver tests, creatinine, platelets, MELD score, baseline HCV-RNA and transient elastography. Overall sustained virologic response (SVR) rate was 98.1%, which was similar for generic and brand drugs (98.2% vs. 98.1%; p=1), and similar with both regimens used (SOF-DCV±RBV: brand: 98.1%, generic 97.8%; p=0.729, SOF-LDV±RBV: brand 98.2%, generic 100%; p=0.729). AST and ALT decreased significantly with initiation of therapy with both generic and original drugs. CONCLUSION: Generic and brand DAAs are equally effective for achieving SVR and improving aminotransferases.

Female sexual dysfunction among Egyptian patients with chronic hepatitis C.

INTRODUCTION: Chronic hepatitis C is associated with many extrahepatic manifestations that impact and impair the quality of life. Hepatitis C virus (HCV) infection has a high prevalence in Egypt and carries with the diagnosis many social impacts and stigmatization correlates that further impair social function. This might negatively impact patients and their sexual function. Sexuality and sexual function have not been studied well in patients with HCV, especially in women. AIM: To investigate sexual dysfunction in Egyptian women with chronic hepatitis C. MAIN OUTCOME MEASURES: Female Sexual Function Index (FSFI) scores of patients with hepatitis C, both total and for individual domains, were compared with those of controls. METHODS: The self-administered FSFI questionnaire was completed by 112 sexually active female patients with chronic hepatitis C without liver cirrhosis prior to initiation of therapy by pegylated interferon and ribavirin. Their results were compared to those of 225 age- and socioeconomic class-matched sexually active healthy females. RESULTS: Significantly more patients than controls had questionnaire scores below the threshold of female sexual dysfunction (FSD) (79% vs. 21%, P < 0.05), and the mean total score for the patients was significantly lower than that for controls (19.54 ± 6.2 vs. 28.43 ± 4.9 P < 0.001). The patients' scores in all domains of the questionnaire were significantly lower than those of the controls. CONCLUSION: Chronic hepatitis C negatively impacts female sexual function, affecting all domains of the sex cycle; this warrants further studies and needs to be addressed as part of a comprehensive therapy plan to improve patients' quality of life.